Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:19]([O:21][CH3:22])=[O:20])[C:7]2[NH:8][C:9]3[CH:10]=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CCOC(C)=O>[CH2:23]([N:8]1[C:9]2[CH:10]=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][C:14]=2[C:15]2[N:16]=[C:4]([Br:3])[CH:5]=[C:6]([C:19]([O:21][CH3:22])=[O:20])[C:7]1=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(OC)ccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)nc2c3ccc(OC)cc3n(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
Sodium hydride (81 mg, 2 0 mmol) was added to a solution of methyl 2-bromo-7-methoxy-5H-pyrido[3,2-b]indole-4-carboxylate (450 mg, 1.34 mmol) in THF (6 mL) in an ice bath. After 20 min this was removed from the bath and left stirring at RT for 0.5 h. Benzyl bromide (276 mg, 1.61 mmol) was added. After stirring at RT for 3 days, this was diluted with EtOAc, washed with water, brine, and dried over Na2SO4 Removal of the solvent followed by radial chromatography (elution with DCM) afforded methyl 5-benzyl-2-bromo-7-methoxy-5H-pyrido[3,2-b]indole-4-carboxylate (130 mg, 0.31 mmol, 23% yield). MS (ESI) m/z 425.0 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.27 (1H, d, J=8.55 Hz), 7.59 (1H, s), 7.17-7.24 (3H, m), 6.97 (1H, dd, J=8.70, 1.98 Hz), 6.88-6.93 (2H, m), 6.84 (1H, d, J=1.83 Hz), 5.67 (2H, s), 3.86 (3H, s), 3.70 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[CH:8]1([CH2:12][N:13]([CH2:27][CH3:28])[C:14]2[N:19]=[C:18]3[N:20]([CH3:24])[N:21]=[C:22]([CH3:23])[C:17]3=[CH:16][C:15]=2[CH:25]=O)[CH2:11][CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH:8]1([CH2:12][N:13]([C:14]2[N:19]=[C:18]3[N:20]([CH3:24])[N:21]=[C:22]([CH3:23])[C:17]3=[CH:16][C:15]=2[CH2:25][NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)[CH2:27][CH3:28])[CH2:11][CH2:10][CH2:9]1
Reactant: CCN(CC1CCC1)c1nc2c(cc1C=O)c(C)nn2C
Reactant: Cc1cc(N)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(CC1CCC1)c1nc2c(cc1CNc1cc(C)on1)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Methyl-isoxazol-3-ylamine (0.37 g, 3.8 mmol) was added to a solution of 6-(cyclobutylmethyl-ethyl-amino)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (0.54 g, 1.9 mmol) in anhydrous chloroform (20 mL) and acetic acid (0.2 mL) under nitrogen. After stirring for 15 min at RT, sodium triacetoxyborohydride (1.20 g, 5.7 mmol) was added slowly and this mixture was stirred at RT overnight. After evaporation of chloroform in vacuo, water (30 mL) and ethyl acetate (30 mL) were added to the residue. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated to give title compound, which was taken on without further purification.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][C@H:15]2[CH2:20][CH2:19][CH2:18][O:17][CH2:16]2)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C.CCOC(C)=O>[N:29]([CH2:12][C@@H:13]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][O:17][CH2:16]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C[C@H]2CCCOC2)NC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
The solution of (S)-2-(tert-butoxycarbonylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propyl 4-methylbenzenesulfonate (132 mg, 0.32 mmol) and NaN3 (62 mg, 0.95 mmol) in anhydrous DMF was heated to 80° C. under N2 atmosphere for 1.5 hr, cooled to rt and diluted with EtOAc, and washed with H2O (3×20 mL), followed by brine, and dried over anhydrous Na2SO4, and filtered, and concentrated under reduced pressure. The resulted slurry was purified through flash chromatography on silica gel (eluted with gradient system: 0-30% EtOAc in hexane) to afford tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate 58 mg, yield 64%. MS ESI+ve m/z 307 (M+Na).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([F:20])[CH:18]=3)[C:13]([C:22]#[N:23])=[CH:12]2)=[CH:7][C:6]=1[O:24]COC)[CH3:2].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([F:20])[CH:18]=3)[C:13]([C:22]#[N:23])=[CH:12]2)=[CH:7][C:6]=1[OH:24])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(F)c(F)cc32)cc1OCOC
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(F)c(F)cc32)cc1O
Temperature: 70 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a solution of 4-(3-cyano-5,6-difluoroindol-1-yl)-2-methoxymethoxybenzoic acid ethyl ester (0.12 g) in a mixed solvent of tetrahydrofuran (1.5 mL) and ethanol (3 mL) was added 2 mol/L hydrochloric acid (1.0 mL), and this mixture was stirred at 70° C. overnight. After cooling to ambient temperature, the precipitated solid was collected by filtration, and washed with water and n-hexane, and dried under reduced pressure at 40° C. to give the title compound (0.074 g).
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:97][O:98][C:99](=[O:111])[CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH3:110])[CH2:16][S:17][CH2:18][C@H:19]([NH:79]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:20](=[O:78])[NH:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:77])[CH:37]([CH2:56][S:57][C:58]([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[NH:38]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1CCCCC1>C(#N)C>[C:1]([O:14][C@H:15]([CH2:97][O:98][C:99](=[O:111])[CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH3:110])[CH2:16][S:17][CH2:18][C@H:19]([NH2:79])[C:20](=[O:78])[NH:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:77])[CH:37]([NH2:38])[CH2:56][S:57][C:58]([C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCOCCOCCOCCCNC(=O)C(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OC(=O)CCCCCCCCCCC
Solvent: C1CCNCC1
Solvent: CC#N
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCCOCCOCCOCCCNC(=O)C(N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)CCCCCCCCCCC
Reaction time: 0.5 h

