Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.I[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[Br:13][C:14]1[CH:15]=[C:16]([C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]#[N:35])=[N:21]S(C(C)(C)C)=O)[CH:17]=[CH:18][CH:19]=1>O1CCCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:20]2([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[C:28]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]([NH2:35])=[N:21]2)[CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1ccccc1C#N
Reactant: Ic1ccncc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2ccccc21
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a solution of tert-butyllithium (1.7 M in pentane, 3.5 mL, 6.0 mmol) in tetrahydrofuran (20 mL) at −105° C. was a solution of 4-iodopyridine (0.68 g, 3.3 mmol) in tetrahydrofuran (10 mL) added drop wise. Next was a solution of N-[(3-bromophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2-sulfinamide (1.2 g, 3.0 mmol) in tetrahydrofuran (10 mL) added. After 1 h at −105° C. was the reaction quenched by addition of water. The resulting mixture was partitioned between ethyl acetate and water, the organic phase was dried over magnesium sulfate and evaporated. The residue was dissolved in methanol (25 mL) and treated with hydrochloric acid (2 M in diethylether, 3.0 mL, 6.0 mml) over night. The reaction mixture was concentrated and then partitioned between aqueous saturated sodium bicarbonate and chloroform, the organic phase was dried over magnesium sulfate and concentrated. Purification by column chromatography using a stepwise gradient of methanol in ethyl acetate (5-10%) with 1% triethylamine afforded the title compound (0.66 g, 61%). 1H NMR (CDCl3) δ 8.56-8.48 (m, 2 H), 7.60-7.38 (m, 6 H), 7.27-7.21 (m, 3 H), 7.21-7.14 (m, 1 H), 5.16 (br s, 2 H); MS (AP) m/z 364, 366 [M+1]+.
Reaction SMILES: [ClH:1].Cl.Cl.CNC(C1C2C=C(C3C(C)=CN=C(NCCCN4CCN(C)CC4)N=3)SC=2C=CC=1)=O.[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[C:55]([CH3:56])=[CH:54][N:53]=[C:52]([Cl:57])[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:37][CH2:36]1.[CH3:58][N:59]1[CH2:64][CH2:63][N:62]([CH2:65][CH2:66][NH2:67])[CH2:61][CH2:60]1>>[ClH:57].[ClH:1].[ClH:57].[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[C:55]([CH3:56])=[CH:54][N:53]=[C:52]([NH:67][CH2:66][CH2:65][N:62]5[CH2:63][CH2:64][N:59]([CH3:58])[CH2:60][CH2:61]5)[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:37][CH2:36]1
Reactant: Cc1cnc(Cl)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Reactant: CN1CCN(CCN)CC1
Agent: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCN(C)CC4)ncc3C)cc12
Agent: Cl
Product: Cc1cnc(NCCN2CCN(C)CC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of 2-{5-methyl-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide tri-hydrochloride, the title compound is synthesized from [2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 2-(4-methylpiperazin-1-yl)-ethylamine and isolated as a yellow solid. ES+(m/z) 451 [M(free base)+H].
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1.[CH3:17][C@H:18]1[CH2:23][NH:22][CH2:21][CH2:20][NH:19]1.Cl.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.O>[CH3:17][C@@H:18]1[NH:19][CH2:20][CH2:21][N:22]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)[CH2:23]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C[C@H]1CNCCN1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2ccc(C#N)cn2)CCN1
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.2 %

