Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@H:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]([CH3:17])=[CH:10][C:11]([Cl:16])=[N:12][C:13]=3[CH:14]=2)[O:5][C:4]([CH3:19])([CH3:18])[C@@H:3]1[OH:20].[C:21]([BH3-])#[N:22].[Na+].C(=O)([O-])O.[Na+]>CO>[Cl:16][C:11]1[CH:10]=[C:9]([CH3:17])[C:8]2[CH:7]=[C:6]3[O:5][C:4]([CH3:19])([CH3:18])[C@H:3]([OH:20])[C@@H:2]([NH:22][CH2:21][CH2:15][CH2:2][CH2:3][CH3:4])[C:15]3=[CH:14][C:13]=2[N:12]=1
Reactant: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)[C@H](O)[C@H]3N
Reactant: [BH3-]C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCN[C@H]1c2cc3nc(Cl)cc(C)c3cc2OC(C)(C)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
To a solution of (3R*,4S*)-4-amino-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol (60 mg, 0.205 mmol) in methanol (1.2 mL), butyl aldehyde (35 mg, 0.041 mmol) was added, and the resulting mixture was stirred at room temperature for 20 minutes. Sodium cyanoborohydride (52 mg, 0.82 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. Upon the completion of the reaction, saturated sodium hydrogencarbonate aqueous solution was added thereto, and the resulting solution was extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over magnesium sulfate and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=3/1) to obtain the aimed product (yield: 41%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12]Cl>>[Cl:12][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: ClCl
Reactant: Nc1ccc(C(F)(F)F)cn1
Product: FC(F)(F)c1ccc(NCl)nc1

Procedure:
The method according to claim 1, wherein 2-amino-5-trifluoromethylpyridine is reacted with chlorine to form 2-chloroamino-5-trifluoromethylpyridine, which is then subjected to a rearrangement reaction in the presence of at least one carboxylic acid selected from the group consisting of formic acid, acetic acid and propionic acid to obtain 2-amino-3-chloro-5-trifluoromethylpyridine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]([F:15])[F:14])[C:8]1[N:16]([CH3:29])[C:17](=[O:28])[C:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=[CH:19][C:7]2=1)(=[O:3])[CH3:2].CC(O[CH:35](N(C)C)[N:36]([CH3:38])[CH3:37])(C)C>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[C:17](=[O:28])[N:16]([CH3:29])[C:8]2[N:9]([CH:13]([F:15])[F:14])[C:10]3[C:6]([C:7]=2[CH:19]=1)=[CH:5][C:4]([C:1](=[O:3])/[CH:2]=[CH:35]/[N:36]([CH3:38])[CH3:37])=[CH:12][CH:11]=3
Reactant: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C(F)F
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)/C=C/C(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C(F)F

Procedure:
The process is carried out as for preparation 1.10 above, using compound A: 6-acetyl-3-(2,4-dichlorophenyl)-9-difluoromethyl-1-methyl-1,9-dihydropyrido[2,3-b]indol-2-one and Bredereck's reagent.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:10]([F:25])[C:9]=2[F:26])=[N:6][CH:7]=1.[OH-].[Na+].OO>O1CCCC1>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[CH:3][C:2](/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:7][N:6]=2)=[C:9]([F:26])[C:10]=1[F:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCC/C=C/c1cnc(-c2ccc(OCCCCCCCCCC)c(F)c2F)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 153.9 %