Procedure:
A solution of (23R,27R)-23-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1-(9H-fluoren-9-yl)-3,6,22-trioxo-5-(tritylthiomethyl)-2,11,14,17-tetraoxa-25-thia-4,7,21-triazaoctacosane-27,28-diyl didodecanoate in acetonitrile (0.1M) was stirred at room temperature. Piperidine (final conc. 20%) was then added and the reaction stirred for 30 minutes. After concentration, the product was purified by flash chromatography on an ISCO COMBIFLASH® system using an initial gradient of 0-100% EtOAc, then 0-10% MeOH/DCM to give (22R,26R)-4,22-diamino-5,21-dioxo-1,1,1-triphenyl-10,13,16-trioxa-2,24-dithia-6,20-diazaheptacosane-26,27-diyl didodecanoate.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)=[CH:5][CH:4]=1.[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:9]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)=[CH:20][CH:19]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: FC(F)(F)c1ccc(Nn2cnnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1ccc(N(Cc2ccc(Br)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.23 Gram of 4-[(4-trifluoromethylphenyl)-amino]-4H-1,2,4-triazole, 0.28 g of 4-bromobenzyl bromide and 0.17 g of anhydrous potassium carbonate were added to 5 ml of acetonitrile and the mixture was stirred for 3 hours at room temperature. The solvent was removed by distillation and water was added to the residue, which was then extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to give crude crystals from the chloroform eluate. The crude crystals were recrystallized from a mixed solvent of ethyl acetate/ether to give 0.22 g of 4-[N-(4-bromobenzyl)-N-(4-trifluoromethylphenyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11])[CH:5]=O.C1C(/C=N/O)=CC=[N+:17](C[N+]2C=CC(/C=N/O)=CC=2)C=1.[Br-].[Br-].B>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11])[CH2:5][NH2:17]
Reactant: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Reactant: COc1c(F)cc(C=O)cc1F
Agent: B
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1c(F)cc(CN)cc1F
Yield: 50 %

Procedure:
The reaction of 3,5-difluoro-4-methoxybenzaldehyde methoxime, (7 g, 35 mmole) and 0.98M borane in tetrahydrofuran (46 ml) substantially as described in 1B above produced 3 g, (50%) of the title compound as a clear oil.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][O:14][S:1](=[O:4])(=[O:3])[NH2:2])=[CH:9][CH:8]=1
Reactant: OCCOc1ccc(Cl)cc1
Reactant: NS(=O)(=O)Cl
Product: NS(=O)(=O)OCCOc1ccc(Cl)cc1
Yield: 48 %

