Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([CH2:13]O)[CH2:11][CH2:10][C:9]2=[O:15])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:35](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.N(C(OCC)=O)=NC(OCC)=O>C(#N)C.ClCCl>[NH2:35][CH2:13][C@@H:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9](=[O:15])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: O=C1CC[C@H](CO)N1c1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: NC[C@H]1CCC(=O)N1c1ccc(F)cc1
Reaction time: 24 h
Yield: 24.1 %

Procedure:
To a dichloromethane (10 mL)-acetonitrile (2.0 mL) solution of (R)-1-(4-fluorophenyl)-5-(hydroxymethyl)pyrrolidin-2-one (500 mg, 2.39 mmol) synthesized in Reference Synthesis Example 215, triphenylphosphine (753 mg, 2.87 mmol), di-tert-butyl iminodicarboxylate (626 mg, 2.87 mmol), and diethyl azodicarboxylate (40% toluene solution) (1.25 g, 2.87 mmol) were added at room temperature and the resultant mixture was stirred for 1 hour and 30 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure and 4 M hydrogen chloride/1,4-dioxane solution (7.5 mL) was added to the obtained residue, followed by stirring the resultant mixture for 1 day. After completion of the reaction, water and ethyl acetate were added to the reaction solution and the resultant mixture was washed with ethyl acetate. Thereafter, 1 M sodium hydroxide aqueous solution was added to the water phase and extraction from the resultant mixture with chloroform was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of the title compound (120 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH:14][C:24]([NH:23][C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[S:25])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2ccccc2n1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2ccccc2n1NC(=S)NC(=O)c1ccccc1
Reaction time: 8 h
Yield: 70.1 %

Procedure:
1-Amino-1H-indole-2-carboxylic acid methyl ester (18.56 g, 0.098 mol) was dissolved in tetrahydrofuran (800 mL). Benzoyl isothiocyanate (13.1 mL, 0.098 mol) was added and the reaction was allowed to stir overnight. The solvent was removed in vacuum and the solid residue was triturated with ether. The solid was collected by filtration to yield the 1-(3-benzoyl-thioureido)-1H-indole-2-carboxylic acid methyl ester (24.27 g, 70%), which was used in the next step without further purification. 1H-NMR (CDCl3) δ 12.81 (br s, 1H), 9.29 (br s, 1H), 7.95 (d, J=7.2 Hz, 2H), 7.68 (m, 2H), 7.57 (m, 2H), 7.42 (m, 2H), 7.38 (s, 1H), 7.24 (m, 1H), 3.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([CH2:15][CH3:16])[C:11]([O:13]C)=[O:12])[CH:5]=[N:6][C:7]=1[Cl:8].[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([CH2:15][CH3:16])[C:11]([OH:13])=[O:12])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CCC(Oc1cnc(Cl)c(Cl)c1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: CCC(Oc1cnc(Cl)c(Cl)c1)C(=O)O

Procedure:
Methyl 2-(5,6-dichloro-3-pyridyloxy)butyrate was hydrolysed with aqueous sodium hydroxide, using a similar procedure to that described in Example1, Stage 2 to provide 2-(5,6-dichloro-3-pyridyloxy)butyric acid as a solid, m.p. 117–118° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](O)=[O:5].[C:12](N1C=CN=C1)([N:14]1C=CN=C1)=O.Cl.CN.C(N(C(C)C)CC)(C)C>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:14][CH3:12])=[O:5]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(F)cccc1F

Procedure:
The title compound was prepared from 2,6-difluorobenzoic acid (10 g, 63.2 mmol), carbonyldiimidazole (10.26 g, 63.5 mmol), methylamine hydrochloride (4.27 g, 63.25 mmol) and diisopropylethyl amine according to the procedure used for example 84 (Step A) to give near quantitative yield of the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[H][H]>[Ni]>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH2:12])=[CH:8][CH:9]=1
Reactant: N#CCc1ccc(OC(F)(F)F)cc1
Reactant: [H][H]
Agent: [Ni]
Product: NCCc1ccc(OC(F)(F)F)cc1

