Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[F:13][CH:14]([F:24])[O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.FC(F)(F)C1C=C(Cl)C=CC=1C(O)C1C=CC=CC=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:20]([OH:21])[C:19]1[CH:22]=[CH:23][C:16]([O:15][CH:14]([F:13])[F:24])=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1ccccc1[Mg]Br
Reactant: O=Cc1ccc(OC(F)F)cc1
Agent: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Product: OC(c1ccc(OC(F)F)cc1)c1ccccc1C(F)(F)F
Yield: 63.9 %

Procedure:
This material was prepared from 2-(trifluoromethyl)phenylmagnesium bromide (16 mmol) and 4-(difluoromethoxy)benzaldehyde (2.09 mL, 15 mmol) using the procedure described for compound (96). The product was obtained as an amber gum (3.05 g, 64%).
Reaction SMILES: [C:1]([S:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[C:1]([S:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[S:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)SC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)SC(=S)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of S-t-butyl thiobenzoate (1.94 g, 0.01 mol) and Lawesson's reagent (2.43 g, 0.006 mol) in anhydrous toluene (10 mL) was refluxed for 25 hours. After cooling to room temperature, the reaction mixture was concentrated and the residue subjected to column chromatography (Kieselgel-60, 70-230 mesh, petroleum spirit/diethyl ether 19:1) The title compound was obtained as an oil, 1.37 g (65.5%). 1H-nmr (CDCl3) d (ppm): 1.69 (s, 9H, 3×CH3), 7.36 (m, 2H, meta-ArH), 7.50 (m, 1H, para-ArH) and 7.88 (d, 2H, ortho-ArH). 13C-nmr (CDCl3) d (ppm): 28.2, 52.2, 126.6, 128.1, 131.7 and 147.0. The signal due to C═S (d>220.0 ppm) was beyond the frequency range of the spectrum.
Reaction SMILES: [CH2:1]([C:6]1([C:23]#[C:24][C:25]2([OH:36])[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:27][CH2:26]2)[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:37]([CH:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)[CH2:38][CH3:39]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:37]([CH:40]1[CH2:45][CH2:44][CH:43]([C:46]([O:36][C:25]2([C:24]#[C:23][C:6]3([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10][CH:9]([CH:12]4[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]4)[CH2:8][CH2:7]3)[CH2:26][CH2:27][CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:29][CH2:30]2)=[O:47])[CH2:42][CH2:41]1)[CH2:38][CH3:39]
Reactant: CCCC1CCC(C(=O)O)CC1
Reactant: CCCCCC1CCC(C2CCC(C#CC3(O)CCC(CCCCC)CC3)(CCCCC)CC2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCC1CCC(C2CCC(C#CC3(OC(=O)C4CCC(CCC)CC4)CCC(CCCCC)CC3)(CCCCC)CC2)CC1
Reaction time: 8 h

Procedure:
1.10 g of 1-(4,4′-dipentylbicyclohexyl-4-ylethynyl)-4-pentylcyclohexanol and 0.394 g of 4-propylcyclohexanecarboxylic acid are dissolved in 4 ml of dichloromethane, and 0.283 g of 4-(dimethylamino)pyridine is added. 5.569 g of N,N-dicyclohexylcarbodiimide dissolved in 3 ml of dichloromethane are then added dropwise to the reaction mixture. The mixture is stirred overnight and subjected to conventional work-up, giving 1-(4,4′-dipentylbicyclohexyl-4-ylethynyl)-4-pentylcyclohexyl 4-propylcyclohexanecarboxylate (C 66 SmB 171 I, Δε −0.02).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=O)C.[O:28]=[S:29]1(=[O:43])[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)[CH2:31][CH2:30]1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[O:43]=[S:29]1(=[O:28])[CH2:30][CH2:31][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:3])=[N:40][CH:41]=2)[CH2:33][CH2:34]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cn1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 5-(1,1-dioxothiomorpholin-4-ylmethyl)-pyridin-2-ylamine (Step 104.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 585.9 [M+H]+; tR=3.96 min (System 1); TLC: Rf=0.39 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]#[N:9])[NH:5][CH:6]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]#[N:9])[NH:5][C:6]=1[C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: N#CCc1cc(Br)c[nH]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Product: N#CCc1cc(Br)c(C(=O)c2ccc(Cl)cc2)[nH]1

