Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([O:18][C:19]([C@:21]1([N:34]=[N+:35]=[N-:36])[C@@H:26](O)[CH2:25][C@@H:24]2[C@H:22]1[C@@:23]2([F:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:20])[CH3:17].N1C=CC=CC=1.C(OCC)C>ClCCl>[CH2:16]([O:18][C:19]([C@:21]1([N:34]=[N+:35]=[N-:36])[C@@H:26]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH2:25][C@@H:24]2[C@H:22]1[C@@:23]2([F:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:20])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H](O)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H](OS(=O)(=O)C(F)(F)F)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Temperature: -77 °C
Reaction time: 0.5 h

Procedure:
0.36 mL of trifluoromethane sulfonic acid anhydride dissolved in 1.2 mL of dichloromethane was added dropwise to 364 mg of (1R,2R,3S,5R,6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 6.1 mL of dichloromethane and 0.21 mL of pyridine at −77° C. to −69° C., under a nitrogen atmosphere. The mixture was stirred for 30 minutes at −77° C., and further stirred for 30 minutes at ice-cooling. 30 mL of diethyl ether was added thereto, and after the solids were filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=5:1), thereby yielding 487 mg of (1R,2R,3S,5R,6R)-2-azido-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C(=O)([O-])[O-].[K+].[K+]>[Cu]=O.N1C=CC=CC=1>[N:11]1([C:2]2[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)c1cccc(Br)c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CC(=O)c1cccc(-n2ccnc2)c1
Temperature: 25 °C
Yield: 15.4 %

Procedure:
A mixture of 25 g of 3'-bromoacetophenone, 9.0 g of imidazole, 18 g of anhydrous potassium carbonate, 1.0 g of copper oxide (CuO) and 30 ml of pyridine is refluxed for 64 hours. The mixture is cooled to room temperature, filtered and the filter cake washed with 50 ml of pyridine and 3×50 ml of dichloromethane. The combined filtrates are concentrated to dryness under vacuum. The residue is partitioned between 250 ml of dichloromethane and 150 ml of water. The emulsion is clarified by filtration through a pad of diatomaceous earth. The organic layer is separated, dried (MgSO4) and filtered through a pad of hydrous magnesium silicate. The pad is washed with 50 ml of dichloromethane and the combined filtrate is concentrated on a steam bath to 150 ml and while hot 300 ml of hexane is added. The mixture is cooled to room temperature, activated carbon added and the mixture filtered through diatomaceous earth. The filtrate is cooled to -10° C. and filtered to give 3.6 g of crystals, mp 69°-71° C. The filtrate is treated with activated carbon, filtered and the filtrate evaporated to give 12 g of crystals, mp 62°-65° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].[Cl:17]Cl>ClC1C=CC=CC=1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([Cl:17])=[O:10]
Reactant: ClCl
Reactant: Cc1nn(C)c(Cl)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: Cc1nn(C)c(Cl)c1C(=O)Cl
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
To a solution of 48 g of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 230 ml of chlorobenzene under protective gas are added 51.8 g of potassium carbonate. Subsequently, while illuminating with a mercury lamp, 24 g of chlorine gas are introduced at 20° C. within 4 hours. After the gas introduction has ended, the reaction solution is stirred with illumination at 20° C. for a further 20 minutes. The solid is filtered off and washed with a little chlorobenzene. After the solvent has been removed, 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride is obtained in a yield of 95%.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[F:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[N:13][NH:14]2)=[CH:10][C:9]=1[NH2:17]>C(#N)C.C(OCC)C.S([O-])([O-])(=O)=O.[Cu+2]>[F:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[N:13][NH:14]2)=[CH:10][C:9]=1[NH:17][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: C=C1CC(=O)O1
Reactant: Nc1cc2cn[nH]c2cc1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOCC
Solvent: CC#N
