Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12]([NH2:14])=[O:13])[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1.[N+](C1C=CC([N:31]([CH:35]2[CH2:40][CH2:39][C:38](=[N:41][O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:37][CH2:36]2)[C:32](=O)[O-:33])=CC=1)([O-])=O.C(=O)([O-])[O-].[Na+].[Na+].O>C(#N)C>[Cl:2][C:3]1[N:7]2[CH2:8][CH2:9][N:10]([C:32]([NH:31][CH:35]3[CH2:40][CH2:39][C:38](=[N:41][O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:37][CH2:36]3)=[O:33])[CH2:11][C:6]2=[C:5]([C:12]([NH2:14])=[O:13])[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1
Reactant: NC(=O)c1c(-c2cccc(F)c2)c(Cl)n2c1CNCC2
Reactant: CC(C)(C)ON=C1CCC(N(C(=O)[O-])c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)ON=C1CCC(NC(=O)N2CCn3c(Cl)c(-c4cccc(F)c4)c(C(N)=O)c3C2)CC1
Temperature: 60 °C

Procedure:
A suspension of 0.27 (0.82 mmol) of 6-chloro-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide hydrochloride, 0.37 g (1.06 mmol) of 4-nitrophenyl[4-[(1,1-dimethylethoxy)imino]cyclohexyl]-carbamate and 0.33 g (2.45 mmol) of sodium carbonate in 30 ml of acetonitrile is heated at 60° C. for 3 hours. After cooling, the mixture is poured into water and the product is extracted with dichloromethane. After drying over sodium sulfate and filtration, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of dichloromethane/ethyl acetate (60/40 to 20/80), to give 0.18 g of 6-chloro-7-(3-fluorophenyl)-N2-[4-[(1,1-dimethylethoxy)imino]cyclohexyl]-3,4-dihydropyrrolo-[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a yellowish powder, after evaporating the fractions down to a small volume of solvent, filtering off the crystallized product, washing with ethyl acetate and drying under reduced pressure.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=O.N1C=CC=CC=1.[OH-].[Na+].[CH2:14]([N:16]=[C:17]=[S:18])[CH3:15]>O>[CH2:14]([N:16]1[C:3](=[O:5])[CH2:2][NH:1][C:17]1=[S:18])[CH3:15]
Reactant: NCC(=O)O
Reactant: CCN=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCN1C(=O)CNC1=S
Temperature: 40 °C
Yield: 90 %

Procedure:
Glycine 36 (150 mg, 2.0 mmol) was dissolved in H2O (5.0 mL) and pyridine (5.0 mL) solution. The pH of the solution was adjusted to about 9.0 as shown by an indicator paper by the addition of 1M NaOH. The solution was heated to 40° C. and kept at that temperature during the reaction. Ethyl isothiocyanate 35 (0.263 mL, 3.0 mmol) was added with vigorous stirring. Small portions of 1M NaOH was added to keep the pH at about 9.0. The reaction was completed when the alkali consumption ceased (1 h). Pyridine and excess alkyl isothiocyanates were then removed by repeated extraction with equal volumes of benzene. Subsequently, an amount of conc. HCl (0.75 mL) was added and the mixture was refluxed for 2 h. The residue was extracted with ethyl acetate (2×150 mL). The organic layer was dried with brine and MgSO4, then concentrated in vacuo. Flash column chromatography on silica gel (hexane:ethyl acetate=2:1) of the residue afforded the desired product 37 in 90% yield (258 mg, pale yellow solid). 1H NMR (400 MHz, CDCl3): 6.88 (br, 1H), 4.06 (d, J=1.2 Hz, 2H), 3.89 (q, J=7.2 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9](Cl)=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-:25].[K+].CS(C)=O>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([F:25])=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2F)cc1
Temperature: 120 °C

Procedure:
A round bottom flask is charged with 2-tert-butyl-4-chloro-5-(4-tert-butylbenzyl)thio 3(2H)-pyridazinone (100 mg, 0.27 mmol) and to it is added potassium fluoride (23.4 mg, 0.40 mmol) and 2 ml dimethyl sulfoxide. This is heated to 120° C. for 6 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. This is washed with water and dried. Purification by flash chromatography (silica gel; ethyl acetate/hexanes) gave the above mentioned compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:14][CH2:13]1)[CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15].[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH:12]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:11][CH:10]=3)[C:5]([CH3:16])([CH3:15])[CH2:6][CH2:7]2)[CH2:14][CH2:13]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCN(C2CC2)c2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC1(C)CCN(C2CC2)c2ccc(C#C[Si](C)(C)C)cc21

