Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[C:13]([N:15]([CH3:29])[C:16](=[O:28])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH3:27])[CH:25]=3)[NH:20][CH:19]=2)=[O:14])=[CH:3]1>CN(C=O)C.[C].[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4]([CH:12]2[CH:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH3:27])[CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:28])[N:15]([CH3:29])[C:13]2=[O:14])=[CH:3]1
Reactant: Cc1ccc2[nH]cc(C3=C(c4cn(C)c5ccc(C)cc45)C(=O)N(C)C3=O)c2c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]cc(C3C(=O)N(C)C(=O)C3c3cn(C)c4ccc(C)cc34)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
To a solution of 2-(1,5-dimethyl-1H-indol-3-yl)-3-(5-methyl-1H-indol-3-yl)-N-methylmaleimide (100 mg, 0.26 mmol) in DMF (5 mL) was added a small amount of 10% palladium-carbon, and the whole was stirred at room temperature for 1 day under hydrogen atmosphere. The palladium-carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane =2:1) to obtain 3-(1,5-dimethyl-1H-indol-3-yl)-4-(5-methyl-1H-indol-3-yl)-1-methyl-2,5-dioxopyrrolidine (71 mg, 70.2%) as pale red solids.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)([CH2:7]2)[CH2:5]1)(=[O:3])[CH3:2].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C.C([O-])(=O)C.[Na+]>[C:1]([N:4]1[CH2:9][CH:8]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=3)([CH2:7]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC2CC2(c2ccc(N)cc2)C1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C23CC2CN(C(C)=O)C3)cc1

Procedure:
A solution of 3-acetyl-1-(p-aminophenyl)-3-azabicyclo[3.1.0]hexane in aqueous acetic acid-sodium acetate is treated with acetic anhydride at ambient temperature. The reaction mixture is chilled and filtered to give 3-acetyl-1-(p-acetamidophenyl)-3-azabicyclo[3.1.0]hexane.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To an ice cooled solution of 54 g (0.5 mol) of benzyl alcohol and 75.75 g (104.3 ml, 0.75 mol) of triethylamine in 1800 ml of dichloromethane is added dropwise 63 g (42.57 ml, 0.55 mol) of methanesulfonyl chloride. The temperature of the reaction mixture during the addition is ca. 10°. The reaction mixture is then stirred for 1.5 hours at 10°. The reaction mixture is then diluted with dichloromethane, washed with ice water, cold 10% HCl, saturated KHCO3, saturated NaCl and dried (MgSO4). Solvent is removed in vacuo to yield the benzyl methanesulfonate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[C:33]([OH:46])=[C:34]([S:42](Cl)(=[O:44])=[O:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>C(Cl)Cl>[Cl:31][C:32]1[C:33]([OH:46])=[C:34]([S:42]([N:15]([CH2:14][C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)(=[O:44])=[O:43])[CH:35]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:37]=1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(Cl)c1O
Reactant: Fc1ccc(CNCc2cccc(-c3ccc(Cl)cc3)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cc(C(F)(F)F)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1cccc(-c2ccc(Cl)cc2)c1
Temperature: 0 °C
Yield: 57 %