Procedure:
reducing the (4-trifluoromethoxyphenyl)acetonitrile using hydrogen in the presence of a nickel catalyst to form 2-(4-trifluoromethoxyphenyl)ethylamine.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]1>C(O)C.C(N(CC)CC)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][Br:2])[CH2:21][CH2:20]1
Reactant: COc1cc2ncnc(N3CCC(CCO)CC3)c2cc1OC
Reactant: BrP(Br)Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(N3CCC(CCBr)CC3)c2cc1OC
Reaction time: 16 h

Procedure:
Phosphorus tribromide (9.7 g) was added at room temperature to a stirred solution of 1-(6,7-dimethoxyquinazolin-4-yl)-4-(2-hydroxyethyl)piperidine (7.5 g) in ethanol free chloroform (200 cm3) and triethylamine (5.0 cm3). After stirring for 16 hours the volatile material was removed in vacuo and the residue was taken into aqueous sodium carbonate solution and extracted with chloroform (3×50 cm3). The dried (MgSO4) extracts were evaporated and the residue was chromatographed on "Florisil" (Trade Mark, Hopkin and Williams) eluting with chloroform to afford 1-(6,7-dimethoxyquinazoline-4-yl)-4-(2-bromoethyl) piperidine 1/4 H2O as a white solid, m.p. 191° (5.6 g).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]1([CH2:27][C:28]([OH:30])=O)[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([OH:26])=O)[CH:18]=1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:24](=[O:26])[CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:27][C:28]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:30])[CH:18]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)Cc1cccc(CC(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)c1
Yield: 82.8 %

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 800 mg (4.1 mmol) 1,3-phenylenediacetic acid afforded, after flash chromatography (EtOAc), 1.93 g (84%) of the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[N:41][CH:40]=[CH:39][N:38]=2)[CH:34]=[CH:35][CH:36]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[CH:42]=[N:41][CH:40]=[CH:39][N:38]=5)[CH:32]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: ClCc1cccc(-c2cnccn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccc(-c4cnccn4)c3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 2-(3-Chloromethylphenyl)pyrazine (307 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[4-phenyl-1-[4-[3-(2-pyrazinyl)benzyloxy]benzyl]-3-pyrrolyl]propionate (647 mg, yield: 83%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: OC(CCl)CCCl
Product: NC(=O)c1ccc(OCC(O)CCCl)cc1
Yield: 25 %

Procedure:
Utilizing the procedure of Preparation 16, 1,4-dichloro-2-butanol was reacted with 4-hydroxybenzamide to give white title compound, m.p. 150°-153° C. in 25% yield. The recrystallizing solvent was 95% ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][S:17][CH2:18][C:19](Cl)=[O:20]>CC(C)=O>[CH3:16][S:17][CH2:18][C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CSCC(=O)Cl
Solvent: CC(C)=O
Product: CSCC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 42.9 %

