Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12](O)[CH:11]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[N+:16]([C:15]1[CH:10]=[CH:11][C:12]([O:8][C:7](=[O:9])[CH2:6][CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:13][CH:14]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)SCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(=O)SCCC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred ice cold solution of ethyl acetate (75 ml.) containing 3-(acetylthio)propanoic acid (7.4 g. 50 mmol.) and p-nitrophenol (8.4 g., 60 mmol.) dicyclohexylcarbodiimide (10.3 g., 50 mmol.) is added in portions. After thirty minutes, the ice bath is removed and the solution stirred at room temperature overnight. The precipitated dicyclohexylurea is filtered off, ethyl acetate evaporated, and the residue dissolved in ethanol. The 3-(acetylthio)propanoic acid p-nitrophenyl ester crystallizes out, yield 8.6 g. (63.7%), m.p. 71°-73°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].Cl[C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[O:23])=[CH:20][NH:19][C:15]=2[N:16]=[CH:17][N:18]=1>>[CH3:8][NH:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:1][C:13]2[C:14]3[C:21]([C:22](=[O:23])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[CH:20][NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:3]=1
Reactant: Cc1ccccc1C(=O)c1c[nH]c2ncnc(Cl)c12
Reactant: CNC(=O)c1cccc(N)c1
Product: CNC(=O)c1cccc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4C)c23)c1

Procedure:
N-Methyl-3-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzamide was synthesized using 3-amino-N-methylbenzamide and ((4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone according to the general procedure A. An off-white solid was obtained. M.p.>300° C.; 400 MHz 1HNMR (DMSO-d6) δ 11.47 (s, 1H), 8.48-8.47 (m, 2H), 8.24-8.20 (m, 2H), 7.60 (s, 1H), 7.52-7.45 (m, 4H), 7.40-7.32 (m, 2H), 2.86 (d, J=4.4 Hz, 3H), 2.34 (s, 3H); LCMS [M+H] 386.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20]>>[NH2:16][C:15]1[CH:14]=[C:13]([C:19]([F:21])([F:22])[F:20])[C:12]([O:11][CH3:10])=[CH:18][C:17]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: O=Cc1ccccc1Cl
Reactant: COc1ccc(N)cc1C(F)(F)F
Product: COc1cc(C(=O)c2ccccc2Cl)c(N)cc1C(F)(F)F

Procedure:
(2-amino-5-methoxy-4-trifluoromethylphenyl)-(2-chlorophenyl)-methanone (Xee) was prepared by reacting 2-chlorobenzaldehyde with 0.0263 moles of 4-methoxy-3-trifluoromethyl aniline in a manner analogous to Example 1. MH+/Z=330.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:11][C:10]3[CH:13]=[CH:14][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)[CH2:28][CH2:27]2)[CH:21]=1)=[O:18]
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(N4CCOCC4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(4-morpholinyl)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 422.5 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([F:25])[C:20]=1[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:33]1[N:38]=[CH:37][C:36]([CH2:39][O:40][CH3:41])=[CH:35][N:34]=1>CS(C)=O.CCOC(C)=O>[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([F:25])[C:20]=1[S:21]([CH3:24])(=[O:22])=[O:23])[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:13][CH2:14][N:15]([C:33]2[N:38]=[CH:37][C:36]([CH2:39][O:40][CH3:41])=[CH:35][N:34]=2)[CH2:16][CH2:17]1
Reactant: COCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1c(F)cc(COC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3COCc3cc(F)c(S(C)(=O)=O)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.9 %