Procedure:
Triethylamine (4.13 g, 3 mL, 40.8 mmol, 4 eq) is added to a solution of 6-chloro-nicotinonitrile (1.38 g, 10 mmol, 1 eq), (S)-2-methyl-piperazine (1.00 g, 10 mmol, 1 eq) in DMF (15 mL), and the resulting solution is stirred at rt for 14 h. A white precipitate of triethylamine hydrochloride forms in the course of the reaction. Water (15 mL) and EtOAc (100 mL) are added, the organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure to a white residue. The solid is further dried under high vacuum to yield the desired product as a white solid (1.4 g, 69%).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([NH:14][C:15](OC)=[O:16])[C:11]([F:13])=[CH:12][C:7]=2[S:6][C:5]1=[O:19])([CH3:3])[CH3:2].[H-].[Na+].[NH2:22]/[C:23](/[C:30]([F:33])([F:32])[F:31])=[CH:24]\[C:25]([O:27]CC)=O.O>CN(C)C=O>[CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([N:14]3[C:25](=[O:27])[CH:24]=[C:23]([C:30]([F:31])([F:32])[F:33])[NH:22][C:15]3=[O:16])[C:11]([F:13])=[CH:12][C:7]=2[S:6][C:5]1=[O:19])([CH3:3])[CH3:2]
Reactant: COC(=O)Nc1cc2c(cc1F)sc(=O)n2C(C)C
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1c(=O)sc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Yield: 41.8 %

Procedure:
To a solution of 3-isopropyl-6-fluoro-5-methoxycarbonylamino -2(3H)-benzothiazolone (2.8 g) in N,N-dimethylformamide (10 g), sodium hydride (0.4 g) and ethyl 3-amino-4,4,4-trifluorocrotonate (0.9 g) were added, and the resultant mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by column chromatography to give 1-[3-isopropyl-6-fluoro-2(3H) -benzothiazolon -5-yl]-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine -2,6-dione (0.8 g).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>>[CH3:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCCCN
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: COCCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 75.5-76.8° C. and MS: m/e=298 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and 4-methoxy-butylamine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7](Cl)(=[O:9])[CH3:8].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)([O-:13])=[O:12]>ClCCl>[C:7]([N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:19][CH:18]=2)[CH2:21][CH2:22]1)(=[O:9])[CH3:8]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 722.1 %

Procedure:
Powdered potassium carbonate (276 mg, 2 mmol) and then acetyl chloride (0.14 mL, 2 mmol) were added to a solution of 1-(4-nitrophenyl) piperazine (2.1 g, 1 mmol) (Acros Organics) in dichloromethane (75 mL). The mixture was stirred at room temperature overnight and then further quantities of powdered potassium carbonate (500 mg, 3.6 mmol) and acetyl chloride (0.2 mL, 2.8 mmol) were added. The mixture was stirred at room temperature overnight, then it was filtered and the filter cake was washed with dichloromethane. The solvent was evaporated from the filtrate, and the residue was chromatographed (0-66% acetone/dichloromethane) to give 1-acetyl-4-(4-nitrophenyl)piperazine (1.8 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=1)[O:5][CH2:6][CH2:7][NH:8]C(=O)OC(C)(C)C.Cl.[OH-].[Na+]>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=1)[O:5][CH2:6][CH2:7][NH2:8]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(F)cc(S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)cc(OCCN)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.6 %

Procedure:
A mixture of tert-butyl 2-[3-fluoro-5-(methylsulfonyl)phenoxy]ethyl-carbamate (1.4 g, 4.2 mmol) in EtOH (18 ml) was added HCl (1.25 M in EtOH, 6 ml). The mixture was stirred at ambient temperature for 20 h. The aqueous phase was made basic by addition of aqueous NaOH (1 M, 50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic phase was washed with brine (75 ml), dried (Na2SO4) and evaporated to yield the title compound (0.77 g, 77%). MS m/z (relative intensity, 70 eV 298 (M+, 18), 296 (M+, 18), 109 (bp), 107 (99), 82 (15).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>C(Cl)Cl>[CH3:18][O:17][C:15](=[O:16])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][CH2:11][C:12]([N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[CH2:21][O:20][CH3:19])=[O:14]
Reactant: COC(=O)C(CCC(=O)O)NC(=O)OC(C)(C)C
Reactant: COC[C@@H]1CCCN1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: COC[C@@H]1CCCN1C(=O)CCC(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.9 %

