Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:49])([C:38](=[O:48])[NH:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:3]([OH:37])[CH:4]([NH:8][C:9](=[O:36])[CH2:10][N:11]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:14]=[C:13]([NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)=[O:25])[C:12]1=[O:35])[CH:5]([CH3:7])[CH3:6].Cl>>[F:49][C:2]([F:1])([C:38](=[O:48])[NH:39][CH2:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:3](=[O:37])[CH:4]([NH:8][C:9](=[O:36])[CH2:10][N:11]1[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][CH:14]=[C:13]([NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)=[O:25])[C:12]1=[O:35])[CH:5]([CH3:6])[CH3:7]
Reactant: Cc1cccc(COC(=O)Nc2ccc(-c3ccccc3)n(CC(=O)NC(C(C)C)C(O)C(F)(F)C(=O)NCCc3ccccc3)c2=O)n1
Agent: Cl
Product: Cc1cccc(COC(=O)Nc2ccc(-c3ccccc3)n(CC(=O)NC(C(=O)C(F)(F)C(=O)NCCc3ccccc3)C(C)C)c2=O)n1

Procedure:
N-[3,3-Difluoro-2-hydroxy-1-isopropyl-3-(N-phenethylcarbamoyl)propyl]-2-[3-(6-methylpyrid-2-ylmethoxycarbonylamino)-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl]acetamide was oxidized using a procedure similar to that described in Example 1.i., but omitting the hydrochloric acid wash. The crude material was purified by chromatography, with methanol:chloroform (1:99) as the eluent. The resulting material was triturated with diethyl ether and petroleum ether to give a solid which was triturated with petroleum ether to yield the title compound; TLC: Rf =0.31, chloroform:methanol (30:1); 300 MHz NMR: 9.20 (t,1), 8.68 (s,1), 8.50 (d,1), 7.91 (d,1), 7.71 (t,1), 7.48-7.11 (m,14), 6.22 (d,1), 5.18 (s,2), 4.83-4.75 (m,1), 4.50 (broad s,2), 2.76 (t,2), 2.27-2.12 (m,1), 8.48 (d,3), 7.36 (d,3); MS: m/z=674(M+ 1). Analysis for C37H37F2N5O6 : Calculated: C, 64.18; H, 5.54; N, 10.40; Found: C, 64.21; H, 5.72; N, 10.10.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH:18]([CH3:20])[CH3:19])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5]/[C:4](=[C:12]3/[C:13]([CH:18]([CH3:20])[CH3:19])=[N:14][NH:15][C:16]/3=[O:17])/[CH:3]=2)=[CH:24][CH:23]=1
Reactant: CC(C)C1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: Nc1ccc(S)cc1
Product: CC(C)C1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1

Procedure:
Example 20 was synthesized from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-isopropyl-1H-pyrazol-5(4H)-one and 4-aminothiophenol according to the procedure described in Example 19. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (bs, 6H) 3.33 (bs, 1H) 5.87 (s, 1H) 6.78 (d, J=8.34 Hz, 2H) 7.31 (d, J=8.34 Hz, 2H) 7.52 (bs, 1H) 7.77 (bs, 1H) 8.03 (d, J=8.34 Hz, 1H); ESI-MS: m/z calc'd for C21H20N4OS 376.47. found 377.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([CH2:16][OH:17])=[C:14]([C:18]([F:21])([F:20])[F:19])[S:13][N:12]=2)=[CH:7][CH:6]=1)([F:4])[CH3:3].O[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[C:25]([CH3:36])[C:24]=1[CH3:37]>>[F:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:15]([CH2:16][O:17][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([CH3:36])[C:24]=3[CH3:37])=[C:14]([C:18]([F:19])([F:20])[F:21])[S:13][N:12]=2)=[CH:9][CH:10]=1)([F:1])[CH3:3]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CC(F)(F)c1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Product: Cc1c(CCC(=O)O)ccc(OCc2c(-c3ccc(C(C)(F)F)cc3)nsc2C(F)(F)F)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling [3-[4-(1,1-difluoroethyl)phenyl]-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 7.79 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.4 Hz, 1H), 6.710 (d, J=8.4 Hz, 1H), 5.12 (s, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.52 (t, J=8.4 Hz, 2H), 2.23 (s, 3H), 2.05 (s, 3H), 1.90-2.02 (m, 3H). Mass spectrum (ESI, m/z): Calcd. for C24H22F5NO3S, 498.1 (M−H). found 498.1.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]([CH:10]([F:12])[F:11])([F:9])[F:8])([F:4])([F:3])[F:2].[Br:13]Br.C(=O)=O>>[C:1]([CH:5]([O:6][C:7]([CH:10]([F:11])[F:12])([F:8])[F:9])[Br:13])([F:4])([F:3])[F:2]
Reactant: FC(F)C(F)(F)OCC(F)(F)F
Reactant: BrBr
Agent: O=C=O
Product: FC(F)C(F)(F)OC(Br)C(F)(F)F
Temperature: 475 °C