Procedure:
Following general procedure D and using 6-bromo-1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 51, 0.8 g, 2.86 mmol), (trimethylsilyl)acetylene (5 mL, 35 mmol), triethyl amine (10 mL), anhydrous tetrahydrofuiran, copper(I)iodide (0.080 g, 0.42 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.240 g, 0.34 mmol), the title compound was obtained as an oil (0.67 g, 79%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:12])[NH:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:20]([CH3:31])[C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[CH3:30])=[O:22].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:12][CH:20]([CH3:31])[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])=[O:22])=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH][nH]c1=O
Reactant: Cc1ccc(C(=O)C(C)Br)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(OC(C)C(=O)c2ccc(C)cc2C)n[nH]c1C

Procedure:
To a well stirred mixture of 5-methyl-3-oxo-2,3-dihydro-1H-pyrazole4-carboxylic acid ethyl ester (200 mg, 1.18 mmol, 1 eq.) and K2CO3 (179 mg, 1.29 mmol, 1.1 eq.) in DMF (5 ml) is added dropwise a solution of 2-bromo-1-(2,4-dimethyl-phenyl)-propan-1-one (Intermediate BA) (298 mg, 1.23 mmol, 1.05 eq.) in DMF (2.5 ml) at 50° C. After the addition, the reaction mixture is further stirred at 50° C. for 1 h then poured into water (50 ml) and extracted with EtOAc (2×25 ml). The combined organic fractions are dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting crude residue is purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [iso-hexane/DCM 1:1]/TBME 95:5→7:3) to yield the title compound as a white solid. TLC: RF=0.74 (iso-hexane/DCM/TBME 1:1:2); HPLC: AtRet=2.30; MS: m/z 331.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.24 (t, J 7.1, 3H), 1.43 (d, J 6.8, 3H), 2.31 (s, 6H), 2.33 (s, 3H), 4.15 (m, 2H), 5.75 (q, J 6.8, 1H), 7.13 (m, 2H), 7.83 (m, 1H), 12.24 (br. s., 1H).
Reaction SMILES: [OH:1][C:2]([CH:11]([CH3:13])[CH3:12])=[CH:3][C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[CH3:15][O:16][NH2:17].C(O)C>C(OCC)(=O)C>[CH3:15][O:16][N:17]=[C:4]([CH2:3][C:2](=[O:1])[CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=O)C=C(O)C(C)C
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(=O)C(C)C)=NOC
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
A mixture of 5.0 g of ethyl 4-hydroxy-5-methyl-2-oxo-3-hexenoate, 2.46 g of O-methylhydroxylamine hydrochloride and 10 ml of ethanol was stirred at room temperature for 6 hours. After ethyl acetate was poured into the reaction mixture, the organic layer was washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 5.32 g of ethyl 2-methoxyimino-5-methyl-4-oxohexanoate of the formula:
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]=[C:15]([CH:25]([CH3:27])[CH3:26])[C:14]=2[CH:28]=O)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:28][C:14]1[C:15]([CH:25]([CH3:27])[CH3:26])=[N:16][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:18][C:13]=1[C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=1
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=C(Br)Br
Reaction time: 0.33 h
Yield: 102.2 %

Procedure:
A solution of carbon tetrabromide (2.204 gm, 6.65 mmol) in CH2Cl2 (8 ml) was added over a 12 minute period to a cold (-12° C.) solution of 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (1.415 gm, 4.43 mmol) (the preparation of which is described in Example 1) and triphenylphosphine (3.488 gm, 13.3 mmol) in CH2Cl2 (25 ml). After the addition was complete, the cooling bath was removed and the mixture was stirred for 20 minutes. The solution was quenched with saturated NaHCO3 and extracted 3× with CH2Cl2. The combined organic layers were washed with saturated NaHCO3, dried (Na2SO4), filtered and stripped to give a yellow oil. The oil was chromatographed (flash, Merck SiO2, 40% CH2Cl2 in hexane) to give 3-(2,2-dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine as a colorless foam (2.152 gm, 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C>[Br:19][C:8]1[CH:7]=[C:6]([CH2:10][CH3:11])[C:4]([NH2:5])=[C:3]([CH2:1][CH3:2])[CH:9]=1
Reactant: CCc1cccc(CC)c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCc1cc(Br)cc(CC)c1N
Temperature: 25 °C
Yield: 51.4 %

