Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[N:4][NH:3]1.P(Cl)(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[Cl:20][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(-c2cnc(=O)[nH]n2)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2cnc(Cl)nn2)cc1
Temperature: 100 °C
Yield: 17.3 %

Procedure:
A mixture of methyl 4-(3-oxo-2,3-dihydro-1,2,4-triazin-6-yl)benzoate (13.4 g, 0.0580 mol), phosphoryl chloride (30 mL, 0.3 mol) in chloroform (50 mL) was refluxed (oil-bath temperature about 100° C.) for 2 h. After cooling to RT, the mixture was concentrated to remove excess phosphoryl chloride. The residue was dissolved in methylene chloride and poured into ice-water, and carefully neutralized with K2CO3. The organic layer was separated and the aqueous solution was extracted with methylene chloride. The combined organic phases were dried over Na2SO4, concentrated, and further purified by chromatography to afford the desired product (2.5 g, 17%). LCMS: (M+H)=249.9. 1H NMR (300 MHz, CDCl3): in ppm, 3.98 (s, 3H), 8.18 (d, 2H), 8.24 (d, 2H), 8.96 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:5]=[CH:4][C:3]=1[NH2:19].C([O-])([O-])=O.[Na+].[Na+].[CH3:26][C:27]1([CH3:36])[CH2:32][CH2:31][C:30](B(O)O)=[CH:29][CH2:28]1>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C:27]1([CH3:36])[CH2:32][CH2:31][C:30]([C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][S:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)(=[O:12])=[O:11])[CH:5]=[CH:4][C:3]=2[NH2:19])=[CH:29][CH2:28]1
Reactant: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1Br
Reactant: CC1(C)CC=C(B(O)O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)CC=C(c2cc(CCS(=O)(=O)N3CCOCC3)ccc2N)CC1
Temperature: 80 °C
Yield: 139 %

Procedure:
A solution of 40.0 mg (0.114 mmol) of 2-bromo-4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamine (as prepared Example 26, step (e)) in toluene (4 mL) and EtOH (2 mL) was treated with 458 μL (0.229 mmol) of 2.0 M aqueous Na2CO3 and 29.8 mg (0.226 mmol) of 4,4-dimethyl-cyclohex-1-enylboronic acid. The mixture was degassed via sonication, placed under Ar, treated with 13.2 mg (0.0110 mmol) of Pd(PPh3)4, and heated to 80° C. for 5 h. The mixture was cooled to RT, diluted with EtOAc (10 mL), and washed with saturated aqueous NaHCO3 (1×10 mL) and brine (1×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 60.0 mg of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C20H30N2O3S, 379.2 (M+H). found 379.1.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[CH2:9]([N:11](CC)[CH2:12][CH3:13])[CH3:10].N1CCCC1>ClCCl>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([N:11]1[CH2:12][CH2:13][CH2:10][CH2:9]1)=[O:5]
Reactant: CCN(CC)CC
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(CCl)C(=O)N1CCCC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
3-Chloro-2,2-dimethyl-propionyl chloride (0.5 g, 3.2 mmol) was stirred in dichloromethane (20 mL) at RT with triethylamine (0.9 mL, 6.4 mmol). The reaction mixture was cooled to 5° C. and then pyrrolidine (0.32 mL, 3.9 mmol), was added drop wise. After addition the reaction was stirred at RT for 1 hr, and then the reaction mixture was washed with saturated sodium hydrogen carbonate solution (2×50 mL), brine (50 ml), dried (Na2SO4) and concentrated in vacuo to afford 3-chloro-2,2-dimethyl-1-pyrrolidin-1-yl-propan-1-one as a yellow solid, 0.576 g, 94%. To this intermediate, 3-chloro-2,2-dimethyl-1-pyrrolidin-1-yl-propan-1-one (0.57 g, 3 mmol) in anhydrous THF (20 mL) was slowly added a 1M anhydrous THF solution of lithium aluminium hydride (7.5 mL, 7.5 mmol) at room temperature. The resulting clear solution was stirred overnight at room temperature under nitrogen to give a cloudy suspension. Water (0.3 mL) was carefully added to the reaction mixture followed by 15% w/v aqueous sodium hydroxyde solution (0.3 mL) and water (0.9 mL). The reaction was filtered and the filtrate evaporated to dryness to give the title compound which was used without further purification.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[N:7][C:8]=1[CH:9]=C)=C.[O:18]=[O+][O-].[BH4-].[Na+].[CH3:23][OH:24]>ClCCl>[OH:24][CH2:23][C:3]1[CH:4]=[C:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[N:7][C:8]=1[CH2:9][OH:18]
Reactant: CO
Reactant: O=[O+][O-]
Reactant: C=Cc1cc(C(=O)OC(C)(C)C)cnc1C=C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cnc(CO)c(CO)c1
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 5,6-diethenylpyridine-3-carboxylate (19.0 g, 82 mmol) in dichloromethane (821 mL) at −78° C. was added ozone gas. The ozone bubbled though the solution until saturated (1 h). Nitrogen gas was then bubbled through the solution. The mixture was diluted with methanol (821 mL) and sodium borohydride (7.77 g, 205 mmol) was added. After 15 min, the mixture was quenched with saturated aqeuous sodium bicarbonate and washed with dichloromethane (3×). The combined organics were washed with brine, dried with magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→15% methanol/dichloromethane) gave the title compound. MS: m/z=240.3 (M+1).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-:3].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.Cl[CH:14]([Si:16]([CH3:19])([Cl:18])[Cl:17])Cl.O=P(Cl)(Cl)Cl>[Cl-].[Al+3].[Cl-].[Cl-].CCCCCC>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[CH:14]([Si:16]([CH3:19])([Cl:18])[Cl:17])[C:6]1[CH:11]=[C:10]([Cl:1])[CH:9]=[CH:8][C:7]=1[Cl:3]
Reactant: Clc1ccc(Cl)cc1
Reactant: [Cl-]
Reactant: C[Si](Cl)(Cl)C(Cl)Cl
Agent: [Al+3]
Solvent: CCCCCC
Solvent: O=P(Cl)(Cl)Cl
Product: C[Si](Cl)(Cl)C(c1cc(Cl)ccc1Cl)c1cc(Cl)ccc1Cl
Temperature: 150 °C
Reaction time: 1 h
Yield: 351.5 %

