Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[C:11]3/[C:12](=[O:28])[NH:13][C:14]4[C:19]/3=[CH:18][C:17]([NH:20]C(=O)OC(C)(C)C)=[CH:16][CH:15]=4)[CH:8]=2)[CH:3]=[N:2]1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([O-:35])=[O:30].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[C:11]3/[C:12](=[O:28])[NH:13][C:14]4[C:19]/3=[CH:18][C:17]([NH3+:20])=[CH:16][CH:15]=4)[CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)/C(=C\c1ccc3cn[nH]c3c1)C(=O)N2
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([O-])C(F)(F)F
Product: [NH3+]c1ccc2c(c1)/C(=C\c1ccc3cn[nH]c3c1)C(=O)N2
Yield: 56 %

Procedure:
To (E)-tert-butyl 3-((1H-indazol-6-yl)methylene)-2-oxoindolin-5-ylcarbamate (15 mg, 0.040 mmol) in CH2Cl2 (2 mL) was added TFA (0.1 mL). After 1.5 hrs the solvent was removed and the product precipitated with ether and filtered washing with ether to give 9 mg, 56% of the title compound as a brown solid. 1H NMR (400 MHz, d6-DMSO) δ 13.41 (s, 1H), 10.79 (s, 1H), 9.25-8.90 (bs, 3H), 9.01 (s, 1H), 8.14 (s, 1H), 8.00-7.96 (m, 2H), 7.82 (d, J=8.5 Hz, 1H), 7.56 (s, 1H), 7.09-7.07 (m, 1H), 6.86 (d, J=8.1 Hz, 1H); MS ESI 277.0 [M]+, calcd for [C16H13N4O]+ 277.11.
Reaction SMILES: [CH:1]1([N:7]([C@@H:19]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[O:25])[CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][C:17]#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.CI>>[CH:1]1([N:7]([C@@H:19]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[O:25])[CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH3:17])=[CH:14][N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)[C@@H]2CCN(C(=O)c3cccs3)C2)s1
Agent: O[C@H](CS)[C@@H](O)CS
Solvent: CI
Product: CSc1cnc(NC(=O)N(C2CCCCC2)[C@@H]2CCN(C(=O)c3cccs3)C2)s1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-1-[1-(thiophene-2-carbonyl)-pyrrolidin-3(R)-yl]-urea, dithioerythritol and methyliodide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[C:10]=1[CH3:11].FC1C(C)=C[C:16]2[O:20]C=CC=2C=1.BrN1[C:28](=[O:29])CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH3:28][O:29][CH:7]([O:20][CH3:16])[CH2:8][O:9][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]([CH3:11])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2occc2cc1F
Reactant: Cc1c(F)ccc2occc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(COc1ccc(F)c(C)c1)OC