Procedure:
A solution of 0.90 g (0.005 mole) of 4-bromopyrrole-2-acetonitrile and 0.87 g of p-chlorobenzoyl chloride (0.0005 mole) in 10 ml of methylene chloride is chilled in a dry-ice acetone bath to -30° C and is stirred while treated with 0.58 mg of anhydrous stannic chloride (0.005 mole). An orange solid precipitates. The reaction mixture is allowed to warm slowly over 1 hour to 5° C and is poured and scraped into ice-water. The whole is extracted with chloroform and the combined organic layers are washed successively with aqueous N,N-dimethylamino-1,3-propanediamine, 3N hydrochloric acid, aqueous sodium bicarbonate solution, and brine, and are dried over sodium sulfate. The viscous oil which results from evaporation of the solvent is vacuo is chromatographed on silica gel (Mallinkrodt CC-7) packed with benzene and eluated with a benzene-ether gradient. The desired material is eluted with 15% ether in benzene and recrystallized from methanol to give 4-bromo-5-(p-chlorobenzoyl)pyrrole-2-acetonitrile as a beige solid; m.p. 185°-186° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:9])=[N:6][C:7]=1[NH2:8].O.[CH:23]([CH:25]=O)=O>C1(C)C=CC=CC=1>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][CH2:16][NH:15][C:3]1[C:2]2[C:7](=[N:8][CH:23]=[CH:25][N:1]=2)[N:6]=[C:5]([CH3:9])[C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=CC=O
Reactant: CCOC(=O)c1c(C)nc(N)c(N)c1NCCCN(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(C)nc2nccnc2c1NCCCN(C)C

Procedure:
3 g. of crude 5,6-diamino-4-[[3-(dimethylamino)propyl]-amino]-2-methylpyridine-3-carboxylic acid, ethyl ester and 1 g. of glyoxal-monohydrate are refluxed in 20 ml. of toluene for 4 hours. After evaporation of the solvent and addition of a small amount of charcoal, the residue is extracted with 50 ml. of boiling gasoline. On cooling 8-[[3-(dimethylamino)propyl]amino]-6-methylpyrido[2,3-b]pyrazine-7-carboxylic acid, ethyl ester precipitates, m.p. 42°-44° (gasoline).
Reaction SMILES: [NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1.[C:19]([O-])(=O)C.C[NH3+].CS(C)=O>CO>[CH3:19][NH:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Reactant: CC(=O)[O-]
Agent: C[NH3+]
Solvent: CS(C)=O
Solvent: CO
Product: CN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 58 %