Procedure:
4-((1R,2R)-2-(((3,5-difluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidine hydrochloride (Step C product, 100 mg, 0.25 mmol) was dissolved in DMSO (3 ml) at RT under N2 and Cs2CO3 (288 mg, 0.884 mmol) was added. The mixture was stirred at RT for 5 min and 2-chloro-5-methoxymethylpyrimidine (Intermediate 18, 48 mg, 0.3 mmol) in DMSO (0.5 mL) was added. The mixture was stirred at 60° C. overnight. The mixture was diluted with EtOAc, washed with sat. NH4Cl, dried over MgSO4, and evaporated to dryness. The crude material was purified by preparative TLC (60% EtOAc in hexane) to afford 50.5 mg (41.5%) of the desired product. LC/MS (m/z): 482 (M+H)±1H NMR (500 MHz, CDCl3) δ 8.30 (s, 2H), 7.15 (dd, 2H), 4.80-4.64 (m, 4H), 4.25 (s, 2H), 3.60 (m, 2H), 3.37 (s, 3H), 3.35 (s, 3H), 2.93-2.80 (m, 2H), 1.96-1.80 (m, 2H), 1.40-1.10 (m, 4H), 0.94-0.71 (m, 2H), 0.12-0.08 (m, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1C.[CH3:12][O:13][C:14](=[O:21])[C@H:15]([CH2:17][CH2:18][S:19][CH3:20])[NH2:16].C(N(CC)CC)C>CN1CCCC1=O>[CH3:12][O:13][C:14](=[O:21])[CH:15]([NH:16][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1)[CH2:17][CH2:18][S:19][CH3:20]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CCSC)Nc1ccc([N+](=O)[O-])cc1
Temperature: 90 °C

Procedure:
1 g of 4-fluoro-3-methylnitrobenzene, 0.694 g of L-methionine methyl ester and 1.09 ml of triethylamine were added to a solution of 5 ml of N-methylpyrrolidinone. The reaction medium was heated at 90° C. for 7 hours and, after cooling to room temperature, was poured into an ice water mixture. The reaction medium was then extracted with ethyl acetate and the organic phase was dried and concentrated to dryness. After purification by chromatography on a column of silica, 4-methylsulfanyl-2-(4-nitrophenylamino)butyric acid methyl ester (28) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C([O-])([O-])=[O:20].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[C:3]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:17][CH2:18]3)[NH:13][N:12]=2)=[N:4][C:5]([C:8]([NH2:9])=[O:20])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
The mixture of 5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-2-carbonitrile (1.0 g, 3.85 mmol, 1.0 eq) and K2CO3 (2.0 g, 14.49 mmol, 3.8 eq) in DMSO (20 mL) was stirred at room temperature, and 30% hydrogen peroxide (3 mL) was added dropwise. The reaction mixture was stirred at rt for 1 h, water was added and the suspension was filtered to afford 5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-2-carboxamide (950 mg, 89%). LC-MS (m/z)=279.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCCO)C>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Solvent: CCOCCO
Product: O=[N+]([O-])c1ccc(Cl)cc1NC1CCN(Cc2ccccc2)CC1
Yield: 35.3 %

Procedure:
A solution of 38.4 g of 2,4-dichloro-1-nitrobenzene in 160 ml of 2-ethoxyethanol is heated to 100° C. A solution of 152.23 g of N-benzyl-4-aminopiperidine in 40 ml of 2-ethoxyethanol is then added slowly. The mixture is refluxed for 5 hours. The solvent is evaporated off under vacuum, the residue is taken up with H2O, extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using isopropyl ether as the eluent to give 24.4 g of the expected product after crystallization from isopropyl ether. M.p.=84° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19](=S)[NH:20][S:21]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26][CH3:27])(=[O:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[CH3:31][NH2:32]>C(#N)C.Cl[Hg]Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:32][CH3:31])=[N:20][S:21]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26][CH3:27])(=[O:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCN(CC)S(=O)(=O)NC(=S)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reactant: CN
Agent: Cl[Hg]Cl
Solvent: CC#N
Product: CCCN(CC)S(=O)(=O)N=C(NC)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reaction time: 4 h
Yield: 77 %

