Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])([O-:3])=[O:2].CS[C:15]1[S:16][CH2:17][CH2:18][CH2:19][N:20]=1>[Cl-].[Zn+2].[Cl-]>[N+:1]([C:4](=[C:15]1[NH:20][CH2:19][CH2:18][CH2:17][S:16]1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])([O-:3])=[O:2]
Reactant: O=C(C[N+](=O)[O-])c1ccccc1
Reactant: CSC1=NCCCS1
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C(C(=C1NCCCS1)[N+](=O)[O-])c1ccccc1
Reaction time: 2.5 h

Procedure:
A mixture of 3.3 g of 2-nitroacetophenone and 2.94 g of 2-(methylthio)-5,6-dihydro-4H-1,3-thiazine was heated to 115° and 100 milligrams of zinc chloride was added. Heating and stirring was continued at 115°-120° for 2.5 hours. After cooling, the mixture was filtered (with the aid of ethyl acetate) through a short column of florosil to give an amber oil. The oil was chromatographed on silica gel using dry-column technique and a 1:1:2 mixture of tetrahydrofuran/ethyl acetate/hexane for development to give 1 as a salmon-colored solid, m.p.: 137°-140°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C.O>[O:1]1[CH2:2][CH2:3][C:4]2[CH:9]=[C:8]3[C:7](=[CH:6][C:5]1=2)[C:13](=[N:17][OH:18])[CH2:12][CH2:11][CH2:10]3
Reactant: NO
Reactant: O=C(O)CCCc1ccc2c(c1)CCO2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCCc2cc3c(cc21)OCC3

Procedure:
A mixture containing 46 g of the compound of Example 1, 60 g of hydroxylamine hydrochloride and 60 g of anhydrous sodium acetate in 410 ml of ethanol is brought to reflux for 5 hours. The mixture is then cooled and diluted with water, extracted with methylene chloride, dried and evaporated to dryness. The dry residue is recrystallized in ethanol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH2:21][CH2:22][N:23]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:24][CH:25]=3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:33])[F:34])([C:28]([F:29])([F:30])[F:31])[OH:27])[CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: OC(C1=NN(c2cccc(C3=CCNCC3)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.7 %