Procedure:
1-(4′-Chlorobiphenyl-3-yl)-N-(4-fluorobenzyl)methanamine (Compound A of Example 232, 200 mg, 0.6 mmol, 1.0 eq) was dissolved in dry DCM (20 mL) then stirred and cooled to 0° C. Triethylamine (186 mg, 1.86 mmol, 3.0 eq) was added slowly and the mixture was stirred for 30 minutes. 3-Chloro-2-hydroxy-5-(trifluoromethyl)benzene-1-sulfonyl chloride (180 mg 0.6 mmol 1.0 eq) dissolved in DCM was added to the above solution and the resulting mixture was stirred for 12 h at ambient temperature. The solution was concentrated under reduced pressure and the residue was purified by silica gel (240-280) column chromatography using 20-30% ethyl acetate/hexane as the eluent to afford the title compound (0.2 g, 56%). 1H NMR (400 MHz, CD3OD) δ 7.92 (d, 1H), 7.79 (d, 1H), 7.43 (d, 5H), 7.32-7.29 (t, 1H), 7.27-7.25 (m, 2H), 7.23 (s, 1H), 7.15-7.13 (d, 1H), 6.98-6.94 (t, 2H), 4.89 (s, 1H), 4.58-4.53 (d, 2H). MS (ESI): 585.8 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C(Cl)Cl>[CH3:21][S:22]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: NCCSc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)NCCSc1cccc2nccn12
Yield: 78.1 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (9.63 g, 49.8 mmoles) and triethylamine (7.64 ml) in methylene chloride (150 ml) was added methanesulfonyl chloride (3.85 ml, 49.7 mmoles) with stirring under ice-cooling and was stirred under ice-cooling for 1 hour. The reaction solution was poured into water and stirred. Then, the crystals precipitated were filtered off, washed with water and dried to obtain 10.53 g of the desired product (77.9%, colorless crystals).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][OH:12])[C:5]=2[O:4][CH2:3][CH2:2]1>C1COCC1.[O-2].[Mn+4].[O-2].O=[Mn]=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[O:12])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OCc1cccc2c1OCCO2
Agent: O=[Mn]=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cccc2c1OCCO2
Temperature: 60 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
A solution of 2,3-dihydro-1,4-benzodioxin-5-ylmethanol (Intermediate A1) (commercially available from Aldrich) (3 g, 18.1 mmol) in THF (100 mL) was treated with manganese(IV) oxide, activated (commercially available from Aldrich): MnO2 (10 g, 115 mmol) at rt. The mixture was heated to 35° C. for 2 h and 60° C. for 4 h followed by 18 h at room temperature (rt). The mixture was filtered through celite and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel with 20% EtOAc:hexanes to give 2,3-dihydro-benzo[1,4]dioxine-5-carbaldehyde (Intermediate A2) 2.6 g (88%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[N:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1.[F:19][C:20]1([F:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:19][C:20]1([F:26])[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[CH:7]=[CH:6][N:5]([C:8]3[N:18]=[CH:17][CH:16]=[CH:15][C:9]=3[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=2)[CH2:22][CH2:21]1
Reactant: FC1(F)CCNCC1
Reactant: CCOC(=O)c1cccnc1-n1ccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cccnc1-n1ccc(CN2CCC(F)(F)CC2)n1
Yield: 94 %

Procedure:
The mixture of ethyl 2-(3-(chloromethyl)-1H-pyrazol-1-yl)nicotinate (500 mg, 1.882 mmol), 4,4-difluoropiperidine (328 mg, 2.7 mmol), and K2CO3 were stirred at room temperature in acetonitrile (25 mL) until completion of the reaction. The mixture was concentrated, pardoned between water and dichlormethane (60 mL), the organic layer separated, washed twice with water, dried (MgSO4), filtered and dried to give a brown oil, which then was purified by chromatography over silica gel (CH2Cl2+methanol) to yield 620 mg of the title compound as clear oil. ESI-MS [M+H]+: 351.15.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[C:38]([C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Br)=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39]>CN(C=O)C.CCOCC.Cl>[C:38]([C:42]1[CH:43]=[CH:44][C:45]([CH2:46][N:19]2[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:34])([O:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][CH:25]=4)[C:4]([OH:3])=[O:35])=[CH:8][CH:9]=3)[N:17]([CH3:22])[C:18]2=[O:21])=[CH:48][CH:49]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc(C(C)(C)C)cc2)CC1CCOc1ccc(CC(C)(Oc2ccc(C(F)(F)F)cc2)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a mixture of 80 mg of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 16 mg of NaH (0.40 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 minute Then 0.07 mL of 4-tert-butylbenzyl bromide is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl. (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.5 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 40 mg (40%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.51 (d, 2H, J=8.8 Hz), 7.38-7.32 (m, 2H), 7.16 (t, 4H, J=8.8 Hz), 6.95 (d, 2H, J=8.8 Hz), 6.76 (d, 2H, J=8.8 Hz), 4.37, 4.28 (ABq, 2H, J=14.8 Hz), 4.24 (bs, 1H), 3.97 (t, 2H, J=6.0 Hz), 3.74-3.67 (m, 1H), 3.44 (t, 1H, J=9.2 Hz), 3.31, 3.16 (ABq, 2H, J=13.8 Hz), 3.07 (t, 1H, J=9.2 Hz), 2.85 (s, 3H), 2.27-2.18 (m, 1H), 1.98-1.89 (m, 1H), 1.50 (s, 3H), 1.29 (s, 9H). HRMS (ES+) m/z exact mass calcd for C34H40N2O5F3 (m+1) 613.2889, found 613.2872.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:17])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([Cl:16])[CH:9]=1)=[O:6].[CH2:18]([N:20]1[C:32]2[CH:31]=[CH:30][C:29]([C:33](O)=[O:34])=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.[Cl-].[Na+].O>[Cl:16][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][CH:3]([CH3:17])[CH2:2][NH:1][C:33]([C:29]2[CH:30]=[CH:31][C:32]3[N:20]([CH2:18][CH3:19])[C:21]4[C:26]([C:27]=3[CH:28]=2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:34])[CH:13]=[CH:12][C:11]=1[C:14]#[N:15]
Reactant: CC(CN)CC(=O)Nc1ccc(C#N)c(Cl)c1
Reactant: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2cc(C(=O)NCC(C)CC(=O)Nc3ccc(C#N)c(Cl)c3)ccc21
Yield: 52.4 %