Procedure:
To a 250 ml, three-necked, frame dried, round bottom flask equipped with a magnetic stirrer, a reflux condenser, and a dropping funnel, aluminum chloride 1.28 g (9.60 mmol) and 1,4-dichlorobenzene 62.89 g (428 mmol) were placed under dry nitrogen atmospheric pressure. After (dichloromethyl) methyldichlorosilane 14.12 g (72.31 mmol) was added to the solution, the reaction mixture was heated for 7 hours at 150° C. The aluminum chloride catalyst was quenched with POCl3 1.47 g (9.59 mmol) and then stirred for another 1 hour to complete the deactivation. Freshly distilled hexane (100 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane was distilled, the reaction products were vacuum distilled at 0.2 torr to give 14.14 g of [bis(2,5-dichlorophenyl)methyl] methyldichlorosilane (bp; 154° C./0.2 torr, yield; 47%).
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].CI>C1COCC1>[CH3:12][CH:4]([C:3](=[O:10])[CH:2]([CH3:1])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)C(=O)C(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.3 %

Procedure:
A solution of ethyl 4-methyl-3-oxopentanoate (3.0 g, 19.0 mmol) and potassium carbonate (7.86 g, 56.9 mmol) in THF (40 mL) was stirred at room temperature for 3 h under N2 (g). The mixture was cooled to 0° C. and methyl iodide (3.23 g, 22.8 mmol) was added dropwise over 5 min. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Subsequent filtration and concentration provided ethyl 2,4-dimethyl-3-oxopentanoate (2.89 g, 89% yield) as a clear yellow oil that was used without further purification. MS (EI) for C9H16O3: 172 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:17]([O:18][CH:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[OH-].[Na+]>ClCCl>[NH2:7][C:8]1[C:17]([O:18][CH:19]2[CH2:20][CH2:21][CH:22]([OH:25])[CH2:23][CH2:24]2)=[CH:16][C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2.[NH2:7][C:8]1[C:17]([O:18][CH:19]2[CH2:24][CH2:23][CH:22]([O:30][C:29](=[O:31])[C:28]([F:33])([F:32])[F:27])[CH2:21][CH2:20]2)=[CH:16][C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cc2ccccc2cc1OC1CCC(O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Nc1cc2ccccc2cc1OC1CCC(O)CC1
Product: Nc1cc2ccccc2cc1OC1CCC(OC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of [3-(4-hydroxy-cyclohexyloxy)-naphthalen-2-yl]-carbamic acid tert-butyl ester (0.15 g, 0.58 mmol) and trifluoroacetic acid (0.2 mL) in dichloromethane (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was basified by addition of an aqueous solution of sodium hydroxide and was extracted twice with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 75/25) to give 38 mg of 4-(3-amino-naphthalen-2-yloxy)-cyclohexanol and 66 mg of trifluoroacetic acid 4-(3-amino-naphthalen-2-yloxy)-cyclohexyl ester. The trifluoroacetate was treated with a solution of sodium hydroxide (11 mg) in ethanol (2 mL) and water and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was partitioned between water and dichloromethane, the organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford additional 40 mg of 4-(3-amino-naphthalen-2-yloxy)-cyclohexanol.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH2:15](O)[CH2:16][CH2:17][CH3:18].Cl>CCCCCC.C(OCC)(=O)C>[C:1]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CCCCO
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCOC(=O)/C=C/c1ccc(O)c(OC)c1
Yield: 99 %

