Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH3:9][N:10]([CH2:12][CH:13]1[CH2:22][C:21]2[C:16](=[CH:17][C:18]([O:23]C)=[CH:19][CH:20]=2)[NH:15][CH2:14]1)[CH3:11]>>[CH3:11][N:10]([CH2:12][CH:13]1[CH2:22][C:21]2[C:16](=[CH:17][C:18]([OH:23])=[CH:19][CH:20]=2)[NH:15][CH2:14]1)[CH3:9]
Reactant: COc1ccc2c(c1)NCC(CN(C)C)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CC1CNc2cc(O)ccc2C1
Yield: 115.1 %

Procedure:
A solution of 3-(N,N-dimethylamino)methyl-1,2,3,4-tetrahydro-7-methoxyquinoline dihydrochloride (1.0 g) 48% hydrobromic acid (10 ml) was heated under reflux for 4 hr. The reaction mixture was poured into 10% aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-hexane to obtain the titled compound (0.81 g). The melting point of its dihydrochloride was 151-152° C. (recrystallizing solvent; methanol-diisopropyl ether).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:5]2.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([N:34]=[C:35]=[O:36])[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1>>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([NH:34][C:35]([NH:15][CH2:14][CH2:13][CH2:12][N:7]2[CH:6]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)=[O:36])[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: COc1cc(N=C=O)cc(OC)c1
Reactant: NCCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Product: COc1cc(NC(=O)NCCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)cc(OC)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 238-b) as a starting material, and using 3,5-dimethoxyphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:30])=O>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:30])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1
Product: O=C(Cl)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
A solution of 4-(dibenzylsulfamoyl)benzoic acid (24 g; 63 mmoles) in thionyl chloride (50 ml) was boiled under reflux for 2.5 hours and the excess of thionyl chloride removed under reduced pressure. 4-(dibenzylsulfamoyl)benzoyl chloride (25 g) was obtained as an oil which was used in the next step without purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[N:32]1([CH2:38][CH2:39]O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.O1C2C=CC(C3(C(NC4C=CC(C(OCCCO)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])[O:31][CH2:39][CH2:38][N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: OCCN1CCCCC1
Agent: COc1ccccc1C(OCCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Product: COc1ccccc1C(OCCN1CCCCC1)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-methoxyphenyl)(2-(piperidin-1-yl)ethoxy)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and 2-(piperidin-1-yl)ethanol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((3-hydroxypropoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[K].S([O-])([O-])(=O)=O.[Mg+2].CC1[N+:32]([CH2:33][C:34]2[CH:35]=[N:36][C:37](C)=[N:38][C:39]=2N)=CSC=1CCO.Cl.[Cl-].[OH:47][C:48](CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=[O:49].C([O-])(=O)C.[NH4+]>S([O-])([O-])(=O)=O.[Mn+2]>[NH2:32][C@H:33]([C:48]([OH:49])=[O:47])[CH2:34][C:35]1[N:36]=[CH:37][NH:38][CH:39]=1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Agent: [Mn+2]
Agent: CC(=O)[O-]
Agent: Cl
Product: N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