Product: CC(=O)CC(=O)Nc1cc2cn[nH]c2cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diketene (stabilized w/copper sulfate, 1.0 mL, 12.9 mmol, 1.5 equiv) was added to a suspension of 6-fluoro-1H-indazol-5-amine (1.3 g, 8.6 mmol, 1 equiv) in acetonitrile (8 mL) at 0° C. over 30 minutes. The reaction mixture was then stirred at room temperature for 16 hours. The mixture was diluted with cold diethyl ether (20 mL) and the solid product was collected by filtration and washed several times with cold diethyl ether. The title compound was isolated as a pale brown powder (1.49 g, 74%). MS m/z 236 [M+H]+
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)=[O:9])([CH3:4])[CH3:3].[H][H]>C(O)C.ClCCl.[Pd]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)=[O:9])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)Nc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)c1cc(C(=O)Nc2ccc(N)cc2)cc(C(C)(C)C)c1O
Yield: 49.3 %

Procedure:
In a 250 ml Parr flask, 2.4 g (6.5 mmoles) of 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide is dissolved in 50 ml of an absolute ethanol/dichloromethane mixture (1/1) in the presence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen, at 30° C., for one hour. After filtration on celite, the filtrate is concentrated under vacuum. The evaporation residue is taken up in 25 ml of a 1 M HCl solution. The precipitate formed is filtered and rinsed with 50 ml of diethyl ether followed by 50 ml of ethyl acetate. The amine is released from its salt by agitation in a mixture of 50 ml of ethyl acetate and 50 ml of 1 M NaOH. After decanting, the organic phase is washed with 25 ml of IM NaOH and 25 ml of brine. The organic solution is dried over sodium sulphate, filtered, rinsed and concentrated to dryness under reduced pressure to produce 1.09 g (49%) of a white powder. Melting point: 220-221° C.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([N:11]([CH:21]=[C:22]=[O:23])[O:12][C:13]1[CH:14]=[N:15][N:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=1)=O.C1([SH:30])C=CC=CC=1.[C:31]1(C)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:31]1([C:9]([N:11]([CH:21]=[C:22]=[O:23])[O:12][C:13]2[CH:14]=[N:15][N:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=2)=[S:30])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccccc1
Reactant: Sc1ccccc1
Reactant: CC(C)n1cc(ON(C=C=O)C(=O)Cl)cn1
Solvent: CCN(CC)CC
Product: CC(C)n1cc(ON(C=C=O)C(=S)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
g (0.04 mol) of triethylamine were added dropwise to a solution of 9.8 g (0.04 mol) of N-chlorocarbonyl-N-[1-iso-propyl-pyrazol-4-yl-oxy]-carbonyl-methylamine--which had been prepared analogously to Example 2--and 4.4 g (0.04 mol) of thiophenol in 100 ml of toluene. The mixture was subsequently stirred at room temperature for 4 hours and was then extracted twice by shaking with 25 ml of water each time. The organic phase was dried over sodium sulphate and evaporated in vacuo. The residue was subjected to incipient distillation under a high vacuum. 12 g (94% of theory) of N-phenylthiocarbonyl-N-[1-isopropyl-pyrazol-4-yl-oxy]-carbonyl-methylamine were thus obtained as a brown oil with a refractive index nD20 of 1.5662.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:11]=[C:10]([N:12]2[C:20]3[C:15](=[C:16]([O:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26])[CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:29][CH3:30]>C1COCC1.CCO>[CH3:30][NH:29][S:25]([CH2:24][CH2:23][CH2:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]2[C:10]1[CH:9]=[CH:8][N:7]=[C:6]([S:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:11]=1)(=[O:27])=[O:26]
Reactant: CCCCSc1nccc(-n2ccc3c(OCCCS(=O)(=O)Cl)cccc32)n1
Reactant: CN
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCSc1nccc(-n2ccc3c(OCCCS(=O)(=O)NC)cccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-[1-(2-Butylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-propane-1-sulfonyl chloride (10.97 mmol) was dissolved in THF (25 mL) and added dropwise to H2NMe (30 mL) in EtOH at 0° C. and stirred for 30 min, and then allowed to warm to RT The reaction mixture was then poured into ice water, extracted with EtOAc, washed with water and brine, dried with sodium sulfate, filtered, and the solvent removed in vacuo to yield 3-[1-(2-butylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-propane-1-sulfonic acid methylamide.