Procedure:
2,6-diethylaniline (7 g, 46.9 mmol) was dissolved in 50 mL of DMF in a round-bottom flask and cooled with an ice-water bath. N-bromosuccimide (NBS) (9.18 g, 51.6 mmol) was dissolved in 100 mL of DMF and added dropwise to the flask via a dropping funnel. The reaction was warmed slowly to room temperature and reacted overnight before it was quenched by ice water. The product was extracted with dichloromethane and washed with lithium chloride solution. After evaporating solvent, the residue was purified by silica gel column chromatography. 5.5 g (51.4% yield) of product was obtained.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]([C:31](=[O:33])[CH3:32])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=3[O:29][CH3:30])=[CH:17][CH:16]=2)[CH:8]=1)C.O.[OH-].[Li+].O1CCCC1>O>[C:31]([N:6]([CH2:5][C:4]([OH:34])=[O:3])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=3[O:29][CH3:30])=[CH:19][CH:20]=2)[CH:8]=1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)CN(C(C)=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(N(CC(=O)O)C(C)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask containing {acetyl-[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenyl]-amino}-acetic acid ethyl ester (10 mg, 0.02 mmol) was added lithium hydroxide hydrate (2 mg, 0.05 mmol), tetrahydrofuran (0.5 mL) and water (0.5 mL). The reaction was stirred at room temperature overnight, diluted with ethyl acetated (25 mL) and washed with aqueous HCl (0.1 M, 25 mL) and brine (25 mL), dried over magnesium sulfate, concentrated and dried from hexanes/methylene chloride mixtures to yield {acetyl-[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenyl]-amino}-acetic acid as an off white solid (12 mg, 127%) LC-MS (ES) calculated for C24H21F2NO5, 441.14; found m/z 442 [M+H]+.
Reaction SMILES: [Br:1]Br.[C:3]([CH:5]([C:9](=[O:11])[CH3:10])[C:6]([NH2:8])=[S:7])#[N:4].C(=O)(O)[O-].[Na+].C(OC)(C)(C)C>C(O)(=O)C>[NH2:8][C:6]1[S:7][N:4]=[C:3]([Br:1])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)C(C#N)C(N)=S
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: CC(=O)c1c(Br)nsc1N

Procedure:
Add bromine (195; mL, 3.81; mol) over 10; min to a heated solution of 2-cyano-3-oxo-thiobutyramide (550; g, 3.86; mol) in glacial acetic acid (5.80; L) at 40° C. and stir at room temperature for 15; h. Filter the reaction mixture, wash the collected solid with water and dry overnight under vacuum to give a dark red solid (1151; g). Slurry the solid with stirring in a saturated aqueous solution of sodium bicarbonate (8; L) for 30; min and filter. Wash the collected solid with water and dry overnight under vacuum to give a dark red solid (1022; g). Slurry the solid with stirring with methyl t-butyl ether (5.90; L) over 1 hour, filter and retain the filtrate. Repeat the above methyl t-butyl ether extraction process twice on recovered solid retaining the filtrate after each extraction. Combine the filtrates and concentrate to give the title compound as a yellow solid which is carried on without further purification (598; g, 72%). MS (m/z): 221, 223; (M+1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5](=[O:21])[NH:6][C:7]([CH3:20])=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].Br[CH2:23]/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27]>C1COCC1>[Br:3][C:4]1[C:5](=[O:21])[N:6]([CH2:23]/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27])[C:7]([CH3:20])=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: COC(=O)/C=C/CBr
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/Cn1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of NaH (277 mg, 11 mmol) in anhydrous THF (30 ml), which was cooled to 0° C., was slowly added 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (3.3 g, 10 mmol). The resulting slurry was stirred for 15 min, after which methyl 4-bromocrotonate (1.4 ml, 12 mmol) was added to the reaction. The ice bath was removed and the reaction was heated to reflux for 16 h. The reaction was quenched by the addition of 1N NH4Cl. The layers were separated and the aqueous layer was extracted with CH2Cl2 (5×). The organics were combined, dried, and concentrated in vacuo. The crude yellowish material was then triturated with Et2O to give, after filtration and drying, 1.8 g (43%) of a white solid. 1H-NMR (DMSOd6/300 MHz) δ 7.65 (app q, J=8.7 hz, 1H), 7.36 (app dt, J=12.0, 3.0 hz, 1H); 7.17 (dt, J=8.4, 1.8 Hz, 1H); 6.94 (dt, J=15.9, 4.5 Hz, 1H); 6.57 (s, 1H), 5.52 (d, J=15.9 Hz, 1H), 5.29 (s, 2H), 4.84 (m, 2H), 3.63 (s, 3H), 2.33 (s, 3H). ES-HRMS m/z 428.0301 (M+H calcd for C18H17BrF2NO4=428.0310).
Reaction SMILES: Cl.[CH2:2]([C:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=2)[O:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][N:6]([CH3:16])[CH2:5]1)[CH3:3].Br>>[CH2:2]([C:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[O:9][CH:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:7][N:6]([CH3:16])[CH2:5]1)[CH3:3]
Reactant: CCC1(c2cccc(OC)c2)CN(C)CC(c2ccccc2)O1
Agent: Br
Agent: Cl
Product: CCC1(c2cccc(O)c2)CN(C)CC(c2ccccc2)O1

