Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][CH2:41][CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C(Cl)Cl.CO>[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][CH2:41][CH:42]1[CH2:47][CH2:46][N:45]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:5]([C@H:14]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:16])[CH2:4]2)[CH2:44][CH2:43]1
Reactant: c1ccc(CCCC2CCNCC2)nc1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(CCCc4ccccn4)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 96.8 %

Procedure:
The title compound was prepared from 42 mg (0.096 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (from EXAMPLE 33, Step E) and 36 mg (0.18 mmol) of 4-(2-pyridylpropyl)piperidine.2 TFA (from EXAMPLE 72, Step B) using a procedure analogous to that described in EXAMPLE 71, Step A. Flash chromatography using 25:1 v/v CH2Cl2/MeOH provided 58 mg (97%) of the title compound: 1H NMR (500 MHz) δ 0.94-3.28(35H), 3.82 (s, 3H), 5.11 (ABq, J=11.9, 2H), 6.88-7.35 (11H), 7.58-7.61 (m, 1H), 8.52 (d, J=4.1, 1H); ESI-MS 624 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([Cl:20])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 50 mL round bottom flask, dissolved 4-(4-methylpiperazin-1-yl)benzoic acid (1.00 g, 4.50 mmol) in dichloromethane (5.0 mL). Added oxalyl chloride (1.2 mL, 9.1 mmol) and N,N-dimethylformamide (2 drops). Stirred at RT for 2 hours. Concentrated and isolated 4-(4-methylpiperazin-1-yl)benzoyl chloride as an off-white solid. LC/MS of methyl ester (quenched with methanol) revealed an MS (M+H)+ of 235; Calc'd 234.29 for C13H18N2O2 (methyl ester).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7].Br[C:16]([CH3:21])([CH3:20])[C:17](Br)=[O:18].Cl>C(Cl)Cl>[CH3:20][CH:16]1[CH2:21][C:13]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH:14]=2)[C:17]1=[O:18]
Reactant: CC(C)(Br)C(=O)Br
Reactant: CC(C)Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)Cc1ccc2c(c1)CC(C)C2=O
Temperature: 0 °C
Yield: 83 %

Procedure:
17.3 g (125 mmol) of aluminum trichloride were added with ice cooling to a solution of 6.7 g (50 mmol) of isobutyl benzene in 30 ml of methylene chloride. 11.9 g (52 mmol) of 2-bromoisobutyryl bromide were subsequently added rapidly, and the mixture was refluxed for 15 hours. The reaction mixture was poured into 100 ml of ice water, 25 ml of conc. aqueous HCl were added, and the mixture was extracted 3 times with 50 ml of diethyl ether in each case. The combined organic phases were washed with 50 ml each of saturated aqueous NaHCO3 solution and NaCl solution and dried (MgSO4). After removal of the solvent on a rotary evaporator, the crude product was chromatographed on 100 g of silica gel (hexane/methylene chloride 1:1), giving 8.4 g (83%) of 1 as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[C:16](Cl)[C:15]([CH:19]([CH3:21])[CH3:20])=[C:14]([O:22][C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:24]=2[CH3:31])[N:13]=1.C([O:35][CH2:36][CH3:37])(=O)C>CN(C=O)C>[CH2:3]([O:10][C:12]1[N:17]=[C:16]([O:35][CH2:36][C:37]2[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=2)[C:15]([CH:19]([CH3:21])[CH3:20])=[C:14]([O:22][C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:24]=2[CH3:31])[N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(C)c(C)c(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C)c(Oc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
Sodium hydride (60%, 81 mg, 1.98 mmol. 3 eq.) was added to benzyl alcohol (205 μl, 1.98 mmol, 3 eq.) in 10 mL DMF. The mixture was stirred at room temperature for 15 minutes and then added to 2,4-dichloro-5-isopropyl-6-(2,3,5-trimethyl-phenoxy)-pyrimidine (320 mg, 0.66 mmol, 1 eq.). The reaction was heated to 70° C. for 1 hour. The reaction was cooled down to room temperature. Ethyl acetate was added and washed with brine. The organic layer was concentrated down and purified (silica gel, 0-50% EtOAC/hexane) to give white solid (260 mg, 84%). LC-MS shows 469.2 (M+1). 1H NMR (300 MHz, CDCl3): δ 7.3-7.5 (m, 10H), 6.91 (s, 1H), 6.72 (s, 1H), 5.41 (m, 4H), 3.48 (m, 1H), 2.38 (s, 6H), 2.0 (s, 3H), 1.36 (d, 6H).
Reaction SMILES: CC1(C)[C:9]2[NH:8][C:7]([CH2:10][CH2:11][CH3:12])=[N:6][C:5]=2[CH2:4][O:3]1.[OH-:14].[Na+].[CH3:16][C:17]([CH3:19])=[O:18]>>[OH:18][C:17]([C:9]1[N:8]=[C:7]([CH2:10][CH2:11][CH3:12])[NH:6][C:5]=1[C:4]([OH:14])=[O:3])([CH3:19])[CH3:16]
Reactant: CC(C)=O
Reactant: CCCc1nc2c([nH]1)C(C)(C)OC2
Reactant: [OH-]
Agent: [Na+]
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Yield: 96 %