Procedure:
Part B: To a stirred suspension of 3-(4-chlorophenyl)-N-(((ethyl)propyl-amino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-thiocarboxamide (2.32 gram, 5 mmol) in acetonitrile (20 mL) is added cold methylamine (4 mL). To the resulting solution is added a solution of HgCl2 (1.5 gram) in acetonitrile (10 mL). The resulting black suspension is stirred for four hours. The precipitate is removed by filtration. The filtrate is concentrated in vacuo, dissolved in dichloromethane and successively washed with aqueous 0.5 N NaOH solution and water, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil is crystallized from diethyl ether to give 3-(4-chlorophenyl)-N′-(((ethyl)propylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (1.78 gram, 77% yield). Melting point (MP):129-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)[C:4]=2[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](C=O)[CH:23]=1.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH:17]3[CH3:30])[C:4]=2[CH:3]=1.[ClH:1]
Reactant: O=Cc1cccnc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Clc1ccc2c(c1)N(C1CCCNC1)c1ccccc1S2
Agent: [Na+]
Product: CC1C(N2c3ccccc3Sc3ccc(Cl)cc32)CCCN1c1cccnc1
Product: Cl

Procedure:
2-chloro-10-(1-pyridin-3-yl-methylpiperidin-3-yl)-10H-phenothiazine was prepared by treatment of 2-chloro-10-piperidin-3-yl-10H-phenothiazine (240 mg, 0.757 mmol) and 3-pyridinecarboxaldehyde (81 mg, 0.757 mmol) with sodium triacetoxyborohydride (224 mg, 1.06 mmol) to provide after treatment with ethereal HCl, the sub-titled compound (136 mg, 41%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:26])[CH2:6][CH2:7][NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][C:15]=1[C:16]([F:19])([F:18])[F:17])=[O:10]>C1COCC1.CO.O>[C:20]1([C:13]2[O:14][C:15]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:9]([NH:8][CH2:7][CH2:6][C:5]([OH:26])=[O:4])=[O:10])[N:12]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCNC(=O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CCNC(=O)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
NaOH (309.7 mg, 7.7 mmol) was added to 3-[(2-phenyl-5-trifluoromethyloxazole-4-carbonyl)amino]propionic acid methyl ester (265 mg, 0.77 mmol) dissolved in THF/MeOH/water (25 mL, 4:2:1). The reaction mixture was stirred at 25° C. for 12 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH 2 and extracted with ethyl acetate. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the desired compound (250 mg, 98%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[C:24]1([N:30]=[C:31]=[S:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:31](=[S:32])[NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: S=C=Nc1ccccc1
Reactant: O=C1c2ccccc2SCCC1(CO)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2SCCC1(CO)COC(=S)Nc1ccccc1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]thiepin-5-one (252 mg, 1.06 mmol) in 13 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.16 ml, 1.16 mmol) and phenyl isothiocyanate (277 μl, 2.3 mmol). The mixture was stirred at 80° C. for 36 hours, concentrated and purified by column chromatography on silica gel (eluent: 4:1 diisopropyl ether/hexane). The product was obtained in a yield of 48 mg (12%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=O)=[CH:4][C:3]=2[O:2]1.S(Cl)([Cl:16])=O>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([Cl:16])=[O:13])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
3,4-methylenedioxyphenyl acetic acid, 50.4 grams, 0.28 mole, was reacted with an excess amount of thionyl chloride, 58 grams, 0.49 moles, in a 250 milliliter round bottom flask at 60° C. for 3 hours. The product mixture resulting was cooled to room temperature, about 25° C., and any excess thionyl chloride was removed with a water aspirator. Pure, about 99.5 percent purity, 3,4-methylenedioxyphenylacetylchloride was isolated as a light reddish oil by vacuum distillation yielding 48.2 grams, an 80 percent yield of product. The boiling point of the aforementioned product was 116° C. at 1.4 millimeters of mercury. IR (neat): 1,795 cm-1 (C=O).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11]C)=O)[CH:4]=1.[Cl-].[NH4+:14].CCOC(C)=O.O>N>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH2:14])=[O:11])[CH:4]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: [NH4+]
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 214.4 %

