Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=2)[C:26](OC)=[O:27])[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1>ClCCl.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:24]=[C:25]([CH2:26][OH:27])[CH:30]=[CH:31][CH:32]=2)[CH2:15][CH:16]([OH:21])[C:17]([F:18])([F:19])[F:20])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCc1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a solution of methyl 3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate (197 mg, 0.00044 mol) in 2.0 mL of dichloromethane at −40° C. was slowly added a 1.0 M solution of lithium aluminum hydride in THF (1.1 mL, 0.0011 mol). The reaction mixture was stirred at −40° C. for 1 h, then diluted with ethyl acetate and quenched with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was determined to contain a significant amount of unreacted starting material by HPLC at this stage. The crude material was resubjected to the reaction conditions using 2 mL of anhydrous tetrahydrofuran and 1.0 M lithium aluminum hydride (1.3 mL, 0.0013 mol) at −40° C. for 1 h, then diluted with ethyl acetate and quenched with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 2:3 ethyl acetate:hexane to afford 99 mg (54%) of the desired 3-[[(3-phenoxyphenyl)-(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzenemethanol product as a white solid. Anal. calcd. for C23H22F3NO3: C, 66.18; H, 5.31; N, 3.36. Found: C, 65.98; H, 5.39; N, 3.22. HRMS calcd. 418.1630 [M+H]+, found: 418.1636. 1H NMR (C6D6) δ7.08-6.92 (m, 8H), 6.89-6.80 (m, 2H), 6.56 (s, 1H), 6.46 (d, 1H), 6.38 (d, 1H), 4.26 (s, 2H), 4.21 (d, 2H), 3.77 (appq, 1H), 3.52 (d, 1H), 1.92 (bs, 1H), 0.96 (bs, 1H). 19F NMR (C6D6) δ−78.91 (d, 3F).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH:20](C(O)=O)[CH2:19][C:18]2[CH:17]=[C:16]3[C:11]([O:12][C@@H:13]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[C:14](=[O:24])[NH:15]3)=[CH:10][C:9]=2[CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl.COC(=O)[C@@H](N)CC1C=CC(C2C=CC=CC=2)=CC=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:20][CH2:19][C:18]2[CH:17]=[C:16]3[C:11]([O:12][CH:13]([C:25]4[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:29][CH:30]=4)[C:14](=[O:24])[NH:15]3)=[CH:10][C:9]=2[CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Product: CC(C)OC(=O)N1CCc2cc3c(cc2C1)OC(c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Yield: 136.1 %

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-isopropyl ester (120 mg) was coupled with (S)-2-amino-3-biphenyl-4-yl-propionic acid methyl ester hydrochloride according to general procedure A to provide (S)-7-(S)-2-biphenyl-4-yl-1-methoxycarbonyl-ethylcarbamoyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid isopropyl ester (151 mg, LC/MS: m/z 825).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]3)[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[OH:22][CH:23]([CH3:26])[CH2:24][NH2:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[OH:22][CH:23]([CH3:26])[CH2:24][NH:25][C:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:10]2[NH:11][CH:12]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[N:9]=2)[CH2:18][CH2:17]1)=[O:21]
Reactant: CC(O)CN
Reactant: O=C(O)[C@H]1CC[C@H](c2nc(-c3cccc(Br)c3)c[nH]2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)CNC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(Br)c3)c[nH]2)CC1

Procedure:
The solution of trans-4-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-cyclohexyl-carboxylic acid (1.22 mmol), 2-hydroxy-propylamine(3.65 mmol) and BOP (1.22 mmol) in DMF (6 mL) was stirred overnight at room temperature. The mixture was diluted with water, extracted with EtOAc, washed with saturated NaHCO3, dried over Na2SO4, and concentrated under vacuum. The residue was purified with flash chromatography (90:10:1 CH2Cl2/MeOH/NH4OH) to give trans-4-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-cyclohexane-carboxylic acid (2-hydroxy-propyl) amide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9]O)[CH:6]=[C:5]([O:11][CH3:12])[N:4]=1.P(Br)(Br)[Br:14].CCCCC>C(Cl)Cl>[Br:14][CH2:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH3:12])[CH:6]=1
Reactant: BrP(Br)Br
Reactant: COc1cc(CO)cc(OC)n1
Solvent: ClCCl
Solvent: CCCCC
Product: COc1cc(CBr)cc(OC)n1
Reaction time: 10 h