Procedure:
CF3CH2OCF2CF2H (110 g.) was reacted with bromine (125 g.) by passing a mixture of the two diluted with a stream of nitrogen through a 12 inch × 1 inch glass tube heated to 475°C. The effluent product was condensed in a "Dry Ice" trap and purified by fractional distillation and preparative gas chromatography to give CF3CHBrOCF2CF2H., b.p. 80°C., nD25 1.3155. This product analyzed as follows:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)[N:4]=1.C(N(CC)CC)C.[CH:29]([S:32](Cl)(=[O:34])=[O:33])([CH3:31])[CH3:30]>C(Cl)Cl>[F:21][C:2]([F:1])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][S:32]([CH:29]([CH3:31])[CH3:30])(=[O:34])=[O:33])=[CH:14][CH:13]=2)[N:4]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
A mixture of ({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amine (100 mg, 0.339 mmol), triethylamine (0.07 ml, 0.51 mmol) in DCM (10 ml) was stirred in an ice bath under argon. Then isopropylsulfonyl chloride was added (148 mg in total, 1 mmol) in DCM (1 ml) dropwise with stirring. The reaction mixture was allowed to stir at room temperature for 16 hr. Then the reaction mixture was washed with water (20 ml), separated the organic layer and dried with sodium sulphate. Solvent was removed by rotary evaporation and the sample purified by MDAP to give the title compound as an off white solid (51 mg, 37%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([N:24]4[CH2:29][CH2:28][S:27][CH2:26][CH2:25]4)=[O:22])=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Reactant: C1CSCCN1
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)N2CCSCC2)s1
Yield: 59 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using thiomorpholine instead of 4-aminotetrahydropyran, to the title compound (61 mg, 59%) which was obtained as a yellow solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) and trituration from diethyl ether. MS: m/e=417.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]34[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:24][CH:18]([C:19]5([F:27])[F:26])[CH2:17]3)[CH2:23]4)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.C(N=C=NCCCN(C)C)C.[N:39]1([S:43]([NH2:46])(=[O:45])=[O:44])[CH2:42][CH2:41][CH2:40]1>CN(C)C1C=CN=CC=1.ClCCl>[N:39]1([S:43]([NH:46][C:9](=[O:11])[C:8]2[CH:12]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([O:14][CH2:15][C:16]34[CH2:17][CH:18]5[CH2:24][CH:22]([CH2:21][CH:20]([C:19]5([F:27])[F:26])[CH2:25]3)[CH2:23]4)=[CH:6][C:7]=2[F:13])(=[O:45])=[O:44])[CH2:42][CH2:41][CH2:40]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
To a mixture of 5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)-methoxy)-2-fluorobenzoic acid (0.25 g, 0.66 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.29 g, 1.51 mmol) and 4-dimethylaminopyridine (0.19 g, 1.51 mmol) in anhydrous dichloromethane (10 mL) was added azetidine-1-sulfonamide (0.13 g, 0.99 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours. The mixture was quenched with 1N hydrochloride acid (30 mL), followed by extraction with ethyl acetate (100 mL). The organic layer was washed with water (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, the crude product was crystallized from ethyl acetate and hexanes and recrystallized from acetonitrile and water to afford the title compound as colorless solid (0.24 g, 73%): 1H NMR (300 MHz, DMSO-d6) δ 11.61 (s, 1H), 7.17 (d, J=8.3 Hz, 1H), 6.94 (d, J=12.9 Hz, 1H), 4.05 (t, J=7.7 Hz, 4H), 3.72 (s, 2H), 2.25-1.98 (m, 6H), 1.88-1.69 (m, 10H), 0.94-0.87 (m, 2H), 0.70-0.65 (m, 2H); MS (ES+) m/z 499.1 (M+1); MS (ES−) m/z 497.2 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][CH2:23][OH:24])[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][CH2:23][O:24][C:35]3[CH:36]=[CH:37][C:32]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:33][CH:34]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCCOc1ccc(Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 79.6 %

