Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH2:17][C:18]2[NH:33][C:21]3=[N:22][CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=4)[CH:25]=[C:20]3[N:19]=2)[CH:11]=1>ClCCl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH2:17][C:18]2[NH:33][C:21]3=[N:22][CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:1](=[O:3])[CH3:2])=[CH:28][CH:27]=4)[CH:25]=[C:20]3[N:19]=2)[CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccnc(CCc2nc3cc(-c4ccc(N)cc4)cnc3[nH]2)c1
Solvent: ClCCl
Product: COc1ccnc(CCc2nc3cc(-c4ccc(NC(C)=O)cc4)cnc3[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.025 ml of acetic acid anhydride are added to 0.086 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-(4-aminophenyl)-3H-imidazo[4,5-b]pyridine (example 27) in 2 ml of dichloromethane and the mixture is stirred at ambient temperature for three hours. The solvent is evaporated in vacuo and the residue is is chromatographed on a silica gel column (dichloromethane/methanol 18:1+2% aqueous ammonia solution (25% strength)). Concentration of the chromatographically pure fractions and drying gives 0.085 g of the title compound as a solid of m.p. 220–221° C. The mass spectrum shows the molecular peaks MH+ and 2MNa+ at 388.4 and 797.0 Da.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10]C2N=C(NC3CCCCCC3)N=C(N(C)C3CCN(C)CC3)N=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N:34]1[C:41]([Cl:42])=[N:40][C:38]([Cl:39])=[N:37][C:35]=1Cl.ClC1C=C(C=CC=1OC)N.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:35]2[N:34]=[C:41]([Cl:42])[N:40]=[C:38]([Cl:39])[N:37]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N(C)C3CCN(C)CC3)n2)cc1Cl
Agent: COc1ccc(N)cc1Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl

Procedure:
This reaction scheme illustrates synthesis of compound 137 by reaction of cyanuric chloride with 3-chloro-4-methoxyaniline using sodium hydroxide (NaOH) as base at 0-5° C. to yield (3-chloro-4-methoxy phenyl)-(4,6-dichloro-[1,3,5]triazine-2-yl) amine (compound 101), which on reaction with cycloheptylamine in presence of NaOH under reflux gave 6-chloro-N-(3-Chloro-4-methoxyphenyl)-N′-cycloheptyl-[1,3,5]triazine-2,4-diamine (compound 133). Compound 133 on reaction with 1-methyl-(4-methylamino)piperidine yields, the final compound 137.
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:14].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>CN(C=O)C>[Si:22]([O:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:14])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: Cc1cc(C#N)cc(C)c1OCC(C)(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C#N)cc(C)c1OCC(C)(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.9 %

Procedure:
To a solution of 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile (2.90 g, 13.2 mmol) in anhydrous DMF (20 mL) was added imidazole (2.7 g, 40 mmol) and tert-butyidimethylsilylchloride (2.19 g, 14.6 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3 d. Water (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude compound was purified by column chromatography to give 4-[2-(tert-butyidimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (2.24 g, 54%). N-Butyl lithium (6.2 mL, 6.6 mmol, 1.6 M solution in hexanes) was added to a solution of 2,4-dimethoxy-6-N-dimethylbenzamide (0.9 g, 4.3 mmol) in anhydrous THF (10 mL) drop-wise at −10° C. over a period of 10 min under nitrogen. The stirring was continued at 0° C. for 1 h. The reaction mixture was cooled to −50° C. A solution of 4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (1.58 g, 4.73 mmol) in anhydrous THF (5 mL) was quickly added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The stirring was continued at room temperature for 1 h. An aqueous ammonium chloride solution (10 mL) was added followed by ethyl acetate (100 mL). The organic layer was separated, washed with water (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 0-5% methanol in CH2Cl2 as eluent) to give 3-{4-[2-(tert-butyidimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylphenyl}-6,8-dimethoxy-2H-isoquinolin-1-one (0.82 g, 37%), as a white solid.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:4]=1[NH2:5].Cl.C(OC1C=CC([NH:27]N)=CC=1)(=O)C1C=CC=CC=1>>[ClH:1].[F:2][C:3]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:4]=1[NH:5][NH2:27]
Reactant: Nc1ccc(F)cc1F
Reactant: NNc1ccc(OC(=O)c2ccccc2)cc1
Agent: Cl
Product: NNc1ccc(F)cc1F

Procedure:
The 2,4-difluorophenylhydrazine hydrochloride (m.p. 244°-246° C.) was prepared from 2,4-difluoroaniline hydrochloride using a procedure similar to that described in Example 5 for the preparation of 4-benzoyloxyphenylhydrazine hydrochloride.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:14]([O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][C:25]2[CH:26]=[CH:27][C:22]([O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])=[CH:23][CH:24]=2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccnn1Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2ccnn2Cc2ccccc2)cc1
Reaction time: 12 h
Yield: 44.7 %