Procedure:
1 g of (2,6-dimethoxypyridin-4-yl)methanol, prepared according to J. Heterocl. Chem., 1974, 11, 251, is dissolved in 20 ml of CH2Cl2, 0.84 ml of PBr3 is added and then the mixture is left stirring at AT for 10 hours. Pentane is added and the precipitate formed is filtered off, washed with pentane and then dried to produce 850 mg of the expected compound.
Reaction SMILES: [CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:19][C:18]([C:20]3[CH:28]=[C:27]4[C:23]([CH:24]=[C:25]([C:29]([OH:31])=O)[NH:26]4)=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>>[CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:19][C:18]([C:20]3[CH:28]=[C:27]4[C:23]([CH:24]=[C:25]([C:29]([N:65]5[CH2:70][CH2:69][O:68][CH2:67][CH2:66]5)=[O:31])[NH:26]4)=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc3cc(C(=O)O)[nH]c3c2)o1)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc3cc(C(=O)N4CCOCC4)[nH]c3c2)o1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-{5-[((S)-cyclohexyl-methylcarbamoyl-methyl)-carbamoyl]-furan-2-yl}-1H-indole-2-carboxylic acid (20 mg, 0.047 mmol) is added subsequently HATU (10 mg, 0.052 mmol), DIEA (0.026 mL, 0.142 mmol), and morpholine (4.5 mg, 0.052 mmol). The reaction is stirred at room temperature for 2 h and is directly purified by reversed phase (HPLC). 7.0 mg, 30%, LC/MS ESI m/z (M+H)+=493.43.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:20]([CH2:22][C:23](O)=[O:24])#[N:21].CN(C=O)C.CCN=C=NCCCN(C)C.Cl>O>[C:20]([CH2:22][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1)=[O:24])#[N:21]
Reactant: N#CCC(=O)O
Reactant: COC(=O)c1ccc(CCc2ccc(N)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)CC#N)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
To a mixture of 43.9 g of methyl 4-[2-(4-aminophenyl)ethyl]benzoate, 22.3 g of cyanoacetic acid, and 150 mL of DMF was added 49.5 g of EDCI/hydrochloride under ice-cooling. After stirring at room temperature for 24 hours, to the reaction mixture was added 450 mL of water at room temperature. After vigorous stirring at room temperature for 30 minutes, the precipitate was collected by filtration to obtain 54.2 g of methyl 4-(2-{4-[(cyanoacetyl)amino]phenyl}ethyl)benzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][C:10]([OH:12])=O.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.ClCCl.CO.N>>[ClH:1].[N:19]1([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:10](=[O:12])[C:9]#[C:8][C:7]3[CH:6]=[CH:5][C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:3][C:2]=3[Cl:1])=[CH:30][CH:31]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)C#Cc1ccc(-c2ccccc2)cc1Cl
Reactant: Nc1ccc(CN2CCCCC2)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: Cl
Product: O=C(C#Cc1ccc(-c2ccccc2)cc1Cl)Nc1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 3.8 from (3-chlorobiphenyl-4-yl)propynoic acid and 4-piperidin-1-ylmethylphenylamine. Yield: 0.35 g (75% of theory); melting point: 260° C.-265° C.; C27H25ClN20*HCl (M=465.41); calc.: molecular ion peak (M+H)+: 429/31 (Cl); found: molecular ion peak (M+H)+: 429/31 (Cl); Rf value: 0.6 (silica gel, dichloromethane/methanol/ammonia (90:10:0.1)).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5](/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=1.[CH3:20][O:21][CH:22](OC)N(C)C>>[CH3:20][O:21]/[CH:22]=[C:15](\[C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)/[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)Cc1sc(C)nc1/C=C/c1ccccc1
Agent: CO/C=C(/C(=O)OC)c1sc(C)nc1/C=C/c1ccccc1
Product: CO/C=C(/C(=O)OC)c1sc(C)nc1C=Cc1ccccc1
Temperature: 22.5 °C
Reaction time: 3 h

