Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].Cl[C:16]1[N:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[N:17]=1.O>CN(C=O)C>[Cl:23][C:18]1[CH:19]=[C:20]([Cl:22])[N:21]=[C:16]([N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[N:4]=[C:3]2[CH:2]([F:1])[F:12])[N:17]=1
Reactant: FC(F)c1nc2ccccc2[nH]1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)c1nc2ccccc2n1-c1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.2 %

Procedure:
0.84 g (5 mmol) of 2-difluoromethylbenzimidazole dissolved in DMF (25 ml) was added and reacted with 60% sodium hydride (0.24 g, 6 mmol) at room temperature for 30 minutes. This suspension was added to a solution of 2,4,6-trichloropyrimidine (0.92 g, 5 mmol) dissolved in DMF (25 ml) and stirred at room temperature for 1.5 hours. The reaction solution was poured into water and the resulting precipitates were recrystallized from methanol to obtain 0.98 g (yield: 62%) of 4,6-dichloro-2-(2-difluoromethylbenzimidazol-1-yl)pyrimidine. (2) 0.32 g (1.0 mmol) of 4,6-dichloro-2-(2-difluoro-methylbenzimidazol-1-yl)pyrimidine, 0.16 g (1.0 mmol) of cis-2,3-dimethylmorpholine hydrochloride and 0.3 g (2.2 mmol) of anhydrous potassium carbonate were added to DMF (10 ml) and stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.33 g (yield: 84%) of 4-chloro-2-(2-difluoro-methylbenzimidazol-1-yl)-6-(cis-2,3-dimethylmorpholino)-pyrimidine. (3) 0.33 g (0.8 mmol) of the obtained 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-(cis-2,3-dimethyl-morpholino)pyrimidine dissolved in morpholine (0.70 g, 8.0 mmol) was stirred at 70° C. for 1 hour. The solvent was removed under the reduced pressure from the reaction mixture and the residue was purified by silica gel column chromatography to obtain 0.326 g (yield: 90%) of the titled compound as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CC(N(C)C)=O.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1cnnc(Cl)c1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C(F)(F)F)cnn2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
3-Chloro-5-trifluoromethyl-pyridazine (200 mg) was added to piperazine-1-carboxylic acid tert-butyl ester (231 mg) in dimethylacetamide (3 mL), and the reaction mixture was stirred at 100° C. for 3 hours. After such time, the reaction mixture was allowed to cool down to room temperature and diluted with ethyl acetate. The solid was filtered off and washed with ethyl acetate. The filtrate was then concentrated in vacuo and then purified by column chromatography (SiO2, Heptane/EtOAc) to yield the title compound as a white solid (364 mg). MS (m/e): 333.4 (M+H+, 100%)
Reaction SMILES: C([N:4]([C:6](=[O:37])[C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:8]=1[CH:15]1[C:20]([C:21](=O)[CH3:22])=[C:19]([CH3:24])[N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[C:17](=[O:35])[N:16]1[CH3:36])[NH2:5])(=O)C.[OH-:38].COC(NS([N+](CC)(CC)[CH2:48][CH3:49])(=O)=O)=O>ClCCl>[C:21]([C:20]1[CH:15]([C:8]2[CH:9]=[CH:10][C:11]([C:13]#[N:14])=[CH:12][C:7]=2[C:6]2[O:37][C:48]([CH3:49])=[N:5][N:4]=2)[N:16]([CH3:36])[C:17](=[O:35])[N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)[C:19]=1[CH3:24])(=[O:38])[CH3:22]
Reactant: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Reactant: [OH-]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)N(N)C(C)=O
Solvent: ClCCl