Procedure:
20.3 g (0.1 mole) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred with 14.9 g (0.12 mole) of 2-methylmercaptoacetyl chloride and 400 ml of absolute acetone for 10 hours at room temperature. The product was filtered off under suction at 10° C., washed with cold acetone and dried at 70° C. under reduced pressure. 12.5 g (43%) of 6-[p-(2-methylmercaptoacetylamino)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained. Mp.: 220°-222° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:25])[NH:11][N:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=1.N>>[Cl:34][C:29]1[CH:28]=[C:27]([N:11]2[C:10](=[O:25])[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:13]=[N:12]2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Cc2ccc(F)cc2)cc1
Reactant: Fc1ccc(Br)cc1Cl
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 62 substituting 4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-bromo-2-chloro-1-fluorobenzene in place of 4-iodo-1-fluorobenzene (yield: 0.110 g, 74%). mp 153-156° C. 1H NMR (300 MHz, DMSO d6) δ 3.30 (s, 3H), 3.89 (bs, 2H), 7.02-7.07 (m, 4H), 7.59 (m, 1H), 7.65-7.72 (m, 4H), 8.07 (m, 2H), 8.12 (s, 1H). MS (DCI/NH3) m/z 487 (M+H)+, 504 (M+NH4)+. Anal. calc. for C24H17ClF2N2O3S.0.25H2O: C, 58.65; H, 3.58; N, 5.64. Found: C, 58.41; H, 3.56; N, 5.36.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([O:24][CH3:25])[CH2:22][CH3:23])[C:17]([OH:19])=O)[C:10](=[O:26])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([O:24][CH3:25])[CH2:22][CH3:23])[C:17]([NH:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:39][CH:40]=3)=[O:19])[C:10](=[O:26])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCC(CC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O)OC
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C(CC(CC)OC)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
620 mg (1.53 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoic acid (mixture of racemic diastereomers), 253 mg (1.53 mmol) of ethyl 4-aminobenzoate, 218 mg (1.53 mmol) of Oxima and 239 μl (1.53 mmol) of DIC in 15.3 ml of dimethylformamide were reacted according to General Method 5B. The crude product was purified by flash chromatography (120 g cartridge, 85 ml/min, cyclohexane/ethyl acetate gradient). Yield: 634 mg (70% of theory)
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH2:30]O)[CH:26]=[CH:27][C:28]=1[F:29].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:30][C:25]5[CH:26]=[CH:27][C:28]([F:29])=[C:23]([F:22])[CH:24]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1ccc(F)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)c(F)c4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 18.4 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (3,4-difluorophenyl)methanol (153 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (40 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[S:10][CH2:9][C:8]3[S:12][CH2:13][CH2:14][S:15][C:7]=3[C:6]=2[C:5]([CH3:16])=[C:4]([C:17]([OH:19])=[O:18])[CH:3]=1.[C:20](Cl)(=[O:24])[C:21](Cl)=O>C(Cl)Cl.CN(C)C=O>[CH3:1][C:2]1[C:11]2[S:10][CH2:9][C:8]3[S:12][CH2:13][CH2:14][S:15][C:7]=3[C:6]=2[C:5]([CH3:16])=[C:4]([C:17]([O:19][C:2]2[CH2:3][CH2:4][CH2:21][C:20](=[O:24])[CH:1]=2)=[O:18])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C(=O)O)c(C)c2c1SCC1=C2SCCS1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)OC2=CC(=O)CCC2)c(C)c2c1SCC1=C2SCCS1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.78 g of the title compound of Step A in 35 mL of methylene chloride was added 0.66 mL of oxalyl chloride (purchased from Aldrich Chemical Co.) and 2 drops of N,N-dimethylformamide. The mixture was refluxed for 2 h and was then concentrated under reduced pressure to dryness. The resulting residue was redissolved in 30 mL of methylene chloride and the solution was evaporated to dryness again. Another 30 mL of methylene chloride was added to the residue and the solution was cooled to about 0° C. To this solution was added 0.31 g of 1,3-cyclohexanedione (purchased from Aldrich Chemical Co.) followed by addition of 1.0 mL of triethylamine. The mixture was stirred overnight while warming to room temperature. Saturated aqueous sodium bicarbonate was then added to the reaction mixture and the mixture was extracted with methylene chloride. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to dryness. Chromatography of the crude product on silica gel eluting with a mixture of hexanes:ethyl acetate (8:1 and then 4:1) yielded 0.58 g of the title compound of Step B as a yellow solid melting at 120°-126° C. 1H NMR (CDCl3): δ 2.15 (m, 2H), 2.36 (s, 3H), 2.46 (t, 2H), 2.66 (t, 2H), 2.67 (s, 3H), 3.07 (m, 2H), 3.24 (br s, 2H), 3.41 (m, 2H), 6.00 (s, 1H), 7.60 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH:11]1([CH:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O.O1CCOCC1>[CH:11]1([CH:17]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[O:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OC(C1CCCCC1)C1CCCCC1
Reactant: O=C(O)c1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(OC(C2CCCCC2)C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To a solution of 3-hydroxybenzoic acid (1.61 g, 8.2 mmol), dicyclohexylmethanol (1.61 g, 8.2 mmol), triphenylphosphine (2.05 g, 7.82 mmol) and dioxane (35 ml) was added diethyl azodicarboxylate (1.41 ml, 8.94 mmol), and the resultant mixture was refluxed for 3 days. The reaction mixture was allowed to warm up to room temperature, poured into chilled water and extracted with diethyl ether. The organic layer was concentrated, and the residue was dissolved in a mixture of methanol (20 ml), tetrahydrofuran (6.5 ml) and water (2.0 ml), mixed with potassium hydroxide (1.16 g) and stirred for 2 hours. The mixture was poured into chilled water, acidified, and extracted with ethyl acetate. The organic layer was concentrated, and the resultant residue was recrystallized from hexane to give the titled compound (0.43 g, yield 18%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.Cl[CH2:11][C:12]#[N:13].C(N(CC)CC)C>CCOCC>[OH:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:11][C:12]#[N:13])[CH2:2][CH2:3]1
Reactant: N#CCCl
Reactant: OCCC1CCNCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: N#CCN1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.7 %