An aqueous solution medium having a composition of 10% of glucose, 0.5% of ammonium sulfate, 0.15% of potassium primary phosphate, 0.1% of magnesium sulfate, 0.001% of ferrous sulfate, 0.001% of manganese sulfate, 300 μg/l of thiamine hydrochloride, 350 μg/l of biotin, 5 ml/dl of Aji-Eki® and 0.5% of ammonium acetate, at pH 7.0, was charged in an amount of 300 ml into separate small sized glass jar fermenters. After sterilizing in an autoclave, the various L-histidine-producing bacterial strains shown in Table 14, which had been previously grown in bouillon slants at 30° C. for 24 hours, were inoculated thereon. Then, incubation was carried out at 31.5° C. for 48 hours at 1200 rpm at an aeration rate of 1/2 volume per minute, while keeping the pH at 6.5 by the addition of ammonia gas. After completion of the fermentation, the yield of L-histidine produced and accumulated in the solution based on glucose was determined and is shown in Table 14.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[C:4]([CH3:17])[C:3]=1[OH:18].Br[CH2:20][CH2:21][CH3:22].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:17][C:4]1[CH:5]=[C:6]([B:8]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:7]=[C:2]([CH3:1])[C:3]=1[O:18][CH2:20][CH2:21][CH3:22]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1c(C)cc(B2OC(C)(C)C(C)(C)O2)cc1C
Temperature: 25 °C

Procedure:
A mixture 2,6-Dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (500 mg, 2.02 mmol, 1 eq.), 1-bromopropane (793 mg, 6.45 mmol, 3.2 eq.), and K2CO3 (334 mg, 2.42 mmol, 1.2 eq.) in acetone (20 mL) is heated at 65° C. for 4 days. After cooling to room temperature, the reaction is concentrated, diluted with EtOAc and sequentially washed with H2O and saturated aqueous NaCl. The organic solution is dried over Na2SO4 and concentrated to give 2-(3,5-Dimethyl-4-propoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:36]2[C:41](=[O:42])[C:40]3[S:43][C:44]4[CH2:49][CH2:48][CH2:47][CH2:46][C:45]=4[C:39]=3[CH:38]=[N:37]2)[C:5]([CH2:31][O:32]C(=O)C)=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH2:25][NH:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.O[Li].O>C1COCC1.CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([N:36]2[C:41](=[O:42])[C:40]3[S:43][C:44]4[CH2:49][CH2:48][CH2:47][CH2:46][C:45]=4[C:39]=3[CH:38]=[N:37]2)[C:5]([CH2:31][OH:32])=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH2:25][NH:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1
Reactant: C=CC(=O)NCCNc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: C=CC(=O)NCCNc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
To a mixture of 105f (125 mg, 0.183 mmol) in THF (6 mL), i-PrOH (2 mL) and H2O (2 mL) was added LiOH.H2O (37 mg, 0.915 mmol). The reaction mixture was stirred at rt for 16 h and concentrated. The residue was partitioned between water and DCM. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was washed with EA and dried to give 105 (73 mg, 60%) as gray solid. 1H NMR (500 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.48 (s, 1H),), 8.20 (s, 1H), 8.12 (s, 1H), 7.42 (s, 1H), 7.38-7.32 (m, 2H), 7.23 (t, J=8.0 Hz, 1H), 6.52 (s, 1H), 6.35 (d, J=8.0 Hz, 1H), 6.21-6.15 (m, 1H), 6.05-6.02 (m, 1H), 5.95 (d, J=8.0 Hz, 1H), 4.73 (s, 1H), 4.33 (s, 2H), 3.59 (s, 3H), 3.28-3.25 (m, 5H), 2.93 (bs, 2H), 2.84 (bs, 2H), 1.88 (bs, 4H). ESI-LCMS: m/z=642 [C34H34FN7O5+H]+
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([F:16])[C:7]1=2)C.[OH-].[Li+].Cl>C1COCC1.O>[F:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([O:17][C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[CH:14]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(F)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1OB(O)c2cc(Oc3cnccn3)cc(F)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 13.8 %