Procedure:
The title compound was prepared by procedures of Example 22 from sulfamoyl chloride and 2-(4-chlorophenoxy)ethanol in 48% yield. A white solid, mp 117°-119° C. was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[CH3:17][O:18][C:19](=[O:26])[CH:20]([O:24][CH3:25])[C:21](O)=[O:22]>>[CH3:17][O:18][C:19](=[O:26])[CH:20]([O:24][CH3:25])[C:21]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)=[O:22]
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: COC(=O)C(OC)C(=O)O
Product: COC(=O)C(OC)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1
Yield: 41 %

Procedure:
The title compound is prepared in analogy to example 2 from 4-(3-Fluoro-benzyloxy)-phenylamine and 2-methoxy-malonic acid monomethyl ester (Swan et al.; J. Chem. Soc. Perkin Trans. 1; 1985; 1757-1766). Yield=41%. Colorless solid. MS: m/e=348.2 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[Li].[CH3:14][N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].[Cl-].[NH4+]>CCOCC.C1C=CC=CC=1>[CH3:14][NH:15][C:16](=[O:21])[CH2:17][CH2:18][C:19](=[O:20])[C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: [Li]c1cc(C(F)(F)F)ccc1OC
Reactant: CN1C(=O)CCC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CNC(=O)CCC(=O)c1cc(C(F)(F)F)ccc1OC
Reaction time: 8 h

Procedure:
A solution of 2-methoxy-5-trifluoromethylphenyllithium in ether was added to a cold stirred solution of N-methylsuccinimide in benzene. The resultant mixture was allowed to stand overnight and was then decomposed with ammonium chloride solution to give N-methyl 3-(2-methoxy-5-trifluoromethylbenzoyl)propionamide.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[CH:21][C:20]=3[CH:34]([O:40][CH3:41])[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[CH:21][C:20]=3[CH:34]([O:40][CH3:41])[CH2:35][C:36]([CH3:37])([CH3:38])[CH3:39])[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)cc2C(CC(C)(C)C)OC)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)c(C(CC(C)(C)C)OC)c2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-3-(1-methoxy-3,3-dimethylbutyl)-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)propanoate (385 mg) in ethanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (3.0 mL), and the reaction mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (250 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([NH:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2)=[O:6])[CH3:2].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]([NH:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH2:12][NH:13]2)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])ccc2ncccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])ccc2c1C=CCN2
Reaction time: 4 h
Yield: 78 %

Procedure:
A solution of the product from Example 85 (5 g, 17.5 mmol) in 80 mL acetic acid was treated with sodium cyanoborohydride (2.2 g, 35 mmol) portionwise under an argon atmosphere and stirred for 4 hours. Water (100 mL) was added to the reaction mixture, and the resulting solid was collected by filtration and dried (3.9 g, 78% yield).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1B(O)O>>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1ccco1
Product: Nc1nnc(-c2ccco2)c(-c2ccccc2)n1
Yield: 35.3 %