Procedure:
Apart from the above, inner atmosphere of a four-necked flask equipped with a stirring device, a reflux condenser and a thermometer was replaced with nitrogen gas, and then the flask was charged with 1.4 g (3.3 mmol) of 5-bromo-2-(4-decyloxy-2,3-difluorophenyl)-pyrimidine, 0.06 g (0.05 mmol) of tetrakis-triphenylphosphine-palladium, 0.6 g (15 mmol) of sodium hydroxide and 15 ml of tetrahydrofuran. Subsequently, 13 ml of a solution prepared by dissolving 5 mmol of the above-obtained E-1-nonenylcatecholborane in tetrahydrofuran was dropwise added thereto at room temperature. Then, the whole mixture was heated under reflux with stirring for 7 hours. After cooling the reaction mixture to room temperature, 3 ml of 10% aqueous solution of sodium hydroxide and 1 ml of 30% aqueous solution of hydrogen peroxide were added, and the resulting mixture was stirred for one hour. The mixture was extracted with ether, and the organic layer was twice washed with each 10 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 1.2 g (yield 78%) of 2-(4-decyloxy-2,3-difluorophenyl)-5-(1-trans-nonenyl)-pyrimidine. ##STR18##
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[C:21]1([CH2:20][CH2:19][CH2:18][N:1]2[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cnn(CCCc2ccccc2)c1

Procedure:
To a solution of ethyl 4-pyrazole carboxylate (3.57 mmol) in acetone (30 ml) was added potassium carbonate (35.7 mmol) and 1-bromo-3-phenylpropane (3.57 mmol). The suspension was refluxed overnight, after which the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer dried over magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to give an oil, which was purified by preparative TLC, to give ethyl 1-(3-phenylpropyl)pyrazole-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:13][C:14](=[O:17])[CH2:15]Cl)([CH2:11][OH:12])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.CC(O)(C)C.CC(C)([O-])C.[K+].Cl>CC(OC)(C)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:11][OH:12])[NH:13][C:14](=[O:17])[CH2:15][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCl)NC(CO)(CO)c1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COC(C)(C)C
Solvent: O
Product: O=C1COCC(CO)(c2cccc(Br)c2)N1

Procedure:
A suspension of N-[1-(3-bromo-phenyl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide (3.24 g, 10.04 mmol) and 35 ml of t-BuOH was treated with potassium tert-butoxide (1.127 g, 10.04 mmol). The mixture was heated at reflux for 1 h and neutralized with 10 ml of 1N HCl. Water and TBME were added, and the precipitate was filtered off. The organic phase of the filtrate was separated, dried with sodium sulfate and chromatographed on silica gel (EtOAc/MeOH 1-2%) to give the title compound in the form of a colourless solid. TLC (EtOAc/MeOH 1%): Rf=0.23; HPLC: RtH2=2.839 min; 1H-NMR (400 MHz, CD3OD): 7.70 (s, 1H), 7.53-7.47 (m, 2H), 7.35 (t, 1H), 4.17 (s, 2H), 4.08 (d, 1H), 3.98 (d, 1H), 3.91 (d, 1H), 3.87 (d, 1H); MS: 287, 289 [(M+H)+].
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[O:10]([CH2:17][CH2:18][CH2:19][N:20]1[CH2:30][CH2:29][CH:23]([C:24]([O:26]CC)=O)[CH2:22][CH2:21]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+].[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>O1CCCC1.CO>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:24]([C:34]2[CH:33]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)([CH:23]2[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:30][CH2:29]2)[OH:26])=[CH:4][CH:5]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C1CCN(CCCOc2ccccc2)CC1
Agent: O=C(O)C(=O)O
Agent: [Cl-]
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(CCCOc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5.10 g (0.21 mole) of magnesium turnings and a crystal of iodine in 800 ml of drytetrahydrofuran (distilled from lithium aluminum hydride) was added a solution of 36.75 g (0.21 mole) of p-bromofluorobenzene in 100 ml of tetrahydrofuran. The reaction flask was cooled in an ice bath during this addition, and the reaction mixture was under an atmosphere of nitrogen. The mixture was stirred at ambient temperature for 1 hr. A solution of 20.17 g (0.0693 mole) of ethyl N-(3-phenoxypropyl)isonipecotate in 100 ml of tetrahydrofuran was added and the solution was stirred at room temperature for 16 hr. The mixture was poured into an icy solution of ammonium chloride and the aqueous mixture was extracted with methylene chloride. The methylene chloride solution was extracted with dilute sodium hydroxide and was dried over magnesium sulfate. The solvent was removed in vacuo to give a gummy residue. The residue was treated with a solution of oxalic acid in methanol and the salt was recrystallized from methanol-ether to give 24.17 g (66.2%) of white, crystalline solid, m.p. 153°-155° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:25]1[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=1>>[N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:25]4[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=4)[CH:16]=3)[CH2:11][CH2:10]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N#Cc1cnc(Cl)s1
Reactant: Nc1cc(N2CCN(CCN3CCOCC3)CC2)ncn1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCN(CCN4CCOCC4)CC3)ncn2)s1

