Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[NH3:15]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:14])[C:9]([NH2:15])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)c1ccc(Cl)cc1
Reactant: N
Solvent: CC(C)(C)O
Product: C[C@@H](C(N)=O)c1ccc(Cl)cc1
Yield: 42.8 %

Procedure:
A mixture of 5 g of racemic ethyl 2-(4-chlorophenyl)-propionate and 50 ml of tert-butanol is treated at 50° C. with stirring with 1 g of lipase from Candida antarctica (Novozym 435, activity 7000 PLU/g). Ammonia is then passed into the reaction mixture with stirring at 50° C. until it is saturated. The mixture is stirred at 50° C. for a further 28 hours and during the course of this a slow stream of ammonia is continuously passed through the apparatus. The mixture is then worked up by filtering off the biocatalyst, washing it with tert-butanol and ethanol, concentrating the filtrate under reduced pressure and stirring the residue which remains with a mixture of petroleum ether:di-isopropyl ether=9:1. The product obtained in crystalline form is filtered off, washed with petroleum ether and dried. In this manner 1.78 g (42.8% of theory, conversion 44 area per cent GC) of (R)-2-(4-chloro-phenyl)-propionamide having an ee value of 96.1% are obtained.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13])=[N+:2]=[N-:3].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:21][C:22]([O:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH:15]=1.N12CCCN=C1CCCCC2>CN(C)C=O>[N:1]([CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH:20]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[CH2:21][C:22]([O:24][CH:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:23])[C:8](=[O:12])[C:7]1=[O:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCN1CCNC(=O)C1=O
Reactant: O=C(C=Cc1cccnc1)OC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCCN1CCN(C(CC(=O)OC(c2ccccc2)c2ccccc2)c2cccnc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.2 %

