Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([CH3:36])[C:8]2[C:9]([CH3:35])=[C:10]([CH:24]=[C:25]([C:27]3[CH:28]=[N:29][C:30]([CH:33]=O)=[CH:31][CH:32]=3)[CH:26]=2)[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][NH:38][CH3:39].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([N:7]([CH3:36])[C:8]2[C:9]([CH3:35])=[C:10]([CH:24]=[C:25]([C:27]3[CH:28]=[N:29][C:30]([CH2:33][N:38]([CH3:39])[CH3:37])=[CH:31][CH:32]=3)[CH:26]=2)[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)nc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a stirred solution of compound 3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methylbenzamide (1 equiv.) and dimethylamine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 8 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the title compound (0.017 g, 11% yield). LCMS: 516.35 (M+1)+; HPLC: 90.32% (@254 nm) (Rt; 4.203; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.78 (s, 1H), 8.18 (t, 1H), 8.05 (d, 1H, J=6 Hz), 7.50 (d, 1H, J=8.4 Hz), 7.34 (s, 1H), 7.20 (s, 1H), 5.86 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.75 (bs, 2H), 2.75 (m, 1H), 2.65 (s, 3H), 2.34 (bs, 6H), 2.22 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.69-1.71 (m, 4H), 1.54-1.56 (m, 2H), 1.42-1.45 (m, 2H), 1.08-1.23 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:44]=[CH:45][N:46]([CH3:48])[CH:47]=2)=[CH:38][C:37]=1[CH3:49].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:49])=[CH:38][C:39]([C:43]6[N:44]=[CH:45][N:46]([CH3:48])[CH:47]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2cn(C)cn2)cc(C)c1Cl
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cn(C)cn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(4-chloro-3,5-dimethyl-phenyl)-1-methyl-imidazole following a procedure analogous to that described in Step 5 of Intermediate 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]([F:25])([F:24])[C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[C:14](Cl)=[O:15].Cl.[OH-].[Na+]>ClCCl.N1C=CC=CC=1>[F:9][C:10]([F:24])([F:25])[C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=1)[C:14]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:15]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
2-Aminophenol (120 mg, 1.1 mmol) was dissolved in dichloromethane (5 mL). A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (300 mg, 1.1 mmol) in dichloromethane (3 mL) and pyridine (0.5 mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (5 mL), added dropwise 2 N sodium hydroxide (0.1 mL, 0.2 mmol), and stirred at room temperature for 30 minutes. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (288 mg, 73.6%) as a light pink crystal.
Reaction SMILES: C(OC(N1CCC(NCC2C=CC=CC=2)C(O)C1)=O)(C)(C)C.[C:23]([OH:32])(=[O:31])[C@H:24]([C@@H:26]([C:28]([OH:30])=[O:29])[OH:27])[OH:25]>C(#N)C.O>[C:23]([OH:32])(=[O:31])[CH:24]([CH:26]([C:28]([OH:30])=[O:29])[OH:27])[OH:25]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(O)C1
Solvent: CC#N
Solvent: O
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
Concentrate the mother liquor of Preparation 77 to obtain enantio enriched (3S,4S)-3-hydroxy-4-phenethyl-piperidine-1-carboxylic acid tert-butyl ester L-(+)-tartaric acid salt (0.0377 mol, 17.2 g). Add 4% aqueous potassium carbonate solution (500 mL) and stir for 30 min. Extract the free amine with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the free amine (11.0 g). Heat a mixture of 4-benzylamino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.0361 mol, 11.0 g) and D-(−)-tartaric acid (0.0397 mol, 5.97 g, 1.1 equiv.) in acetonitrile/water (20:1) (100 ml) at 75° C. for 4 h. Concentrate the reaction mixture under reduce pressure to obtain crude tartaric acid salt. Crystallize the residue from acetonitrile three times. Filter the crystals and dry under vacuum to obtain the title compound (14.8 g, 90%). HPLC (Column: Chiralcel OD-H (250 mm*4.6 mm); solvent system: isopropanol/0.1% triethylamine in hexanes (8:92); flow rate: 0.800 ml/min; wavelength: 258 nm): 96.4% ee. tR 8.714 min. tR for opposite enantiomer ((3R,4R)-3-Hydroxy-4-phenethyl-piperidine-1-carboxylic acid tert-butyl ester.L-(+)-tartaric acid salt) 9.502 min.
Reaction SMILES: C(O[C:4]1[CH:5]=[N:6][C:7]([C:10]2[CH:34]=[CH:33][CH:32]=[CH:31][C:11]=2[C:12]([NH:14][C@H:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[NH:20][C:21]2C=N[C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)=[O:13])=[N:8][CH:9]=1)C.Cl.[F:36][C:37]1C(N[C@H]2CCC[C@@H]2N)=NC=C(C(F)(F)F)[CH:42]=1.N1C=CC=NC=1C1C=CC=CC=1C(O)=O>>[F:36][C:37]1[C:21]([NH:20][C@H:16]2[CH2:17][CH2:18][CH2:19][C@@H:15]2[NH:14][C:12](=[O:13])[C:11]2[CH:31]=[CH:32][CH:33]=[CH:34][C:10]=2[C:7]2[N:6]=[CH:5][CH:4]=[CH:9][N:8]=2)=[N:22][CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:42]=1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F
Reactant: CCOc1cnc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)nc1
Agent: Cl
Agent: O=C(O)c1ccccc1-c1ncccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ccccc1-c1ncccn1