Procedure:
To a solution of 3-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]propan-1-ol (1.00 g, 3.11 mmol), 4-benzylphenol (572 mg, 3.11 mmol) and triphenylphosphine (1.22 g, 4.67 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.18 g, 4.67 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.21 g (yield: 79.6%)
Reaction SMILES: CS[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[Cl:10][C:11]1[CH:37]=[CH:36][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C@@H:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[CH2:24][NH2:25])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>CC(O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C@@H:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=4)[CH2:24][NH:25][C:3]3=[CH:4][N+:5]([O-:7])=[O:6])=[CH:18][CH:17]=2)=[CH:36][CH:37]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NC[C@@H](Nc1ccc(Oc2ccc(Cl)cc2)cc1)c1cccc(C(F)(F)F)c1
Solvent: CC(C)O
Product: O=[N+]([O-])C=C1NC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 80 °C

Procedure:
1,1-Bis(methylthio)-2-nitroethylene (13.1 mg, 0.079 mmol) and (S)—N1-(4-(4-chlorophenoxy)phenyl)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diamine prepared from Example 173 Step A (16.1 mg, 0.040 mmol) are dissolved in iPrOH (0.4 mL) and heated at 80° C. for 2 h. The solvent is removed and the residue is purified by preparatory LC/MS to provide the title compound; HPLC-MS calculated for C23H17ClF3N3O3 (M+H+) 476.1, found 476.1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH3:34][S:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:40][C:39]1[CH:43]=[CH:44][C:36]([S:35][CH3:34])=[CH:37][CH:38]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CSc1ccc(C(=O)Cl)cc1
Product: CSc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(F)c23)cc1

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 2-(3) and 4-(methylthio)benzoyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 451 (M+NH4) 1H-NMR (DMSO-d6) δ 2.42 (s, 3H), 3.23-3.31 (m, 1H), 3.37-3.48 (m, 3H), 3.62-3.70 (m, 2H), 4.04 (s, 2H), 4.54 (t, J=5.7 Hz, 1H), 5.10 (d, J=5.3 Hz, 1H), 5.17 (d, J=5.0 Hz, 1H), 5.21 (d, J=5.7 Hz, 1H), 5.37 (d, J=9.2 Hz, 1H), 6.74 (dd, J=11.3, 8.0 Hz, 1H), 7.07 (td, J=8.0, 5.2 Hz, 1H), 7.15-7.22 (m, 4H), 7.24 (s, 1H), 7.36 (d, J=8.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>CC#N>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[C:7]([Br:14])[CH:6]=1)[CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl 4-aminophenylacetate (1.79 g, 10 mmol, 1 eq.) in MeCN (50 mL), N-bromsuccinimide (1.78 g, 10 mmol, 1 eq.) was added slowly. The mixture was stirred at r.t. for 72 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between water (50 mL) and Et2O (50 mL). The org. phase was washed with sat. aq. NaCl soln. (1×50 mL), dried over MgSO4, and concentrated in vacuo to give (4-amino-3-bromo-phenyl)-acetic acid ethyl ester as an orange oil. The product was used without further purification.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1([S:12]([C:15]#[N:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(C)C=CC=CC=1.Cl([O-])(=O)(=O)=O.[Na+]>C(O)CCC>[C:6]1([S:12]([C:15]2[CH:4]=[CH:3][CH:2]=[CH:1][N:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C/C=C/C=O
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccccn1
Temperature: 110 °C
Yield: 92.5 %