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30]>C(Cl)Cl>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:33]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:34])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: CC(C)N=C=O
Reactant: Fc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)NC(=O)N1CC(OC(c2ccc(F)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]azetidine hydrochloride (162) (150 mg, 0.42 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (2.62 mmol/g; 475 mg, 1.26 mmol), molecular sieves and iso-propyl isocyanate (42 μL, 0.42 mmol). The resultant mixture was shaken at ambient temperature for 16 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (24 mL), then evaporated to afford the desired product as a colourless glass which gave a white solid on scratching (126 mg, 74%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C@H:8]1[CH2:13][N:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:11]([CH3:26])[CH2:10][N:9]1[C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:32])([F:31])[F:30].[CH3:36][NH:37][CH3:38].CCOC(C)=O>C(Cl)Cl>[CH3:7][C@H:8]1[CH2:13][N:12]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23](=[O:24])[N:37]([CH3:38])[CH3:36])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C@H:11]([CH3:26])[CH2:10][N:9]1[C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:30])([F:31])[F:32]
Reactant: CNC
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(C(=O)N(C)C)cc1
Yield: 7.7 %

Procedure:
Oxalyl chloride (0.08 ml, 0.88 mmol) was added to a solution of (R)-[(2S,5R)-2-methyl-5-methyl-4-(4-carboxyphenylsulphonyl)-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (320 mg, 0.73 mmol) (Example 4) in DCM (25 ml). The resultant mixture was stirred at ambient temperature for 4 hours, evaporated to dryness, the residue treated with 40% aqueous dimethylamine (0.82 ml, 7.3 mmol) and the resultant mixture was stirred at ambient temperature overnight. The mixture was treated with EtOAc (25 ml), washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with 50% EtOAc in DCM as eluent to give a solid which was recrystallized from EtOAc/hexane to give the title compound as a solid (26 mg, 0.056 mmol). Mp: 86-87° C.; NMR: 0.95 (d, 3H), 1.25 (dd, 3H), 1.65 (s, 3H), 2.95 (s, 3H), 3.1 (s, 3H), 3.25 (dd, 1H), 3.5 (dd, 1H), 4.2 (m, 2H), 4.5 (s, 1H), 4.8 (s, 1H), 7.5 (d, 2H), 7.85 (d, 2H); m/z: 464.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.O.[C:11](=[O:14])([O-])[O-:12].[K+].[K+]>C1COCC1>[C:3]([O:12][C:11]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)=[O:14])([CH3:7])([CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1CCCNC1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of nipecotic acid, 2.0 g (16.0 mmol) in 20 mL of THF and 20 mL of water was added 4.7 g (33.6 mmol) of potassium carbonate and 3.5 g (16.0 mmol) of Boc-anhydride. The resulting solution was stirred overnight at ambient temperature then concentrated to dryness. The residue was dissolved in water, washed with ether and acidified to pH=2 with 5N HCl. The acidic aqueous layer was extracted with 20% isopropanol/chloroform. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to yield 3.2 g (86%) of the desired mixture of isomers as a white solid. MS (ion spray) 228.2 (M−1).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH:45]([CH3:47])[CH2:44][C:43]=3[CH:48]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH:45]([CH3:47])[CH2:44][C:43]=3[CH:48]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(-c2ccc3c(c2)CC(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(-c2ccc3c(c2)CC(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.95 g), sodium hydrogen carbonate (2.82 g) and dimethyl sulfoxide (14 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.42 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (14 mL), N,N′-carbonyldiimidazole (0.68 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.63 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.11 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][O:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:27][CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[ClH:27].[ClH:27].[ClH:27].[CH3:42][O:41][C:39]1[CH:40]=[C:35]([C:31]2[CH:30]=[C:29]([CH2:28][N:24]3[CH2:23][CH2:22][CH:21]([O:20][CH2:19][C:17]4[CH:16]=[CH:15][N:14]=[C:13]([C:5]5[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=5)[CH:18]=4)[CH2:26][CH2:25]3)[CH:34]=[CH:33][N:32]=2)[CH:36]=[C:37]([O:45][CH3:46])[C:38]=1[O:43][CH3:44]
Reactant: COc1cc(-c2cc(COC3CCNCC3)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(-c2cc(COC3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)ccn2)cc(OC)c1OC