Procedure:
A suspension of 1-benzyl-1H-pyrazol-5-amine (5.0 g), (4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)boronic acid (15 g), copper acetate (11 g), pyridine (12 mL) and molecular sieves 4A (10 g) in tetrahydrofuran (150 mL) was stirred for 12 hr. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (4.9 g, 45%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][CH2:7][CH2:8][C:9]1([CH3:16])[NH:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].[N-]=[N+]=[N-]>O.CN(C)C=O>[N:1]([CH2:6][CH2:7][CH2:8][C:9]1([CH3:16])[NH:13][C:12](=[O:14])[NH:11][C:10]1=[O:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(CCCCl)NC(=O)NC1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(CCCN=[N+]=[N-])NC(=O)NC1=O
Reaction time: 21 h

Procedure:
A solution of sodium azide (13 g, 0.2 mol) in water (100 ml) was added to a solution of 5-(3-chloropropyl)-5-methyl-2,4-imidazolidinedione (19.06 g, 0.1 mol) in dimethylformamide (900 ml.) and the mixture was kept at 75° C. for 21 hours. Iodometric determinations of azide ions indicated the consumption of the expected quantities of azide at that time. The mixture was concentrated to a syrup which was redissolved in chloroform (200 ml.), filtered, diluted with chloroform (500 ml.) and water (100 ml.), the chloroform phase was collected after equilibration and combined with four additional chloroform extracts which were dried (MgSO4) and concentrated. Crystalline 5-(3-azidopropyl)-5-methyl-2,4-imidazolidinedione was obtained from chloroform/petroleum ether (17.3 g, 88%), m.p. 104° C. after one recrystallization from the same solvent.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:22]3[CH2:26][CH2:27][CH2:28][C:21]=3[S:20][C:19]=2[N:18]=[C:17]1[CH3:29]>>[C:1]12([CH2:11][C:12]([NH:15][N:16]3[C:24](=[O:25])[C:23]4[C:22]5[CH2:26][CH2:27][CH2:28][C:21]=5[S:20][C:19]=4[N:18]=[C:17]3[CH3:29])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1nc2sc3c(c2c(=O)n1N)CCC3
Product: Cc1nc2sc3c(c2c(=O)n1NC(=O)CC12CC4CC(CC(C4)C1)C2)CCC3

Procedure:
1-Adamantaneacetyl chloride (BBB-SCI) and 5-amino-6-methyl-1,2,3,5-tetrahydro-8-thia-5,7-diaza-cyclopenta[a]inden-4-one (Matrix) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.57-1.77 (m, 14 H) 1.88-2.01 (m, 3 H) 2.03-2.19 (m, 2 H) 2.36 (s, 3 H) 2.38-2.44 (m, 2 H) 2.82-3.00 (m, 4 H) 10.82 (s, 1 H); MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH:5]=[CH:4]1.[CH3:27][S:28]([CH2:31][C:32](O)=[O:33])(=[O:30])=[O:29]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:24][CH2:25]2)[CH:5]=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Reactant: CS(=O)(=O)CC(=O)O
Agent: Cl
Product: CS(=O)(=O)CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1

Procedure:
The title compound, off-white solid (77 mg, 60%), MS (ISP) m/z=447.4 [(M+H)+], mp 201° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl-amine dihydrochloride (intermediate A) (115 mg, 0.29 mmol) and 2-methanesulfonyl-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6](=[O:15])[N:5]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:4](=[O:23])[CH:3]=1.[NH2:24][C:25]1[N:30]([CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:29](=[O:38])[N:28]([CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[C:27](=[O:46])[C:26]=1[N:47]=O.C([C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[C:54]([OH:56])=[O:55])=O>>[CH:32]1([CH2:31][N:30]2[C:25]([NH2:24])=[C:26]([NH2:47])[C:27](=[O:46])[N:28]([CH2:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[C:29]2=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1.[CH:17]1([CH2:16][N:5]2[C:4](=[O:23])[C:3]3[N:24]=[C:25]([C:52]4[CH:51]=[CH:59][CH:58]=[CH:57][C:53]=4[C:54]([OH:56])=[O:55])[NH:1][C:2]=3[N:7]([CH2:8][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:6]2=[O:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Reactant: Nc1cc(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Product: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Product: O=C(O)c1ccccc1-c1nc2c(=O)n(CC3CCCCC3)c(=O)n(CC3CCCCC3)c2[nH]1
Yield: 85 %