Procedure:
The 5-(2-chloro-phenyl)-1-[3-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.055 mmol) in the form of a yellow liquid, methanesulfonyl chloride (7.6 mg, 0.066 mmol), and triethylamine (31.0 uL, 0.221 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 14.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH:1]1([S:6]([CH:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Mn]([O-])(=O)(=O)=[O:26].[K+]>CO.O>[CH:1]1([S:6]([CH:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])(=[O:26])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=C(Nc1nccs1)C(c1ccc(Cl)c(Cl)c1)S(=O)C1CCCC1
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Nc1nccs1)C(c1ccc(Cl)c(Cl)c1)S(=O)(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
A solution of rac-2-cyclopentanesulfinyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (20 mg, 0.05 mmol) in methanol (2 mL) was stirred at 25° C. as a solution of potassium permanganate (9 mg, 0.06 mmol) in water (0.5 mL) was added. The mixture was stirred at 25° C. for 30 min and then was filtered. The filter cake was washed with dichloromethane and the combined filtrates were washed with sodium bicarbonate solution (10 mL) and brine (10 mL), then were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (Biotage Flash 12M column, 50/50 hexanes/ethyl acetate) to provide rac-2-cyclopentanesulfonyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide(10 mg, 48% yield) as a colorless oil: EI-HRMS m/e calculated for C16H16N2O3S2Cl2 (M+) 417.9979, found 417.9977.
Reaction SMILES: [O:1]1CCCC1.[F:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][C:12]2[S:16][C:15]([C:17]#N)=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C>O>[F:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][C:12]2[S:16][C:15]([CH:17]=[O:1])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(Oc2ccc(F)cc2)s1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Product: O=Cc1ccc(Oc2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a tetrahydrofuran (150 mL) solution of 5-(4-fluoro-phenoxy)-thiophene-2-carbonitrile (6.10 g, 27.8 mmol) described in Manufacturing Example 91-1-1 was added dropwise diisobutyl aluminum hydride (0.97 M n-hexane solution, 43.0 mL, 41.7 mmol) on a dry ice-ethanol bath (−78° C.)under nitrogen atmosphere, which was stirred for 2 hours at room temperature. The reaction solution was added to water, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (3.4 g, 55.0%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][CH2:15][N:16]1[C:25](=[O:26])[CH:24]2[CH:27]=[CH:28][CH:29]=[C:22]3[CH:23]2[C:18](=[CH:19][CH:20]=[CH:21]3)[C:17]1=[O:30])[CH3:12])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH3:12])[CH2:13][CH2:14][CH2:15][N:16]1[C:25](=[O:26])[CH:24]2[CH:27]=[CH:28][CH:29]=[C:22]3[CH:23]2[C:18](=[CH:19][CH:20]=[CH:21]3)[C:17]1=[O:30]
Reactant: CN(CCCNC(=O)OC(C)(C)C)CCCN1C(=O)C2=CC=CC3=CC=CC(C1=O)C32
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCCN)CCCN1C(=O)C2=CC=CC3=CC=CC(C1=O)C32
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
To a solution of [3-[[3-(1,3-dioxo-3a,9b-dihydro-1H,3H-benzo[de]isoquinolin-2-yl)propyl]methylamino]propyl]carbamic acid tert-butyl ester (0.34 g, 0.81 mmol) in CH2Cl2 (24 ml) was added trifluoroacetic acid (6 ml). The reaction mixture was stirred at room temperature for 16 h at which point the reaction was completed by TLC. All solvents were removed under reduced pressure to give 2-[3-[(3-aminopropyl)methylamino]propyl]-3a,9b-dihydro-benzo[de]isoquinoline-1,3-dione (0.24 g, 92%) as an oil, which was used directly in the next reaction. 1H-NMR [MeOD, _, ppm]: 8.64 (m, 2H), 8.54 (m, 2H), 7.92 (m, 2H), 4.45 (m, 2H, 2CH2NO), 3.55 (m, 4H, 2CH2), 3.33 (m, 2H, CH2), 3.22 (s, 3H, N(CH3)), 2.44 (m, 4H, 2(CH2)).
Reaction SMILES: [CH2:1]([C@@H:4]1[C@@H:8](/[CH:9]=[CH:10]/[C@@H:11]([O:24][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C@H:7]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:6][C@@H:5]1[OH:40])[CH:2]=[CH2:3].[C:41](O)(=[O:47])[CH2:42][CH2:43][CH2:44][CH:45]=[CH2:46].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:41]([O:40][C@H:5]1[CH2:6][C@@H:7]([O:32][Si:33]([C:36]([CH3:37])([CH3:39])[CH3:38])([CH3:35])[CH3:34])[C@H:8](/[CH:9]=[CH:10]/[C@@H:11]([O:24][Si:25]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:30][CH3:31])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C@H:4]1[CH2:1][CH:2]=[CH2:3])(=[O:47])[CH2:42][CH2:43][CH2:44][CH:45]=[CH2:46]
Reactant: C=CC[C@@H]1[C@@H](/C=C/[C@H](COc2cccc(C(F)(F)F)c2)O[Si](CC)(CC)CC)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Reactant: C=CCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: C=CCCCC(=O)O[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](/C=C/[C@H](COc2cccc(C(F)(F)F)c2)O[Si](CC)(CC)CC)[C@H]1CC=C
Temperature: 40 °C
Yield: 90.7 %

Procedure:
A 50 ml two-necked round-bottom flask was flame dried and allowed to be cooled under nitrogen. (1S,2R,3R,4R)-2-allyl-4-(tert-butyldimethylsilyloxy)-3-((R,E)-3-(triethylsilyloxy)-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)cyclopentanol (1 g, 1.66 mmol) in 10 ml of DMF, 0.05 g (0.33 mmol) of DMAP, 0.21 g (1.83 mmol) of 5-hexenoic acid, and 0.41 g (2.00 mmol) of N,N′-dicyclohexylcarbodiimide were added to the reaction flask. The reaction mixture was heated at 40° C. for 24 hours. The reaction was quenched with 10 ml saturated aqueous sodium bicarbonate. The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off and organic solvent was evaporated off under vacuum. The crude product was purified by chromatography and then concentrated under reduced pressure to provide 1.05 g of the title compound (90.52% yield).
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:21]=[N:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O.[NH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:38])([C:34]([F:37])([F:36])[F:35])[C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:24]=1[OH:39]>N1C=CC=CC=1>[Cl:12][C:13]1[CH:21]=[N:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:38])([C:30]([F:31])([F:32])[F:33])[C:34]([F:35])([F:36])[F:37])[CH:26]=[CH:25][C:24]=1[OH:39])=[O:17]
Reactant: Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: O=C(O)c1ccncc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a mixture of 0.58 g of WSC and 5 ml of pyridine 5 ml, 0.48 g of 3-chloroisonicotinic acid was added. The reaction mixture was stirred at room temperature for 25 minutes. To the reaction mixture, 0.75 g of 2-amino-4-(heptafluoroisopropyl)phenol was added and was stirred while heating at 60° C. for three hours. The reaction mixture was cooled to room temperature, the 0.24 g of 3-chloroisonicotinic acid and 0.29 g of WSC was added and stirred while heating at 60° C. for 1.5 hours and then at 80° C. for 1.3 hours. The mixture reaction was cooled to room temperature, and then concentrated under reduced pressure. Then, water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.90 g of 3-chloro-N-[2-hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:23])=[C:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[S:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34]1[CH2:38]OC[CH2:35]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:23])=[C:8]([CH:18]([CH2:35][CH2:34][CH3:38])[C:19]([O:21][CH3:22])=[O:20])[C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[S:4][CH:3]=1
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2scc(C)c2c1-c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2scc(C)c2c1-c1ccc(C)cc1
Yield: 96.2 %