Procedure:
2-Ethyl-2-(3-methoxyphenyl)-4-methyl-6-phenylmorpholine hydrochloride (Isomer B from Example 22) (607 mg) was heated under reflux with concentrated hydrobromic acid (5 ml) for 1.25 h. On cooling crystals and a dark gum separated. The hydrobromic acid was removed under reduced pressure and the gummy product re-evaporated with portions of isopropyl alcohol. The product was recrystallised from isopropyl alcohol to give the title compound of apparently 2R*,6S* configuration (422 mg), mp 250°-252° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[C:4]([F:19])[CH:3]=1.[CH3:20][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:20][O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:16]([Cl:18])=[N:17][C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:19]
Reactant: O=C(O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Reaction time: 1 h
Yield: 93 %

Procedure:
To a suspension of 2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid (5.00 g, 14.5 mmol) in methanol/benzene (1:1, 100 mL) under N2 was added (trimethylsilyl)diazomethane (2.0 M solution in hexanes) dropwise until the bubbling caused by gas evolution ceased. Solids precipitated out of solution. The reaction was allowed to stir for 1 hour. Excess (trimethylsilyl)diazomethane was quenched by the dropwise addition of glacial acetic acid. The precipitated solids were filtered and washed with methanol. The filtrate was concentrated to a smaller volume and additional solids precipitated out of solution that were filtered and washed with methanol. The solids were combined and dried under vacuum to yield 4.82 g (93%) of pure desired product as a dark pink solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([CH:21]=[O:22])[CH:15]=2)[N:7]=1)=[O:5])[CH3:2].[C:23]([Cu])#[N:24].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([C:23]#[N:24])=[CH:10][CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([CH:21]=[O:22])[CH:15]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Oc2ccc(Br)c(C=O)c2)ccc1Br
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(Oc2ccc(Br)c(C=O)c2)ccc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.1 %

Procedure:
To a solution of 3-bromo-6-(4-bromo-3-formyl-phenoxy)-pyridine-2-carboxylic acid ethyl ester (23, 1.8 g, 4.19 mmol) in DMF (6 mL) was added CuCN (0.75 g, 8.38 mmol) in portions at 130° C. and heated for 4 hour. The mixture was cooled to room temperature and ethyl acetate (100 mL) was added. The mixture was stirred for 10 minutes, filtered, and washed with ethyl acetate (2×50 mL). The filtrate was washed with water (2×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography (25% ethyl acetate/hexanes) to yield compound 24 (0.3 g, 19%) as a white solid. 1H NMR 400 MHz (DMSO-d6) δ: 10.20 (s, 1H), 8.51 (d, J=8.6 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.76 (s, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.55 (dd, J=8.5, 2.7 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H); MS (ES) m/z: 377 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:12](Br)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15]>>[CH2:12]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: COC(=O)c1ccccc1O
Product: CC(C)=CCC/C(C)=C/COc1ccccc1C(=O)O
Yield: 74.3 %

