Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[C:8]([O:10][CH3:11])=[O:9].P(Cl)(Cl)(Cl)=O.C[CH2:18][O:19]CC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][N:2]1[C:6]([CH:18]=[O:19])=[C:5]([CH3:7])[CH:4]=[C:3]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOCC
Reactant: COC(=O)c1cc(C)cn1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1cc(C)c(C=O)n1C
Temperature: 90 °C
Yield: 84 %

Procedure:
A solution of methyl 1,4-dimethylpyrrole-2-carboxylate (2.5 g, 0.016 m) in 20 ml of dried 1,2-dichloroethane was added over two minutes to a stirred mixture of phosphorous oxychloride (2.3 ml) and dried, N,N-dimethylformamide (1.94 ml) in 50 ml of dichloroethane, and the resultant mixture heated at 90° C. (bath temperature) for 45 minutes. The cooled reaction mixture was treated with excess ice-water and ether, 10% aqueous sodium carbonate (50 ml) added, the ether layer removed and the aqueous phase re-extracted two times with fresh ether, and the combined ether layers washed well with water and dried over anhydrous sodium sulfate. Concentration of the ether solution yielded 2.48 g (84%) of methyl 1,4-dimethyl-5-formylpyrrole-2-carboxylate as a yellow solid.
Reaction SMILES: N1C=CN=C1[C:6]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C@@H:23]1[C:18]([CH:19]=[C:20]([O:27][CH2:28][O:29][CH3:30])[CH:21]=[CH:22]1)=[CH:17][CH2:16]3)=[O:7].Cl.[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH2:36].C(N(CC)CC)C.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O1CCOCC1.O>[CH3:32][O:33][C:34]([CH2:35][NH:36][C:6]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C@@H:23]1[C:18]([CH:19]=[C:20]([O:27][CH2:28][O:29][CH3:30])[CH:21]=[CH:22]1)=[CH:17][CH2:16]3)=[O:7])=[O:37]
Reactant: COCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](OC(=O)c5ncc[nH]5)CC[C@@H]34)[C@H]2C=C1
Reactant: COC(=O)CN
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: COCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](OC(=O)NCC(=O)OC)CC[C@@H]34)[C@H]2C=C1
Reaction time: 72 h
Yield: 64.3 %

Procedure:
To a solution of 17β-imidazolylcarbonyloxy-3-methoxymethyloxy-1,3,5-estratriene (1.14 g) in dioxane (25 ml) were added glycine methyl ester hydrochloride (1.05 g), triethylamine (1.16 ml), and diazabicycloundecene (1.25 ml). The resultant mixture was refluxed under heating and stirring for 3 days. After cooling, the reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was chromatographed on a silica gel column (100 g), eluting with hexane-ethyl acetate to give 17β-methoxycarbonylmethylaminocarbonyloxy-3-methoxymethyloxy-1,3,5-estratriene (0.77 g, Yield: 64%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[Br-].[CH3:19][O:20][N:21]1[CH2:25][CH2:24][CH:23]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:22]1=[O:45].C(N(CC)CC)C>C(O)C>[CH3:19][O:20][N:21]1[CH2:25][CH2:24][C:23](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:12]([OH:13])=[C:11]([C:14]([CH3:15])([CH3:16])[CH3:17])[CH:10]=2)[C:22]1=[O:45]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CON1CCC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CON1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 67.9 %

Procedure:
27.6 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde, 54.0 g of (N-methoxy-2-pyrrolidone-3-yl)triphenylphosphonium bromide and 33.0 ml of triethylamine were heated at 50° C. in ethanol for four hours. After distilling the ethanol off, the residue was dissolved in chloroform, washed with water and then a saturated saline solution and dried over anhydrous magnesium sulfate. After distilling the chloroform off, the residue was treated with the column chromatography, using silica gel and a carrier liquid of benzene and acetone and recrystallized with a mixture of ethyl acetate and hexane to give 26.5 g of the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:18]C(OC(C)(C)C)=O)[CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1.C(Cl)Cl.CO>[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([NH2:18])[CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Reaction time: 1 h
Yield: 103.6 %