Procedure:
1,3-Bis(cyclohexylmethyl)-5,6-diaminouracil was prepared as in part (d) of Example 1 by reduction of 1, 6-amino 1,3-bis(cyclohexylmethyl)-5-nitrosouracil (2.00 g) and immediately condensed with 3-formylbenzoic acid (Aldrich, 1.424 g) by the method of J. Perumattam (Synthetic Commun. 1989, 19: 3367-3370) to give title compound as an off-white solid (2.27 g, 85%), m.p. >250° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1)[CH3:25]>>[CH:24]([C:26]1[CH:30]=[C:29]([CH2:31][NH:32][C:20]([C:10]2[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:21])[O:28][N:27]=1)([CH3:25])[CH3:23]
Reactant: CC(C)c1cc(CN)on1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Product: CC(C)c1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)nn2)on1

Procedure:
The title compound was synthesized in analogy to Example 41, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and 3-(1-methylethyl)-5-isoxazolemethanamine (CAN. 543713-30-0) as starting materials, LC-MS (UV peak area/ESI) 100.0%, 455.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.O=[C:23]([CH2:27][CH3:28])[C:24]([OH:26])=[O:25]>C(O)C>[CH3:28][C:27]1[C:15]([C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([C:11]([F:21])([F:20])[F:10])[CH:13]=2)=[N:6][C:5]2[C:7]([C:23]=1[C:24]([OH:26])=[O:25])=[CH:8][CH:9]=[C:3]([S:2][CH3:1])[CH:4]=2
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CCC(=O)C(=O)O
Reactant: CSc1cccc(N)c1
Solvent: CCO
Product: CSc1ccc2c(C(=O)O)c(C)c(-c3cccc(C(F)(F)F)c3)nc2c1
Temperature: 25 °C
Yield: 16.4 %

Procedure:
A solution of 3-(methylthio)aniline (1.392 g, 10.0 mmol) and 3-(trifluoromethyl)benzaldehyde (1.741 g, 10.0 mmol) in ethanol (30 mL) was stirred at reflux for 1 h. 2-Oxobutanoic acid (1.021 g, 10.0 mmol) was added portionwise. The reaction mixture was stirred at reflux for additional 3 h, cooled to room temperature, and stirred overnight. The mixture was filtered and the solid material collected to give 3-methyl-7-(methylthio)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.62 g, 16% yield). MS (m/z) 378.0 (M+H+).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[C:15]1([CH3:27])[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH2:25]O)(=[O:23])=[O:22])=[CH:17][CH:16]=1>O=S(Cl)Cl>[C:15]1([CH3:27])[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH2:25][O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:13]([CH3:14])=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[CH:6]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(S(=O)(=O)CCOC(=O)c2ccc(C)c(S(=O)(=O)Cl)c2)cc1
Yield: 99.5 %

Procedure:
A heterogeneous mixture of 3-chlorosulfonyl-4-methylbenzoic acid (11.7 g, 50.0 mmol) in 18 mL of SOCl2 was refluxed for 3 h. After the excess of SOCl2 was removed, the residual brown oil was dissolved in 50 mL of CH3CN, and then 2-(p-tolylsulfonyl)ethanol (9.4 g, 47.0 mmol, 0.95 eq.) was added. The mixture was heated to reflux temperature for 24 h. Thereafter most of CH3CN was removed, the resulting oil was purified by short column chromatography (CH2Cl2 to 1% MeOH in CH2Cl2) to give a light brown oil, which solidified on standing. The solid was dried further under vacuum to yield 19.5 g (99%) of 3-chlorosulfonyl-4-methylbenzoic acid 2-(p-tolylsulfonyl)ethyl ester (Intermediate 49).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:11][O:12][CH2:13][CH2:14][Br:15]>>[BrH:15].[C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:14][CH2:13][O:12][CH3:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: CC(C)(C)c1cnc(N)s1
Product: Br
Product: COCCn1cc(C(C)(C)C)sc1=N