Procedure:
A mixture of 2.53 gm (0.01 mol) of (E)-2-[(amino)phenylmethylene]-benzo[b]thiophen-3(2H)-one, 40.0 gm (0.44 mol) of methylammonium acetate and 10 ml of dimethylsulfoxide was heated for 5 hours to a reaction temperature of 130° to 140° C. Working up was in accordance with Example 65, and the desired compound, m.p. 154°-155° C. (methanol), was obtained with a yield of 58% of theory. The product was identical to that of Example 2 according to elemental analysis and thin-layer chromatogram.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product of Example 22A (3.7 g, 13.6 mmoles) in tetrahydrofuran (110.0 ml) and methanol (37.0 ml) was added 2 N sodium hydroxide (19.0 ml) and the solution was stirred at ambient temperature for about 16 hours. The reaction mixture was concentrated in vacuum down to the water layer, was cooled with an ice bath, and was acidified by addition of 2N hydrochloric acid. The precipitate was filtered off and was dried in vacuum to provide the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1.C(N(CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[O:40]=[C:41]1[CH2:46][S:45][C:44]2[CH:47]=[CH:48][C:49]([C:51](O)=[O:52])=[N:50][C:43]=2[NH:42]1>CN(C=O)C>[CH3:1][N:2]([CH2:3][CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1)[C:51]([C:49]1[CH:48]=[CH:47][C:44]2[S:45][CH2:46][C:41](=[O:40])[NH:42][C:43]=2[N:50]=1)=[O:52]
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(CC1CCN(C(=O)OC(C)(C)C)C1)C(=O)c1ccc2c(n1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
To a solution of 1,1-dimethylethyl 3-[(methylamino)methyl]-1-pyrrolidinecarboxylate (153 mg, 0714 mmol) in DMF (2 mL) were added triethylamine (0.1 mL, 0.714 mmol) followed by DPPA (0.154 mL, 0.714 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (150 mg, 0.714 mmol). After stirring at room temperature for 24 h, the solution was partitioned between ethyl acetate and K CO solution (5% in H O). The aqueous layer was extracted several times with ethyl acetate. The organic fractions were combined, dried over MgSO, concentrated and purified with column chromatography (silica, 0-5% MeOH in DCM) to provide the title compound as an off-white solid (240 mg, 83%): LC/MS (ES) m/e 407 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:35]1[N:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1>>[CH3:1][O:2][CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:35]3[N:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cc1ccc(Cl)nn1
Reactant: COC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Product: COC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccc(C)nn3)cc2)C(=O)O1

Procedure:
The title compound was prepared from (R)-6-(methoxymethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 3-chloro-6-methylpyridazine following a procedure analogous to that described in Example 14. Mass spectrum (ESI+): m/z=418 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:48]=[CH:47][CH:46]=[CH:45][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH:12]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:13]1)#[N:2].C([Sn]([N:62]=[N+:63]=[N-:64])(CCCC)CCCC)CCC>CC1C=CC=CC=1C>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][O:28][CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH:17]2[CH2:16][CH2:15][N:14]([C:38]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[CH2:13][CH:12]2[O:11][CH2:10][CH2:9][O:8][C:7]2[CH:45]=[CH:46][CH:47]=[CH:48][C:6]=2[CH2:5][CH2:4][CH2:3][C:1]2[NH:64][N:63]=[N:62][N:2]=2)=[CH:19][CH:20]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCCC#N)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCCc2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.40 g of tert-butyl 3-{2-[2-(3-cyanopropyl)phenoxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 55a) and 0.34 ml of tributyltin azide in 8 ml of o-xylene is stirred at 145° C. over 19 hours. The reaction mixture is concentrated by evaporation, the residue is taken up in 12.5 ml of 40:10:1 dichloromethane-methanol-25% conc. ammonia and stirred at room temperature over 1 hour. The mixture is concentrated by evaporation. The title compound is obtained as a yellow resin from the residue by means of flash chromatography (SiO2 60F). Rf=0.65 (40:10:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.61.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].N([C:15]1[NH:16][CH2:17][CH2:18][N:19]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1>CC(C)=O>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH:4][C:15]1[NH:19][CH2:18][CH2:17][N:16]=1
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: NCC(O)c1ccccc1
Solvent: CC(C)=O
Solvent: Cc1ccccc1C
Product: OC(CNC1=NCCN1)c1ccccc1
Temperature: 160 °C

Procedure:
A mixture of 15.8 parts β-hydroxy-phenethyl-amine, 13 parts 2-nitramino-2-imidazoline and 8 parts xylene is stirred and heated for 30 minutes at 160°C. (oil-bath). After cooling the reaction mixture to a temperature of about 70°C., there are added 40 parts acetone. The whole is filtered warm and after cooling the filtrate to room temperature, the precipicated product is filtered off and dried, yielding 2-(β-hydroxy-phenethyl-amino)-2-imidazoline; m.p. 147°-149°C.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25].CCN(C(C)C)C(C)C.[CH3:36][N:37]([CH3:43])[C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:40]4[CH2:41][CH2:42][C@@H:38]([N:37]([CH3:43])[CH3:36])[CH2:39]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25]
Reactant: CN(C)[C@@H]1CCNC1
Reactant: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)CCC1(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](N(C)C)C4)ccc23)CCC1(F)F