Procedure:
This compound was prepared according to the procedure C from methyl 2-(3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.080 g; 0.246 mmol), LHMDS 1N in THF (0.280 mL; 0.280 mmol), 1-iodopropane (0.040 mL; 0.410 mmol) in DMF (3.5 mL) for 3.5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.087 g (96%) of the title compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][C:12]1[CH:20]=[CH:19][C:15]2=[N:16][S:17][N:18]=[C:14]2[CH:13]=1)C.Cl>O1CCCC1.[Li+].[OH-].O>[N:16]1[S:17][N:18]=[C:14]2[CH:13]=[C:12]([O:11][C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4]([OH:21])=[O:3])[CH:20]=[CH:19][C:15]=12
Reactant: CCOC(=O)c1cccnc1Oc1ccc2nsnc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccnc1Oc1ccc2nsnc2c1
Yield: 23.4 %

Procedure:
A solution of 2-(benzo[2,1,3]thiadiazol-5-yloxy)-nicotinic acid ethyl ester (0.74 g, 2.5 mmol) in tetrahydrofuran (2.78 ml) and 1 M LiOH (2.7 ml) was stirred over night. The mixture was diluted with water and acidified to pH 1 with 2 N hydrochloric acid and filtered to give a pale yellow solid (160 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][NH:67][C:68]([CH3:71])([CH3:70])[CH3:69])C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][NH:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: CC(C)(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Product: CC(C)(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-(2-tert-butylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=549, obsd.=549).
Reaction SMILES: O=C(C)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.[CH3:19][C:20]([CH3:31])([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:19][C:20]([CH3:31])([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](=[O:22])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)C(C)(C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
Ethyl 3-oxobutanoate (1.09 g, 8.3 mmol) in methylene chloride (16 mL) was mixed with anhydrous magnesium chloride (158 mg, 1.66 mmol), and the reaction solution was cooled to 0° C., mixed with pyridine (1.34 mL, 16.6 mmol), stirred for 30 minutes, then mixed with 2,2-dimethyl-3-phenylpropanoyl chloride (1.64 g, 8.3 mmol) and stirred for another 30 minutes at the same temperature. The reaction solution was warmed to room temperature and stirred for 20 hours. The methylene chloride was distilled off under reduced pressure, and the residue was with ethanol (2 mL) and at room temperature for 2 days and with toluene (2 mL) at 60° C. for 5 hours. After completion of the reaction, the reaction solution was washed with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (50 mL×2). The solvent was removed from the resulting organic layer under reduced pressure, and the resulting brown oil was purified by intermediate pressure silica gel column chromatography (silica gel12 g, ethyl acetate:hexane=1:19 to 1:9) to give 370 mg of the desired product as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11].[F:32][C:33]([F:42])([F:41])[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[C:8]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH:38][C:37]1[CH:39]=[CH:40][C:34]([C:33]([F:41])([F:42])[F:32])=[CH:35][CH:36]=1)=[O:11]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COc1c(C)c(Cc2cccc(C(=O)O)c2-c2ccncc2)c(OC)c(OC)c1OC
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)c(Cc2cccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c2-c2ccncc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To a solution of 3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (18 mg, 0.0424 mmol) in methylene chloride (3 ml) were added 4-trifluoromethylaniline (10.2 mg, 0.0633 mmol), triethylamine (8.6 mg, 0.0851 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (21.5 mg, 0.1272 mmol) followed by stirring at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (17 mg, 0.0300 mmol, 71%).
Reaction SMILES: [CH2:1]([O:10][C:11]([C:13]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:17]([C:28]([OH:30])=[O:29])=[C:16]([CH3:31])[NH:15][C:14]=1[CH3:32])=[O:12])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:48]([S:50][CH2:51][CH2:52]O)[CH3:49]>CN(C)C1C=CN=CC=1.ClC(Cl)C>[N+:25]([C:21]1[CH:20]=[C:19]([CH:18]2[C:17]([C:28]([O:30][CH2:49][CH2:48][S:50][CH2:51][CH3:52])=[O:29])=[C:16]([CH3:31])[NH:15][C:14]([CH3:32])=[C:13]2[C:11]([O:10][CH2:1][CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:12])[CH:24]=[CH:23][CH:22]=1)([O-:27])=[O:26]
Reactant: CCSCCO
Reactant: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC=Cc2ccccc2)=C(C)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: CCSCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC=Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Yield: 97.9 %