Procedure:
5.0 grams of 4,4-dimethyl-2-propyl-4,6-dihydrofuro[3,4-d]imidazole (formula II) from Example 1, 30 ml of acetone and 50 ml of 10% sodium hydroxide solution were added into 250 ml eggplant flask and refluxed until the reaction completed. Part of the solvent was removed by evaporation, and then the reactant was adjusted to acidic by dropwise addition of concentrated hydrochloric acid. The precipitation was filtered, collected and dried to give 5.3 grams of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid (formula III), resulting in a yield of 96%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH:15]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=3[CH3:34])[C@H:15]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3].[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=3[CH3:34])[CH:15]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCCNC2c2cccc(F)c2)c1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)N1CCCC(C(=O)Nc2cccc(C(C)(C)C)c2)C1c1cccc(F)c1
Product: Cc1ccccc1C(=O)N1CCC[C@H](C(=O)Nc2cccc(C(C)(C)C)c2)[C@@H]1c1cccc(F)c1
Reaction time: 0.17 h
Yield: 128 %

Procedure:
To a solution of 2-(3-fluorophenyl)piperidine-3-carboxylic acid (3-tert-butylphenyl)amide (prepared above, 177.3 mg, 0.5 mmol) in 2 mL of dichloromethane was added Et3N (100 μL, excess), and 2-methylbenzoyl chloride (92.3 mg, 0.6 mmol) at room temperature. The resulting solution was then stirred at this temperature until completion of the reaction (10 min.). The reaction mixture was then directly loaded onto a silica gel column, and was purified by using ISCO (30% EtOAc in hexane) to give the final product 2-(3-fluorophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid (3-tert-butylphenyl)amide (151.2 mg, 64% yield). 1H NMR (400 MHZ, CDCl3, mixture of rotomers): δ 7.91 (s, 0.6H), 7.85 (s, 0.4H), 7.18-7.46 (m, 9H), 7.11 (m, 1H), 6.95 (m, 1H), 6.67 (d, J=1.2 Hz, 1H), 3.36 (d, J=1.6 Hz, 0.4H), 3.26 (d, J=1.6 Hz, 1H), 3.05 (m, 1H), 2.89 (t, J=1.2 Hz, 1H), 2.45 (s, 1H), 2.02-2.40 (m, 4H), 1.70-1.84 (m, 3H), 1.44-1.64 (s, 1H), 1.32 (s, 6H), 1.25 (s, 1H). MS: (ES) m/z 473.2 (MAI).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]([O:10]CC2C=CC=CC=2)[C:5]([CH3:19])([CH3:18])[N:4]=1.O>C(O)C.[Pd]>[ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]([OH:10])[C:5]([CH3:19])([CH3:18])[N:4]=1
Reactant: CC1(C)N=C(N)N=C(N)N1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(C)N=C(N)N=C(N)N1O
Yield: 69.4 %