Procedure:
To a solution of ethyl-2-(4-fluoro-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (166 mg, 0.50 mmol) in THF (2 mL) was added dropwise an aqueous solution of lithium hydroxide (102 mg, 2.5 mmol) in water (3 mL) at 0° C. The reaction mixture was stirred at room temperature for 1.5 h and acidified to pH=2 at 0° C. with a diluted HCl solution. The resulting mixture was extracted with ethyl acetate (2×15 mL), the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by HPLC to give the title compound as a white solid (21 mg, Yield: 13.8%). 1H NMR (400 MHz, DMSO-d) δ 12.50 (s, 1H), 9.50 (s, 1H), 8.61-8.62 (d, J=2.8 Hz, 1H), 8.42-8.43 (d, J=2.8 Hz, 1H), 8.24-8.25 (m, 1H), 7.31-7.33 (m, 1H), 5.61-5.64 (m, 1H), 2.97-3.02 (m, 1H), 2.37-2.43 (m, 1H). MS (ESI) m/z=305 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)[CH2:5][CH:6]=[CH2:7].C(=O)(O)[O-].[Na+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C.O>[Cl:14][C:10]1[CH:9]=[C:8]([CH:4]([CH2:5][CH:6]=[CH2:7])[CH2:3][N:2]([CH3:1])[S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])[CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C=CCC(CNC)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCC(CN(C)S(=O)(=O)c1ccccc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
N-Methyl-(2-(3-chlorophenyl)pent-4-enyl)amine (202 mg, 1.03 mmol) was dissolved in 10 mL of ethyl acetate. A solution of sodium bicarbonate (766 mg, 10.3 mmol) in water (10 mL) was added followed by benzenesulfonyl chloride (363 mg, 4.06 mmol), and the heterogeneous mixture was stirred overnight at room temperature. The mixture was extracted with 5 mL of ethyl acetate followed by an additional 2×15 mL of ethyl acetate. The combined organic layers were dried over sodium sulfate, decanted, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with 10-20% ethyl ether in hexane to give 223 mg the title compound. 1NMR (400 MHz, CDCl3): δ 7.72 (d, 2H, J=8 Hz), 7.58 (tt, 1H, J=8, 1 Hz), 7.50 (t, 2H, J=8 Hz), 7.24 (d, 1H, J=8 Hz), 7.20 (dt, 1H, J=8, 1 Hz), 7.14 (t, 1H, J=1 Hz), 7.10 (dt, 1H, J=8, 1 Hz), 5.63 (ddt, 1H, J=17, 10, 7 Hz), 5.00 (dm, 1H, J=17 Hz),4.97 (dm, 1H, J=10 Hz) 3.42-3.34 (m, 1H), 3.00-2.90 (m, 2H), 2.61 (s, 3H), 2.56 (dtm, 1H, J=14, 6 Hz), 2.36 (dtm, 1H, J=14, 7 Hz). Mass spectrum (NH3 /CI): m/z=350 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:3]=1[CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[C:7]([CH3:43])=[N:6]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:3]=1[CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[C:7]([CH3:43])=[N:6]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cc(F)ccc4F)c2C)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cc(F)ccc5F)c4C)c3c2)cc1NS(C)(=O)=O
Yield: 17.3 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(2,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy phenyl)methanesulfonamide (100 mg, 0.14 mmol) was hydrolyzed by lithium hydroxide (30.3 mg, 0.722 mmol), THF/Methanol/water (3/3/1 ml) to afford 13 mg (28.2% yield) of the titled compound after purification by column (SiO2-eluted by 2% MeOH in CHCl3). 1H NMR (CDCl3, 300 MHz): δ 9.37 (s, 1H), 8.54 (s, 1H), 7.84-7.78 (m, 2H), 7.37-7.35 (m, 1H), 7.02-6.99 (m, 1H), 6.95-6.85 (m, 1H), 6.80-6.60 (m, 2H), 5.29 (s, 2H), 3.94 (s, 3H), 2.99 (s, 3H), 2.25 (s, 3H), 2.17 (s, 3H). MS: m/z=538.1 (M+1), HPLC Purity: 91.44%, (Method: B).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].C(=O)([O-])[O-].[K+:14].[K+]>O>[C:1]([O-:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[K+:14]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)C[C@H](O)C(=O)[O-]