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1-c1nnc(C)o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-5-cyano-benzoic acid acetyl hydrazide (intermediate 13) (15 mg, 0.03 mmol) is suspended in dichloromethane (1 mL) and (methoxycarbonylsulfamoyl)triethyl-ammonium hydroxide (Burgess reagent)(17.4 mg, 0.07 mmol) is added. The mixture is stirred at room temperature for 3 days. The solvent is removed under reduced pressure and purification is performed by reversed phase HPLC. Yield: 6.4 mg; ESI mass spectrum [M+H]+=496; Retention time HPLC: 1.04 min (HPLC method Z018_S04).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1)=[O:4].N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=CC(S(Cl)(=O)=O)=C[CH:21]=1.C(=O)(O)[O-].[Na+]>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:13][C:20]([CH3:30])([CH3:25])[CH3:21])=[O:12])=[N:9][CH:10]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
5-(Methoxycarbonyl)pyridine-2-carboxylic acid (7.72 g, 42.65 mmol) was suspended in tert-butanol (70 mL) and pyridine (25 mL) and cooled in an ice-water bath. 4-Toluenesulfonyl chloride (19.4 g, 102 mmol) was added in one portion and the mixture was stirred 30 minutes in the ice-water bath. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was then slowly poured into a stirring mixture of saturated aqueous sodium bicarbonate (300 mL) and ethyl ether (150 mL). The resulting two-phase mixture was then extracted with ethyl ether (3×150 mL). The extracts were combined, washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (5.8 g, 51% yield) was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([C@@H:25](O)[CH3:26])[CH:22]=[CH:23][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:18][C:19]1[CH:20]=[C:21]([C@H:25]([O:17][C:14]2[CH:13]=[CH:12][C:11]([CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=2)[CH3:26])[CH:22]=[CH:23][CH:24]=1
Reactant: C[C@H](O)c1cccc(Cl)c1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(OCC)c1ccc(O[C@H](C)c2cccc(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and (1S)-1-(3-chlorophenyl)ethanol (99 mg, 0.630 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (142 mg, yield: 90%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.[CH2:20]([Mg]Br)[CH3:21]>O1CCCC1.CCOCC>[CH2:20]([C:2]1([OH:1])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:4][CH2:3]1)[CH3:21]
Reactant: O=C1CCC(CNC(=O)OCc2ccccc2)CC1
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC1(O)CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a vigorous stirring solution of benzyl (4-oxocyclohexyl)methylcarbamate (1 g) in tetrahydrofuran (20 mL) at −78° C. was slowly added 1 M ethylmagnesium bromide (11.48 ml, 11.48 mmol) in ether. After completion of the addition, the mixture was stirred at −78° C. for 2 hours and was warmed to 0° C., and stirred in an ice bath for 30 minutes. The reaction was quenched with a cold NH4Cl aqueous solution. The precipitates were filtered off and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane and loaded onto Analogix purification system, and was eluted with 0-50% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Cu](C#N)[C:12]#[N:13]>O.C(OCC)(=O)C>[C:12]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2)#[N:13]
Reactant: N#C[Cu]C#N
Reactant: Brc1cccc2cc[nH]c12
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc2cc[nH]c12
Temperature: 200 °C
Reaction time: 2.5 h
Yield: 54.8 %

Procedure:
Combine 7-bromoindole (4.72 g, 24.0 mmol) and copper cyanide (4.30 g, 48.1 mmol) in 1-methyl-2-pyrrolidine (40 mL). Heat to 200° C. After 2.5 hours, cool to room temperature, add water-ethyl acetate (200 mL, 1/1) to give a solid. Filter through the celite, extract the filtrate with ethyl acetate, combine the organic layers, wash with brine, dry over Na2SO4, filter and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with hexanes:ethyl acetate (10:1) to give (1.87 g) of the title compound as a yellow solid: 1H NMR (300 MHz, DMSO-d6)) 6.64-6.66 (m, 1H), 7.17 (t, 1H, J=7.6 Hz), 7.51-7.53 (m, 1H), 7.60-7.62 (m, 1H), 7.94 (d, 1H, J=8.0H), 12.03 (br, 1H).