Procedure:
In a manner similar to Reference Example 1, methyl 2-hydroxybenzoate (7.61 g) was reacted with geranyl bromide (10.9 g) and then hydrolyzed to yield 10.2 g (75%) of 2- geranyloxybenzoic acid.
Reaction SMILES: [CH3:1][C:2]([C:5]([CH3:13])([CH2:10][CH:11]=C)[C:6]([O:8][CH3:9])=[O:7])([CH3:4])[CH3:3].[O:14]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][C:2]([C:5]([CH3:13])([CH2:10][CH:11]=[O:14])[C:6]([O:8][CH3:9])=[O:7])([CH3:4])[CH3:3]
Reactant: O=[O+][O-]
Reactant: C=CCC(C)(C(=O)OC)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(C)(CC=O)C(C)(C)C
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of the olefinic ester, methyl 2-(1,1-dimethylethyl)-2-methyl-4-pentenoate (2.76 g, 15 mmol), in dry CH2Cl2 (60 mL) was reacted with ozone at -78° C. When excess ozone was observed (blue coloration), nitrogen was bubbled through the solution, and Ph3P (5.90 g, 22.5 mmol) was added in one portion while stirring. The system was allowed to warm to room temperature (ca. 2 h) and stirred for 2 more hours. The solvent was removed in vacuo and the residue triturated with hexanes (150 mL). The precipitated Ph3PO (ca. 5.78 g) was filtered off and the filtrate concentrated in vacuo to give 2.80 g of the crude product as a colorless viscous residue. Flash chromatography over silica gel (hexanes-EtOAc, 19:1) afforded 2.12 g (76%) of the aldehyde as a colorless oil.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[ClH:12].[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:12].[C:3]([CH:2]([N:26]1[CH2:25][CH2:24][N:23]([C:21](=[O:22])[CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[OH:13])[CH2:28][CH2:27]1)[CH3:11])(=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cc1ccccc1O)N1CCNCC1
Reactant: CC(Br)C(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)c1ccccc1)N1CCN(C(=O)Cc2ccccc2O)CC1

Procedure:
A mixture of 2-bromo-1-phenylpropan-1-one (3 mmol), N-(2-hydroxy-phenyl acetyl)piperazine hydrochloride (2.5 mmol) and K2CO3 (8.75 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-18), 0.65 g (67%), M+ 353.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[CH:14]=[O:15])[CH2:10][NH:9][CH2:8][CH2:7]2.C([O-])([O-])=O.[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:13]([CH:14]=[O:15])=[C:4]([O:3][CH3:2])[CH:5]=2)[CH2:10]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2c(cc1C=O)CNCC2
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1C=O)CN(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
To a mixture of 6-methoxy-1,2,3,4-tetrahydro-isoquinoline-7-carbaldehyde hydrochloride (114 mg, 0.5 mmol) and freshly dried K2CO3 (173 mg, 1.25 mmol) in anhydrous dimethylformamide (5 mL), benzyl chloride (69 μL, 76 mg, 0.6 mmol) was added and the mixture was stirred at room temperature for 24 h. The mixture was poured into water (25 mL) and extracted with diethyl ether (3×10 mL). The combined organic layers were washed with brine (3×5 mL), dried over MgSO4 and concentrated. The title compound (112 mg, 0.40 mmol, 80%) was obtained as a yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][CH:9]=2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>CN1C(=O)CCC1>[O:10]1[CH:11]=[CH:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:16][C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=2)=[CH:9]1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=[N+]([O-])c1cc(-c2ccoc2)ccc1F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(Nc2ccc(-c3ccoc3)cc2[N+](=O)[O-])c1
Temperature: 110 °C
Yield: 33.5 %

Procedure:
5-(3-furanyl)-1-(3-(ethoxycarbonyl)phenyl)benzimidazole(6c1) To a solution of 1d (2.07 g, 10 mmol) in NMP (2 ml) was added ethyl 3-aminobenzoate (1.82 g, 11 mmol) and triethylamine and the mixture was heated to 110° C. in a nitrogen atmosphere overnight. The mixture was diluted with ice-water and extracted with ethyl acetate. The concentrated extract was purified by column-chromatography on silica gel using a mixture of petroleum ether and ethyl acetate (9:1 v/v) to yield ethyl 3-(N-(4-(3-furanyl)-2-nitrophenyl))aminobenzoate (1.18 g, 34%). This ester was hydrogenated in ethanol at ambient pressure using Pd (5% on activated carbon) as the catalyst. The resulting diamine (1.07 g) was treated with triethyl orthoformate (1.11 ml, 6.64 mmol) and a catalytic amount of pTSA in refluxing THF (10 ml). Column-chromatographic work-up of the concentrated reaction mixture using ethyl acetate as the eluent afforded 6c1 (0.66 g, 56%). M.p. 87-89° C.