Temperature: 10 °C
Reaction time: 4 h
Yield: 135.9 %

Procedure:
26.8 g (0.2 mole) of L-malic acid and 13.8 g (0.1 mole) of potassium carbonate are dissolved in 200 ml of water. The solution (pH 4.1) is concentrated under reduced pressure to make the total weight thereof 60 g. The concentrated solution is cooled to 10° C., and the mixture (i.e., the mixture of the concentrated solution and crystals precipitated) is stirred at the same temperature for 4 hours. After stirring, the mixture had a pH of 5.1. The crystalline precipitates are collected by filtration, washed with an aqueous 80% methanol solution, and dried at 35° C. in air for 16 hours. 23.4 g of monopotassium L-malate are obtained as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22](Cl)(=[O:24])=[O:23])[CH:3]=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>>[N:26]1([S:22]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]3[O:8][C:9]4[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=4[C:6]=3[CH:5]=2)(=[O:24])=[O:23])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)Cl)cc3c2C1
Reactant: c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)n4ccc5ccccc54)cc3c2C1
Yield: 45 %

Procedure:
The product of step B and indole were reacted using the procedure of Example 41, step C to provide tert-butyl 8-(1H-indol-1-ylsulfonyl)-6-chloro-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (35 mg, 45%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.00 (d, J=8.1 Hz, 1H), 7.89 (s, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.58 (d, J=3.6 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.36-7.30 (m, 1H), 7.25-7.20 (m, 1H), 6.69-6.68 (m, 1H), 4.52 (s, 2H), 3.80 (t, J=5.4 Hz, 2H), 2.88 (t, J=5.1 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[S:12]([OH:15])(=O)=[O:13].S(Cl)(Cl)(=O)=O.P(Cl)(Cl)(Cl)=O.S1(CCCC1)(=O)=O.[NH3:33]>CO>[NH3:2].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[S:12]([NH2:33])(=[O:15])=[O:13]
Reactant: Nc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: N
Agent: [Na]
Solvent: O=S1(=O)CCCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O

Procedure:
The commercially available sodium salt of 2-amino-5-nitro-benzenesulfonic acid can be converted to the corresponding sulfonyl chloride with phosphoryl chloride in the presence of a suitable co-solvent, such as sulfolane. Treatment with ammonia, e.g., ammonia solution in methanol or ammonia gas, affords the desired 2-amino-5-nitro-benzenesulfonamide intermediate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][S:16]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([N+:26]([O-:28])=[O:27])[C:20]=2Cl)(=[O:18])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][S:16]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([N+:26]([O-:28])=[O:27])[C:20]=2[OH:32])(=[O:18])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2c(Cl)ccc([N+](=O)[O-])c2Cl)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2c(Cl)ccc([N+](=O)[O-])c2O)CC1
Yield: 58.2 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-[(1-tert-butoxycarbonylpiperidin-4-yl)methyl]-2,6dichloro-3-nitrobenzenesulfonamide (800 mg, 1.89 mmol), 60% NaH (227 mg, 5.67 mmol) and water (41 μL, 2.27 mmol) were reacted to form the desired product (495 mg, 58%). EI-MS (m/z) 447.92, 449.84 (M−).