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.66 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.26 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.56 (m, 1H), 1.27-1.32 (m, 1H), 1.00 (d, 3H). m/z: 481 [M+H]
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([CH:15]2[CH2:17][CH2:16]2)[NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.[Cl:18][C:19]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.Cl[Pd]Cl>[Cl:18][C:19]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([CH:8]([CH:15]3[CH2:17][CH2:16]3)[NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Yield: 84.9 %

Procedure:
A mixture of N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (5 g, 15.66 mmol), 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (as prepared in Example 1, step 1; 4.13 g, 15.66 mmol), sodium carbonate (15.66 mL, 31.3 mmol) and PdCl2 (dppf).CH2Cl2 adduct (0.320 g, 0.392 mmol) in DMF (100 mL) was heated to 100° C. for 25 min. After concentration, the residue was dissolved into CH2Cl2 and filtered through a pad of Na2SO4. The solution was absorbed into celite and concentrated. The residue was purified by flash column (ethyl acetate/heptane, 30%-50%-80%, v/v) and yielded the title compound as a colorless solid (5.0 g). Chiral separation by chiral HPLC (Chiralpak AD-H using Supercritical fluid chromatography. 25% Methanol at 65 grams per minute with supercritical CO2) afforded enantiomer 1 (S)—N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (retention time=3 min), and enantiomer 2 (R)—N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (retention time=4 min). ESI-MS m/z: 376.2 [M+H]+, 1H NMR (400 MHz, CDCl3): δ 0.37-0.40 (m, 1H), 0.51-0.55 (m, 1H), 0.57-0.68 (m, 1H), 0.70-0.77 (m, 1H), 1.15-1.27 (m, 3H), 2.70-2.88 (m, 2H), 3.85 (dd, J=5 Hz, 9 Hz, 1H), 4.68 (d, J=5 Hz, 1H), 7.53 (dd, J=1.5 Hz, 8 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.73 (d, J=8 Hz, 1H), 7.80 (t, J=2 Hz, 1H), 8.67 (d, J=2 Hz, 1H), 8.72 (d, J=2 Hz, 1H).
Reaction SMILES: [OH2:1].[OH2:2].C[N+]([O-])(C)C.[NH:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]2([CH2:20][CH:19]=[CH:18][CH2:17]2)[C:9]1=[O:21]>ClCCl.[Os](=O)(=O)(=O)=O>[OH:1][CH:18]1[CH:19]([OH:2])[CH2:20][C:10]2([C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8][C:9]2=[O:21])[CH2:17]1
Reactant: O
Reactant: O=C1Nc2ncccc2C12CC=CC2
Agent: O=[Os](=O)(=O)=O
Agent: C[N+](C)(C)[O-]
Solvent: ClCCl
Product: O=C1Nc2ncccc2C12CC(O)C(O)C2
Yield: 85.7 %