Reaction SMILES: [CH3:1][N:2]([S:11]([CH3:14])(=[O:13])=[O:12])[C:3]1[O:4][CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.[NH2:15][C@@H:16]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=1)[C@H:17]([OH:29])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:37][C:35]1[CH:36]=[C:31]([CH:32]=[C:33]([F:38])[CH:34]=1)[CH2:30][C@H:16]([NH:15][C:8]([C:6]1[N:7]=[C:3]([N:2]([CH3:1])[S:11]([CH3:14])(=[O:13])=[O:12])[O:4][CH:5]=1)=[O:10])[C@H:17]([OH:29])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[CH:22]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CN(c1nc(C(=O)O)co1)S(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2coc(N(C)S(C)(=O)=O)n2)c1
Reaction time: 2 h

Procedure:
To a 7 ml screw cap vial was added (20.9 mg, 0.0949 mmoles) 2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxylic acid, (36.7mg, 0.1097 mmoles, 1.15 eq.) (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol and (54.6 mg, 0.1436 mmoles, 1.5 eq.) HATU, followed by (1.25 ml) N,N-dimethylformamide. The reaction was placed in an orbital shaker and was left at ambient temperature for 2 hours. The reaction was quenched with (2 ml) 1N HCl. The clear solution was extracted three times with ethyl acetate and the combined organic layers were washed with saturated sodium carbonate solution and then brine. The solution was then dried with magnesium sulfate and evaporated to a clear oil which was purified by preparative HPLC, resulting N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide (15.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[C:9]1([CH:16]=[CH:15][CH:14]=[C:12]([OH:13])[CH:11]=1)[OH:10].CS(C)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:9]2[CH:11]=[C:12]([OH:13])[CH:14]=[CH:15][CH:16]=2)=[N:6][CH:7]=1
Reactant: Oc1cccc(O)c1
Reactant: Fc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: Oc1cccc(Oc2ccc(Cl)cn2)c1
Temperature: 40 °C
Yield: 34.7 %

Procedure:
To a solution consisting of 5-chloro-2-fluoropyridine (1.3 mL, 13 mmol) and resorcinol (2.1 g, 19 mmol) and DMSO (30 mL) was added Cs2CO3 (6.3 g, 19 mmol). The reaction vessel was heated at 40° C. for 22 hours then diluted with CH2Cl2 (60 mL) and washed with saturated aq. NH4Cl (100 mL). The organic layer was dried (MgSO4) and concentrated. The crude residue was purified (FCC) to give the title compound (1.0 g, 37%). MS (ESI+): calcd. for C11H8ClNO2, 221.02. m/z found, 222.1 (M+H)+. 1H NMR (CDCl3): 8.14 (d, J=2.6 Hz, 1H), 7.65 (dd, J=8.7, 2.7 Hz, 1H), 7.26-7.22 (m, 1H), 6.89 (dd, J=8.7, 0.5 Hz, 1H), 6.69-6.65 (m, 2H), 6.60 (t, J=2.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Na].ClCCl.[CH3:13][OH:14]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:14][CH3:13])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CO
Agent: [Na]
Solvent: ClCCl
Product: COc1cc(Cl)ncn1
Temperature: -10 °C
Reaction time: 12 h

Procedure:
3 g of 4,6-dichloropyrimidine were dissolved in 30 ml of dried methanol and mixed dropwise at -10° C. with a solution of 0.46 g of sodium in 20 ml of dried methanol and stirred at -10° C. for 5 hours and at room temperature for 12 hours. The solution was rotated in, the residue taken up with 50 ml of dichloromethane and a little activated carbon was added. After filtration, rotation in to dryness took place. The initially liquid residue became crystalline solid when left to stand. 2.5 g of 4-chloro-6-methoxypyrimidine were obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:36]=[CH:35][C:10]([CH2:11][C:12]2[C:13]3[CH:34]=[CH:33][CH:32]=[CH:31][C:14]=3[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)C.O.[NH2:39][NH2:40]>CCO>[NH:39]([C:4](=[O:3])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C:12]2[C:13]3[CH:34]=[CH:33][CH:32]=[CH:31][C:14]=3[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)=[CH:19][CH:18]=2)=[CH:35][CH:36]=1)[NH2:40]
Reactant: CCOC(=O)COc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)COc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Yield: 100 %

Procedure:
A mixture of 3-[4-(2-ethoxy-2-oxoethoxy)benzyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (400 mg), hydrazine hydrate (2 mL), and EtOH (50 mL was refluxed for 3.5 hours, cooled, and evaporated in vacuo to give the title compound as an amorphous solid (0.4 g, 100%).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][O:13][C:14](=[O:19])[CH2:15][C:16]([CH3:18])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.[CH3:20][O:21][C:22](=[O:27])/[CH:23]=[C:24](\[NH2:26])/[CH3:25].[F:28][C:29]([F:39])([F:38])[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O.[ClH:40]>CC(C)=O.C(O)C.C(O)(C)C>[ClH:40].[CH3:1][N:2]([CH2:11][CH2:12][O:13][C:14]([C:15]1[CH:33]([C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([C:29]([F:28])([F:38])[F:39])[CH:31]=2)[C:23]([C:22]([O:21][CH3:20])=[O:27])=[C:24]([CH3:25])[NH:26][C:16]=1[CH3:18])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1
Reactant: CC(=O)CC(=O)OCCN(C)Cc1ccc(C)cc1
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)Cc2ccc(C)cc2)C1c1cccc(C(F)(F)F)c1

Procedure:
In 3 ml. of isopropyl alcohol were dissolved 1.07 g. of acetoacetic acid β-(N-methyl-N-p-methylbenzylamino)ethyl ester, 0.466 g, of β-aminocrotonic acid methyl ester, and 0.705 g. of m-trifluoromethyl benzaldehyde and the solution was refluxed for 6 hours. The reaction mixture was concentrated, subjected to a silica gel column chromatography (diameter 4 cm, height 15 cm.), and then the effluents containing the aimed product obtained were collected and concentrated. The residue thus obtained was dissolved in acetone and after adjusting the solution to pH 1-2 with an ethanol solution saturated with hydrogen chloride, the solution was concentrated. Then, by crystallizing the residue formed with acetone, 0.8 g. of 2,6-dimethyl-4-(3'-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-β-(N-methyl-N-p-methylbenzylamino)ethyl ester hydrochloride was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[C:20]([I:21])=[CH:19][N:18]=[C:17]([NH2:22])[N:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].C(N([CH2:28][CH3:29])CC)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>O1CCCC1>[I:21][C:20]1[C:15]([O:14][C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:6]=[CH:7]3)=[N:16][C:17]([N:22]([C:31]([O:33][C:29]2[CH:28]=[CH:36][CH:35]=[CH:34][CH:39]=2)=[O:32])[C:31](=[O:32])[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:18][CH:19]=1
Reactant: CNC(=O)n1ccc2cc(Oc3nc(N)ncc3I)ccc21
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)n1ccc2cc(Oc3nc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)ncc3I)ccc21
Yield: 63.8 %

Procedure:
N1-Methyl-5-(2-amino-5-iodo-4-pyrimidyl)oxy-1H-1-indolecarboxamide (205 mg, 0.500 mmol) was suspended in tetrahydrofuran (5.0 ml); triethylamine (0.209 ml, 1.50 mmol) was added thereto while stirring. The suspension was cooled with ice; phenyl chloroformate (0.188 ml, 1.50 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate; and the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and was dried over anhydrous magnesium sulfate. After solvent distillation, the obtained crude product was crystallized from ethyl acetate-hexane; and the crystals were filtered off, and dried under aeration to yield the title compound as white crystals (207 mg, 0.319 mmol, 64%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Cl[CH2:17][C:18]1[C:19]([CH3:24])=[N:20][O:21][C:22]=1[CH3:23]>CN(C)C=O>[CH3:24][C:19]1[C:18]([CH2:17][N:3]2[C:4](=[O:15])[C:5]3[C@@H:6]4[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[C:22]([CH3:23])[O:21][N:20]=1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: Cc1noc(C)c1CCl
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1c(=O)c2c(n1C)[C@]1(C)CC[C@H]2C1(C)C
Temperature: 100 °C
Yield: 41 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 4-chloromethyl-3,5-dimethyl-isoxazole (60 μL, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. A further portion of and 4-chloromethyl-3,5-dimethyl-isoxazole (30 μL, 0.24 mmol) was added and the solution was heated at 100° C. for 2 h. The reaction mixture was evaporated and the residue was diluted with water and extracted with chloroform. The chloroform layer was washed with water, dried (magnesium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 3% methanol/dichloromethane to give (4S,7R)-2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (62 mg, 41%) as an off-white solid. ES(+)-MS (M+H) 316.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11]([O:16][CH3:17])(=[O:15])[C:12]([CH3:14])=O.Cl>CO.[Pd]>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][CH:12]([CH3:14])[C:11]([O:16][CH3:17])=[O:15]
