Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5](S(C)(=O)=O)[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]2=[O:15])(=[O:4])=[O:3].[OH-].[Na+].Cl>CC#N>[CH2:31]([O:30][C:24]1[CH:23]=[C:22]([CH:16]([N:9]2[C:8](=[O:33])[C:7]3[C:11](=[CH:12][CH:13]=[CH:14][C:6]=3[NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:10]2=[O:15])[CH2:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH:27]=[CH:26][C:25]=1[O:28][CH3:29])[CH3:32]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N(S(C)(=O)=O)S(C)(=O)=O)c3C2=O)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NS(C)(=O)=O)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[bis(methylsulfonyl)amino]-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione (0.8 g, 1.39 mmol) and 2N NaOH (1.59 mL, 3.18 mmol) in CH3CN (120 mL) was stirred at room temperature for 8 hours. The mixture was neutralized with 6N hydrogen chloride (0.6 mL) and then concentrated. The residue was dissolved in methylene chloride (90 mL), washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulting solid was slurried in ethanol (50 mL) to give after isolation by filtration 2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4-[(methylsulfonyl)amino]isoindoline-1,3-dione (0.6 g, 86%) as a white solid: mp 191-193° C.; 1H NMR (DMSO-d6) δ 9.31 (s, 1H), 7.85-7.74 (m, 2H), 7.61 (d, J=6.6 Hz, 1H), 7.08 (s, 1H), 7.00-6.91 (m, 2H), 5.80-5.74 (m, 1H), 4.38-4.28 (dd, J=10.5, 14.3 Hz, 1H), 4.19-4.11 (dd, J=4.5, 14.3 Hz, 1H), 4.03 (q, J=6.9 Hz, 2H), 3.73 (s, 3H), 3.27 (s, 3H), 3.00 (s, 3H0, 1.32 (t, J=6.9 Hz, 3H); 13C NMR (DMSO-d6) δ 167.43, 166.71. 148.92, 147.87, 136.26, 135.73, 131.91, 129.40, 125.01, 119.79, 118.39, 117.59, 112.41, 111.76, 63.83, 55.48, 53.00, 47.35, 41.06, 40.63, 14.64; Anal. Calcd. for C21H24N2O8S3+0.05 disulfonamide: C, 50.56; H, 4.86; N, 5.60; S, 13.12. Found: C, 50.25; H, 4.81; N, 5.60; S, 13.12.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1C=C2OCOC2=C[C:20]=1[C:28](=O)C)=[O:17])(=[O:10])=[O:9].[NH2:32][C:33]1[CH:38]=[CH:37]C(C)=CN=1>>[Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[N:32]=[CH:33][C:38]([CH3:37])=[CH:28][CH:20]=1)=[O:17])(=[O:9])=[O:10]
Reactant: Cc1ccc(N)nc1
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl)OCO2
Product: Cc1ccc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)nc1

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6-pyridyl)aminocarbonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148), except that 2-amino-5-picoline was used instead of 2'-amino-4',5'-(methylenedioxy)acetophenone, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6pyridyl)aminocarbonyl]thiophene-3-sulfonamide was obtained, via HPLC purification of the crude reaction mixture, as a bright yellow powder (17% yield, m.p. 158°-160° C.).
Reaction SMILES: C(=O)([O-])[O-].[Cs+2].[CH3:6][O:7][N:8]([CH3:17])[C:9]([C:11]1[N:12]=[C:13](Br)[S:14][CH:15]=1)=[O:10].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>CN(C=O)C.CCOC(C)=O>[CH3:6][O:7][N:8]([CH3:17])[C:9]([C:11]1[N:12]=[C:13]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[S:14][CH:15]=1)=[O:10]
Reactant: c1c[nH]cn1
Reactant: CON(C)C(=O)c1csc(Br)n1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1csc(-n2ccnc2)n1
Temperature: 120 °C
Yield: 91.7 %