Procedure:
A solution of 10.0 grams (0.035 mole) of 4,6-diamino-1,2-dihydro-1-phenylmethoxy-2,2-dimethyl-1,3,5-triazine hydrochloride and 20 ml of water in 30 ml of ethanol was hydrogenated in the presence of 1.0 gram of 5% palladium on charcoal using a Parr hydrogenator. Upon completion of the uptake of the theoretical amount of hydrogen, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to a residual solid. The solid was recrystallized from ethanol, yielding 4.7 grams of 4,6-diamino-1,2-dihydro-1-hydroxy-2,2-dimethyl-1,3,5-triazine hydrochloride, m.p. 241° C. (dec.). The NMR spectrum was consistent with the proposed structure. The reaction was repeated several times to provide sufficient material for the next step.
Reaction SMILES: Br[C:2]1([Br:11])[C:7](=[O:8])NC(=O)NC1=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21]C(=O)C)[CH:17]=[CH:18][CH:19]=1>CCOCC>[Br:11][CH2:2][C:7](=[O:8])/[CH:21]=[CH:20]/[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=1
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Reactant: COc1cccc(C=CC(C)=O)c1
Solvent: CCOCC
Product: COc1cccc(/C=C/C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 14.3 g (50 mmol) of 5,5-dibromobarbituric acid in 300 ml of ether was treated with 17.6 g (0.1 mol) of 4-(3-methoxyphenyl)-3-buten-2-one and the mixture was stirred at room temperature for 20 hours. The separated barbituric acid was filtered off. The filtrate was washed in succession with saturated sodium bicarbonate solution and with water. The organic phase was dried over sodium sulphate and concentrated. Flash chromatography of the residue on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1) yielded (E)-1-bromo-4-(3-methoxyphenyl)-3-buten-2-one as a yellow oil.
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.[Li].Br[C:12]1[N:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]2)=[CH:14][CH:13]=1.C1(C2C=CC=CC=2)C=CC=CC=1.C1COCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:15]2[CH:14]=[CH:13][C:12]([NH2:3])=[N:17][CH:16]=2)[CH2:20][CH2:21]1)[CH3:26]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCN1CCN(Cc2ccc(Br)nc2)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCN1CCN(Cc2ccc(N)nc2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Add lithium 1,1,1,3,3,3-hexamethyl-disilazane (1055 mL) slowly to a degassed mixture of 1-(6-bromo-pyridin-3-ylmethyl)-4-ethyl-piperazine (250 g), dicyclohexylphosphino)biphenyl (18.50 g), tris(dibenzylideneacetone)dipalladium (24.17 g) and THF (250 mL) at 50° C. Heat the mixture at 65° C. overnight. Cool to 37° C. and add water (500 mL). Remove half of the solvent under vacuum and add DCM (2.5 L). Filter over a celite pad and remove part of the solvent. Add methanol (300 mL) and methyl tert-butyl ether (MtBE, 600 mL) to the mixture and cool in an ice bath. Then, add hydrochloric acid 2 M in ethyl ether (800 mL) and a 32% aqueous solution of hydrochloric acid (100 mL). Remove the organic layer, and add an aqueous solution of sodium hydroxide 2 M (2500 mL). Extract the aqueous phase three times with DCM and remove the solvent under vacuum. Solve in 90 mL of toluene at 50° C. until complete dissolution and then add 80 mL of MtBE. Stir overnight at RT. Add additional MtBE (100 mL) for complete precipitation. Filter the solid and dry to afford 108.24 g of the title compound. MS (ES+): m/z=221 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]([CH3:5])=[O:4])[CH3:2].C[CH:7]([OH:9])[CH3:8].[OH2:10].N>O>[CH3:5][C:3](/[CH:1]=[CH:2]/[CH:2]=[C:1]=[CH:3]/[CH:5]=[CH:8]/[C:7]([OH:9])=[O:10])=[O:4]
Reactant: CCC(C)=O
Reactant: CC(C)O
Reactant: O
Agent: N
Product: CC(=O)/C=C/C=C=C/C=C/C(=O)O