Procedure:
6-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]pyrimidin-4-amine 7-4 (1.5 g, 5.13 mmol), sodium hydride (0.41 g, 10.26 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.74 g, 5.13 mmol) were treated as in Scheme 4 above. The product was purified on a silica column eluted with DCM:MeOH:NH4OH (95:5:0.5 and 9:1:0.1) and isolated directly from the appropriate fractions after they were concentrated and the residue was suspended in methanol and filtered. 1H-NMR (CDCl3): 9.27 ppm (s, 1H); 8.45 ppm (s, 1H); 7.90 ppm (s, 1H); 5.87 ppm (s, 1H); 3.72 ppm (m, 4H); 3.65 ppm (s, 4H); 2.57 ppm (m, 8H); 2.50 ppm (s, 4H).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:8](=[O:10])[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)CC1CCCCC1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)CC1CCCCC1

Procedure:
Following General Procedure B′ above, and using cyclohexylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared as a solid having a melting point of 92° C.-93° C. The reaction was monitored by tlc on silica gel (Rf=0.39 in 1:3 EtOAc:hexane) and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9]3[CH2:11][CH2:12][CH2:13][C:8]=3[S:7][C:6]=2[N:5]=[C:4]([CH3:14])[C:3]=1[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>CN(C=O)C>[CH:17]1([C:15]([C:3]2[C:4]([CH3:14])=[N:5][C:6]3[S:7][C:8]4[CH2:13][CH2:12][CH2:11][C:9]=4[C:10]=3[C:2]=2[N:1]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:16])[CH2:19][CH2:18]1
Reactant: Cc1nc2sc3c(c2c(N)c1C(=O)C1CC1)CCC3
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2sc3c(c2c(N2CCCCC2)c1C(=O)C1CC1)CCC3
Reaction time: 0.33 h
Yield: 53.4 %

Procedure:
To a stirred solution of 12 mg (0.044 mmol) of (4-amino-6-methyl-2,3-dihydro-1H-8-thia-7-aza-cyclopenta[a]inden-5-yl)-cyclopropyl-methanone in 2 ml DMF was added 3.0 mg (0.066 mmol) NaH (55% in oil). After 20 minutes, 10 □l (0.044 mmol) of 1,5-dibromo-pentane and stirring was continued at RT over the night. The mixture was poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 6:1) afforded 8 mg (54%) cyclopropyl-(6-methyl-4-piperidin-1-yl-2,3-dihydro-1H-8-thia-7-aza-cyclopenta[a]inden-5-yl)-methanone as a white solid. ES-MS m/e (%): 341 (M+H+, 100).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[O-]CC.[Na+].[N+:17]([CH3:20])([O-:19])=[O:18]>C(O)C>[OH:12][C:9]1([CH2:20][N+:17]([O-:19])=[O:18])[CH2:8][CH2:7][N:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:11][CH2:10]1
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N1CCC(O)(C[N+](=O)[O-])CC1
Reaction time: 0.08 h