Procedure:
Prepared according to the procedure for 2-(5-Ethoxypyrimidin-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 135) from (1S,2S)-1-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 34: 263 mg, 1.00 mmol) and 2-(pyrimidin-2-yl)benzoic acid (CAS number 400892-62-8; 200 mg, 1.00 mmol) except after the reaction was complete it was concentrated in vacuo and the residue was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) and then was purified by reverse phase column chromatography (C18 silica, 0-100% water (0.05% ammonia)/methanol) and triturated with DCM/petrol. The product was further purified by reverse phase column chromatography (C18 silica, 0-100% water (0.1% ammonia)/acetonitrile to afford the title compound.
Reaction SMILES: O[CH:2]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:7][CH:6]=1)[CH2:3][CH3:4].C1CCN2C(=NCCC2)CC1.CS(Cl)(=O)=O>C(Cl)Cl>[CH:2]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:7][CH:6]=1)=[CH:3][CH3:4]
Reactant: CCOC(=O)c1ccc(C(O)CC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC=Cc1ccc(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 24 h

Procedure:
To a solution of ethyl 5-(1-hydroxypropyl)-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4yl-methyl]pyrrole-2-carboxylate (2.0 g, 3.0 mmol) in methylene chloride (100 ml) at 0° C. was added DBU (2.0 ml, 12.0 mmol) followed by methanesulfonyl chloride (0.7 ml, 9.0 mmol). The mixture was stirred overnight at room temperature whereupon an additional aliquot of DBU (2.0 ml) and methanesulfonyl chloride (0.7 ml) were added and the mixture was allowed to stir an additional 24 hours. The mixture was poured into a separatory funnel and washed with water (3×50 ml) and saturated aqueous sodium bicarbonate solution (50 ml) before being dried (MgSO4), filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (150 g, 10-30% EtOAc/hexanes) to give the title compounds as a mixture of cis/trans isomers (ca. 1/4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:56][NH:57][CH2:58][C:59]1[CH:71]=[CH:70][C:62]([CH2:63][N:64]2[CH2:68][CH2:67][CH:66]([OH:69])[CH2:65]2)=[CH:61][CH:60]=1>C(Cl)Cl>[OH:69][CH:66]1[CH2:67][CH2:68][N:64]([CH2:63][C:62]2[CH:70]=[CH:71][C:59]([CH2:58][N:57]([CH3:56])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:24])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:23])=[CH:60][CH:61]=2)[CH2:65]1
Reactant: CNCc1ccc(CN2CCC(O)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(O)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-furan-3-carboxylic acid (35 mg, 0.10 mmol), EDCI (27 mg, 0.14 mmol), HOBt (20 mg, 0.15 mmol), DIPEA (0.03 mL, 0.20 mmol), 1-(4-methylaminomethyl-benzyl)-pyrrolidin-3-ol hydrochloride (30 mg, 0.10 mmol) and DCM (10 mL).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:16][CH:10]([CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:1]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[C:17](=[O:25])[N:2]=2)[N:8]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: COC(=O)c1ccccc1S
Reactant: CCOC(=O)C(C)Cc1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)Cc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 69.8 %