Procedure:
To a three-necked flask there were added crystalline polyester resin (A-1) (56 parts by mass), methyl ethyl ketone (35 parts by mass) and 2-propyl alcohol (9 parts by mass). Next, stirring was carried out with a three-one motor to dissolve the crystalline polyester resin, and then 26 parts by mass of a 5 mass % ammonia water solution was added. Also, ion-exchanged water (94 parts by mass) was slowly added for reverse phase emulsification, and then the solvent was removed. Next, ion-exchanged water was added to adjust the solid concentration (crystalline polyester resin concentration) to 30 mass %, and a crystalline polyester resin dispersion (LA-1) was obtained as a binder resin dispersion for toner. The volume-average particle diameter (D50v) of the resin particles in the dispersion was 223 nm.
Reaction SMILES: [N:1](=[C:3]([CH2:7][CH2:8][CH3:9])[C:4](=O)[CH3:5])O.[CH3:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15].[N:17](Cl)=O.N=C=O>[Zn].C(O)(=O)C>[CH3:10][C:11]1[C:12]([CH2:13][CH2:14][CH3:15])=[N:17][C:4]([CH3:5])=[C:3]([CH2:7][CH2:8][CH3:9])[N:1]=1
Reactant: O=NCl
Reactant: CCCCC(C)=O
Reactant: CCCC(=NO)C(C)=O
Agent: N=C=O
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCc1nc(C)c(CCC)nc1C

Procedure:
c. 2,5-Dimethyl-3,6-dipropyl-pyrazine was prepared by first forming 3-oximino-2-hexanone by reacting 2-hexanone with nitrosyl chloride according to the method of BOUVEAULT, Bull. [3] 31, 1163 (1904). The autocondensation of two molecules of the imino-ketone in the presence of zinc and acetic acid [according to the method described in Chimia 11, 310 (1957)] yielded 2,5-dimethyl-3,6-dipropyl-pyrazine which had a b.p. of 109°-110° C./10 mm. Hg.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH2:22][CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26].COC1CCCC1.Cl>CS(C)=O.O>[CH2:25]([O:24][CH:23]([O:27][CH2:28][CH3:29])[CH2:22][N:9]1[C:10]2[C:5](=[N:4][CH:3]=[C:2]([F:1])[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:12])[CH3:26]
Reactant: CCOC(CBr)OCC
Reactant: O=c1ccc2ncc(F)cc2[nH]1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COC1CCCC1
Solvent: O
Product: CCOC(Cn1c(=O)ccc2ncc(F)cc21)OCC
Yield: 60.7 %

Procedure:
To a suspension of 3.00 g of 7-fluoro-1,5-naphthyridin-2(1H)-one and 5.04 g of potassium phosphate in 12 mL of dimethyl sulfoxide, 4.68 g of 2-bromo-1,1-diethoxyethane was added at room temperature, and the resultant mixture was stirred for 4.5 hours at 94° C. The reaction mixture was cooled, and 21 mL of water and 12 mL of cyclopentyl methyl ether were added thereto. The mixture was adjusted to pH 5.8 with 12 mol/L hydrochloric acid, subsequently the insoluble matter was filtered out, and the filter residue was washed twice with 3 mL of cyclopentyl methyl ether. The organic layers of the obtained filtrate and the wash liquid were separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 3.11 g of 1-(2,2-diethoxyethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one as a light yellow oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:9]=N[CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].Cl[CH2:13][C:14]1[C:15]([C:20]2[N:24]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:23]=[CH:22][CH:21]=2)=[N:16][CH:17]=[CH:18][CH:19]=1.[C:30](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:11][O:10][C:6]1[CH:7]=[CH:30][CH:9]=[C:2]([O:1][CH2:13][C:14]2[C:15]([C:20]3[N:24]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)[C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)Cn1nccc1-c1ncccc1CCl
Reactant: COc1cncc(O)c1C=O
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(OCc2cccnc2-c2ccnn2CC(F)(F)F)c1C=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 3.5 %