Procedure:
6-(Furan-2-yl)-5-phenyl-1,2,4-triazin-3-amine (100 mg, 35%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.3 g, 1.19 mmol) and 2-furanboronic acid (0.16 g, 1.428 mmol) according to the general procedure of Example 1.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([C:10]2([C:18]#[N:19])[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:20][Mg]Br.CCOCC>C1COCC1>[F:17][C:13]1([F:16])[CH2:12][CH2:11][C:10]([C:7]2[CH:8]=[N:9][C:4]([C:1]([OH:3])([CH3:20])[CH3:2])=[CH:5][CH:6]=2)([C:18]#[N:19])[CH2:15][CH2:14]1
Reactant: CC(=O)c1ccc(C2(C#N)CCC(F)(F)CC2)cn1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1ccc(C2(C#N)CCC(F)(F)CC2)cn1
Temperature: -50 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of 1-(6-acetyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (17 mg, 0.064 mmol) in THF (1.2 mL) was cooled at −50° C. and treated with a 3.0 M solution of methylmagnesium bromide in ether (110 μL, 0.32 mmol). After stirring at −50° C. for 3 hours, the reaction was quenched by adding saturated aqueous ammonium chloride (5 mL) and stirred at room temperature for a few minutes. AcOEt (5 mL) was added and the biphasic mixture was stirred vigorously for a few seconds. The layers were separated and the aqueous layer was extracted again with AcOEt (5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by preparative TLC, eluting with 60% AcOEt in hexanes to afford 4,4-difluoro-1-[6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-cyclohexanecarbonitrile as a colorless oil (8.7 mg, 48%). LC-MS (m/z) 280.0 (MH+); tR=1.11.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][C:8]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:15](O)[CH3:16]>>[OH:1][C:2]1[N:10]=[CH:9][C:8]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:15][CH3:16])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)O)cnc1O
Reactant: CCO
Product: CCOC(=O)c1cc(S(=O)(=O)O)cnc1O
Temperature: 80 °C
Yield: 74 %

Procedure:
2-Hydroxy-5-sulfonicotinic acid (500 g, 2.28 mol) was dissolved in ethanol (2.5 L) with stirring and heated to 80° C. After 30 mins 0.5 L of solvent was distilled off, then replaced with fresh ethanol (0.5 L) and taken back to 80° C. After a further 60 mins 1.0 L of solvent was distilled off, then replaced with fresh ethanol (1.0 L) and taken back to 80° C. After a further 60 mins 1.0 L of solvent was distilled off, the reaction cooled to 22° C. and stirred for 16 hr. The precipitated product was filtered, washed with ethanol (0.5 L) and dried at 50° C. under vacuum to afford the title compound (416 g, 74%) as a white solid. Decomposition pt 237° C. δ (DMSOd6): 1.25 (3H, t), 4.19 (2H, q), 7.66 (1H, d), 8.13 (1H, d). m/z (Found:248 [M+H]+, 100%. C8H10NO6S requires 248.22).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28](=[O:36])[C:29]4[CH:34]=[CH:33][CH:32]=[C:31](Br)[CH:30]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:37][N:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O)[CH3:39]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]([C:29]4[CH:30]=[C:31]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[CH2:40][N:38]([CH3:39])[CH3:37])[CH:32]=[CH:33][CH:34]=4)=[O:36])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)c4cccc(Br)c4)cc3)cc2)CC1
Reactant: CN(C)Cc1ccccc1B(O)O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)c4cccc(-c5ccccc5CN(C)C)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(3-bromo-benzoylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-(N,N-dimethylaminomethyl)-phenylboronic acid.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.C[O:45][C:46](=O)[C@@H:47]1[CH2:51][CH2:50][CH2:49][NH:48]1>C(Cl)Cl>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([N:48]1[CH2:49][CH2:50][CH2:51][C@H:47]1[CH2:46][OH:45])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccccc1)c1ccccc1C(=O)N1CCC[C@H]1CO