Procedure:
A mixture of 3 g of the product of Step A and 30 ml of dimethylformamide dimethyl acetal was refluxed for 5 hours and then allowed to return to 25° C. The mixture was evaporated to dryness and the residue was dissolved in 30 ml of tetrahydrofuran and 5 ml of a 2N hydrochloric acid solution. After standing for 3 hours at 25° C., 10 ml of water were added, followed by decanting and extracting with methylene chloride. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was dissolved in 50 ml of acetone and 6 g of potassium carbonate and then 12 ml of methyl iodide were added. The mixture was stirred for 16 hours at 20 to 25° C. and evaporated to dryness. The residue was chromatographed on silica, eluting with a hexane-ethyl acetate mixture (7-3) to obtain 1.8 g of the desired product. Thin layer chromatography; Rf=0.20 [eluant: hexane-ethyl acetate (7-3)].
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=1)[CH2:6][NH2:7])[CH3:2].C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31].O>ClCCl>[Cl:14][C:13]1[C:8]([C:5](=[N:4][O:3][CH2:1][CH3:2])[CH2:6][NH:7][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=2[C:27]([F:26])([F:37])[F:38])=[N:9][CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCON=C(CN)c1ncc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(C(F)(F)F)cc1Cl
Yield: 71.2 %

Procedure:
To a solution of 47 mg of 2-amino-1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanone-O-ethyloxime and 25 mg of triethylamine in 2 ml of dichloromethane, 31 mg of 2-(trifluoromethyl)benzoyl chloride was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 1 hour. After completion of the reaction, the reaction mixture was mixed with 2 ml of water and extracted with dichloromethane (2 ml×1), the resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure liquid chromatography (preparative medium pressure chromatograph: YFLC-Wprep manufactured by Yamazen Science, Inc.) using ethyl acetate-hexane (with a gradient of from 2:18 to 5:15) as the eluent to obtain 48 mg of the desired product as a colorless resinous substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)=[O:4]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of 1H-Indole-5-carboxylic acid methyl ester (1 g, 5.71 mmol) in 10 mL of acetic acid at 0° C., was added sodium cyanoborohydride (1.08 g, 17.18 mmol) over 5 minutes. The mixture was stirred at room temperature for 1 h. Water (3 mL) was added and all the solvents were removed under vacuum. The residue was dissolved in ethyl acetate (150 mL) and saturated NaHCO3 (150 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×75 mL). The combined extracts were washed with brine (150 mL), dried, filtered and evaporated. The residue was purified by flash chromatography (0-50% ethyl acetate in hexane+0.1% triethylamine) to afford 0.99 g (99%) of 19a.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][OH:16])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[C:19]=1[N:26]=[C:27]=S.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.O>[Cl:12][C:11]1[C:2]2[N:1]=[C:27]([NH:26][C:19]3[C:20]([CH3:25])=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=3[Cl:17])[N:13]([CH2:14][CH2:15][OH:16])[C:3]=2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCO
Reactant: Cc1cc(Cl)cc(Cl)c1N=C=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3Cl)n(CCO)c12
Temperature: 60 °C
Reaction time: 24 h
Yield: 30.3 %