Procedure:
Cesium(II)carbonate (1.36 g, 4.18 mmol) was added to a solution of 2-bromo-thiazole-4-carboxylic acid methoxy-methyl-amide (500 mg, 1.99 mmol) and imidazole (135 mg, 1.99 mmol) in DMF (5 mL) under a nitrogen atmosphere at r.t. prior to heating at 120° C. for 40 minutes in the microwave reactor. The reaction was then cooled to r.t., diluted with EtOAc (100 mL), washed with 1M NaOH (75 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated to a white solid. Purification was achieved using column chromatography (CH2Cl2 to 9:1 CH2Cl2/MeOH) to afford 435 mg (92%) of 2-imidazol-1-yl-thiazole-4-carboxylic acid methoxy-methyl-amide as a white solid. [M+H]+ 239.02.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:13])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Cc1ccc(Br)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Br)ccc1CBr
Temperature: 25 °C

Procedure:
4-Bromo-1-methyl-2-trifluoromethyl-benzene (3 g, 12.55 mmol), N-bromosuccinimide (2.68 g, 15.06 mmol, 1.2 eq) and dibenzoylperoxid (60 mg, 2.5 mmol, 0.02 eq) are stirred in carbon tetrachloride under ultraviolet light at reflux for 5 h. The reaction mixture is cooled to RT, filtered and the filtrate is concentrated in vacuo. The residue is carefully purified by chromatography (silicagel, pure hexanes) to afford the title compound as a colorless liquid.
Reaction SMILES: [CH:1]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:10]([OH:12])=[O:11])=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>[C].[Pd].C(O)C>[CH2:1]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC=Cc1cc(C(=O)O)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCc1cc(C(=O)O)ccc1OC
Yield: 71.9 %

Procedure:
3-(1-Hexenyl)-4-methoxybenzoic acid (160 mg, 0.683 mmol) and ethanol (7 ml) were mixed, and to this solution was added 10% palladium-carbon catalyst (30 mg). The mixture was stirred at room temperature for 3 hours in a steam of hydrogen. The palladium-carbon catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by washing with hexane to give 3-hexyl-4-methoxybenzoic acid (116 mg, 72%) as colorless crystals.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NCCC1C=CC(O)=C([OH:22])C=1>CN(C)C1C=CN=CC=1.O1CCCC1.CCCCCC.C1C=CC=CC=1>[CH:10]1([NH:9][C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:22])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: NCCc1ccc(O)c(O)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
DHA is first converted to DHA anhydride in the presence of dicyclohexyl carbodiimide. This is then reacted with dopamine in the presence of 4-dimethylaminopyridine as the acid acceptor in tetrahydrofuran. In a typical experiment 300 mg of DHA (0.009 M) was dissolved in a mixture of 3 ml hexane and 4 ml benzene and stirred under nitrogen. Next, a solution of 0.00615 M of dicyclohexyl carbodiimide in 4 ml benzene (0.1267 g) was stirred together with the DHA for 3 hr at room temperature. A white precipitate of dicyclohexyl urea formed as the reaction proceeded. The dicyclohexyl urea was filtered off to give a clear solution of the anhydride in benzene. This was concentrated down to 2 ml in a rotary evaporator and diluted with 10 ml of tetrahydrofuran (dry). The freshly prepared anhydride was then added to a solution of dopamine hydrobromide (0.1053 g) (or 0.005 M) in the presence of 0.009 M of 4-diethylaminopyridine (0.098 g). The initially cloudy mixture after stirring for 30 min at room temperature gave a mixture of a clear liquid and a brown precipitate. At the end of the reaction, 0.2 ml of water was added to the mixture, and stirring was continued for an additional 30 min to completely hydrolyze any remaining unreacted anhydride. The liquid phase was isolated and evaporated to dryness to yield a brown viscous solid. This was then dissolved in 70% ethanol in water (25 ml), and the solution was then passed through a mixed-bed ion exchange resin containing a strong acidic resin based on polystyrene sulfonic acid and a strong basic resin based on quanternary amonium substituents such as tetramethyl amonimum hydroxide (RG501, Fisher Scientific, Cambridge, Mass.) using 90% ethanol in water as the eluent. This resin removes from the mixture unreacted dopamine, dimethylaminopyridine, as well as the liberated DHA molecule. The effluent from the column (a pale yellow solution) was then evaporated in a rotary evaporator to give a solid. The product was recrystallized from aqueous ethanol (yield=75%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[S:28][C:29]([CH2:32][N:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=2)=[CH:21][N:20]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[S:28][C:29]([CH2:32][N:33]([CH3:34])[CH3:35])=[CH:30][CH:31]=3)=[CH:21][N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)s1
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3ccc(CN(C)C)s3)c(=O)[nH]2)o1