Procedure:
To a solution of N-carbethoxy-4-piperidone (11.34 g, 66.24 mmol) in nitromethane (5.3 mL) and ethanol (2 mL) was added a solution of sodium ethoxide in ethanol (2.67 M, 1.24 mL, 3.31 mmol). The mixture was stirred for 5 min and a solution formed from which a solid precipitated. After 1.5 h, water (100 mL) was added and the solid was isolated by filtration, washed with water (100 mL), and dried under vacuum with heat to yield the product ethyl 4-hydroxy-4-(nitromethyl)piperidine-1-carboxylate as an off white solid, 9.58 g (62%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:24][C:22]=2C=1>CN(C=O)C.O.CCN(CC)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:24][CH3:22])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CNC(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
5-Bromo-2-pyridinecarboxylic acid (D10) (1 g) was dissolved in dry DMF (50 ml) and treated with methylamine hydrochloride (0.42 g), EDC (1.2 g), HOBT (0.56 g) and Et3N (2.4 ml). The reaction was stirred at rt overnight then poured into water (200 ml) and extracted with DCM (50 ml). The organic extract was washed with brine (5×50 ml), dried (magnesium sulfate) and evaporated to give the title compound (D11) as a yellow crystalline solid (0.45 g). LCMS electrospray (+ve) 349 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12]C)=O)[CH:6]=1.N(C1C=C(C=CC=1)C(O)=O)=C=S.COC(OC)C(N)C.[C:37]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])[CH3:38].[Li]>OS(O)(=O)=O.CO>[C:41]([O:40][C:37](=[O:39])[CH2:38][C:10]([C:9]1[CH:14]=[CH:15][CH:16]=[C:7]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)[CH:8]=1)=[O:12])([CH3:44])([CH3:43])[CH3:42]
Reactant: COC(=O)c1cccc(-n2cnc(C)c2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: COC(OC)C(C)N
Agent: O=C(O)c1cccc(N=C=S)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cc1cn(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1

Procedure:
Prepared from methyl 3-(4-methyl-imidazol-1-yl)-benzoate [prepared the corresponding acid from 3-isothiocyanatobenzoic acid and 2-aminopropionaldehyde dimethyl acetal according to J. Med. Chem. 1987, 30, 1342, followed by refluxing in conc. H2SO4/MeOH] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a yellow-brown oil (10.69 g).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH3:8])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COCCOCCOCCOCCOCCOCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCOCCOCCOCCOCCOCCOC(=O)OC(C)Cl

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate was reacted with 2,5,8,11,14,17-hexaoxanonadecan-19-ol (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give 1-chloroethyl 2,5,8,11,14,17-hexaoxanonadecan-19-yl carbonate. This was then reacted with 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 21-oxo-2,5,8,11,14,17,20,22-octaoxatetracosan-23-yl-4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. LCMS (ES+) m/z calcd. for C47H60Cl2F2N3O13 [(M+H)+]: 982, found: 982.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[N:22]([CH2:25][CH3:26])[CH2:21][CH2:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:25]([N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]=[CH:16][C:17]=2[C:23]1=[O:24])[CH3:26]
Reactant: CCN1CCc2nc(N3CCN(Cc4ccccc4)CC3)ncc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCN1CCc2nc(N3CCNCC3)ncc2C1=O
Yield: 96.1 %

Procedure:
Dissolved in 20 ml of ethanol was 0.70 g of 2-(4-benzylpiperazino)-6-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (Referential Example 38), followed by an addition of 10% Pd-C. The resultant mixture was stirred at 60° C. for 4 hours in a hydrogen atmosphere. After allowing the reaction mixture to cool down, the catalyst was filtered off and the filtrate was concentrated to obtained 0.50 g of 6-ethyl-5-oxo-2-piperazino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine as crystals (yield: 96%). The crystals were purified by their immersion in ethyl acetate.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.CN(C)C(=O)C.[C:21](Cl)(=O)[CH2:22][CH3:23]>O>[CH2:22]([C:23]1[O:1][N:2]=[C:3]([CH2:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[N:14]=1)[CH3:21]
Reactant: CCC(=O)Cl
Reactant: NC(Cc1ccc([N+](=O)[O-])cc1)=NO
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCc1nc(Cc2ccc([N+](=O)[O-])cc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a mixture of N′-hydroxy-2-(4-nitrophenyl)ethanimidamide (6.17 g) and N,N-dimethylacetamide (50 mL) was added propionyl chloride (3.22 g) at room temperature. The reaction mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue and xylene (200 mL) was heated under reflux for 15 hrs. with azeotropic dehydration. The reaction mixture was concentrated and the obtained residue was subjected to silica gel column chromatography to give 5-ethyl-3-(4-nitrobenzyl)-1,2,4-oxadiazole as brown crystals (4.40 g, yield 60%) from a fraction eluted with hexane-ethyl acetate (3:1-2:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 69-70° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[CH3:16])=[CH:4][CH:3]=1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:17]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[CH3:16])[C:5]2[CH:6]=[CH:7][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][CH2:28][CH3:29])=[O:26])=[CH:3][CH:4]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(O)ccc1C(=C1CCCCC1)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2C)cc1
Temperature: 140 °C
Yield: 60 %