Procedure:
A solution of the compound obtained in Step 3 (158 mg, 0.63 mmol), 9-ethyl-9H-carbazole-3-carboxylic acid (150 mg, 0.63 mmol), HATU (262 mg, 0.69 mmol) and TEA (0.096 mL, 0.69 mmol) in DMF (5 mL) was stirred at 50° C. for 14 hr. To the reaction solution was added brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 80% ethyl acetate/hexane) to give the title compound (156 mg, 0.330 mmol, 52.6%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)[C:6]=2[CH:20]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B(O)O)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)[C:6]=4[CH:20]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(-n2cnc3ccc(Br)cc32)cc1
Product: CS(=O)(=O)c1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(F)cc4)cc32)cc1

Procedure:
The title compound, white solid (12 mg, 14%), MS (ISP) m/z=433.4 [(M+H)+], mp 247° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-methylsulfonyl-phenyl)-1H-benzo[d]imidazole (intermediate O) (70 mg, 199 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (49.2 mg, 239 μmol).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:6]=1.N1C=CC(B(O)O)=CC=1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:10]=[CH:9][C:8]=2[O:11][CH3:12])=[C:15]([CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:16]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Agent: OB(O)c1ccncc1
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(Br)cc1CN1C(=O)O[C@H](c2ccccc2)[C@@H]1C

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[4-bromo-2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid methyl ester and 4-pyridineboronic acid.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:33]>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cc2ccc(F)cc2)cc1
Reactant: N
Product: NS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-benzyl-4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3,4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.5723 g 34%). mp 120–123° C. 1H NMR (300 MHz, DMSO d6) δ 3.83 (bs, 2H), 5.30 (bs, 2H), 6.95–7.06 (m, 4H), 7.28–7.40 (m, 5H), 7.48 (m, 2H), 7.60 (m, 2H), 7.91 (m, 2H), 7.95 (s, 1H). MS (DCI/NH3) m/z 450 (M+H)+, 467 (M+NH4)+. Anal. calc. for C24H20FN3O3S: C, 64.13; H, 4.48; N, 9.35. Found: C, 63.76; H, 4.71; N, 9.02.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][C:35]([F:38])([F:37])[CH2:34][CH2:33][C@@H:32]2[C:39]2[CH:40]=[N:41][N:42](COC)[CH:43]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.Cl>C(O)C.ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][C:35]([F:38])([F:37])[CH2:34][CH2:33][C@@H:32]2[C:39]2[CH:43]=[N:42][NH:41][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COCn1cc([C@H]2CCC(F)(F)C[C@@H]2Oc2cc(F)c(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ccncn3)cc2Cl)cn1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(O[C@H]2CC(F)(F)CC[C@@H]2c2cn[nH]c2)cc1F
Yield: 42.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 147e by using the 5-chloro-4-({(1S*,2R*)-5,5-difluoro-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (0.20 g, 0.29 mmol) prepared in Example 152a, triethylsilane (0.20 mL), dichloromethane (2.0 mL), trifluoroacetic acid (2.0 mL), ethanol (1.0 mL) and 2 M hydrochloric acid (5.0 mL), to yield the title compound (0.060 g, 42%) as a colorless solid.
Reaction SMILES: S(=O)(=O)(O)O.N([O-])=O.[Na+].N[C:11]1[CH:12]=[CH:13][C:14]2[O:19][C:18]([CH2:22][F:23])([CH2:20][F:21])[CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[CH:26]=1.[BrH:27].[Br-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O.C(O)(=O)C>[Br:27][C:11]1[CH:12]=[CH:13][C:14]2[O:19][C:18]([CH2:22][F:23])([CH2:20][F:21])[CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[CH:26]=1
Reactant: N#CC1=CC(CF)(CF)Oc2ccc(N)cc21
Reactant: Br
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: N#CC1=CC(CF)(CF)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 ml of concentrated sulfuric acid was heated at 40° C. and 760 mg of sodium nitrite acid was added therein. Then, the reaction solution was cooled to room temperature and 20 ml of an acetic acid solution of 2.0 g of 6-amino-4-cyano-2,2-bis(fluoromethyl)-2H-1-benzopyran was added therein. The reaction solution was dropped into 12 ml of an aqueous hydrobromic acid solution of cuprous bromide prepared in advance from 4.2 g of copper (II) sulfate pentahydrate, 2.6 g of sodium bromide and 1.1 g of sodium sulfite under ice-cooling. The resultant mixture was heated to room temperature and stirred for 1 hour. Water was added therein and the mixture was extracted with methylene chloride. An organic layer was washed with an aqueous 2N hydrochloric acid solution and an aqueous 1N sodium hydroxide solution and dried. The solvent was distilled. The obtained residue was purified according to silica gel column chromatography (developing solution, AcOH:hexane=1:5) and recrystallized by a mixed solvent of ethyl acetate and hexane to obtain 690 mg of 6-bromo-4-cyano-2,2-bis(fluoromethyl)-2H-1-benzopyran with a melting point of 105°-107° C.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][CH2:7][C:8]1[C:9]([CH3:53])=[N:10][C:11]([CH3:52])=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[N:30][N:31]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:32]=2)=[CH:18][CH:17]=1>ClCCl>[CH3:53][C:9]1[C:8]([CH2:7][NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[C:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:29]=[N:30][N:31]([C:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:32]=3)=[CH:20][CH:21]=2)[CH:12]=[C:11]([CH3:52])[N:10]=1
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CN)c(C)n1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)NCc1c(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)cc(C)nc1C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
(Example 51A): A solution of ethyl isocyanate (71 mg) and 3-aminomethyl-2,6-dimethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl)methoxy]pyridine (628 mg) in dichloromethane (15 ml) was left to stand for 2 hours. The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with methanol/dichloromethane (7:93 v/v), to give 2,6-dimethyl-3-(ethylaminocarbonylamino)methyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (602 mg), as a foam: NMR (CDCl3): 1.0(t,3H), 2.5(s,3H), 2.65(s,3H), 3.0-3.1(m,2H), 4.1(br t, 1H), 4.4(d,2H), 4.5(br d, 1H), 5.0(s,2H), 6.6(s,2H), 6.8-7.0(m,6H), 7.1-7.55 (complex m,16H), 7.9(dd,1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][CH2:8][C@@H:9]([C:25](N1[C@H](C)COC1=O)=[O:26])[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH2:8][C@@H:9]([CH2:25][OH:26])[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@@H]1COC(=O)N1C(=O)[C@H](CCC(=O)OC(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
(S)-tert-butyl 4-((R)-5-tert-butoxy-2-((R)-4-methyl-2-oxooxazolidine-3-carbonyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate (4.12 g, 7.36 mmol) was dissolved in 4:1 THF and methanol (200 mL) and cooled to 0° C. Sodium borohydride (557 mg, 2 eq) was added slowly. After 10 min., the mixture was warmed up to rt slowly. The mixture was stirred 2 hr at rt. The mixture was concentrated, redissolved in EtOAc (300 mL), washed with 1% HCl solution (100 mL), brine (60 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by ISCO (40 g column, 10-65% EtOAc in Hexanes gradient, check TLC with Ninhydrin stain) to afford 2.86 g of (S)-tert-butyl 4-((R)-5-tert-butoxy-2-(hydroxymethyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate as a white solid. MS ESI+m/v 410 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[CH:4]([Br:16])[C:5]1[CH:6]=[CH:7][C:8]([S:11]([Cl:14])(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Yield: 16.3 %