Procedure:
To a solution of 3-hydroxy-5-methoxyisonicotinaldehyde (0.13 g, 0.88 mmol) in DMF was added 3-(chloromethyl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridine (0.24 g, 0.88 mmol) (INT-2) and potassium carbonate (0.49 g, 3.52 mmol) and the reaction mixture was heated (60° C.). After 3 hours, the reaction mixture was filtered through a plug of silica (MeOH/CH2Cl2, 0-20%). Purification of the resulting residue by Prep-HPLC, provided 2-methoxy-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (12 mg, 5% yield). NMR (400 MHz, Chloroform-d) δ 10.54 (s, 1H), 8.71 (dd, J=5.0, 1.8 Hz, 1H), 8.23 (s, 1H), 8.21 (ddd, J=7.9, 1.7, 0.7 Hz, 1H), 8.10 (s, 1H), 7.67 (dd, J=1.9, 0.5 Hz, 1H), 7.46 (dd, J=8.0, 4.5 Hz, 1H), 7.26 (d, J=0.5 Hz, 3H), 6.56 (dd, J=1.9, 0.5 Hz, 1H), 5.23 (s, 2H), 5.28-5.15 (m, 2H), 4.04 (s, 3H); MS (ESI) m/z 393 [M+Hr.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[S:12]1[CH:16]=[C:15]([CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[NH2:19])[N:14]=[CH:13]1.C1COCC1.[C:28]1([C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N+]=[N-])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)(=O)C>C(O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[C:28]1([CH:34]([O:21][C:20](=[O:22])[C@H:18]([CH2:17][C:15]2[N:14]=[CH:13][S:12][CH:16]=2)[NH2:19])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N[C@@H](Cc1cscn1)C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N[C@@H](Cc1cscn1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a solution of 38.85 g of the compound (43) (112.8 mmol) in ethanol (200 ml)-THF (600 ml) was added diphenyldiazomethane (39 g, 201 mmol) little, by little over 30 min. at room temperature with stirring. After the reaction mixture was stirred for 1 h at room temperature, to the mixture was added diphenyldiazomethane (10 g, 51.5 mmol) and the resulting mixture was stirred for 1 h. To the reaction mixture was added acetic acid (0.1 ml) for quenching the excess reagent and the mixture was concentrated in vacuo. The residue (92 g) was crystallized by adding ether (1 L) to give 49.05 g (96.1%) of the compound (44).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[O:6]/[C:5](=[C:7]2/[C:8](=[O:17])[NH:9][C:10]3[C:15]/2=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)/[CH:4]=[C:3]1[C:18]1[CH:19]=[N:20][C:21]([CH:24]=[CH2:25])=[CH:22][CH:23]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.O>CN(C=O)C>[CH3:1][C:2]1([CH3:26])[O:6]/[C:5](=[C:7]2/[C:8](=[O:17])[NH:9][C:10]3[C:15]/2=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)/[CH:4]=[C:3]1[C:18]1[CH:19]=[N:20][C:21]([CH2:24][CH2:25][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:22][CH:23]=1
Reactant: C1COCCN1
Reactant: C=Cc1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)ccc43)OC2(C)C)cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(CCN2CCOCC2)nc1
Temperature: 96 °C