Procedure:
To a solution of 4-[(4-bromophenyl)(cyclohexylidene)methyl]-3-methylphenol (29) (0.60 g, 1.68 mmol) in DMF (6 mL) was added ethyl acrylate (0.54 mL, 4.98 mmol), P(o-tolyl)3 (0.056 g, 0.184 mmol), Et3N (0.70 mL, 5.02 mmol), and Pd(OAc)2 (0.023 g, 0.10 mmol). The mixture was heated at 140° C. for 30 min in a microwave. Upon cooling, water (25 mL) was added, and the mixture was extracted with Et2O (3×20 mL). The organics were combined, dried (MgSO4), and concentrated. The crude material was purified by chromatography on silica gel (EtOAc:hexanes) to yield 0.13 g, (60%) of compound 30. 1H NMR (400 MHz, CDCl3): δ 1.32 (t, J=7.1 Hz, 3H), 1.52-1.61 (m, 6H), 1.98-2.01 (m, 2H), 2.06 (s, 3H), 2.32 (m, 2H), 4.24 (q, J=7.1 Hz, 2H), 4.78 (s, 1H), 6.36 (d, J=16.1 Hz, 1H), 6.62-6.63 (m, 2H), 6.96 (m, 1H), 7.13 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.63 (d, J=15.9 Hz, 1H).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:8][CH2:7][CH2:6][NH:5]2)[CH2:3][O:2]1.Cl[CH2:10][C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C@H:23]3[O:27][C:26]([CH3:29])([CH3:28])[N:25]([C:30](=[O:34])[CH:31]([F:33])[F:32])[C@@H:24]3[CH2:35][F:36])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:3]1[C:4]2([CH2:8][CH2:7][CH2:6][N:5]2[CH2:10][C:11]2[N:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[O:27][C:26]([CH3:29])([CH3:28])[N:25]([C:30](=[O:34])[CH:31]([F:33])[F:32])[C@@H:24]4[CH2:35][F:36])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:1][O:2]1
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(CCl)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: C1CNC2(C1)COC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CN4CCCC45COC5)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 55 °C

Procedure:
A mixture of 2-oxa-5-azaspiro[3.4]octane (0.1 mmol, 15.8 mg), 1-{(4S,5R)-5-[4-(6-Chloromethyl-pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidin-3-yl}-2,2-difluoro-ethanone (Example 99, Step 2, 0.09 mmol, 37 mg) and cesium carbonate (0.25 mmol, 81 mg) and acetonitrile (1 mL) was heated to 55° C. for 5 hours. The crude mixture was filtered on a bed of celite and the cake was washed with CH2Cl2 (2 mL). The volatiles were removed. The crude mixtures were used “as is” in step 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([O:16]CC)=[O:15])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([OH:16])=[O:15])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(C)n(-c2ccc(F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)O)nn1-c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
Ethyl 1-(4-fluorophenyl)-5-methylpyrazole-3-carboxylate (3 g) was dissolved in a mixed solvent of ethanol (15 ml) and water (15 ml) and sodium hydroxide (0.6 g) was added. The mixture was stirred at a refluxing temperature for 30 min. Ethanol was evaporated and to the residue was added dilute hydrochloric acid. The obtained solid was recrystallized from aqueous methanol solution to give the title compound (2.1 g), melting point: 177° C.