Procedure:
6.78 g (30 mmol) o-benzoylbenzoic acid and 2.96 ml (30 mmol) of S(+)-2-pyrrolidinemethanol were reacted with 4.05 g (30 mmol) 1-hydroxybenzotriazole hydrate and 6.18 g (30 mmol) of DCC in 150 ml methylene chloride as described in Example 25 for the coupling of o-benzoylbenzoic acid with L-proline methyl ester. The crude reaction mixture was washed with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent removed in vacuo to afford a yellow residue. Flash chromatograohy on silica gel (20:1/methylene chloride:methanol) afforded the title compound which crystallized from ethyl acetate as a white solid (3.99 g (43%)) by the addition of ether until crystallization took place. TLC (90:10/CH2Cl2 :MeOH): Rf =0.50. mp=113-114. 1H NMR (CDCl3) δ: 7.35-7.80 (9m,5H); 4.40-4.50(m,1H); 3.15-4.20(m,5H); 1.55-2.15(m,4H). I.R. (KBr): 1589, 1603, 1660 cm-1. Standard Combustion Analysis Calculated: C,73.77; H,6.19; N,4.53. Found: C,73.40; H,6.16; N,4.41. High Resolution Mass Spectrum: 309.1378±1.3 ppm (calculated for C19H19 NO3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[CH:4][CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2=[C:8]3[N:9]=[C:10]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[NH:11][C:12]3=[C:13]3[C:14]([C:15](=[O:19])[NH:16][CH:17]=[CH:18]3)=[C:4]2[CH:3]=1
Reactant: O=c1cc(-c2[nH]c(-c3ccccc3Cl)nc2-c2ccc(Br)cc2)cc[nH]1
Solvent: C1CCOC1
Product: O=c1[nH]ccc2c3[nH]c(-c4ccccc4Cl)nc3c3ccc(Br)cc3c12

Procedure:
Using the general procedure in Example 1 Step E, the intermediate of Example 3 Step B was was irradiated under a high intensity light in THF. 1H NMR (600 MHz, DMSO) δ: 13.87 (s, 1 H), 13.76 (s, 1 H)*, 11.86 (m, 1 H)*,11.77 (m, 1 H), 10.55 (d, J=2.0 Hz, 1 H), 10.49 (d, J=2.0 Hz, 1 H)*, 8.49 (d, J=8.5 Hz, 1 H), 8.41 (d, J=8.5 Hz, 1 H)*, 7.88 (m, 1 H), 7.88 (m, 1 H)*, 7.86 (m, 1 H), 7.81 (m, 1 H)*, 7.70 (m, 1 H), 7.70 (m, 1 H)*, 7.57 (m, 3 H), 7.57 (m, 3H)*, 7.31 (m, 1 H), 7.24 (m, 1 H)* (note: * denotes peaks derived from the minor tautomer): [M+1]+ 424.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([O:28]CC)=[O:27])=[CH:4][CH:3]=1.[OH-].[K+]>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl(1RS,2RS,3SR)-1-(4-fluorophenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (60 mg, 0.15 mmol) in EtOH (0.5 ml) was added 6M KOH (0.14 ml, 0.84 mmol). The resulting mixture was allowed to stir at room temperature overnight, then was concentrated under reduced pressure. The residue was partitioned between H2O and Et2O. The aqueous phase was acidified with 3M HCl and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford an oil, which was crystallized from EtOAc/hexanes. The title compound was obtained as an off-white crystalline solid (22 mg, 39%); m.p. 146°-149° C.
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([N+:23]([O-])=O)=[CH:18][C:17]=3[Cl:26])[CH:12]=[CH:11][C:10]=2[OH:27])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[NH2:23][C:19]1[CH:18]=[C:17]([Cl:26])[C:16]([O:15][C:13]2[CH:12]=[CH:11][C:10]([OH:27])=[C:9]([S:6]([NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)(=[O:8])=[O:7])[CH:14]=2)=[C:21]([Cl:22])[CH:20]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)NC3CCC3)c2)c(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)NC3CCC3)c2)c(Cl)c1
Reaction time: 3 h
Yield: 128.7 %

Procedure:
To a solution of N-Cyclobutyl-5-(2,6-dichloro-4-nitro-phenoxy)-2-hydroxy-benzenesulfonamide (403 mg, 0.73 mmol) in ethanol (10 mL) at room temperature was added 10% palladium on carbon (60 mg), and the resulting mixture was placed on Parr shaker for 3 hours under 50 psi. hydrogen gas at room temperature. The reaction solution was filtered through Celite®, and the filtrate was concentrated to afford the title compound (379 mg) which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ8.32 (s, 1H), 7.07-7.04 (dd, 1H), 6.95 (m, 2H), 6.67 (s, 2H), 4.68 (d, 1H), 3.81-3.68 (m, 1H), 2.16-2.08 (m, 2H), 1.7-1.58 (m, 4H). MS (APCI−) Calc: 402.1, Found: 401.3 (M−1).