Procedure:
Add 4M HCl in dioxane (100 mL) to a solution of (R)-3-tert-butoxycarbonylamino-piperidine-1-carboxylic acid benzyl ester (71.65 mmol; 23.96 g) in DCM (100 mL) and MeOH (10 mL). Stir 60 min and evaporate. Partition solid between DCM and saturated sodium bicarbonate aqueous, extract three times with DCM, Wash extracts with brine, dry over MgSO4, filter through Celite® and evaporate to give the title compound 17.39 g (74.22 mmol; 104%). MS (ES+): m/z=235 (M+H).
Reaction SMILES: [C:1]12(C)[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=O.[CH:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:20]([O:19][C:12]1([O:16][CH2:17][CH3:18])[CH2:7][CH:1]2[C:8]([CH3:10])([CH3:9])[C:5]1([CH3:6])[CH2:4][CH2:2]2)[CH3:21]
Reactant: CCOC(OCC)OCC
Reactant: CC12CCC(CC1=O)C2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC1(OCC)CC2CCC1(C)C2(C)C

Procedure:
To a flask with reflux condenser, (25 g) camphor and 50 ml absolute ethanol was taken. (36.45 g) (1.5 eq.) triethyl orthoformate and crystals of p-toluenesulfonic acid was added into the reaction mixture. The reaction mixture was heated to reflux overnight. The reaction mixture was cooled and concentrated on rotavapour and was washed with 10% potassium hydroxide solution. Extract it with dichloromethane and concentrated the organic layer on rotavapour, yellow colored liquid product was obtained. 38. g (Quantitative)
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]3[CH2:13][CH2:12]3)[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([NH2:26])[CH:3]=1.[OH-].[Na+].Br[CH2:30][CH2:31][O:32][CH2:33][CH2:34]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]3[CH2:12][CH2:13]3)[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([N:26]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:3]=1
Reactant: Cc1c(Cn2c(C3CC3)nc3c(Br)cc(N)cc32)cccc1C(F)(F)F
Reactant: BrCCOCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Product: Cc1c(Cn2c(C3CC3)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Reaction time: 2.5 h

Procedure:
4-bromo-2-cyclopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-amine (3.42 g, 8.06 mmol) was stirred in 6M sodium hydroxide (70 mL, 420 mmol) solution with 1-bromo-2-(2-bromoethoxy)ethane (5.03 mL, 40.3 mmol) and tetrabutylammonium iodide (0.298 g, 0.806 mmol) at 110° C. After stirring for 2.5 hr the mixture was cooled and the aqueous was decanted and the remaining sticky solid was dissolved in Et2O/EtOAc. The organic was washed with H2O and brine and dried over MgSO4 and concentrated to leave a thick dark residue containing the desired product. The desired product was dissolved in CHCl3, loaded onto a silica column, and was purified by flash chromatography eluting with EtOAc/Hex 20% to 40% over 20 column volumes. The fractions containing the desired compound by TLC were combined and concentrated and the resultant dark oil was triturated with Et2O/Hexanes to provide 4-(4-bromo-2-cyclopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine (1.62 g, 3.28 mmol, 40.7% yield) as a light orange solid. MS (ES+) m/e: 495.1, 495.8 [M+H]+
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[CH2:17][O:16][C:15]2=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:21][NH2:22].ClCCl.CO>O1CCCC1>[N:1]1([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:20])[O:16][CH2:17][C:18]([NH:22][CH3:21])=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN
Reactant: O=C1COC(=O)N1CCCCn1ccc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)COC(=O)NCCCCn1ccc2ccccc21

Procedure:
The procedure is as described in Example 1 (stage 1.4.). Starting from 0.90 g (3.31 mmol) of 3-[4-(1H-indol-1-yl)butyl]-1,3-oxazolidine-2,4-dione, obtained in stage 2.2., and from 5 ml (9.93 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, elution being carried out with a 98/2 mixture of dichloromethane and of methanol, 0.70 g of product is obtained in the form of an amorphous white solid.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[O:15]=[C:16]([CH3:40])[CH:17]([CH2:25][C:26]1[O:27][C:28]([C:31](=[O:39])[NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:30]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[OH-].[Na+].OO>O1CCCC1.O.C(OCC)C>[OH:15][CH:16]([CH3:40])[CH:17]([CH2:25][C:26]1[O:27][C:28]([C:31](=[O:39])[NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:30]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(=O)C(Cc1ccc(C(=O)Nc2ccccc2)o1)C(=O)OC(C)(C)C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C(Cc1ccc(C(=O)Nc2ccccc2)o1)C(=O)OC(C)(C)C
Yield: 59.9 %