Procedure:
A mixture of 2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamine (1.64 g) and 2-nitroamino-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone (2.01 g) in ethanol (10 ml) was heated under reflux for 30 hr. The ethanol was evaporated in vacuo to yield 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone as a brown oil which was washed with hot water by decantation. The residue was dissolved in isopropanol and an excess of ethanolic hydrochloric acid was added to the solution.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1.O.[NH2:15][NH2:16]>>[NH:15]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1)[NH2:16]
Reactant: COCCNCc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Product: COCCNCc1ccc(NN)nc1

Procedure:
3.6 g (17.7 mmol) of N-[(6-chloropyridin-3-yl)methyl]-2-methoxyethanamine [prepared analogously to WO 2004/081007] are initially charged in 4.3 ml (4.4 g, 88.5 mmol) of hydrazine hydrate and stirred at boiling point at a bath temperature of 150° C. for 16 h. The reaction solution is cooled and concentrated, and the residue is purified by column chromatography on silica gel (mobile phase: acetonitrile/water 9:1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[C:38](O)=[O:39]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:38]([C:34]3[NH:33][CH:37]=[CH:36][N:35]=3)=[O:39])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: O=C(O)c1ncc[nH]1
Product: Cc1c(N2CCN(C(=O)c3ncc[nH]3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure Q using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (40.0 mg, 0.09 mmol) and 1H-imidazole-2-carboxylic acid to give (4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)(1H-imidazol-2-yl)methanone. 1H NMR (DMSO-d6) δ ppm 2.13 (br s, 3H), 3.06 (br s, 4H), 3.33-3.39 (m, 4H), 3.69 (br s, 4H), 3.84-3.85 (m, 2H), 4.66-4.69 (m, 2H), 6.50 (br s, 1H), 7.11-7.16 (m, 1H), 7.18-7.20 (m, 1H), 7.28-7.31 (m, 2H), 7.54 (br s, 1H), 7.79 (s, 1H), 8.38 (br s, 1H), 12.96 (s, 1H). Mass Spectrum (ESI) m/e=534.9 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[CH2:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:26](=[O:38])[C:25]([CH3:39])=[N:24]1>>[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:20][CH2:21][CH2:22][N:23]2[C:28](=[O:29])[N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:37])[CH3:36])[C:26](=[O:38])[C:25]([CH3:39])=[N:24]2)[CH2:13][CH2:12]1
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Reactant: Cc1nn(CCCCl)c(=O)n(COCC[Si](C)(C)C)c1=O
Product: Cc1nn(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c(=O)n(COCC[Si](C)(C)C)c1=O

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 2-(3-chloropropyl)-6-methyl-4-[2-(trimethylsilyl)ethoxymethyl]-1,2,4-triazine-3,5(2H,4H)-dione gave 2-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-6-methyl-4-[2-(trimethylsilyl)ethoxymethyl]-1,2,4-triazine-3,5(2H,4H)-dione;
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([Cl:14])[CH:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH2:30])[CH:21]=[CH:22][C:23]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1>>[CH2:1]([C:8]1[N:9]=[C:10]([NH:30][C:20]2[CH:21]=[CH:22][C:23]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:18]([O:17][CH3:16])[CH:19]=2)[CH:11]=[C:12]([Cl:14])[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Clc1cc(Cl)nc(Cc2ccccc2)n1
Product: COc1cc(Nc2cc(Cl)nc(Cc3ccccc3)n2)ccc1-n1cnc(C)c1
Yield: 48 %