Procedure:
The title compound was prepared according to general procedure G described in Scheme 3. 2-(Piperidin-4-yl)ethanol (1.2 g, 9.3 mmol) was treated with 2-chloroacetonitrile (1.4 g, 18.6 mmol), triethylamine (10.4 mL, 74.3 mmol) and stirred at RT for 14 h. The crude reaction mixture was diluted with Et2O (25 mL) and washed with H2O (3×10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a yellow oil (1.56 g, 100%), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH2:10])=O)[N:6]=1.P(Cl)(Cl)(Cl)=O>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]#[N:10])[N:6]=1
Reactant: NC(=O)Cc1csc(N)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#CCc1csc(N)n1

Procedure:
To a solution of 2.0 g (13.0 mmol) of 2-(2-Amino-thiazol-4-yl)-acetamide in 30 ml of dry DMF was added Phosphorus oxychloride (2.3 ml, 25.0 mmol, 2.0 equiv.) dropwise at 0° C.
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11]([C@H:13]1[CH2:15][C@H:14]1[CH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21])=[O:12])([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([N:18]1[CH2:19][CH2:20][CH:16]([CH:14]2[CH2:15][CH:13]2[C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])[C:17]1=[O:21])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C1CC1C1CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.8 %

Procedure:
To 30 ml of a dimethylformamide solution of 2.288 g (10.2 mmol) of 3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one was added 406.2 mg (10.2 mmol) of sodium hydride under cooling with ice, followed by stirring at room temperature for 1.5 hours. Then, 1.81 ml (15.3 mmol) of benzyl chloride was added thereto dropwise, followed by stirring for 2.5 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 1.121 g (35.0%) of 1-benzyl-3-(2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one (isomer A: an isomer attributed to the steric configuration of the cyclopropyl group bonded to the carbon atom of the pyrrolidine ring) as a colorless solid. The column was then eluted with hexane:ethyl acetate=1:1 to give 670.9 mg (20.9%) of 1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one (isomer B: an isomer attributed to the steric configuration of the cyclopropyl group bonded to the carbon atom of the pyrrolidine ring) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:47][C:44]([F:45])([F:46])[C:42]1[CH:41]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:48])[F:49])[CH:43]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][C:25]=1[O:34][C:35]1[N:36]=[CH:37][CH:38]=[CH:39][N:40]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Oc2ncccn2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Oc2ncccn2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(pyrimidin-2-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (115 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(pyrimidin-2-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (96 mg). MS (m/z): 676 [M+H]+
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O)[CH3:2].[BH3-]C#[N:15].[Na+]>C(O)(C)C>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[NH2:15])[CH3:2]
Reactant: CCc1cccc2c1CCC2=O
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: CCc1cccc2c1CCC2N

Procedure:
4-Ethyl-indan-1-one (5.00 g, 31.21 mmol), NaBH3CN (13.70 g, 0.22 mol) and NH4OAc (72.00 g, 0.93 mol) in isopropanol were reacted according to the protocols as outlined in general procedure B to give the desired amine.