Procedure:
43 ml of 1M lithium tri-sec-butylborohydride in tetrahydrofuran solution was added to 14.0 g of tert-butyl 3-oxo-2-{5-(phenylcarbamoyl)-2-furylmethyl}butanoate in 100 ml of tetrahydrofuran at -78° C. under stirring, and the resulting reaction solution was stirred at the same temperature for 1 hour. While the reaction solution was cooled with ice under stirring, 50 ml of 4N aqueous sodium hydroxide was added, and then 35 ml of 35% aqueous hydrogen peroxide was gradually added dropwise. The reaction solution was stirred at room temperature for 1 hour. Ethyl ether and water were added to the reaction solution for extraction, and the organic layer was washed with saturated aqueous sodium thiosulfate and saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=5/1→1/1] to give 8.44 g of the title compound as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:9]([NH:12]C(=O)C)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]#[N:22].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[NH2:27].CS(O)(=O)=O.Cl.C(=O)([O-])[O-].[K+].[K+]>CO.C(O)C>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:5]=[CH:4][C:3]([C:21]#[N:22])=[C:2]2[NH:27][C:26]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[C:24]([Cl:23])[CH:25]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: COCCOc1cc2ncc(C#N)c(Cl)c2cc1NC(C)=O
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCO
Product: COCCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1N
Temperature: 80 °C
Yield: 68.3 %

Procedure:
A mixture of N-(4-chloro-3-cyano-7-(2-methoxyethoxy)quinolin-6-yl)acetamide (6.3 g, 0.0197 mol, 1.00 equiv), 3-chloro-4-(2-pyridylmethoxy)aniline (4.7 g, 0.0201 mol, 1.00 equiv), methanesulfonic acid (0.7 ml, 0.0108 mol) and ethanol (150 ml) was stirred under refluxed for 6 hours and then 0.6N hydrogen chloride (300 ml, 0.18 mol) was added. The mixture was heated to 80° C. for 19 hours, and then cooled to 0° C. to form precipitate. The precipitated solids were filtered and then added to a solution of 1N potassium carbonate (100 ml, 0.1 mol) in methanol (150 ml) and then the mixture was stirred for 3 hours. The resulting mixture was filtered, washed with 1:1 methanol/water (300 ml) and dried to give product 6.4 g. MS (ESI) m/z: 475 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:12][C:13]([SH:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([S:16][C:13]([CH3:15])([CH3:14])[CH3:12])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1c(F)ccc(Br)c1F
Reactant: CC(C)(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1c(Br)ccc(F)c1C=O
Temperature: 50 °C
Yield: 50.7 %

Procedure:
A mixture of 3-bromo-2,6-difluorobenzaldehyde (2.00 g, 9.05 mmol), 2-methyl-2-propanethiol (0.917 mL, 8.13 mmol), and potassium carbonate (1.5 g, 11 mmol) in DMF (6 mL) was heated to 50° C. overnight in a sealed tube. The material was extracted with EtOAc, and washed with water (3×). Purification of the organic layer by column chromatography (1 to 2% EtOAc:hexanes) afforded 1.2 g (51%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.34 (s, 9 H), 7.07-7.16 (m, 1 H), 7.91 (dd, J=9.0, 5.2 Hz, 1H), 10.56-10.63 (m, 1 H).
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][CH:23]([C:27](O)=[O:28])[C:24](O)=[O:25])[CH3:15]>>[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][C:23]1[C:24](=[O:25])[O:9][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:27]=1[OH:28])[CH3:15]
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: CCc1ccccc1SC(C(=O)O)C(=O)O
Product: CCc1ccccc1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (4.17 g, 21.72 mmol) and diethyl ester of [(2-ethylphenyl)thio]propanedioic acid (1.5 g, 10.86 mmol). m.p. 190-192° C.; 1H NMR (400 MHz, DMSO-d6) δ1.25 (t, 3H), 2.78 (q, 2H), 6.89 (s, 1H), 6.92 (m, 1H), 7.08 (m, 2H), 7.2 (m, 1H), 7.58 (m, 3H), 7.86 (m, 2H).
Reaction SMILES: CO[C:3]([NH:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[C:16]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:15]2)[CH2:10][CH2:9]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:3][NH:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[C:16]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[CH:15]2)[CH2:12][CH2:13]1
Reactant: COC(=O)NCCN1CCC(n2cc(-c3ccc(F)cc3)c3cc(C)ccc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNCCN1CCC(n2cc(-c3ccc(F)cc3)c3cc(C)ccc32)CC1