Procedure:
434 mg (1 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid monocinnamyl ester, 226 mg (1.1 mM) of dicyclohexylcarbodiimide, 122 mg (1 mM) of 4-dimethylaminopyridine and 127 mg (1.2 mM) of 2-ethylthioethanol were dissolved in 10 ml of dichloroethane, and refluxed for 2 hours. After the reaction mixture was chilled, insoluble matters were filtered off. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 511 mg of cinnamyl 2-ethylthioethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (yield 98%).
Reaction SMILES: C1(C)C=CC(S(O[CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)(=O)=O)=CC=1.C1C2C(=CC=CC=2)CC1O.[F:31][C:32]1[CH:46]=[CH:45][C:35]2[C:36]([CH:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)=[N:37][O:38][C:34]=2[CH:33]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:31][C:32]1[CH:46]=[CH:45][C:35]2[C:36]([CH:39]3[CH2:40][CH2:41][N:42]([CH:11]4[CH2:12][C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:19]4)[CH2:43][CH2:44]3)=[N:37][O:38][C:34]=2[CH:33]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1ccc(S(=O)(=O)OC2Cc3ccccc3C2)cc1
Agent: OC1Cc2ccccc2C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Fc1ccc2c(C3CCN(C4Cc5ccccc5C4)CC3)noc2c1

Procedure:
0.173 mole of 2-indanyl para-toluenesulfonate (prepared from 2-indanol according to the procedure described in Example 4, stage B), 0.173 mole of 6-fluoro-3-piperid-4-yl-1,2-benzisoxazole, dissolved in 50 ml of toluene, and 0.0346 mole of triethylamine are mixed.
Reaction SMILES: [CH3:1][C@H:2]([NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:3]([OH:5])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:31]([N:30]([CH3:29])[C:3](=[O:5])[C@@H:2]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:1])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 84.9 %

Procedure:
To a-30° C. solution of N-t-Boc-L-alanine (20.0 g, 0.106 mol) and triethylamine (16.8 mL, 0.119 mol) in THF (300 mL) was added isobutyl chloroformate (15.0 mL, 0.114 mol) drop wise. The reaction mixture was warmed to ambient temperature over 1.25 h and then stirred for 3.5 h. The reaction mixture was cooled to 0° C. and a solution of N-methylbenzylamine (14.3 mL, 0.111 mol) and triethylamine (18.8 mL, 0.134 mol) in THF (60 mL) was added drop wise. The reaction mixture was allowed to warm to ambient temperature. After 16 h, saturated NaHCO3 (200 mL) was added and most of the THF was removed under reduced pressure. The remaining aqueous layer was extracted with EtOAc (2×250 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 10% EtOAc in hexanes to 40% EtOAc in hexanes) gave (S)-tert-butyl 1-(benzyl(methyl)amino)-1-oxopropan-2-ylcarbamate (26.3 g, 85%) as a colorless oil. 1H NMR consistent.
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:14]([CH2:16][C:17]([N:20]([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:15]=2)=[CH:7][C:6]=1[C:29]([F:32])([F:31])[F:30].[Cl:33][C:34]1[C:35]2[CH2:42][C:41](=[O:43])[NH:40][C:36]=2[N:37]=[CH:38][N:39]=1>CN(C=O)C>[ClH:33].[CH3:22][N:20]([CH3:21])[C:17]([CH3:19])([CH3:18])[CH2:16][N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[C:6]([C:29]([F:30])([F:31])[F:32])[CH:7]=2)[N:12]=[C:13]1[CH:23]1[CH2:28][CH2:27][N:26]([C:34]2[C:35]3[CH2:42][C:41](=[O:43])[NH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH2:25][CH2:24]1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: CN(C)C(C)(C)Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)C(C)(C)Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc3c2CC(=O)N3)CC1

Procedure:
Combine {2-[4-(4-fluoro-3-trifluoromethyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-1,1-dimethyl-ethyl}-dimethylamine tris hydrochloride (247 μmol; 200 mg); 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (1.5 equiv; 575 μmol; 97.5 mg); TEA (1.92 mmol; 267 μL); DMF (2 mL) and heat in microwave reactor at 160° C. for 30 min. Evaporate and purify on 40 g silica gel with 2-7.5% MeOH/DCM to provide 137.3 mg (0.25 mmol; 66%) of the title compound as the free base. Dissolve in DCM/MeOH, add 1 equiv 1M HCl in ether and evaporate to provide 162.4 mg of the title compound. MS (ES+): m/z=546 (M+H).