Procedure:
To a mixture of 4-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (1.05 g, 4 mmol), (S)-2-(methoxymethyl)-pyrrolidine (0.46 g, 4 mmol), and 1-hydroxybenzotriazole hydrate (HOBt hydrate, 0.54 g, 4 mmol) in CH2Cl2 (10 mL) was added EDC (0.77 g, 4 mmol). The reaction mixture was stirred at ambient temperature for 12 h, diluted with CH2Cl2 (40 mL), washed sequentially with saturated aqueous sodium bicarbonate (20 mL), 0.5 N aqueous citric acid (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a crude viscous oil. The crude oil was purified by flash chromatography (silica gel, 50% ethyl acetate/hexanes) to give the title compound (1.36 g, 95%) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH3:31][N:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)N>>[CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:32]([CH3:31])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3)CC2)c1
Reactant: CN(N)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidinyl]phenyl}propanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 495.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([CH:17]([CH3:19])[CH3:18])[N:3]=1.[CH3:20][SH:21].[Na].O>CCOCC.CS(C)=O>[CH3:20][S:21][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([CH:17]([CH3:19])[CH3:18])[N:3]=1
Reactant: CCC(CC)Nc1nc(Cl)nc(C(C)C)c1[N+](=O)[O-]
Reactant: CS
Agent: [Na]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: CCC(CC)Nc1nc(SC)nc(C(C)C)c1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A solution of 14.4 g (50 m-moles) of 2-chloro-4-(3-pentylamino)-5-nitro-6-isopropyl-pyrimidine in 50 ml of ether is added dropwise to a suspension of 3.5 g (50 m-moles) of sodium methylmercaptan in 50 ml of dimethyl sulphoxide. The reaction mixture is stirred for 1 hour at 20° C, then poured into 0.5 liter of water and extracted with ether. The ethereal extracts are dried over MgSO4, dried and evaporated to yield 14 g of 2-methylthio-4-(3-pentylamino)-5-nitro-6-isopropyl-pyrimidine as an oil (nD20 : 1.5757).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:12]([NH:20][C:21]1[CH:33]=[C:32](Br)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:12]([NH:20][C:21]1[CH:33]=[C:32]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1cc[nH]c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-n2cccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
0.019 mL of 1H-pyrrole, 0.12 g of cesium carbonate, 5.1 mg of tris(dibenzylideneacetone)dipalladium(0), 1.6 mg of tri-tert-butylphosphine tetrafluoroborate and 4.4 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl were added to 1.4 mL of toluene solution containing 10 mg of tert-butyl 2-(benzamido)-4-bromobenzoate at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 3 hours. After the reaction mixture was cooled to room temperature, 5.1 mg of tris(dibenzylideneacetone)dipalladium(0), 1.6 mg of tri-tert-butylphosphine tetrafluoroborate and 4.4 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium, chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane; ethyl acetate=10:1] to obtain 60 mg of tert-butyl 2-(benzamido)-4-(1H-pyrrol-1-yl)benzoate as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([CH2:23][CH3:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:17]2[CH:22]=[C:21]([CH2:23][CH3:24])[S:20][C:18]=2[N:19]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: CCc1cc2c(Cl)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(OC)c(OC)c3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dimethoxybenzylamine with 2,4-dichloro-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-ethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].C([O:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][CH2:31]2)[CH2:25][CH2:24]1)=O)(C)(C)C>>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:19]([NH:21][CH2:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]3([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][CH2:31]3)[CH2:27][CH2:28]2)=[O:18])[C:5]1=[O:13])([CH3:3])[CH3:2]
Reactant: COC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCC1
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Product: COC(=O)C1(CN2CCC(CNC(=O)n3c(=O)n(C(C)C)c4ccccc43)CC2)CCC1

Procedure:
The title compound was prepared according to the procedure described in Step 6 of Example 1 from 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and methyl 1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cyclobutanecarboxylate (step 2 of Example 7).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4](SC)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1>C(O)CCCC>[OH:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: CSc1ncc(C#N)c(O)n1
Solvent: CCCCCO
Product: COc1cccc(Nc2ncc(C#N)c(O)n2)c1