Procedure:
First, 8.22 g (115 mmol) of crotonaldehyde and 9.22 g (55.2 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 677 mg (5.55 mmol) of sodium perchlorate was added. Then the mixture was heated under reflux for 18 hours while agitating at an internal temperature of 110° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 11.2 g of 2-benzenesulfonylpyridine as colorless crystals (purity of 98%, yield of 91% based on benzenesulfonyl cyanide).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:34](=O)([O:40]C(C)(C)C)[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[C:36]([O:35][C:34]([N:18]1[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:16]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:15]=[C:14]1[C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)=[O:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: Fc1ccc(-c2nc(-c3ccc(Oc4ccccc4)cc3)[nH]c2-c2ccncc2)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Oc3ccccc3)cc2)nc(-c2ccncc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-phenoxyphenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole (prepared by the method described in Example 2; 150 mg, 0.37 mmol) in DMF (1 mL) was added solid sodium hydride (8.9 mg of a 60% oil dispersion, 0.37 mmol). The reaction was stirred for 1 h at room temperature and then cooled to -20° C. Di-t-butyl carbonate (85 μL, 0.37 mmol) was added and the reaction was placed in a refrigerator for 4 days. The reaction was quenched by the addition of water and the mixture was extracted with ethyl acetate (3 times). The combined extracts were successively washed with water (2 times) and saturated salt solution and dried over anhydrous sodium sulfate. The solution was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 0-1.5% methanol in methylene chloride to yield the title compound, mass spectrum (CI) m/e=508 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]2)=[S:18])=[CH:14][C:5]2[N:6]([CH2:11][CH2:12][CH3:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.N1C=CC=CC=1.[C:31](Cl)(Cl)=[S:32]>C(Cl)Cl>[F:1][C:2]1[C:15]([N:16]=[C:17]2[N:19]3[N:20]([CH2:21][CH2:22][CH2:23][CH2:24]3)[C:31](=[S:32])[S:18]2)=[CH:14][C:5]2[N:6]([CH2:11][CH2:12][CH3:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCCN1C(=O)COc2cc(F)c(NC(=S)N3CCCCN3)cc21
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN1C(=O)COc2cc(F)c(N=c3sc(=S)n4n3CCCC4)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
To a stirred, cold (-20°) solution of 12.0 g (0.0340 mole) of N-(7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-on-6-yl)aminothiocarbonylperhydropyridazine and 8.69 g (0.110 mole) of pyridine in 300 mL of methylene chloride was added dropwise 3.90 g (0.0340 mole) of thiophosgene. The resulting mixture was stirred at room temperature for approximately 18 hours. The reaction mixture was washed with dilute hydrochloric acid followed by an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was treated with decolorizing charcoal and was filtered through a pad of silica gel. The filtrate was evaporated under reduced pressure leaving a solid residue. This residue (10.4 g) was combined with 3.6 g of a similar residue prepared in a similar manner. The resultant solid (14.0 g) was recrystallized from ethyl acetate and n-heptane to yield 11.7 g of 9-(7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-on-6-yl)imino-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-thione, mp 112°-114° C. (corresponding to Compound 5 of Table 1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][S:17]([NH2:20])(=[O:19])=[O:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2/[CH:14]=[N:20]/[S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1/C=N/S(C)(=O)=O

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (2 g, 7.5 mmol) was mixed with methanesulfonamide (0.714 g, 7.5 mmol) and p-toluenesulfonic acid monohydrate (0.010 g, 0.053 mmol) in toluene. The reaction was heated to reflux for 24 hours with Dean-Stark apparatus in place. Upon cooling the product precipitated from the reaction mixture and was isolated by filtration to afford the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH3:7].C(N(CC)CC)C>ClCCl>[CH2:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:16][CH2:17][CH:18]([C:21]3[CH:22]=[CH:23][C:24]([C@@H:27]([NH:29][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:28])=[CH:25][CH:26]=3)[CH2:19][CH2:20]2)=[CH:13][CH:14]=1)[CH3:7]
Reactant: CCOc1ccc(N2CCC(c3ccc([C@H](C)N)cc3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(N2CCC(c3ccc([C@H](C)NS(C)(=O)=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 17 mg (0.15 mmol) methanesulfonyl chloride is added a solution of 32 mg (0.1 mmol) (S)-1-{4-[1-(4-ethoxy-phenyl)-piperidin-4-yl]-phenyl}-ethylamine (XIII.1) and 42 μL triethyl amine in 2 mL dichloromethane. The mixture is stirred for 2 d at rt. The solvent is removed under reduced pressure and the residue is purified using reversed phase column chromatography (water/MeOH, 0.1% TFA) and the corresponding fractions are concentrated to yield the desired product.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:6]=[N:5]1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[F:29][C:2]([F:28])([F:1])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:30](=[O:32])[CH3:31])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:6]=[N:5]1
Reactant: CC(C)(CO)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(CC(F)(F)F)c1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2OCC(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(2,2,2-trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 486, 1 equivalent), acetic anhydride (3 equivalents), 4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2 equivalents) is stirred at room temperature for 16 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[N:21]1([C:27]2[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([N:24]1[CH2:25][CH2:26][N:21]([C:27]2[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=2)[CH2:22][CH2:23]1)=[O:12])(=[O:3])=[O:4]
Reactant: N#Cc1cnc(N2CCNCC2)s1
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C#N)s2)CC1)C(F)(F)F
Yield: 59 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 59%). MS (m/e): 489.1 (M+H+, 100%), 506.1 (M+NH4+, 78%).