Reactant: Nc1ccc(F)c(F)c1F
Reactant: COC(=O)C(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)Nc1ccc(F)c(F)c1F
Temperature: 40 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
2,3,4-Trifluoroaniline (1.01 g) and methyl pyruvate (0.87 g) were dissolved in methanol (8 ml). After adding 5% Pd-C (0.11 g) and conc. hydrochloric acid (0.03 g), the mixture was stirred at 40° C. under a hydrogen gas pressure of 2.94 MPa (converted from 30 kgf/cm2) for 2 hours. After filtering off Pd-C, the obtained filtrate was concentrated under reduced pressure. Thus the title compound (1.31 g) was obtained as slightly yellowish crystals. Various spectral data of this product was identical with those obtained in Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]=2[C:6]2[C:14]1=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2[nH]c3c(Cl)cccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=C1CCCc2c1c1cccc(Cl)c1n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
8-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.2019 g, 0.92 mmol) is added to a slurry of pentane-washed NaH (0.0275 g, 0.68 mmol) in DMF (1 mL) and after stirring 22 min benzyl bromide (0.13 mL, 0.0011 mol) is added. Starting material remained after 30 min, so additional NaH (0.0140 g, 0.35 mmol) and DMF (1 mL) are added and the mixture is allowed to stir overnight. The mixture is then partitioned between aq. sodium bicarbonate and ethyl acetate and the organic layer is dried over sodium sulfate and concentrated to dryness. The resulting solids are recrystallized from 30% ethyl acetate/hexane and dichloromethane to give 0.1942 g (68%) of the title compound; mp 161-162° C.; MS (ESI+) for C19H16ClNO m/z 310.1 (M+H)+; IR (drift) 1644, 1605, 1538, 1484, 1462, 1447, 1425, 1357, 1188, 1106, 793, 784, 737, 725, 699 cm−1; 1H NMR (CDCl3) δ2.22, 2.59, 2.85, 5.82, 6.95, 7.18, 7.28, 8.28. Anal. Calcd for C19H16ClNO: C, 73.66; H, 5.20; N, 4.52. Found: C, 73.41; H, 5.17; N, 4.57.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:33]3[C:34]([C:37]#[N:38])=[CH:35][CH:36]=[C:32]3[C:12]3([CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[O:11][C:10]=2[CH:39]=1)(=O)C.[Li+].[OH-].C1COCC1>CO>[OH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:33]3[C:34]([C:37]#[N:38])=[CH:35][CH:36]=[C:32]3[C:12]3([CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]4[CH:20]=[CH:21][C:22]([S:25]([CH:28]([CH3:29])[CH3:30])(=[O:27])=[O:26])=[CH:23][CH:24]=4)[CH2:14][CH2:13]3)[O:11][C:10]=2[CH:39]=1
Reactant: CC(=O)OCc1ccc2c(c1)OC1(CCN(C(=O)c3ccc(S(=O)(=O)C(C)C)cc3)CC1)c1ccc(C#N)n1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(C(=O)N2CCC3(CC2)Oc2cc(CO)ccc2-n2c(C#N)ccc23)cc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
(1-Cyano-1′-(4-(isopropylsulfonyl)benzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-yl)methyl acetate (16.2 mg, 0.0297 mmol) was treated with 1M LiOH (1 mL), THF (5 mL) and MeOH (1 mL). The mixture was stirred at room temperature over night. The volatiles were removed and the residue was neutralized with 1N HCl. The mixture was extracted with CH2Cl2 (2×). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 7′-(hydroxymethyl)-1-(4-isopropylsulfonylbenzoyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile (11.3 mg, 75%). ESI-MS m/z calc. 505.58, found 506.5 (M+1)+; Retention time 1.49 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.93 (dd, J=8.2, 6.5 Hz, 3H), 7.73 (d, J=8.3 Hz, 2H), 7.32 (d, J=4.0 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.45 (d, J=4.1 Hz, 1H), 5.39-5.30 (m, 1H), 4.51 (s, 2H), 3.81-3.64 (m, 1H), 3.54-3.42 (m, 2H), 3.41-3.37 (m, 1H), 2.20-2.12 (m, 1H), 2.13-2.03 (m, 1H), 2.01 (t, J=5.9 Hz, 1H), 1.57 (dd, J=12.5, 6.2 Hz, 1H), 1.17 (d, J=6.8 Hz, 6H).