Procedure:
4-Hydroxy-2-(methylthio)pyrimidine-5-carbonitrile (3 mmol) and m-anisidine (3 mmol) in pentan-1-ol was refluxed for 40 h under nitrogen. The reaction mixture was concentrated in vacuo. The residue was washed with water and dried to afford 4-hydroxy-2-(3-methoxyphenylamino)pyrimidine-5-carbonitrile.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15][C@@H:16]2[O:33][C@H:32]([CH2:34][O:35]C(=O)C)[C@H:27]([O:28]C(=O)C)[C@H:22]([O:23]C(=O)C)[C@H:17]2[O:18][CH2:19][CH:20]=[CH2:21])[C@@H:8]([CH2:39][O:40]C(=O)C)[O:7][C@@H:6]1Cl)(=O)C.[CH3:45][OH:46]>>[CH2:19]([O:18][C@@H:17]1[C@@H:22]([OH:23])[C@@H:27]([OH:28])[C@@H:32]([CH2:34][OH:35])[O:33][C@H:16]1[O:15][C@@H:9]1[C@@H:8]([CH2:39][OH:40])[O:7][C@@H:6]([O:46][CH3:45])[C@H:5]([OH:4])[C@H:10]1[OH:11])[CH:20]=[CH2:21]
Reactant: C=CCO[C@H]1[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](Cl)O[C@@H]2COC(C)=O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CO
Product: C=CCO[C@H]1[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](OC)O[C@@H]2CO)O[C@H](CO)[C@H](O)[C@@H]1O
Reaction time: 48 h
Yield: 67 %

Procedure:
Chloride 3 (4.4 g, 6.74 mmol) was dissolved in dry MeOH and left at room temperature for two days. The mixture was neutralized with Dowex 50W (H+) resin, the suspension was filtered and the filtrate was crystallized from EtOH to give 4 (1.8 g, 67%), [α]D -1.8° (c 0.2, H2O), m.p. 22-223° C.; 1H NMR (D2O) δ 5.99 (m, 1H, Hc), 5.36 (m, 1H, Hb), 5.28 (m, 1H, Ha), 4.49 (d, 1H, J1',2' =7.9 Hz, H-1'), 4.41 (d, 1H, J1,2 =8.0 Hz, H-1), 4.34 (m, 1H, Hd), 4.26 (m, 1H, He), 3.99 (broad d, 1H, H-6a), 3.83-3.62 (m, 8H, H-3, H-4, H-5, H-6b, H-3', H-5', H-6', H-6'b), 3.58 (s, 3H, Me), 3.4dd, 1H, J2',3' =10.0 Hz, H-2'), 3.32 (m, H-2). Cale'd for C16H28O11 (396.38) C, 48.48; H, 7.12. Found C, 48.47, H, 7.12.
Reaction SMILES: [H-].[Na+].C1(C)C=CC(S(O[C@H:13]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][C@@H:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:16]#[N:17])(=O)=O)=CC=1.C([C@@]1(C2C=CC(OC)=CC=2)C[C@@H]1CCCCCC)#N>CN(C=O)C>[C:16]([C@:15]1([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH2:14][C@@H:13]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])#[N:17]
Reactant: CCCCCC[C@H](C[C@H](C#N)c1ccc(OC)cc1)OS(=O)(=O)c1ccc(C)cc1
Agent: CCCCCC[C@H]1C[C@@]1(C#N)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC[C@H]1C[C@]1(C#N)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a dispersion of 18 mg (0.75 mmol) of sodium hydride in 10 ml of DMF was added, with cooling with ice, a solution of 300 mg (0.70 mmol) of (2S,4R)-4-p-toluenesulfonyloxy-2-(4-methoxyphenyl)-decanenitrile in 10 ml of DMF. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized by adjusting the pH thereof to 7 with diluted hydrochloric acid, and then subjected to extraction with 250 ml of ether. The resulting ether solution was washed with water, dried with anhydrous magnesium sulfate, and then concentrated. The isomers in the residue were separated by silica gel column chromatography (Kieselgel 60, hexane/ethyl acetate=9/1) and then further separated and purified by high-pressure liquid chromatography for separation (Tosoh Corporation, Japan; Silica-60, 21.5 mmID×300 mm, hexane/ethanol=100/1). Thus, 163 mg (yield 90%, optical purity 94% ee) of a nonpolar product, (1R,2S)-1-cyano-2-hexyl-1-(4-methoxyphenyl)cyclopropane and 7 mg (yield 4%) of a polar product, (1S,2S)-1-cyano-2-hexyl-1-(4-methoxyphenyl)cyclopropane, were obtained.
Reaction SMILES: C[O-].[Na+].C([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][C:9]=1/[CH:16]=[CH:17]/[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1)(=O)C>CO>[OH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][C:9]=1/[CH:16]=[CH:17]/[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1
Reactant: COC(=O)c1ccc(/C=C/c2cc(SC)ccc2OC(C)=O)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(/C=C/c2cc(SC)ccc2O)nc1
Temperature: 60 °C