Procedure:
(4-Chlorosulfonyl-phenyl)-acetic acid methyl ester (13 g, 52.41 mmol) was taken in carbon tetrachloride (262 mL). N-Bromosuccinimide (10.26 g, 57.66 mmol) was added in one lot followed by benzoyl peroxide (1.39 g, 5.766 mmol). The reaction mixture was refluxed for 2 days. The reaction mixture was cooled to room temperature and filtered; filtrate was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated. Product was purified using column chromatography in 3% ethyl acetate:hexane which yielded bromo-(4-chlorosulfonyl-phenyl)-acetic acid methyl ester (2.8 g) as a gummy mass.
Reaction SMILES: Cl[Si](C)(C)C.[Li+].[BH4-].[Br:8][C:9]1[S:10][C:11]([CH:14]=[CH:15][N+:16]([O-])=O)=[CH:12][CH:13]=1.CO>C1COCC1.C(Cl)(Cl)Cl>[Br:8][C:9]1[S:10][C:11]([CH2:14][CH2:15][NH2:16])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Br)s1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: NCCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 234.6 %

Procedure:
Dry THF (30 mL) and chloro trimethyl silane (12.42 mL, 98.24 mmol) were added dropwise to LiBH4 (1.128 g, 51.28 mmol) over a period of 10 minutes under nitrogen atmosphere. This was followed by dropwise addition of 2-bromo-5-(2-nitro-vinyl)-thiophene (I-14a: 3 g, 12.82 mmol) in dry THF (30 mL) over a period of 20 minutes and the resulting mixture was stirred at room temperature for 48 hours. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mixture was quenched with methanol and concentrated to afford 6.2 g of the crude product which was used in the next step without further purification.