Procedure:
To a mixture of trimethylamine-N-oxide dihydrate (408 mg, 3.67 mmol) and spiro[cyclopent-3-ene-1,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (622 mg, 3.34 mmol) in dichloromethane (115 mL) was added osmium tetroxide (25 uL of 2.5% solution in 2-methyl-2-propanol). After 24 h the reaction mixture was concentrated. The crude product was loaded onto a silica gel chromatography column with a minimal amount of methanol and eluted with a gradient of 5 to 20% methanol:dichloromethane to give the title compound (0.63 g). MS: m/z=221.0 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18]I>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[CH2:14][O:15][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H]1COCCN1Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@@H]1COCCN1Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of (3R)-4-benzyl-3-hydroxymethylmorpholine (0.94 g) in tetrahydrofuran (10 ml) was added dropwise to a suspension of sodium hydride (60% oil suspension, 0.22 g) in tetrahydrofuran (20 ml) at room temperature under nitrogen atmosphere and the whole was stirred at 70° C. for 1 hour. After cooling, methyl iodide (0.31 ml) was added thereto and the mixture was stirred at 40° C. for 1 hour. After cooling, the mixture was poured into ice water, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (3:7) as an eluent to give (3R)-4-benzyl-3-methoxymethylmorpholine (0.88 g) as an oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:34]=[CH:33][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:32])[C:15]([CH2:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:35](Cl)([CH3:38])(=[O:37])=[O:36].N1C=CC=CC=1>CC(C)=O>[CH:26]1([CH2:25][C:15]2([CH3:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]([OH:23])=[C:13]([C:8]3[NH:7][C:6]4[CH:33]=[CH:34][C:3]([NH:2][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:4][C:5]=4[S:10](=[O:12])(=[O:11])[N:9]=3)[C:14]2=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC1(CC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 76.4 %

Procedure:
A solution of Example 41H (1.17 g, 2.33 mmol), mesyl chloride (0.720 mL, 9.31 mmol), and pyridine (1.51 mL, 18.61 mmol) in acetone (30 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.968 g, 42%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.84 (m, 7H) 1.34 (m, 4H) 1.53 (m, 3H) 2.20 (m, 2H) 3.07 (m, 3H) 7.57 (m, 3H) 7.76 (m, 3H) 8.17 (m, 1H) 10.28 (m, 1H) 13.83 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.O.[NH2:12][NH2:13]>C(O)CCC>[Br:1][C:2]1[CH:9]=[C:8]2[C:5]([C:6]([NH2:7])=[N:12][NH:13]2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: N#Cc1ccc(Br)cc1F
Solvent: O
Solvent: CCCCO
Product: Nc1n[nH]c2cc(Br)ccc12
Temperature: 25 °C

Procedure:
4-bromo-2-fluorobenzonitrile (67.8 g), hydrazine hydrate (32.8 ml) in n-butanol (410 ml) were heated to 112° C. for five hours. The reaction mixture was allowed to cool down to r.t. The precipitated crystalline solid was filtered off and washed three times with ethylacetate (100 ml each). The product was dried in vacuo at 40° C. mp. 222-225° C.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[SH:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.Cl>C1COCC1>[S:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[S:20][CH2:1][CH:2]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([OH:5])=[O:4]
Reactant: C=C(CCC(=O)OCC)C(=O)O
Reactant: Sc1cccs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(CSc1cccs1)C(=O)O
Temperature: 25 °C
Yield: 53.9 %

Procedure:
Under N2, a mixture of 2-methylene-4-ethoxycarbonylbutyric acid (17 g, 0.09 mol), triethylamine (4.3 g, 0.04 mol) in THF (120 ml) and 2-mercaptothiophene (11 g, 0.095 mol) was heated at reflux. After 24 hours the reaction mixture was cooled to room temperature and poured into 3N HCl (400 ml). The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were backwashed with saturated NaCl, dried, filtered and concentrated to dryness. The residue was chromatographed on a Still column and the product eluted with 15% CH3OH-CHCl3 saturated with NH3 to yield 14 g of 1 wherein R1, R2, R3 and R4 are each H.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[NH:4][C:3]1=[O:14].[NH:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[CH2:27][C@H:16]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:15]1([C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:14])[NH:4][C:5]=3[CH:10]=2)=[O:13])[CH2:20][CH2:19][CH2:18][C@@H:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[CH2:27][C@H:16]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: Cn1c(=O)[nH]c2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1c(=O)[nH]c2cc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)ccc21
Yield: 27 %

Procedure:
The title compound is prepared from 1-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 27% of theory; LC (method 4): tR=1.89 min; Mass spectrum (ESI+): m/z=348 [M+H]+.