Procedure:
A mixture of Example 136A and commercially available 2-bromoethyl methyl ether (Aldrich) was processed using the method described in Example 46A to afford the title compound. MS (ESI+) m/z 215 (M+H)+.
Reaction SMILES: Cl[CH:2]1[N:5]([C:6](=[C:11]2[S:15][C:14]([C:17]([F:20])([F:19])[F:18])([OH:16])[CH2:13][S:12]2)[C:7]([O:9][CH3:10])=[O:8])[C:4](=[O:21])[CH2:3]1>C(Cl)Cl.C(N(CC)CC)C>[OH2:8].[F:18][C:17]([F:20])([F:19])[C:14](=[O:16])[CH2:13][S:12][C:11]1[S:15][C@@H:2]2[CH2:3][C:4](=[O:21])[N:5]2[C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(=C1SCC(O)(C(F)(F)F)S1)N1C(=O)CC1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(SCC(=O)C(F)(F)F)S[C@@H]2CC(=O)N12
Product: O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sulphuryl chloride (59.7 mg, 35.8 μl, 0.442 mmole) was added to a solution of methyl 2-(4-methylthio-2-azetidinon-1-yl)-2-(4-trifluoromethyl-4-hydroxy-1,3-dithiolan-2-ylidene)acetate (166 mg, 0.442 mmole) in methylene chloride (3 ml) at room temperature, with stirring. After this addition, the solution was stirred for 3 minutes and then the solvent was distilled off to give the crude methyl 2-(4-chloro-2-azetidinon-1-yl)-2-(4-trifluoromethyl-4-hydroxy-1,3-dithiolan-2-ylidene)acetate. This 4-chloroazetidinone compound was dissolved in methylene chloride (3 ml) without purification, and triethylamine (185 μl) was added thereto, after which the mixture was stirred at room temperature for 2 hours. The solvent was distilled off from the reaction mixture under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulphate. The solvent was distilled off under reduced pressure and the residue was purified by preparative thin layer chromatography (eluent: a 3:2 by volume mixture of benzene and ethyl acetate), to give 63 mg of the desired product as crystals.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:32][C:33]1[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][C:34]=1[C:35](N(OC)C)=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35](=[O:36])[C:34]3[CH:41]=[CH:42][CH:43]=[C:44]([CH3:45])[C:33]=3[Cl:32])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CON(C)C(=O)c1cccc(C)c1Cl
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1cccc(C)c1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (984 mg, 2.0 mmol) in THF (10 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF, 2.5 mL, 5.0 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of 2-chloro-N-methoxy-3,N-dimethyl-benzamide (852 mg, 4.0 mmol) at 0° C. The mixture was stirred at room temperature for 3 h, quenched with saturated aqueous NH4Cl solution (5 mL), and extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. The residue was column purified (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-[5-chloro-2-(2-chloro-3-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (586 mg) in 52% yield. ESMS m/z (relative intensity): 534.9 [(M-32+H)]+ (70), 588.9 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cccc(Cl)c2Cl)c1Br
Yield: 75 %

Procedure:
2,3-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,3-dichlorobenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 166-169° C., yield 75%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([CH2:19][O:20][CH2:21][C:22]3([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)[CH2:27][CH2:26][N:25]([C:28](OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl>[CH3:28][N:25]1[CH2:26][CH2:27][C:22]([CH2:21][O:20][CH2:19][C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=2)([C:35]2[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccncc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A flask was charged with tert-butyl 4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(pyridin-4-yl)piperidine-1-carboxylate (50 mg, 0.091 mmol) and trifluoroacetic acid (1 mL, 13.0 mmol) in dichloromethane (5 mL) at 0° C. under nitrogen. After 20 min the solvent was evaporated under reduced pressure and the resulting residue dried overnight. The resulting oil was dissolved in dichloromethane (5 mL) and treated with formaldehyde (37 wt. % solution in water, 1.0 mL) at 0° C. After 20 min, the reaction was treated with sodium triacetoxyborohydride (77 mg, 0.363 mmol). The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting residue purified via preparative HPLC. The solvent was evaporated to afford 21 mg (50%). Mass Spec: 466.10 (MH)+. LC tr=2.325 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min).
Reaction SMILES: [CH3:1][O:2][P:3]([O:6]C)[O:4][CH3:5].[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>Cl.C(OCC)(=O)C>[CH3:1][O:2][P:3]([CH2:14][C:13]1[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1)(=[O:6])[O:4][CH3:5]
Reactant: COP(OC)OC
Reactant: CSc1ccc(CCl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COP(=O)(Cc1ccc(SC)cc1)OC
Temperature: 140 °C
Reaction time: 18 h

Procedure:
To trimethylphosphite (8.6 g, 70 mmol) at 140° C. was added 4-methylthiobenzyl chloride (10 g, 58 mmol). The resulting mixture was stirred at 140° C. for 18 h, cooled at 21° C. then diluted with HCl 10% and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (eluting with ethyl acetate) provided the (4-methylsulfanyl-benzyl)-phosphonic acid dimethyl ester compound.
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.S(=O)(=O)(O)O.[C:20]1([OH:30])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(O)C>C1CCCCC1>[C:5]12([C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]=3[OH:30])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: Oc1cccc2ccccc12
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Solvent: CCO
Product: Oc1c(C23CC4CC(CC(C4)C2)C3)ccc2ccccc12
Yield: 20.7 %

Procedure:
A three-necked 100 ml flask is charged with 2.7 g of 1-acetoxyadamantane and 5 ml of cyclohexane in a nitrogen atmosphere. After complete dissolution, there are introduced 1.4 g of concentrated sulfuric acid. In a single portion there is added a suspension of 2 g of 1-naphthol in 15 ml of cyclohexane and one agitates for 45 minutes. 20 ml of ethanol are added and the mixture is filtered. One washes the residue with ethanol and with water and dries on the filter. After recrystallization with cyclohexane, one obtained 0.8 g of the desired product melting at 209.2°-209.6° C.