Procedure:
A mixture of (3E)-3-[5,5-dimethyl-4-(6-vinylpyridin-3-yl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one (50 mg, 0.14 mmol) and morpholine (0.2 mL, 2.3 mmol) in 5 mL of DMF was heated in 96° C. bath under nitrogen for 3 hours. The mixture was cooled to room temperature and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-3-{5,5-dimethyl-4-[6-(2-morpholin-4-ylethyl)pyridin-3-yl]furan-2(5H)-ylidene}-6-fluoro-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 40 mg, 64%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1.I([O-])(=O)(=O)=[O:21].[Na+]>CO.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH3:18])[CH3:17])=[CH:14][CH:15]=1)=[O:21]
Reactant: COC(=O)CCCCCSc1ccc(N(C)C)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCCCCS(=O)c1ccc(N(C)C)cc1
Temperature: 60 °C
Yield: 80.7 %

Procedure:
To a solution of 6-(4-dimethylamino-phenylsulfanyl)-hexanoic acid methyl ester (1.4 g, 5.0 mmol) in methanol (60 mL) was added dropwise at 0° C. a solution of sodium metaperiodate (1.3 g, 6.0 mmol) in distilled water (20 mL). The mixture was heated at 60° C. for 1 hour. The solution was concentrated under reduced pressure to give an oil that was dissolved in ethyl acetate (150 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (100 mL), distilled water (2×50 mL), and lastly with brine (2×50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (100:1 ethyl acetate:triethylamine) to give the title compound (1.2 g, 81%) as a colourless oil.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[CH2:22][C:23](O)=[O:24].[CH:28]12[CH2:35][CH2:34][CH:31]([CH2:32][CH2:33]1)[CH2:30][NH:29]2.C1C=CC=CC=1>C(O)C>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:22][C:23]([N:29]2[CH2:30][CH:31]3[CH2:34][CH2:35][CH:28]2[CH2:33][CH2:32]3)=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CC2CCC1CN2
Reactant: O=C(O)CC(=O)O
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: c1ccccc1
Product: O=C(CC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CC2CCC1CC2

Procedure:
A mixture of 2 parts of triphenyl carbinol and 8 parts of malonic acid are heated at 170° for 3 hours. This mixture is cooled and dissolved in hot ethanol. 3,3,3-Triphenylpropionic acid, melting at 182°, crystallizes from the ethanol upon cooling. 1 Part of 3,3,3-triphenylpropionic acid is refluxed with 5 parts of thionyl chloride for 4 hours and the excess thionyl chloride is removed in vacuum to provide the crude 3,3,3-triphenyl propionyl chloride. 1 Part of this acid chloride is reacted with 2 parts of 2-azabicyclo[2.2.2]octane in 50 parts of benzene. The precipitated amide is filtered and the benzene solution washed with water, dried with magnesium sulfate, and the benzene evaporated. The remaining oil is crystallized to provide 2-(3,3,3-triphenylpropionyl)-2-azabicyclo[2.2.2]octane. 0.9 Parts of this material is reacted with 0.37 parts of lithium aluminum hydride in 15 parts of tetrahydrofuran at reflux for 5 hours. The reaction mixture is cooled and treated with 15% aqueous sodium hydroxide solution to decompose any unreacted lithium aluminum hydride. The reaction mixture is filtered and the solvent is removed in vacuo to provide a residual oil which is taken up in ether. The ether soln. is extracted c 10% HCl forming an insoluble gum, which is dissolved in methylene chloride, dried over anhydrous sodium sulfate and evaporated providing 2-(3,3,3-triphenylpropyl)-2-azabicyclo[2.2.2]octane hydrochloride, melting at 222°-223° C. This compound has the following molecular formula. ##STR31##
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.I[C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: Cc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)cc1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 4-iodotoluene according to the general procedure C. Obtained as an orange solid (542 mg).