Procedure:
A solution of methyl 3-amino-4-chloro-2-[(2-hydroxyethyl)amino]benzoate (290 mg, 1.19 mmol) and 2,4-dichloro-6-methylphenylisothiocyanate (284.4 mg, 1.3 mmol) in tetrahydrofuran (12 mL) was stirred at 45° C. for 62 hr. The mixture was warmed to 60° C. and stirred at 60° C. for 24 hr. 2,4-Dichloro-6-methylphenylisothiocyanate (104 mg, 0.48 mmol) was added to the reaction mixture and the mixture was stirred at 60° C. for 26 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on NH-silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture give a red amorphous (261.4 mg). To a mixture of the amorphous (261.4 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119 mg, 0.62 mmol) in tetrahydrofuran (11.2 mL) was added triethylamine (0.0866 mL, 0.62 mmol) at room temperature. The mixture was stirred at 50° C. for 16 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (156.3 mg, 0.36 mmol, 30%) as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:5]=1.[S:35]1[CH:39]=[CH:38][C:37]([C:40](O)=[O:41])=[CH:36]1>>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][O:23][CH:11]1[CH:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][O:1][C:40]([C:37]3[CH:38]=[CH:39][S:35][CH:36]=3)=[O:41])=[CH:5][CH:6]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12]1
Reactant: O=C(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(=O)c3ccsc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 24(g), by condensing tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl)-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate and thiophene-3-carboxylic acid using 1,1-carbonyldiimidazole as the condensation agent there was obtained tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-[4-(2-thiophen-3-ylcarbonyloxy-ethyl)-phenyl]-piperidine-1-carboxylate as white crystals, MS: 572 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:19](=S)=[S:20].C1(N=C=NC2CCCCC2)CCCCC1.Cl>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[N:5]=[C:19]=[S:20]
Reactant: COc1ccc(OC)c(N)c1
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COc1ccc(OC)c(N=C=S)c1
Reaction time: 3 h
Yield: 57.6 %

Procedure:
To a solution of 2,5-dimethoxyaniline (61.2 g, 0.4 mol) and triethylamine (75 ml, 0.48 mol) in 300 ml of tetrahydrofuran was added carbon disulfide (91.2 g, 0.48 mol) at 5° C. and stirring was continued for 3 hours. To the reaction mixture kept at 5° C. was added N,N'-dicyclohexylcarbodiimide (99 g, 0.48 mol) and stirring was continued for another 3 hours. To the reaction mixture were added 2N HCl solution (100 ml) and hexane (100 ml) and an aqueous layer was separated. n-Hexane (100 ml) was further added to an organic layer and precipitates were filtered off. The solvents were distilled off under reduced pressure and a crude oily product was obtained. Separation and purification by chromatography using a silica gel column gave oily 2,5-dimethoxyphenylisothiocyanate (45 g, yield 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([CH3:15])[CH:12]=[C:13]([C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[O:23])[CH:14]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cn1cccc1C(=O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1cc(C(=O)c2ccncc2)cc1C(=O)c1ccc(Cl)cc1
Yield: 26.9 %