Procedure:
A mixture of 5-fluoro-4-methylbenzofuran and 5-fluoro-6-methylbenzofuran (14.95 g), N-bromosuccinimide (16.57 g), benzoyl peroxide (0.32 g) and carbon tetrachloride (375 ml) was heated under reflux under the illumination of an 80 W flood lamp for 20 h. The mixture was cooled, and filtered and the filtrate evaporated to dryness to give the crude product as an oil (24.0 g). This material was combined with a similar crude product (6.94 g) from an identical reaction run on a smaller scale and purified by chromatography on silica (900 g) using an ether hexane mixture (1:30) as eluant to give the title compound (13.5 g) as an oil.
Reaction SMILES: [CH:1]1([N:4]=[C:5]2[C:9]3[N:10]([CH3:18])[C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][C:16]=4[C:8]=3[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.B.FC(F)(F)C(O)=O>C1COCC1>[CH:1]1([NH:4][CH:5]2[CH:9]3[N:10]([CH3:18])[CH:11]4[CH:16]([CH:8]3[CH2:7][CH2:6]2)[CH:15]=[C:14]([OH:17])[CH:13]=[CH:12]4)[CH2:2][CH2:3]1
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NC1CC1
Agent: B
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN1C2C=CC(O)=CC2C2CCC(NC3CC3)C21
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
3-Cyclopropylimino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol7-ol (8.7 grams) was placed in a 3-neck flask and cooled to 0° C. in an ice-water bath. A 1M solution of borane in THF (540 ml) was added in a dropwise manner. The mixture was stirred for 1 hours while it was slowly warmed to room temperature. The mixture was cooled back down to 0° C. and trifluoroacetic acid (119 ml) was added in a dropwise manner. The solution was stirred for 15 minutes and THF was removed in vacuo. The mixture was neutralized with 10% NaOH solution, extracted with methylene chloride (4×500 ml), dried (Na2SO4) and concentrated to give 3-(N-cyclopropyl)amino-1,2,3,3a,4,8a-hexahydro-4-methylcyclopent[b]indol-7-ol (8.8 grams).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:9]([OH:11])=O.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([OH:24])=O.Cl.[NH2:26][CH2:27][C:28]#[N:29]>>[C:27]([CH2:28][NH:29][C:9]([C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:2]1[NH:1][C:22]([C:14]1[N:13]([CH3:12])[C:21]2[C:16]([CH:15]=1)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:24])=[O:11])#[N:26]
Reactant: N#CCN
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: NC1CCCCCC1C(=O)O
Agent: Cl
Product: Cn1c(C(=O)N[C@H]2CCCCC[C@H]2C(=O)NCC#N)cc2ccccc21

Procedure:
2-[(1-Methyl-1H-indole-2-carbonyl)-amino]-cycloheptanecarboxylic was prepared from 2-Aminocycloheptanecarboxylic acid (Tyger Scientific Inc., Princeton N.J.) using the procedure of Example). 1-Methyl-1H-indole-2-carboxylic acid and aminoacetonitrile hydrochloride were coupled as described in Example 1 to yield 1-Methyl-1H-indole-2-carboxylic acid [(1S,2R)-2-(cyanomethyl-carbamoyl)-cycloheptyl]-amide (compound 98).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:18]([C:23]2[N:27]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[N:26]=[N:25][N:24]=2)[CH:19]=[CH:20][CH:21]=[O:22])=[CH:13][CH:12]=1>O1CCCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:18]([C:23]2[N:27]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[N:26]=[N:25][N:24]=2)[CH:19]=[CH:20][CH:21]([OH:22])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:13][CH:12]=1
Reactant: COCCOCn1nnnc1C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1COCCOC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl acetoacetate dianion (2,6 mL of a freshly prepared 1M solution as described in Example 10) was added to a solution of 5,5-bis(4-fluorophenyl)-4-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-2,4-pentadienal (1.1 g, 2.6 mmoles) in 15 mL of tetrahydrofuran at -40° C. After stirring for 2 hours, analytical TLC eluted with 25% (v/v) ethyl acetate in hexane showed starting aldehyde and therefore, another 1.2 mL of dianion solution was added. The reaction mixture was allowed to warm to 0° C. and then quenched with 1N HCl. The mixture was extracted with methylene chloride, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 1% (v/v) methanol in methylene chloride to give 0.9 g of the title compound as an oil. MS (CI): m/e=557 for (M+H)+ ;
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)=[CH:14][CH:15]=2)[CH2:20]1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1F)N1CCc2ccc(OCCCN3CCCCC3)cc2C1

Procedure:
2-(2-Fluoro-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline is prepared from 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (104 mg, 0.3 mmol), NEt3 (0.14 mL, 1.1 mmol), and 2-fluorobenzenesulfonyl chloride (80 mg, 0.41 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the free base product (85 mg, 66% yld) as an amber oil. MS (ES+) 433.2(M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH:12]=[C:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:8]2=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH:12]=[C:13]([CH2:14][C:15]([OH:17])=[O:16])[C:8]2=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCCc1nnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)O
Temperature: 25 °C