Procedure:
A mixture of 0.5 g of 1-(2-azidoethyl)-2,3-dioxopiperazine, 1.72 g of diphenylmethyl 3-(3-pyridyl)-acrylate, 0.2 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene and 2.5 ml of N,N-dimethylformamide was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, after which 30 ml of ethyl acetate and 20 ml of water were added to the resulting residue and the pH was adjusted to 6 with 2N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with 30 ml of ethyl acetate. The combined organic layer was washed with 20 ml of water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform:methanol=20:1) to obtain 0.71 g of diphenylmethyl 3-[4-(2-azidoethyl)-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionate as a light-brown oil.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15]C)=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCCn1cc(C(C)=O)c2ccc(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1cc(C(C)=O)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
Methyl 3-acetyl-1-butyl-1H-indole-6-carboxylate (2.00 g) was dissolved in methanol (100 mL). Sodium hydroxide (1N) was added until the mixture became slightly cloudy. Methanol was again added (20 mL) until the solution was clear. Sodium hydroxide was again added until the mixture was slightly cloudy. The mixture was allowed to stir at room temperature overnight. The solution was concentrated to half its original volume and hydrochloric acid (2N) was added until the aqueous layer indicated a pH of about one. The mixture was extracted with dichloromethane and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting material was chromatographed on silica gel using MeOH/heptane/dichloromethane (4/20/76) to give 3-acetyl-1-butyl-1H-indole-6-carboxylic acid (1.60 g). MS (ESI+) for C15H17N1O3+H1 m/z 260.13 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6](=[O:18])[CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)[CH3:2].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:29][C:30](=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:6](=[O:18])[CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)[CH3:2]
Reactant: CCOC(=O)CC(=O)CC12CC3CC(CC(C3)C1)C2
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(CC(=O)c1ccccc1)C(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution of 4-adamantan-1-yl-3-oxo-butyric acid ethyl ester, prepared by a modification of Wierenga and Skulnick's procedure (W. Wierenga and H. I. Skulnick, J. Org. Chem., 1979, 44, 310)(3.00 g, 11.0 mmol) in acetone (30 ml) was added sodium iodide (0.55 g, 3.67 mmol) and anhydrous potassium carbonate (3.04 g, 22.0 mmol), then a solution of 2-bromo-1-phenyl-ethanone (2.38 g, 11.5 mmol) in acetone (10 ml). The mixture was stirred at reflux for 36 h, cooled to room temperature and filtered. The filtrate was evaporated, the residue was dissolved in diethyl ether (50 ml) and washed with water (2×20 ml). The organic phase was dried (MgSO4) and the solvent was evaporated. The residue was purified by flash column chromatography (silica, hexane/ethyl acetate 4:1) to afford the product as pale yellow oil (1.92 g, 46%). 1H NMR (300 MHz, CDCl3) 7.98 (2H, m), 7.65 (1H, m), 7.46 (2H, m), 4.19 (3H, m), 3.60 (1H, dd), 5.59 (1H, dd), 2.50 (2H, dd), 1.96 (3H, br s), 1.68 (12H, m), 1.29 (3H, t).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH:3]=1.[CH2:19]([O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)[CH3:20].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:4]2[CH:3]=[C:2]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:31])=[CH:29][CH:28]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: FC(F)(F)c1cc(Cl)cc(-c2cccc(Cl)c2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc(C(F)(F)F)c2)cc1
Temperature: 120 °C
Yield: 28.9 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyridine (0.150 g, 0.51 mmol), 4-aminophenyl acetic acid ethyl ester (0.138 g, 0.77 mmol), palladium acetate (0.006 g, 0.026 mmol), rac-BINAP (0.024 g, 0.038 mmol) and cesium carbonate (0.418 g, 1.28 mmol) in dioxane (5 mL) under argon. The reaction mixture was heated to 120° C. under microwave irradiation for 2 h. After this time, the reaction mixture was cooled and absorbed onto silica (4 g). Purification by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA) afforded the title compound (0.064 g, 28%) as a tacky solid. MW=434.84. 1H NMR (CDCl3, 300 MHz) δ 9.39 (s, 1H), 8.00-7.97 (m, 1H), 7.93-7.86 (m, 1H), 7.57-7.52 (m, 3H), 7.35-7.25 (m, 4H), 7.21 (d, J=3.0 Hz, 1H), 4.09 (q, J=7.2 Hz, 2H), 3.67 (s, 3H), 1.20 (t, J=7.2 Hz, 3H); ESI MS m/z 435 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[C:3]=1[CH:14]=O.[C:16](#[N:19])[CH:17]=[CH2:18].N12CCN(CC1)CC2>C(OCC)(=O)C>[CH3:13][O:12][C:6]1[CH:7]=[CH:8][C:9]2[CH:10]=[CH:11][C:2]3[O:1][CH2:18][C:17]([C:16]#[N:19])=[CH:14][C:3]=3[C:4]=2[CH:5]=1
Reactant: COc1ccc2ccc(O)c(C=O)c2c1
Reactant: C=CC#N
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Product: COc1ccc2ccc3c(c2c1)C=C(C#N)CO3