Reaction SMILES: C(C(CCCC)COC(=O)CC[S:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][C:16]3[N:17]2[CH:20]=[N:21][N:22]=3)=[CH:12][CH:11]=1)C.N#N.CC(C)([O-])C.[K+].Br[CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>CN(C=O)C.CCOC(C)=O.O>[CH2:49]([O:48][C:46](=[O:47])[CH2:45][CH2:44][CH2:43][S:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][C:16]3[N:17]2[CH:20]=[N:21][N:22]=3)=[CH:12][CH:11]=1)[CH3:50]
Reactant: CCCCC(CC)COC(=O)CCSc1ccc2c(-c3ccccc3)cc3nncn3c2c1
Reactant: CCOC(=O)CCCBr
Agent: CC(C)(C)[O-]
Agent: N#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCSc1ccc2c(-c3ccccc3)cc3nncn3c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
11c (100 mg, 0.21 mmol) in DMF (1 mL) was degassed for 5 minutes with N2, and then cooled to 0° C. under N2. Potassium tert-butoxide (29 mg, 0.26 mmol) in DMF (1 mL) was degassed for 5 minutes with N2, and then added to the solution of 11c. The reaction was warmed to room temperature, and LCMS analysis showed no starting material remained after 10 minutes. Ethyl 4-bromobutyrate (0.04 mL, 0.24 mmol) was added, and the mixture was stirred for 20 minutes. The reaction was diluted with EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the desired product, 11d.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(NC(C)C)(C)C.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[S:39](Cl)(=[O:41])=[O:40]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][S:39]([C:35]2[S:34][CH:38]=[CH:37][CH:36]=2)(=[O:41])=[O:40])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc(NS(=O)(=O)c2cccs2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.7 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in tetrahydrofuran (5 mL) were added N,N-diisopropylamine (111 mg, 0.86 mmol), 4-dimethylaminopyridine (7.0 mg, 0.06 mmol) and thiophenesulfonyl chloride (126 mg, 0.69 mmol) and the reaction mixture was stirred at ambient temperature for 4 d. The resulting suspension was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with aqueous sodium carbonate (saturated). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=50:30:20 to 20:60:20) afforded the title compound (95 mg, 33%) as an orange solid. MS: m/e=495.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].O[CH2:11][CH:12]([CH2:14]O)O.[N+](C1C=CC=CC=1)([O-])=O.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[CH3:9])[N:6]=[CH:14][CH:12]=[CH:11]2
Reactant: OCC(O)CO
Reactant: Cc1cc(N)ccc1Br
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cc2ncccc2cc1Br
Reaction time: 3 h
Yield: 31.4 %

Procedure:
A mixture of 4-bromo-3-methylaniline (20 g, 107.5 mmol), ferric sulfate (6.6 g, 43.4 mmol), glycerol (40.8 g, 440 mmol), nitrobenzene (8.12 g, 66 mmol), and concentrated sulfuric acid (23 ml) was heated gently. After the first vigorous reaction, the mixture was boiled for 3 h and then evaporated to remove the excess nitrobenzene. The solution was added a saturated aqueous solution of sodium bicarbonate until pH=7-8, then the solution was filtered and extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The solid was purified by flash column chromatography to give a yellow solid, which was further washed with petroleum ether to give 7.5 g of 6-bromo-7-methyl-quinoline (31% yield): 1H NMR (CDCl3): 2.60 (s, 3H), 7.36 (m, 1H), 7.96 (s, 1H), 8.04 (m, 2H), 8.89 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([CH3:25])([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:27]1([C:33]2[O:34][C:35]([CH3:51])=[C:36]([CH2:38][CH2:39]OS(C3C=CC(C)=CC=3)(=O)=O)[N:37]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[K+].[Br-]>>[CH:27]1([C:33]2[O:34][C:35]([CH3:51])=[C:36]([CH2:38][CH2:39][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:25])([O:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[C:4]([OH:3])=[O:26])=[CH:8][CH:9]=3)[N:37]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(F)(F)F)cc1
Agent: [Br-]
Agent: [K+]
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure of Example 50. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 2H, J=8.8 Hz), 7.16 (d, 2H, J=8.8 Hz), 6.95 (d, 2H, J=8.4 Hz), 6.78 (d, 2H, J=8.4 Hz), 4.11 (t, 2H, J=6.2 Hz), 3.24 and 3.15 (d of ABq, 2H, J=13.8 Hz), 2.95 (t, 2H, J=6.2 Hz), 2.85 (tt, 1H, J=11.6, 3.4 Hz), 2.30 (s, 3H), 2.03-1.95 (m, 2H), 1.83-1.74 (m, 2H), 1.73-1.68 (m, 1H), 1.58-1.47 (m, 1H), 1.49 (s, 3H), 1.38-1.17 (m, 4H). IR (KBr) 3400, 2937, 1735, 1614, 1513, 1328 cm−1. HRMS (ES+) m/z exact mass calcd for C29H33NO5F3 532.2311, found 532.2332.