Procedure:
To a stirred mixture of methyl 4-chloro-2-pyridinecarboxylate hydrochloride (1.0 g, 4.81 mmol) dissolved in conc. aqueous ammonia (32 mL) was added ammonium chloride (96.2 mg, 1.8 mmol, 037 equiv.), and the heterogeneous reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was poured into EtOAc (500 mL) and water (300 mL). The organic layer was washed with water (2×300 mL) and a saturated NaCl solution (1×300 mL), dried (MgSO4), concentrated in vacuo to give 4-chloro-2-pyridinecarboxamide as a beige solid (604.3 mg, 80.3%): TLC (50% EtOAc/hexane) Rf 0.20; 1H-NMR (DMSO-d6) δ 8.61 (d, J=5.4 Hz, 1H), 8.20 (broad s, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.81 (broad s, 1H), 7.76 to 7.73 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][OH:22])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+].O1CCCC1>CO.C(#N)C>[NH2:29][CH:12]([C:10]1[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][OH:22])[CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCCC(CO)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCCC(CO)C1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[3-(hydroxymethyl)piperidin-1-yl]quinolin-7-yl}ethanone (0.0235 g, 0.0737 mmol) and ammonium acetate (0.0568 g, 0.737 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.184 mL, 0.184 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C17H23ClN3O (M+H)+: m/z=320.2; Found: 320.2.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:28][C:25]=2C=O)=[CH:18][C:17]=1[O:38][CH3:39])([CH3:14])[CH3:13]>C(Cl)Cl>[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:28][C:25]=2[OH:6])=[CH:18][C:17]=1[O:38][CH3:39])([CH3:13])[CH3:14]
Reactant: COc1cc(C#Cc2cc(OC)c(OC(C)C)cc2C=O)ccc1OC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc(C#Cc2cc(OC)c(OC(C)C)cc2O)ccc1OC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
m-Chloroperoxybenzoic acid [1.2 g, ALDRICH, 50% (remainder 3-chlorobenzoic acid and water), ca. 7.0 mmol] was added in portions over 0.25 h to a magnetically stirred mixture of 2-[(4-isopropoxy-3-methoxy-phenyl)ethynyl]-5-isopropoxy-4-methoxybenzaldehyde (2.20 g, 5.75 mmol) and KHCO3 (1.73 g, 17.3 mmol) in CH2Cl2 (50 mL) maintained at 0° C. (ice-bath). The resulting slurry was stirred for a further 1 h between 0° C. and 18° C. then filtered through Celite® and the solids thus retained rinsed with CH2Cl2 (1×50 mL). The combined filtrates were concentrated under reduced pressure and the residue treated with NH3 (30 ml of a saturated methanolic solution). After 1 h at 18° C. the reaction mixture was concentrated under reduced pressure and the residue redissolved in CH2Cl2 (200 mL) then concentrated on to silica gel (8 g, 400-200 mesh). The resulting powder was loaded on top of a column of silica (40-10 mesh TLC grade, 10 cm wide×5 cm long) and eluted with 2:1, 1:1 and 1:2 hexane/CH2Cl2 then neat CH2Cl2 (250 ml of each). The appropriate fractions (Rf 0.3 in 1:2 hexane/CH2Cl2) were concentrated under reduced pressure to give the title compound (1.97 g, 92%) as white crystalline masses, mp 130-1° C. IR (KBr disc, cm−1) 3404, 2981, 2935, 1620, 1573, 1513, 1467, 1450, 1418, 1383, 1373, 1330, 1269, 1240, 1214, 1166, 1135, 1113, 951. 1H NMR (300 MHz, CDCl3) δ 7.03 (dd, J=1.8, 8.4 Hz, 1H), 7.00 (d, J=2.1 Hz, 1H), 6.87 (s, 1H), 6.81 (d, J=8.4 Hz, 1 H), 6.53 (s, 1H), 5.81 (s, 1H), 4.52 (septet, J=6.0 Hz, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 1.35 (d, J=6.0 Hz, 12H). 13C NMR+APT (75.5 MHz, CDCl3) δ 151.8 (C), 149.7 (C), 149.3 (C), 147.8 (C), 143.6 (C), 124.6 (CH), 115.0 (C), 114.7 (CH), 114.6 (CH), 114.3 (CH), 102.0 (CH), 100.1 (C), 94.7 (C), 82.2 (C), 71.1 (CH), 71.0 (CH), 56.4 (CH3), 55.7 (CH3), 21.9 (CH3), 21.8 (CH3). MS (70 eV) m/z (%): 370 (M+·), 355 (2, M+·-CH3), 328 (18, M+·-CH(CH3)2], 327 (20, M+·CH2CHCH3), 286 (100, M+·-2×CH2CHCH3), 271 (42, M+·-2×CH2CHCH3—CH3). Anal. Calcd for C22H26O5 C, 71.33; H, 7.07. Found: C, 70.91; H, 7.24.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][C:8]([CH2:10][S:11][CH2:12][CH2:13]N)=[CH:7][CH:6]=1)[CH3:3].[CH:15]1([NH:23][C:24](SC)=[CH:25][N+:26]([O-:28])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(#[N:33])C>>[CH3:3][N:2]([CH2:4][C:5]1[S:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][N:23]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:24]([NH2:33])=[CH:25][N+:26]([O-:28])=[O:27])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)s1
Reactant: CC#N
Reactant: CSC(=C[N+](=O)[O-])NC1CCCCCCC1
Product: CN(C)Cc1ccc(CSCCN(C(N)=C[N+](=O)[O-])C2CCCCCCC2)s1