Procedure:
Under an anhydrous atmosphere, the aldehyde obtained in Step C (2 g: 9.9 mmol) is partially solubilised in acrylonitrile (6.5 ml:49.4 mmol:10 eq.). The solution becomes clear after the addition of 1,4-diazabicyclo[2.2.2]octane (227 mg:2.47 mmol:0.25 eq.) and becomes a red colour when heated at reflux for a period of 18 hours. The reaction medium is then diluted with ethyl acetate and washed in succession with a 1N sodium hydroxide solution (20 ml) and then a 1N hydrochloric acid solution (20 ml). The concentrated organic phases are purified on a flash silica column eluted with an AcOEt/PE mixture (0.1/1).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:33]=[CH:32][C:13]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:31])=[C:20]3[C:24]=2[N:23]([CH3:25])[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21]3)=[CH:12][CH:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][C:10]1[CH:33]=[CH:32][C:13]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:31])=[C:20]3[C:24]=2[N:23]([CH3:25])[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21]3)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2c(Cl)ccc(OCc3ccc(CNC(=O)OC(C)(C)C)cc3)c2n1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c(Cl)ccc(OCc3ccc(CN)cc3)c2n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A mixture of 0.75 g (1.59 mmol) of ethyl 7-[4-(tert-butoxycarbonylaminomethyl)benzyloxy]-4-chloro-1-methyl-2-indolecarboxylate, 5 ml of trifluoroacetic acid and 50 ml of dichloromethane was stirred at 0° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. Thereafter ice water was poured onto the resulting residue and 28% aqueous ammonia was added thereto to render alkaline (pH=9 to 10). The mixture was then extracted three times with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 0.60 g (>99%) of ethyl 7-[4-(aminomethyl)benzyloxy]-4-chloro-1-methyl-2-indolecarboxylate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Br:15])[CH:6]=1)=[O:4].[C:16]([O:24]CC(C1C=C(C(F)(F)F)C=C(Cl)C=1)=O)(=[O:23])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[C:16]([O:24][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Br:15])[CH:6]=1)=[O:4])(=[O:23])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C(CBr)c1cc(Br)cc(C(F)(F)F)c1
Reactant: COC(=O)CCC(=O)OCC(=O)c1cc(Cl)cc(C(F)(F)F)c1
Product: COC(=O)CCC(=O)OCC(=O)c1cc(Br)cc(C(F)(F)F)c1
Yield: 60 %

Procedure:
The title compound was prepared from 2-bromo-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (Reference Example 42) by a procedure similar to the one described for 2-(3-chloro-5-(trifluoromethyl)phenyl)-2-oxoethyl methyl succinate (Reference Example 35) to provide 2-(3-bromo-5-(trifluoromethyl)phenyl)-2-oxoethyl methyl succinate (16.05 g, 60%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[OH:29])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].Br[CH2:31][CH2:32][N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:31][CH2:32][N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)c1c(O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1c(OCCN2C(=O)c3ccccc3C2=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1.90 g (5.0 mmol) of (S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (product of Description 1) were dissolved in 20 ml of THF. 3.80 g (14.9 mmol) of N-(2-bromoethyl)phthalimide dissolved in 15 ml of THF, 2.00 g (14.5 mmol) of K2CO3 and 0.25 g of KI were added and the suspension was stirred at room temperature for 2.5 hours and then refluxed for 2 hours. Additional 1.90 g (7.4 mmol) of N-(2-bromoethyl)phthalimide and a catalytic amount of KI were added and the reaction refluxed for 3.5 hours; additional 0.50 g (2.0 mmol) of N-(2-bromoethyl)phthalimide and a catalytic amount of KI were added and the reaction refluxed for 5 hours.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8]C(=O)C)=[CH:6][CH:5]=[C:4]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[N:3]=1.[OH-].[Na+].Cl>>[CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[N:3]=1
Reactant: CC(=O)Oc1ccc(-n2cncn2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(-n2cncn2)ccc1O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.6 %

Procedure:
Acetic acid 2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-yl ester (125 mg, 0.57 mmol) was added to 2 M aqueous sodium hydroxide solution (1.6 mL) at 0° C. to give a slurry, and the mixture was stirred at 0° C. for 20 min and then at room temperature for 3 h. 2 M Aqueous hydrochloric acid was added to bring the pH to 6, and the mixture was extracted four times with ethyl acetate. The organic layers were combined and the solvent was evaporated to dryness to give 2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-ol (96 mg, 95%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 2.36 (s, 3H), 7.33 (d, 1H, J=8.7 Hz), 7.51 (d, 1H, J=8.5 Hz), 8.18 (s, 1H), 9.12 (s, 1H), 10.19 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][N:3]=1>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:4][CH2:5][CH2:12][CH2:13][CH3:2])=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Solvent: C1CCOC1
Product: CCCCCC(=O)c1ccc(Cl)nc1
Temperature: 0 °C
Yield: 160.5 %