Procedure:
Ethyl 3-(6-cyano-2-pyridyl)-2-methylpropionate (0.79 g, 3.6 mmol) and methyl thiosalicylate (1.2 g, 7.3 mmol) were dissolved in toluene (3 ml), and triethylamine (0.76 ml, 5.4 mmol) was added thereto. The reaction mixture was refluxed for 21 hrs and subjected to a silica gel (70 g) column chromatography. The fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected and concentrated to give the titled compound (0.89 g, 70%) as white crystals.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1.[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17]>O1CCCC1>[CH2:16]([O:15][C:14](=[O:18])[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[N:8]=1)[CH3:17]
Reactant: CCOC(=O)OCC
Reactant: Cc1cccc(Cl)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(Cl)n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
n-Butyl lithium (23% in hexane, 13.2 mL, 47.3 mmol) was added dropwise to a cold solution (−70° C.) of 2-chloro-6-methyl-pyridine (5.0 g, 39.4 mmol) in tetrahydrofuran (30 mL) and stirred for 30 min at −70° C. Diethyl carbonate (5.75 mL, 47.3 mmol) was added slowly and the reaction mixture stirred for 30 min at −70° C. before warning to room temperature and stirring for a further 1 h. The reaction mixture was quenched into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate, filtered and concentrated to yield the crude compound which was purified by column chromatography over silica gel (100-200 mesh), using 9% ethyl acetate in petroleum ether as eluent, to afford (6-chloro-pyridin-2-yl)-acetic acid ethyl ester (2.21 g, 28%) as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:9]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C:23](=[N:27][OH:28])[CH2:22][CH2:21]4)[CH:8]=2)[CH2:3][CH2:2]1.[CH3:29][O:30][CH2:31][CH:32]=O.C([BH3-])#N.C[NH+](C)C.C(O)(=O)C>CO>[CH3:29][O:30][CH2:31][CH2:32][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[O:11][C:10]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)=[C:9]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C:23](=[N:27][OH:28])[CH2:22][CH2:21]4)[CH:8]=2)[CH2:5][CH2:6]1
Reactant: COCC=O
Reactant: ON=C1CCc2cc(-c3cc(C4CCNCC4)oc3-c3ccncc3)ccc21
Agent: C[NH+](C)C
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: COCCN1CCC(c2cc(-c3ccc4c(c3)CCC4=NO)c(-c3ccncc3)o2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
A mixture of the product of Example 31 (0.149 g, 0.4 mmol), methoxy-acetaldehyde (0.037 g, 0.5 mmol) (E. M. Acton et al, J. Med. Chem., 1986, 29, 2074) and polymer bound trimethylammonium cyanoborohydride (200 mg, 0.8 mmol, 4 mmol/g) in methanol (5 ml) containing acetic acid (0.2 ml) was stirred at room temperature for 24 hours. The reaction mixture was then filtered and the resin washed with methanol. The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography eluting with a 1:9:90 mixture of 0.880 ammonia solution:ethanol:chloroform to give the title compound (0.103 g, 60%); MS(ES+) m/e 432 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:5]=2[N:6]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:5]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cc(Br)ccc2s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2cc(Br)ccc2s1
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-5-bromobenzothiazole (32.0 g), N-bromosuccinimide (25.1 g), carbon tetrachloride (700 ml) and a catalytic amount of benzoyl peroxide (0.2 g) was refluxed under irradiation by an UV lamp for 14 hours. The reaction mixture was cooled to room temperature, filtered to remove the precipitated succinimide and the filtrate was evaporated to dryness. The resulting solid was chromatographed over silica gel to obtain the product (7.8 g; m.p. 107° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:14]1[CH2:19]O[CH2:17][O:16][CH2:15]1.CS(O)(=O)=O>C(O)(=O)C.O>[N:13]1([S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH2:17][O:16][CH2:15][O:14][CH2:19]1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C1OCOCO1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2COCOC2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34.8 %

Procedure:
4-Nitrobenzenesulphonamide (2.02 g, 10 mmol) was added to a solution of 1,3,5-trioxane (1.96 g, 20 mmol) in acetic acid (5 ml). The mixture was stirred for 5 minutes and methanesulphonic acid (10 ml) was added slowly. The mixture was then stirred at 35° C. for 20 minutes, cooled to 0° C., diluted with water and extracted with ethyl acetate. The combined extracts were washed twice with water and twice with 5% aqueous sodium hydrogen carbonate solution, and then dried and the volatiles removed by evaporation. The residue was recrystallized from ethanol to give the title compound (955 mg, 35% yield). NMR: 4.87 (s, 2H), 5.30 (s, 4H), 8.20 (d, 2H), 8.42 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])[C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:35][CH:34]=3)[CH2:20][CH2:21]2)=[O:33])=[CH:31][CH:30]=1
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(NS(C)(=O)=O)cc1
Yield: 48.4 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-methoxyphenyl)benzamide (50.0 mg, 0.11 mmol) and methanesulfonyl chloride (0.025 ml, 0.316 mmol), the procedure of Inventive Example 94 was repeated to obtain 29.5 mg (50.7%) of the title compound in a colorless amorphous form.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([O:12][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)c(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97 %