Procedure:
A solution of the crude 1-(1-(N-methoxycarbonyl-2-aminoethyl)-4-piperidyl)-3-(4-fluorophenyl)-5-methyl-1H-indole (8.8 g) in dry tetrahydrofuran (75 ml) was added to a suspension of lithium aluminum hydride (2 g) in dry tetrahydrofuran (75 ml) during 15 min and the reaction mixture was refluxed for 1.5 h. After cooling on an ice bath water (4 ml), 4N aqueous NaOH (2.5 ml) and water (10 ml) were added, succesively. The precipitate was filtered off, the solution was dried (Na2SO4) and the solvents were evaporated. This afforded the title compound, as an oil Yield: 6.9 g.
Reaction SMILES: C[O:2][C:3]([C@@:5]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:7][C@H:6]1[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([NH:21][C:22](=[O:24])[CH3:23])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:4].[OH-].[Li+].Cl>CO.O>[ClH:31].[C:22]([NH:21][C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14][N:9]([CH2:8][C@@H:6]2[CH2:7][C@:5]2([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[C:3]([OH:4])=[O:2])[CH2:10][CH2:11]1)(=[O:24])[CH3:23]
Reactant: COC(=O)[C@@]1(c2ccc(Cl)c(Cl)c2)C[C@H]1CN1CCC(NC(C)=O)(c2ccccc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)NC1(c2ccccc2)CCN(C[C@@H]2C[C@@]2(C(=O)O)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C

Procedure:
The oxalate salt of (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4-dichlorophenyl)cyclopropanecarboxylic acid methyl ester (10 mmol) was dissolved in methanol (80 mL) and water (20 ml). Lithium hydroxide (50 mmol) was added and the mixture was heated to reflux for 2 h. The mixture was cooled to rt and acidified to pH 3 with concentrated hydrochloric acid and the precipitated product (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4-dichlorophenyl)cyclopropanecarboxylic acid hydrochloride was isolated by filtration and dried in vacuo.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[S:17])[S:8][S:9][C:10]=1[C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[O:5])C>C(O)(=O)C.S(=O)(=O)(O)O.O>[C:4]([C:6]1[C:7](=[S:17])[S:8][S:9][C:10]=1[C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(-c2cnccn2)ssc1=S
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1c(-c2cnccn2)ssc1=S
Temperature: 20 °C
Reaction time: 48 h
Yield: 72.1 %