Product: Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyloxy]piperidine (70 mg), 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (22 mg), potassium carbonate (56 mg) and potassium iodide (40 mg) were suspended in acetonitrile (5 mL). The mixture was stirred at room temperature for 5 hr and evaporated. Chloroform and water were added to the residual oil and the organic layer was separated. Aqueous layer was then extracted with chloroform and the organic layers were combined, dried over anhydrous magnesium sulfate and evaporated. The residue was applied to a column of silica gel using chloroform-methanol (40:1) as an eluent. Fractions containing the product were collected and evaporated. The title compound was obtained by converting the free base to a trihydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]([CH3:11])([CH2:9][CH3:10])[C:6]([OH:8])=O.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[CH2:34]([O:36][C:37](=[O:45])[CH2:38][C:39]1[N:40]=[C:41]([NH2:44])[S:42][CH:43]=1)[CH3:35].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:34]([O:36][C:37](=[O:45])[CH2:38][C:39]1[N:40]=[C:41]([NH:44][C:6](=[O:8])[C:5]([O:4][C:3]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:2]=2[F:1])([CH3:11])[CH2:9][CH3:10])[S:42][CH:43]=1)[CH3:35]
Reactant: CCC(C)(Oc1ccc(F)cc1F)C(=O)O
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NC(=O)C(C)(CC)Oc2ccc(F)cc2F)n1
Reaction time: 0.08 h
Yield: 57.7 %

Procedure:
To a solution of 2-(2,4-Difluoro-phenoxy)-2-methyl-butyric acid (0.2 g, 0.87 mmol) in DCM (5 ml) added N-Methyl morpholine (0.6 ml, 5.2 mmol) and HOBt (0.2 g, 1.3 mmol) at 0° C. After stirring at this temperature for 5 min. added (2-Amino-thiazol-4-yl)-acetic acid ethyl ester (0.17 g, 0.92 mmol) and followed by EDCI (0.217 g, 1.3 mmol). The resulting solution was stirred for 12 h. then quenched with sat NH4Cl solution (15 ml). The aqueous phase was extracted with CH2Cl2 (3×50 ml). The organic phase were successively washed with 2% HCl (50 ml), brine (50 ml) and dried over Na2SO4. After evaporation, the residue was purified by flash chromatography to give {2-[2-(2,4-Difluoro-phenoxy)-2-methyl-butyrylamino]-thiazol-4-yl}-acetic acid ethyl ester (0.2 g, 59%). 1H NMR (400 MHz, CDCl3): 1.03 (t, J=7.2 Hz, 3H), 1.28 (t, J=7.6 Hz, 3H), 1.43 (s, 3H), 1.83-1.89 (m, 1H), 2.04-2.1 (m, 1H), 3.73 (s, 2H), 4.2 (q, J=6.8 Hz, 2H), 6.8-6.93 (m, 3H), 7.0-7.04 (m, 1H); MS (EI) m/z: 399 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][SH:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.Br[S:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][S:16][S:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: BrSN1CCOCC1
Reactant: SCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CSSN3CCOCC3)n1-2
Yield: 124.1 %

Procedure:
To a solution of 8-chloro-1-(mercaptomethyl)-6-(2-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine (1.5 g) in methylene chloride (20 ml) is added a solution of 4-(bromothio)morpholine (prepared from 0.47 g of dimorpholinodisulfide) in chloroform at -13° to -20° C., and the resultant mixture is stirred for 1.5 hours. The reaction mixture is mixed with water. The methylene chloride layer is separated, dried and evaporated to remove the solvent. The residue is crystallized from ether and filtered to give 8-chloro-1-(morpholinodithio)methyl-6-(2-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine (1.45 g) as crystals. This material is recrystallized from ethanol to give crystals melting at 149°-155° C. (decomp.).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:49][CH:50]1[C@H:54]2[C@H:55](OC3CCCCO3)[N:56](C(OC(C)(C)C)=O)[C:57]3[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][C:58]=3[C:59](=[O:60])[N:53]2[CH2:52][CH2:51]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[C@H:22]2[C@H:23](OC3CCCCO3)[N:24](C(OC(C)(C)C)=O)[C:25]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:26]=3[C:27](=[O:28])[N:21]2[CH2:20][CH2:19]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:16]([O:17][CH:18]1[C@@H:22]2[CH:23]=[N:24][C:25]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:26]=3[C:27](=[O:28])[N:21]2[CH2:20][CH2:19]1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:49][CH:50]1[C@@H:54]2[CH:55]=[N:56][C:57]3[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][C:58]=3[C:59](=[O:60])[N:53]2[CH2:52][CH2:51]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 78.9 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15g (200 mg, 0.19 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16g (98 mg, 0.15 mmol, 83%) as a solid: [α]20D=+864° (c=0.14, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.32-1.52 (m, 10H, 14-H, 14′-H, 15-H, 15′-H, 16-H), 1.83-1.90 (m, 4H, 13-H, 13′-H), 2.02-2.09 (m, 4H, 2-H, 2′-H), 2.27-2.36 (m, 4H, 1-H, 1′-H), 3.54-3.64 (m, 2H, 3-H, 3′-H), 3.70-3.77 (m, 2H, 11a-H, 11a′-H), 3.78-3.88 (m, 2H, 3-H, 3′-H), 3.93 (s, 6H, 7-OMe, 7′-OMe), 3.99-4.15 (m, 4H, 12-H, 12′-H), 6.80 (s, 2H, 9-H, 9′-H), 7.51 (s, 2H, 6-H, 6′-H), 7.65 (d, 2H, J=4.4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.8, 28.8, 29.2, 29.3, 29.6, 46.6, 53.7, 56.1, 69.0, 110.4, 111.6, 120.0, 140.6, 147.8, 150.9, 162.8, 164.6; IR (neat): 2934, 1622, 1599, 1557, 1505, 1455, 1429, 1382, 1339, 1260, 1216, 1092, 1020 cm−1; MS (FAB) m/z (relative intensity) 681 ([M+2×MeOH]+., 6), 649 ([M+MeOH]+., 12), 617 (M+., 100).