Procedure:
Sodium methoxide (2.29 g, 42.4 mmol) was added to a suspension of 6-[E-2-(-2-acetoxy-5-methylsulfanylphenyl)-vinyl]-nicotinic acid, methyl ester (13.26 g, 38.55 mmol) in methanol (200 mL). The mixture was heated at 60° C. for 3 hours. The reaction mixture was concentrated in vacuo and water was added followed by enough hydrochloric acid (1 M) to acidify the solution. The resultant precipitate was isolated by filtration, washed with water and dried in vacuo. This procedure afforded the product as a yellow solid (8.8 g, 76%) m/z (LCMS) (ESI+) 302 (MH+); (ESI−) 300 (M—H).
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1.B.[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1.CO>C1COCC1>[C:18]1([CH:22]([NH:3][CH2:2][CH2:7][CH:6]2[CH2:7][CH2:2][N:3]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=3)[CH2:4][CH2:5]2)[C:11]2[CH:10]=[CH:9][CH:14]=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=[CH:20][CH:19]=1
Reactant: CC1CCCCN1Cc1ccc(F)c(F)c1
Reactant: C1CCOC1
Agent: B
Solvent: CO
Product: Fc1ccc(CN2CCC(CCNC(c3ccccc3)c3ccccc3)CC2)cc1F
Temperature: 25 °C
Yield: 90 %

Procedure:
To the solution of 4-[2-diphenylmethyl)aminocarbonyl]methyl-1-[(3,4-difluorophenyl)methyl]piperidine (0.12 g, 0.28 mmol) in dry THF 20 ml was added 1M BH3/THF (1.0 ml). The reaction solution was refluxed for 6 hours. After the solution was cooled to room temperature, MeOH (5 ml) was added slowly. The solvent was removed under reduced pressure. 10% HCl/MeOH (10 ml) was added into the residue and the solution was refluxed for 1 hour. Solid NaHCO3 was added after MeOH was evaporated. The mixture was extracted with EtOAc. The combined organic phase was dried over Na2SO4 and evaporated to give the crude product, which was purified by chromatography (Hexane/EtOAc/Et3N=1/2/1%) to a white solid, 0.1 g (90% yield) (“Procedure E”). 1H NMR (CD3Cl) δ 7.39-6.99 (13H, m, Ar—H), 4.79 (1H, s, Ph2CH), 3.39 (2H, s, F2PhCH2), 2.80-2.76 (2H, d, J=11.1 Hz, N(CH)2), 2.60-2.55 (2H, t, J=7.0 Hz, NCH2), 1.93-1.86 (2H, t, J=11.1 Hz, N(CH)2), 1.62-1.58 (2H, d, J=12 Hz), 1.49-1.42 (2H, q, J=6.3 Hz, NCH2CH2), 1.35-1.31 (1H, m, NCH2CH2CH(CH2)2), 1.26-1.19 (2H, t, J=12.0 Hz). The free base was converted into its HCl salt, m.p.=280-281° C. Anal: (C27H30N2F2.2HCl.0.25H2O) Calculated: C, 65.12; H, 6.85; N, 5.62; Found: C, 65.13; H, 6.80; N, 5.28.