Procedure:
A solution of 4-ethoxycarbonyl-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (150 g) [prepared as described in Example 31] in acetic acid (6750 cc), concentrated sulphuric acid (515 cc) and water (515 cc) is heated for 2 hours under reflux. After cooling, the product which crystallises is filtered off and washed successively with acetic acid (100 cc) and carbon disulphide (2 × 100 cc). This product is then suspended in water (1350 cc) and stirred for 48 hours at a temperature of about 20° C. The insoluble product is then filtered off and washed with water (2 × 250 cc). After drying, 4-carboxy-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (97.5 g), melting at 225° C., is obtained.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([OH:11])[C:3]=1[C:4]#[N:5].[CH3:12][O-:13].[Na+]>CO>[OH:11][C:6]1[C:3]([C:4]#[N:5])=[C:2]([O:13][CH3:12])[N:9]=[C:8]([CH3:10])[CH:7]=1
Reactant: C[O-]
Reactant: Cc1cc(O)c(C#N)c(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)cc(O)c1C#N
Temperature: 60 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
A mixture of 2-chloro-4-hydroxy-6-methylnicotinonitrile (2.0 g, 11.9 mmol), sodium methanolate (3.2 g, 59.5 mmol) in methanol (20 mL) was stirred at 60° C. overnight under N2. The mixture was quenched with HCl (1M) to pH=2. It was partitioned between water (500 mL) and ethyl acetate (500 mL), the organic layer was dried and concentrated to afford 4-hydroxy-2-methoxy-6-methylnicotinonitrile (2.0 g brown solid, 100% yield).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH:16]=[O:17].[Cl-].[NH4+]>O1CCCC1>[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH:16]([OH:17])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1cc(F)ccc1F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1cccnc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol) of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran (2 ml) solution of 3-bromopyridine (286 μl, 3 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 60 minutes. Under ice cooling, 2,5-difluorobenzaldehyde (328 μl, 3 mmol) was added dropwise to the resulting brown solution. The temperature of the reaction mixture was raised gradually to room temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride and then, the mixture was extracted with ethyl acetate. The solvent was dried, followed by concentration under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1), whereby the title compound (296 mg, 45%) was obtained as needle crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:10]1[C:11]([CH3:21])=[CH:12][C:13]([C:16]([NH:18][CH2:19][OH:20])=[O:17])=[N:14][CH:15]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:20][CH2:19][NH:18][C:16]([C:13]1[CH:12]=[C:11]([CH3:21])[C:10]([CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:22]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:15][N:14]=1)=[O:17])(=[O:34])[CH3:33]
Reactant: Cc1cc(C(=O)NCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-N-(1-hydroxymethyl)-4-methylpyridine-2-carboxamide (200 mg, 0.44 mmol) obtained in Example 85 in pyridine (2 ml), acetic anhydride (2 ml) was added, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and then the residue was dissolved in ethyl acetate, and was washed with water. The solution was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. The fraction obtained from an elution with hexane:ethyl acetate=10:3 was concentrated under reduced pressure, washed with diethyl ether, and was collected by filtration, to obtain the title compound (86 mg, 0.17 mmol, 39%) as a white solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[C@H:10]([OH:41])[CH2:11][N:12]([CH2:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[CH:32]=1)[C:13]([O:15][CH2:16][CH:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=O)(C)(C)C.[ClH:49]>O1CCOCC1>[ClH:49].[NH2:8][C@@H:9]([CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[C@H:10]([OH:41])[CH2:11][N:12]([CH2:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[CH:32]=1)[C:13]([O:15][CH2:16][CH:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14]
Reactant: COc1cc(CN(C[C@@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)OCC2c3ccccc3-c3ccccc32)cc(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(CN(C[C@@H](O)[C@@H](N)CC2CCCCC2)C(=O)OCC2c3ccccc3-c3ccccc32)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2R,3S)-3-(t-Butoxycarbonylamino)-4-cyclohexyl-1-(N-(3,5-dimethoxybenzyl)-N-((9H-fluoren-9-yl)methoxycarbonyl)amino)butan-2-ol (255.3 mg, 0.39 mmol) was dissolved in 4 M HCl in dioxane (5 mL) and stirred at rt for 1 h. Removal of the solvent afforded (2R,3S)-3-amino-4-cyclohexyl-1-(N-(3,5-dimethoxybenzyl)-N-((9H-fluoren-9-yl)methoxycarbonyl)-amino)butan-2-ol hydrochloride (253 mg, quant) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1>CO.[Ni]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:18]([F:21])([F:19])[F:20])[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: [Ni]
Solvent: CO
Product: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reaction time: 24 h
Yield: 99.5 %

Procedure:
Into a solution 4-methyl-1-(4-nitro-2-(trifluoromethyl)benzyl)piperazine (1.5 g, 5 mmol) in MeOH (250 mL) was added Raney Nickel (0.15 g, 10 wt %). The suspension was stirred under hydrogen atmosphere (50 psi) for 24 hrs and monitored by TLC. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to yield the desired product (1.36 g, 100%).1H NMR (300 MHz, CDCl3) δ: 7.43-7.46 (1 H, d, J=9.0 Hz), 6.91 (1 H, s), 6.77-6.80 (1 H, d J=9.0 Hz), 3.77 (2 H, s), 3.54 (2 H, s), 2.53 (8H, brs), 2.34 (3 H, s).