Procedure:
A solution of 17.5 g (0.08 mole) of (4-chlorophenyl)(1-methyl-1H-pyrrol-2-yl)methanone, 14.4 g (0.088 mole) of isonicotinoyl chloride and 26.6 g of aluminum chloride (0.2 mole) in 280 mL of DCE was heated under reflux for 16 h. After cooling, the mixture was partitioned between CH2Cl2 and dilute NaOH solution. The organic layer was dried and the solvent was evaporated in vacuo. The residue was triturated with ether. The resulting solid was recrystallized from 2-PrOH to give 7 g (27%) of the title compound, mp 174-175° C. ES-MS m/z=325 (M++H). 1H NMR (300 MHz, CDCl3) δ 4.1 (s, 3H); 7.1 (s, 1H); 7.3(dd, 2H); 7.42 (dd, 2H); 7.45 (s, 1H); 7.8 (dd, 2H); 8.8 (dd, 2H). Anal calc'd for: C18H13ClN2O2: C, 66.57; H, 4.03; N, 8.63. Found: C, 66.34; H, 3.94; N, 8.53.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:16])([F:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=1)=[O:20].[OH-].[Na+]>N1C=CC=CC=1>[F:5][C:6]([F:16])([F:15])/[C:7](=[N:27]\[C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][N:24]=1)[C:19]([O:18][CH3:17])=[O:20])/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccnc(/N=C(/c2ccccc2)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
Thionyl chloride (2.2 ml) was added at 0° C. to a pyridine (4.8 ml) solution of 2,2,2-trifluoro-1-phenylethanone (5.1 g) and 2-aminopyridine-4-carboxylic acid methyl ester (4.5 g). The temperature of the reaction solution was increased to room temperature, and the reaction solution was then stirred for 1 hour. Thereafter, the reaction solution was poured into a 1 N sodium hydroxide aqueous solution, and the mixed solution was then extracted with ethyl acetate. Organic layers were gathered, and the gathered organic layer was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=2:1-1:1), so as to obtain the title compound (2.5 g) in the form of a yellow liquid.
Reaction SMILES: ClCCCCO[C:7]1([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([Cl:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].[I-].[K+].[C:35]([OH:47])(=[O:46])[CH2:36][C:37]([CH2:42][C:43]([OH:45])=[O:44])([C:39]([OH:41])=[O:40])[OH:38].[OH2:48]>CC(C)=O>[C:35]([OH:47])(=[O:46])[CH2:36][C:37]([CH2:42][C:43]([OH:45])=[O:44])([C:39]([OH:41])=[O:40])[OH:38].[CH2:28]([N:30]([CH2:31][CH3:32])[CH2:43][CH2:42][CH2:37][CH2:39][O:48][C:10]1[CH:9]=[CH:8][C:7]([C:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[Cl:21])=[CH:12][CH:11]=1)[CH3:29]
Reactant: CCNCC
Reactant: ClCCCCOC1(C(=C(Cl)c2ccccc2)c2ccccc2)C=CC=CC1
Reactant: O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCCCOc1ccc(C(=C(Cl)c2ccccc2)c2ccccc2)cc1
Reaction time: 18 h

Procedure:
Combine (E and Z)-1-(4-chlorobutoxy)phenyl-2-chloro-1,2-diphenyl ethylene (20.2 mol), diethylamine (25 L, 241.7 mol), and potassium iodide (3.5 kg, 21.1 mol) in water (15 L). Heat to reflux. After 18 hours, evaporate the reaction mixture in vacuo to give an aqueous residue. Extract two times with ethyl acetate. Evaporate the organic layer in vacuo to give a residue. Combine the residue and acetone (50 L). Add a solution of citric acid (8 kg) in acetone (40 L). Heat to form a solution and cool to give solid. Collect the solid by filtration, rinse with acetone, and dry to give (E and Z)-1-[4-(4-diethylaminobutoxy)phenyl]-1,2-diphenyl-2-chloro-ethylene citrate salt.
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=O.Cl.NC1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH2:29])=[O:28].C(=O)(O)[O-].[Na+]>C(O)(=O)C.ClCCl>[N:13]1([C:10]2[CH:9]=[CH:8][C:7]([C:5]3[N:23]4[CH:24]=[N:25][C:26]([C:27]([NH2:29])=[O:28])=[C:19]4[N:2]=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CN(C)C=CC(=O)c1ccc(N2CCOCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: NC(=O)c1ncn2c(-c3ccc(N4CCOCC4)cc3)ccnc12
Yield: 78.3 %

Procedure:
A mixture of 15.0 g of 3-dimethylamino-4'-morpholinoacrylophenone (prepared as described in Example 13) and 7.26 g of 4-amino-5-imidazolecarboxamide hydrochloride in 250 ml of glacial acetic acid was stirred and heated at reflux for 5 hours. The solution was evaporated in vacuo to give a black oil that was then dissolved in dichloromethane and then saturated sodium bicarbonate solution was added. A precipitate was formed which was collected by filtration as a yellow crystalline solid. The solid was triturated with ether then filtered to give 11.3 g of the product of the example as yellow crystals, mp 274°-277° C.