Procedure:
6-Chloro-N-methoxy-N-methyl-nicotinamide (6.20 g, 30.90 mmol) is suspended in anhydrous tetrahydrofuran (200 mL), and cooled to 0° C. with stirring under nitrogen. N-pentyl magnesium bromide (23 mL, 2.0M in diethyl ether, 46 mmol) is slowly added to the reaction over 1 h. The reaction is allowed to warm slowly to room temperature and monitored by TLC. Upon complete consumption of starting material, the reaction is carefully neutralized with 1N hydrochloric acid, extracted with diethyl ether, washed, dried, and concentrated. The 1-(6-chloro-pyridin-3-yl)-hexan-1-one (5.2 g, 24.8 mmol) 80% yield, is used without further purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)(=[O:8])[CH3:7].[C:30]([O-])(=[O:32])C.[Na+]>CN(C=O)C>[C:6]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][C:21]([CH:30]=[O:32])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCc1ccc(N(c2ccccc2)c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
DMF (2.63 g, 0.036 mol) was added to a three-neck flask (50 mL) equipped with a condenser, CaCl2 drying tube, and a glass stopper and cooled in an ice bath. Phosphorus oxychloride (1.8 g, 0.012 mol) was then added dropwise, and the resulting mixture stirred for 5 minutes and then allowed to warm slowly to room temperature. A solution of 4-(N,N-diphenylamino)benzyl acetate (1.88 g, 0.0059 mol) in DMF (20 mL) was then added dropwise. After addition was complete, the mixture was heated to 70° C. and stirred overnight. The mixture was then poured over ice (20 g) and the product obtained by filtration after slowly neutralizing the solution in an ice bath with saturated sodium acetate solution to pH 6. After washing with deionized water and drying, the product was recrystallized by dissolving in a small quantity of chloroform and pouring into excess hexane to yield the desired product (1.21 g, 60%). m.p. 86-89° C.; 1H NMR δ: 2.12(s, 2H, CH3), 5.09 (s, CH2), 7.0-7.37 (m, 12H, phenyl), 7.65-7.70 (d, 2H, phenyl), 9.81 (s, 1H, CHO). Analysis: Calculated for C22H19NO3: C, 76.52%; H, 5.51%; N, 4.06%. Found: C, 76.27%; H, 5.72%; N, 4.01%.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]#[N:25])=[CH:18][CH:17]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCc2nnn[nH]2)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 48.1 %

Procedure:
A mixture of 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionitrile (0.7 g), sodium azide (0.411 g), ammonium chloride (0.337 g) and N,N-dimethylformamide (15 ml) was stirred for 24 hours at 120° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried, then the solvent was distilled off to leave 5-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]ethyl]tetrazole (0.38 g, 48%), which was recrystallized from ethyl acetate--hexane to give colorless prisms, m.p.143°-144° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][CH2:13][O:14][CH3:15].C([O-])([O-])=O.[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC>CC(C)=O>[CH3:15][O:14][CH2:13][CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COCCBr
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1ccc([N+](=O)[O-])cc1
Yield: 104.1 %