Procedure:
To a solution of biphenyl indolizinyl tert-butyl ester (0.039 mmol, the title compound of Example 3231) in 0.5 mL of chloroform is added 0.25 mL of TFA, and the progress of the reaction is monitored by 1H NMR. The resulting solution is stirred at room temperature until the reaction is complete. The mixture is quenched with methanol and concentrated in vacuo. The residue is purified to give the title compound of Example 3232.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:24][CH3:25])[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]2[OH:23])(=[O:3])[CH3:2].[C:26](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.ClCCl>[C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:24][CH3:25])[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:26])[CH:13]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]2=[O:23])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cnc2ccc(N(CC)CCOC(C)=O)cc2c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: ClCCl
Product: CCOC(=O)c1cn(C)c2ccc(N(CC)CCOC(C)=O)cc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 124.4 %

Procedure:
To a flask containing ethyl 6-[[2-(acetyloxy)ethyl](ethyl)amino]-4-hydroxy-3-quinolinecarboxylate (0.17 g) in DMF (5 mL) is added potassium carbonate (0.21 g) and iodomethane (0.05 mL). The reaction is tightly capped and heated to 90° C. After 3 hours, the reaction is cooled to room temperature, diluted with dichloromethane, filtered and concentrated under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 4% to 8% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.22 g of the title compound as a orange solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[NH2:10][OH:11].S([O-])([O-])(=O)=O.[Na+].[Na+].Cl[C:20](Cl)(Cl)[CH:21]([OH:23])O>Cl.O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:21](=[O:23])[CH:20]=[N:10][OH:11]
Reactant: NO
Reactant: Nc1ccccc1F
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NO)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.9 %

Procedure:
A solution of 39.4 g of 2-fluoroaniline in 32.4 ml of concentrated hydrochloric acid and 215 ml of water and then a solution of 77.6 g of hydroxylamine hydrochloride in 355 ml of water were added to a mixture of 886 g of sodium sulfate hydrated with 10 moles of water, 64.55 g of chloral hydrate and 850 ml of water and the mixture was heated to reflux with stirring over 45 minutes and reflux was maintained for 5 minutes. The mixture was cooled to 25° C. and held there for 45 minutes. The product was washed with water and dried at room temperature and then at 70° C. under reduced pressure to obtain 56.8 g of N-(2-fluorophenyl)-2-hydroxyimino-acetamide melting at 120° C.
Reaction SMILES: [NH3:1].[C:2](=[S:4])=[S:3].[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1>C(#N)C>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:11][C:2](=[S:4])[S-:3])=[CH:8][CH:7]=1.[NH4+:1]
Reactant: N
Reactant: NCc1ccc(Cl)cc1
Reactant: S=C=S
Solvent: CC#N
Product: S=C([S-])NCc1ccc(Cl)cc1
Product: [NH4+]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
260 ml. of concentrated ammonia solution were treated under an atmosphere of argon, and while cooling by means of ice/methanol bath at ≤-10° C. within about 20 minutes, with 164.5 g. of carbon disulfide and the mixture was subsequently stirred for an additional 15 minutes at the same temperature. 245 G. of 4-chlorobenzylamine dissolved in 122 ml. of acetonitrile were then slowly added, the temperature still maintained at ≤-10° C. Subsequently, the mixture was stirred overnight at room temperature and then cooled in an ice-bath to 0° C. The precipitated crystals were removed by filtration under suction, washed successively with acetonitrile and diethyl ether and dried to a constant weight under reduced pressure at 70°-80° C., and 390 g. of ammonium (N-4-chlorobenzyl)dithiocarbamate having a melting point of 140°-142° C. was obtained.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[S:17][C:16]([NH:18][C:19](=[O:28])[C:20]4[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=4)=[N:15][C:14]=3[C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:38](CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C1COCC1>[CH:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[S:17][C:16]([NH:18][C:19](=[O:28])[C:20]4[CH:21]=[CH:22][C:23]([CH2:26][NH:38][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:24][CH:25]=4)=[N:15][C:14]=3[C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C(=O)Nc2nc(-c3ccc(F)cc3)c(N3CCN(C4CCCCC4)CC3)s2)cc1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)NCc1ccc(C(=O)Nc2nc(-c3ccc(F)cc3)c(N3CCN(C4CCCCC4)CC3)s2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.15 g of the compound of Example 149 was suspended in 5 ml of THF, 0.2 ml of triethylamine and a solution of 35 mg of methanesulfonyl chloride in 2 ml of THF were sequentially added thereto under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, mixed with water, and extracted with EtOAc. The obtained organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the thus-obtained residue was recrystallized from EtOAc-hexane mixed solvent to obtain 0.12 g of N-[5-(4-cyclohexylpiperazin-1-yl)-4-(4-fluorophenyl)thiazol-2-yl]-4-(methanesulfonylaminomethyl)benzamide. The obtained compound was suspended in 5 ml of EtOAc, 0.2 ml of 1M HCl-EtOAc solution was added under ice cooling, and the mixture was stirred overnight. The thus-precipitated solid was filtered and dried to obtain 111 mg of N-[5-(4-cyclohexylpiperazin-1-yl)-4-(4-fluorophenyl)thiazol-2-yl]-4-(methanesulfonylaminomethyl)benzamide hydrochloride.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9](Cl)[C:5]=1[C:6]([OH:8])=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([SH:25])[CH:22]=[CH:23][CH:24]=1.Cl>O1CCCC1.CCCCC>[Cl:3][C:4]1[C:5]2[C:6](=[O:8])[C:22]3[C:21](=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=3)[S:25][C:9]=2[C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: COc1cccc(S)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(=O)c3c(Cl)ccc([N+](=O)[O-])c3sc2c1
Reaction time: 20 h