Procedure:
The title compound was prepared in analogous manner as described in example 62 from 2-benzyl-4,6-dichloro-pyrimidine and 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine. Obtained as yellow solid in 48% yield after column chromatography of the crude product on silica gel using dichloromethane/methanol (98:2 and then 95:5 v/v) as eluent.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[CH2:3][OH:4].[Br:16][CH2:17][CH:18]=O.B(F)(F)F>[N+](C)([O-])=O>[CH3:1][C:2]1([CH3:15])[C:5]2[C:10](=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=2)[CH:18]([CH2:17][Br:16])[O:4][CH2:3]1
Reactant: O=CCBr
Reactant: COc1ccc(C(C)(C)CO)cc1OC
Agent: FB(F)F
Solvent: C[N+](=O)[O-]
Product: COc1cc2c(cc1OC)C(C)(C)COC2CBr

Procedure:
A 2,2-Dimethyl-2-(3,4-dimethoxyphenyl)ethanol (0.95 g, 0.0045 m) is stirred with 1.07 g (0.0054 m) of the ethyl acetal of bromoacetaldehyde and 0.19 g (0.0014 m) of BF3 .etherate in 25 ml of nitromethane for 15 hours. The mixture is partitioned between methylene chloride and aqueous sodium carbonate. The organic phase is dried over sodium sulfate and concentrated to yield 1.52 g of 4,4-dimethyl-6,7-dimethoxy-1-bromomethylisochroman. The nmr is consistent with the assigned structure.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O:13][C:14](=[O:17])[CH2:15]Cl>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:15][C:14]([OH:17])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCl
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)c1ccc(OCC(=O)O)cc1
Yield: 93.8 %

Procedure:
94% pure acid (melting point 93° to 95° C., 1.4% of residual phenol) was prepared in an analogous manner in a yield of 93.8% of theory from 4-tert-butylphenol and methylchloroacetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:23][N:22]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13].[NH2:33][OH:34].[NH4+].[Cl-]>C1COCC1>[OH:34][NH:33][CH:10]([CH2:9][CH2:8][CH2:7][C:2]1[N:1]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:22]=[CH:23][C:24]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[CH:25][N:26]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: O=S(=O)(/C=C/CCCc1ncccn1)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Reactant: NO
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred solution of 2-(4-{[(1E)-5-pyrimidin-2-ylpent-1-en-1-yl]sulfonyl}piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidine (8.79 g, 18.6 mmol) in THF (90 mL) was added 50% aqueous solution of hydroxylamine (18 mL) and the reaction stirred at room temperature for 2 hours. A saturated solution of NH4Cl (200 mL) was then added and then this was extracted twice with extracted with EtOAc (2×250 mL), combined organics washed with brine (250 mL), dried (MgSO4), filtered and concentrated in vacuo to give 2-(4-{[2-(hydroxyamino)-5-pyrimidin-2-ylpentyl]sulfonyl}piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidine as a pale yellow solid (8.96 g, 17.7 mmol, 95%).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:7]([C:8]([O-:10])=[O:9])=[C:6]1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([OH:3])=[O:2]>[OH-].[Na+]>[C:1]([CH2:4][N:5]1[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:7]([C:8]([OH:10])=[O:9])=[C:6]1[C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)([OH:3])=[O:2]
Reactant: Cc1cc(=O)c(C(=O)[O-])c(-c2ccc(Cl)cc2)n1CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)c(C(=O)O)c(-c2ccc(Cl)cc2)n1CC(=O)O
Yield: 72.3 %