Procedure:
A mixture of 40 g of 4-nitrophenol, 41 g of 1-bromo-2-methoxyethane, 45 g of K2CO3 and 80 ml of tris[2-(2-methoxyethoxy)ethyl]amine in 80 ml of acetone is refluxed for 20 hours. An insoluble material is filtered off and the filtrate is concentrated under vacuum. The residue is taken up with water and the precipitate formed is filtered off and washed with water. The precipitate is dissolved in AcOEt, washed with a 1N solution of NaOH, with water, with a 1N solution of HCl and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 59 g of the expected product, which is used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4](Br)[N:3]=1.[NH3:19]>O1CCOCC1.CO>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:7]=[C:2]([Br:1])[N:3]=[C:4]([NH2:19])[CH:5]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Reactant: N
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)c2cc(N)nc(Br)c2)cc1
Temperature: 130 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
0.196 g (0.0005 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 10 ml of dioxane, treated with 1.0 ml of sat. NH3 in methanol and stirred in an autoclave at 130° C. for 72 hrs. After removal of the solvent the residue was taken up in ethyl acetate, washed with sat. NH4Cl solution, water and sat. sodium chloride solution, dried over MgSO4 and the solvent was removed. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:2 and 1:1. There was obtained 0.117 g (71%) of 4-(4-aminobenzenesulphonyl)-6-bromopyridin-2-ylamine as a yellowish, amorphous solid; m.p.: 204-205° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[N:11]=[N:12][N:13]([CH3:15])[N:14]=2)[CH:3]=1.[ClH:16]>C(O)C.[Pd]>[ClH:16].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([C:10]2[N:11]=[N:12][N:13]([CH3:15])[N:14]=2)[CH:3]=1
Reactant: Cn1nnc(-c2cc(F)ccc2C#N)n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cn1nnc(-c2cc(F)ccc2CN)n1
Reaction time: 3 h
Yield: 91 %

Procedure:
A solution of 4-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-benzonitrile, (330 mg, 1.62 mmol) in ethanol (15 mL) was mixed with 6N HCl (1 mL) and 10% Pd—C (200 mg) under nitrogen. The mixture was then stirred under hydrogen (1 atm) for 3 hrs. After removing the catalyst, the filtrate was concentrated in vacuo to provide 360 mg (Yield 91%) of the title compound as an off-white solid; 1H NMR (500 MHz, DMSO-D6) δ ppm: 4.42 (2H, d, J=2.75 Hz) 4.49 (3H, s) 7.48-7.56 (1H, m) 7.78 (1 H, dd, J=8.7, 5.7 Hz) 7.86 (1H, dd, J=9.8, 2.8 Hz) 8.45 (3H, s); LC/MS m/z 208.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:5][NH:6]2.[Li]C(C)(C)C.[C:27](=[O:29])=[O:28]>C1COCC1.CCOC(C)=O>[C:18]([Si:15]([CH3:17])([CH3:16])[O:14][CH2:13][CH2:12][C:4]1[C:3]2[C:2]([C:27]([OH:29])=[O:28])=[CH:10][CH:9]=[C:8]([CH3:11])[C:7]=2[NH:6][CH:5]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc(Br)c2c(CCO[Si](C)(C)C(C)(C)C)c[nH]c12
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)c2c(CCO[Si](C)(C)C(C)(C)C)c[nH]c12
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a suspension of KH (1.85 g of 30 wt % in oil, 13.85 mmol) in THF (100 mL) was added a solution of 4-bromo-3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methyl-1H-indole (3.40 g, 9.24 mmol) in THF (10 mL) at 0° C. After stirring for 40 minutes, the solution was cooled to −78° C. and tert-BuLi (10.9 mL of 1.7 M in pentane, 18.47 mmol), precooled to −78° C., was added. After stirring for 1 hour at −78° C., the reaction mixture was transferred to the flask containing anhydrous CO2 (dry ice, 100 g) via cannula under N2 atmosphere at −78° C. The suspension was warmed to room temperature very slowly using cold bath. The mixture was diluted with EtOAc (200 mL) and the organic solution was washed with 1 N HCl (2×200 mL), H2O (200 mL) and brine (200 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 15% EtOAc in hexanes) to give 0.74 g (41% based on the recovered SM) of title compound as a white solid. 1H NMR (CDCl3): 300 MHz δ 8.26 (bs, 1H), 7.84 (d, J=7.56 Hz, 1H), 7.32 (d, J=2.46 Hz, 1H), 7.12 (d, J=7.56 Hz, 1H), 3.98 (t, J=6.39 Hz, 2H), 3.33 (t, J=6.39 Hz, 2H), 2.63 (s, 3H), 0.89 (s, 9H), −0.08 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=O)[CH3:25])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:24]([CH3:25])[CH2:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: COc1ccc(CC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1-(4-methoxy-phenyl)-propan-2-one.