Procedure:
The requisite 1-chloro-6-methoxy-4-nitrothioxanthone was prepared as follows: To a prewashed (pentane) suspension of NaH in 500 ml of tetrahydrofuran cooled to 0° was added dropwise over about 25 minutes a solution of 35.4 g of 2,6dichloro-5-nitrobenzoic acid in 200 ml of tetrahydrofuran. After about five minutes a solution of 20 g of m-methoxybenzenethiol in 50 ml of tetrahydrofuran was added, and the mixture was stirred for 20 hours as it gradually came to ambient temperature. The mixture was treated with a 10% aqueous hydrochloric acid solution, extracted into ethyl acetate, dried, and the solvent was removed in vacuo. The orange gum was purified by flash chromatography on SiO2 with a 90:5:0.5 mixture of methylene chloride:methanol:acetic acid. The resulting oil was sufficiently pure for use in the next step. A solution of this material (24.8 g) in 120 ml of trifluoroacetic acid was treated with 60 ml of trifluoroacetic anhydride and allowed to stir at room temperature for 30 minutes. The solution was diluted with acetonitrile, and the precipitate was collected and triturated with boiling acetonitrile to give 15.8 g of the product, mp 254°-258°.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])=[O:6].[CH2:14]([Cl:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[Cl-:21].[CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH2:9][N+:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:12])[CH3:11])=[O:6]
Reactant: CC(C)CCC(=O)OCCN(C)C
Reactant: ClCc1ccccc1
Solvent: CC#N
Product: CC(C)CCC(=O)OCC[N+](C)(C)Cc1ccccc1
Product: [Cl-]

Procedure:
A solution of 46.83 g (0.25 mol) of 2-(N,N-dimethylamino)ethyl 4-methylvalerate (prepared as described in Example 1) and 31.65 g (0.25 mol) of benzyl chloride in 250 ml of acetonitrile was heated at reflux for 1.25 hours. The reaction mixture was then concentrated to a viscous oil and used in the ion exchange step with no further purification.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:12]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=2)=[C:14]([CH2:26][CH2:27][CH3:28])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].ClC1C=CC=[C:34]([C:38]([O:40]O)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[C:38]([O:40][CH2:23][C:19]1[CH:18]=[C:17]([O:16][C:15]2[CH:24]=[CH:25][C:12]([C:3]([O:8][CH2:9][O:10][CH3:11])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:29])[F:30])=[CH:13][C:14]=2[CH2:26][CH2:27][CH3:28])[CH:22]=[CH:21][N:20]=1)(=[O:39])[CH3:34]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(COC(C)=O)c1
Temperature: 140 °C
Yield: 55.6 %