Procedure:
A solution of 2-[[[5-(dimethylamino)methyl-2-thienyl]methyl]thio]ethanamine (1.00 g) and 1-cyclooctylamino-1-methylthio-2-nitroethene (1.17 g) in acetonitrile (4 ml) was heated at reflux temperature for 8 days. The solvent was then evaporated in vacuo and the residue partitioned between water (25 ml) and ethyl acetate (25 ml). The aqueous phase was then extracted with ethyl acetate (2×25 ml) and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography on alumina using pentane/chloroform mixtures as eluant to give N-[2-[[5-(dimethylamino)methyl-2-thienyl]methyl]thioethyl]-N-cyclooctyl-2-nitro-1,1-ethenediamine (0.62 g) as an orange oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]3[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=3[Cl:37])=[CH:25][CH:24]=2)(=O)=O)=CC=1>O1CCCC1>[Br:36][C:34]1[CH:33]=[CH:32][C:31]([Cl:37])=[C:30]([CH:35]=1)[CH2:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][O:6][C@@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[CH:28][CH:27]=1
Reactant: O[C@@H]1CCOC1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(Cc3cc(Br)ccc3Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1Cc1ccc(OCCO[C@@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a stirred solution of (R)-tetrahydrofuran-3-ol (320 mg, 3.63 mmol) in dry tetrahydrofuran (10 mL) was added sodium hydride (145 mg, 3.63 mmol, 60%) slowly under 0° C. The reaction was stirred at this temperature for 30 min and then 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl 4-methylbenzenesulfonate (intermediate AB) (300 mg, 0.61 mmol) was added. The reaction was warmed to room temperature and then heated to reflux overnight. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to a yellow oil. The crude oil was purified by flash chromatography to get 200 mg of colorless oil (80% yield).
Reaction SMILES: CO[CH:3]([O:15]C)[C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[NH2:7].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl.CCOCC>[CH:3]([C:4]1[CH:5]=[C:6]([NH:7][C:24](=[O:26])[CH3:25])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)=[O:15]
Reactant: CC(=O)Cl
Reactant: COC(OC)c1cc(N)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)Nc1cc(C=O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-(dimethoxymethyl)-5-(trifluoromethyl)aniline in dichloromethane (5 ml) at 0° C., triethyl amine (0.2 ml) was added followed by acetyl chloride. Reaction mixture was stirred at rt for 2 h. Then dichloromethane was removed under reduced pressure. Reaction mixture was diluted with ether, washed with water, brine and dried. Crude residue was column chromatographed to yield 170 mg of the amide. Then solvent was removed and the crude residue was column purified (40% ethylacetate/60% hexanes) to yield 100 mg of N-(3-(dimethoxymethyl)-5-(trifluoromethyl)phenyl)acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[F:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[F:37]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCO1
Product: N#Cc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCO2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-[5,6-difluoro-1-(tetrahydro-pyran-2-ylmethyl)-1H-benzoimidazol-2-yl]-phenol and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Brown powder (32%). MS (Turbo Spray): m/z=512.4 (M+H).