Procedure:
4.0 gms of 1-carboxymethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinate is suspended in 40 gms of 5% aqueous sodium hydroxide solution and heated at 80°-85° for two hours. The reaction mixture is cooled and acidified to give a white precipitate. This precipitate is collected by filtration to yield 2.9 gms of 1-carboxymethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinic acid. mp (CH3CN)=158-62.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[O:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[CH2:2][CH2:3][CH3:4].[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19]>>[CH2:1]([N:5]([C:6]1[O:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)C(=O)Cl
Reactant: CCCCNc1nc(-c2ccccc2)co1
Product: CCCCN(C(=O)C(C)C)c1nc(-c2ccccc2)co1

Procedure:
2-(N-butylamino)-4-phenyloxazole was acylated with isobutyryl chloride as described in Example 9. An almost colourless oil was obtained on distillation. WT.= 4.9 g., b.p. 140° C. (air-bath temperature)/1 mm., 80%.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[F:18][C:19]([F:29])([F:28])[CH:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[F:29][C:19]([F:18])([F:28])[CH:20]([NH:27][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Reactant: NC(c1ccccn1)C(F)(F)F
Product: O=C(NC(c1ccccn1)C(F)(F)F)c1cc(OCC2CC2)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and 2,2,2-Trifluoro-1-pyridin-2-yl-ethylamine (CAN 503173-14-6) as starting materials and isolated (17.2 mg, 29%) as colorless oil; MS (ESI, m/z): 392.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:21])=O>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:5][Cl:21])=[CH:7][CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: O=S(Cl)Cl
Reactant: COc1c(CO)cccc1Oc1ccccc1Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1c(CCl)cccc1Oc1ccccc1Cl

Procedure:
A mixture of 2-methoxy-3-(2-chlorophenoxy)benzyl alcohol (5.5 g), thionyl chloride (3 ml) and pyridine (one drop) in benzene (40 ml) was treated in a similar manner to that of Example 3-(6) to give oily 2-chlorophenyl 2-methoxy-3-chloromethylphenyl ether (6.4 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:44]=[N:45][C:46]([CH3:49])=[CH:47][CH:48]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:50])=[CH:38][C:39]([C:43]6[N:44]=[N:45][C:46]([CH3:49])=[CH:47][CH:48]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1ccc(-c2cc(C)c(Br)c(C)c2)nn1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccc(C)nn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-(4-bromo-3,5-dimethyl-phenyl)-6-methyl-pyridazine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 26): tR=0.75 min; Mass spectrum (ESI+): m/z=539 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH:30]12[CH2:35][CH:34]1[CH2:33][NH+:32]([CH2:36][B-](F)(F)F)[CH2:31]2>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][N:32]5[CH2:33][CH:34]6[CH:30]([CH2:35]6)[CH2:31]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: F[B-](F)(F)C[NH+]1CC2CC2C1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CC4CC4C3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and (3-azonia-bicyclo[3.1.0]hex-3-yl)methyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=0.96 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C@@H:17]([NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[C:7]2[C:3]=1[C:4]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:5][N:6]2[CH3:34].C1C=C(Cl)C=C(C(OO)=[O:48])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C@@H:17]([NH:27][C:28](=[O:33])[C:29]([F:32])([F:30])[F:31])[CH2:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)=[N+:13]([O-:48])[CH:14]=[CH:15][CH:16]=2)=[C:7]2[C:3]=1[C:4]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])=[N:5][N:6]2[CH3:34]
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cccnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)C(F)(F)F)c21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3ccc[n+]([O-])c3[C@H](Cc3cc(F)cc(F)c3)NC(=O)C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)—N-(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2,2,2-trifluoroacetamide (57B, 8.0 g, 13.61 mmol) in DCM (70 mL) was added mCPBA (3.659 g, 16.33 mmol) in 4 portions over a 15 minute period. The reaction mixture was stirred at room temperature for 16 hours. Upon completion, the reaction was quenched with 1M aqueous NaHSO3 and saturated aqueous NaHCO3. The organic layer was collected and the aqueous layer was extracted an additional time with DCM. The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and purified by silica gel column chromatography, eluting with 50-100% EtOAc in hexanes to give the title compound. MS (m/z) 604.10 [M+H]+.