Procedure:
To a solution of 4-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-2-methylpyridine (780 mg, 1.78 mmol) in chloroform (2 mL), m-chloroperbenzoic acid (2.05 g) was added at room temperature and the resultant mixture was stirred. After completion of the reaction, the reaction solution was added with an aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and then dried using sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The obtained residue was added with acetic anhydride and heated at a surrounding temperature of 140° C. After completion of the reaction, the reaction solution was added with methanol (4 mL) at room temperature, then neutralized by adding a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (490 mg, yield 56%) was obtained as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.C(N(CC)CC)C.[C:23](=[S:25])=[S:24].[CH3:26]I>CO.O>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:23]([S:25][CH3:26])=[S:24]
Reactant: S=C=S
Reactant: CI
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CSC(=S)N1Cc2[nH]c3ccccc3c2C[C@H]1CO
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
(3S)-3-Hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (30.3 g) is dissolved in a mixture of methanol (300 ml) and water (80 ml), and thereto are added triethylamine (15.9 g) and CS2 (11.9 g). The mixture is stirred at 20° C. for 30 minutes, and thereto is added dropwise methyl iodide (22.35 g). The mixture is stirred at 20°-25° C. for 1.5 hour and distilled to remove the solvent. The residue is dissolved in ethyl acetate and washed with 5% HCl and water, dried over sodium sulfate and distilled to remove the solvent. The residue is recrystallized from aqueous ethanol to give the title compound (42.0 g, 90%) as colorless needles, m.p. 114°-116° C., [α]D20 +159.0° (c=1, methanol). NMR (CDCl3, δ): 2.62 (s, 3H, CSSCH3), Mass m/e: 292 (M+), 244 (M+ --CH3SH).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=4)[CH:17]=[CH:16][C:15]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2>[O-2].[Mn+2].ClCCl>[CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[CH:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]=[O:27])=[CH:24][CH:25]=4)[CH:17]=[CH:16][C:15]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(CO)cc4)ccc3-c3ccccc3)ccc21
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C=O)cc4)ccc3-c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
640 mg (1.4 mmol) of the alcohol obtained in Example 51, 2.50 g (28.7 mmol) of manganese oxide and 50 ml of dichloromethane are mixed together in a 500 ml round-bottomed flask. The reaction medium is stirred for twenty hours at room temperature, the manganese oxide is then filtered off and the dichloromethane is evaporated off. The residue obtained is purified by chromatography on a column of silica eluted with a mixture composed of 80% heptane and 20% ethyl acetate. After evaporation of the solvents, 90 mg (14%) of the expected compound are collected in the form of a white powder with a melting point of 120–122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]([C:8]#[C:9][CH3:10])=[N:6][CH:7]=1.[C:20]1([CH3:33])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28]([O:31][NH2:32])(=[O:30])=[O:29]>CC#N>[CH3:27][C:22]1[CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]([CH3:33])[C:21]=1[S:28]([O-:31])(=[O:30])=[O:29].[NH2:32][N+:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([O:11][CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:17])[CH3:18])[C:5]=1[C:8]#[C:9][CH3:10]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: CC#Cc1ncc(Cl)cc1OCOCC[Si](C)(C)C
Solvent: CC#N
Product: CC#Cc1c(OCOCC[Si](C)(C)C)cc(Cl)c[n+]1N
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-chloro-2-(prop-1-yn-1-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine 6.58 (969 mg, 3 mmol) in MeCN (10 mL) was cooled to 0° C. under argon. O-(mesitylsulfonyl)hydroxylamine (700 mg, 3 mmol, prepared using a procedure similar to that reported in Org. Proc. Res. Dev. 2009, 13, 263-267) was added, and mixture was warmed to rt. After 2 hours, reaction mixture was concentrated under reduced pressure to yield 1-amino-5-chloro-2-(prop-1-yn-1-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate which was used in the next step without further purification. LCMS [M+H]+: 314.91.