Procedure:
A mixture of 2,3-difluoro-6-nitrophenol (15.1 g), benzyl bromide (10.8 mL) and potassium carbonate (11.9 g) in N,N-dimethylformamide (60 mL) was stirred at room temperature for 15 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with successively water and brine, dried (MgSO4), filtered, and concentrated to give the title compound (22.1 g, 97%) as a light yellow solid. MS 264 (MH+).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[CH:16][CH:15]=1>CN(C=O)C>[CH2:25]([O:24][CH:20]([O:21][CH2:22][CH3:23])[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:15][CH:16]=1)[CH3:26]
Reactant: CCOC(OCC)c1ccc(CBr)cc1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(OCC)c1ccc(CC(C(=O)OC)C(=O)OC)cc1
Reaction time: 1 h

Procedure:
To a solution of dimethyl malonate (4.96 mL, 43 mmol) in DMF (80 mL) was added NaH (1.3 g 80% in mineral oil). After 20 min. a solution of 1-(bromomethyl)-4-(diethoxymethyl)benzene (2.37 g, 8.7 mmol) in DMF (5 mL) was added via double-tipped needle. After 1 h at 0° C., the reaction was quenched by the addition of saturated NH4Cl solution. The product was extracted with Et2O and the organic layer wash washed with H2O and brine. After drying (MgSO4) and filtration, the solvent was removed under vacuum. The crude was purified by flash chromatography (1:10 EtOAc/hexane) to yield a colorless oil (1:42 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)=[O:15])=[CH:8][CH:7]=1)=[O:4].C(OC(N1CCNCC1)=O)C.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([C:19]2[CH:20]=[CH:21][C:16]([C:14](=[O:15])[CH2:13][CH2:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:24])([F:23])[F:1])=[CH:7][CH:8]=3)=[CH:17][CH:18]=2)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:37])[CH3:38]
Reactant: O=C(CCc1ccc(NC(=O)C(F)(F)F)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCOC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)CCc3ccc(NC(=O)C(F)(F)F)cc3)cc2)CC1
Yield: 64 %

Procedure:
Similarly following the procedure described in Example 5, but substituting 3-(4-amino-phenyl)-1-(4-fluorophenyl)propan-1-one with 2,2,2-trifluoro-N-{4-[3-(4-fluorophenyl)-3-oxopropyl]phenyl}acetamide, and 1-ethoxycarbonylpiperazine with 1-tert-butoxycarbonylpiperazine in Example 5a, gave the title compound as a beige colored solid (64%). The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)CO
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)COC(=O)c1ccc(Cl)nc1
Temperature: 80 °C
Yield: 92 %

Procedure:
To a solution of 10 g (56.8 mmol) of 6-chloropyridine-3-carbonyl chloride in 100 mL of anhydrous toluene are added under argon, at room temperature, 15 g (170.4 mmol) of 2,2-dimethylpropanol. The reaction medium is then heated at 80° C. for 6 hours. After cooling to room temperature, the medium is concentrated and the residue obtained is taken up in 800 mL of EtOAc, washed successively with water (2×200 mL), with saturated NaHCO3 solution (2×200 mL) and with brine (100 mL), dried over Na2SO4, then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of from 0 to 5% EtOAc. 11.9 g of 2,2-dimethylpropyl 6-chloropyridine-3-carboxylate are obtained in the form of a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([OH:9])=[N:6][C:7]=1[CH3:8].FS([C:15]([F:20])([F:19])C(O)=O)(=O)=O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([O:9][CH:15]([F:20])[F:19])=[CH:4][C:3]=1[CH3:10]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: Cc1cc(O)nc(C)c1Br
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(OC(F)F)nc(C)c1Br

Procedure:
A mixture of 5-bromo-4,6-dimethylpyridin-2-ol obtained in Preparation Example 23(1) (500 mg), 2-(fluorosulfonyl)difluoroacetic acid (0.307 mL) and sodium sulfate (70.3 mg) was stirred in an acetonitrile solvent (10 mL) at room temperature for 3.5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was then concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 10%) to give the title compound (68.6 mg).