Procedure:
Ferulic acid (5 g) and then n-butyl alcohol (50 ml) containing hydrogen chloride (4%) were placed in an egg-plant type flask (200 ml), and heated under reflux for about 2 hours. The disappearance of the starting material was confirmed by thin layer chromatography (TLC: n-hexane/ethyl acetate=2/1), then the solvent was evaporated under reduced pressure by a rotary evaporator. Benzene was added to the residue, and then, the solvent was again evaporated by a rotary evaporator to obtain the crude product. The resulting crude product was separated and purified by silica gel column chromatography (diameter=5.5×8.5 cm; 70 g; n-hexane/ethyl acetate=2/1) to obtain the above-identified compound (6.25 g, 99%) as colorless oil.
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])O.S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.Cl.Cl.N[OH:26]>>[CH3:22][C:19]1[CH:18]=[C:17]2[C:16](=[CH:21][CH:20]=1)[NH:15][C:2](=[O:26])[C:3]2=[O:5]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: NO
Reactant: Cc1ccc(N)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: Cc1ccc2c(c1)C(=O)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
An aqueous solution (222 ml) containing 16.7 g (0.10 mol) of chloral hydrate was mixed with 243 g of sodium sulfate, an aqueous solution (56.0 ml) containing 10.0 g (93.3 mmol) of p-toluidine and 9.56 of concentrated hydrochloric acid and an aqueous solution (242 ml) containing 20.5 g (0.29 mol) of hydroxylamine hydrochloride in this order and the resulting mixture was heated under reflux with stirring for 30 minutes. After cooling to room temperature, the mixture was filtered with suction to collect the yellowish brown precipitate. The precipitate was dissolved in 500 ml of a 1.5N sodium hydroxide solution and neutralized with 2M hydrochloric acid. The resulting mixture was filtered and the filtrate was acidified with 2M hydrochloric acid. The thus precipitated isonitroso compound was collected by filtration and washed with iced water followed by drying. The dried product was added to 62 g of concentrated sulfuric acid which had been heated to 60° C. over 40 minutes and the mixture was further heated at 75° C. for 10 minutes. After cooling to room temperature, the resulting mixture was poured into 160 ml of iced water followed by filtration to obtain 10.0 g of 5-methylisatin.
Reaction SMILES: [Br:1][C:2]1([CH:16]=[CH:15][N:14]=[C:13]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH2:25]([OH:27])C.[OH-].[K+].[OH-].[Na+].[CH3:32]O>>[CH3:32][O:4][C:3]([O:27][CH3:25])([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:2]1([Br:1])[CH:16]=[CH:15][N:14]=[C:13]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1
Reactant: CO
Reactant: O=C(C1=NC=CC(Br)(C(=O)Nc2ccccc2)C1)c1ccccc1
Reactant: CCO
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: COC(Nc1ccccc1)(OC)C1(Br)C=CN=C(C(=O)c2ccccc2)C1
Yield: 80 %

Procedure:
4-Bromo-2-benzoyl-isonicotinanilide (12.7 g) was treated as in Synthesis 11 except that ethyl alcohol was replaced by methyl alcohol and potassium hydroxide by sodium hydroxide (3 g). The titled compound was obtained in an amount of 11.4 g (yield: 80%). m.p. 189°-190° C.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)=[N:21][CH:22]=3)[N:6]2[CH:36]=1)=O.[CH3:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=1.Cl[Si](C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([CH:36]=[C:3](/[CH:1]=[CH:37]/[C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:4]=3)[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:27][CH2:28]4)=[N:21][CH:22]=3)=[CH:8][N:9]=2)[CH2:12][CH2:13]1
Reactant: Cc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(C=O)cn34)cn2)CC1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)cn2)CC1
Temperature: 25 °C

Procedure:
To a solution of compound 19a (50.0 mg, 0.101 mmol) in DMF (3 mL) was added 2-methylquinoline (13.2 μL, 0.101 mmol) and chlorotrimethylsilane (38.6 μL, 0.304 mmol). The reaction mixture was stirred in a 10 mL sealed tube for 2 h at 80° C. After cooling to rt, the reaction mixture was poured into water (20 mL). The mixture was adjusted to basic using saturated NaHCO3 solution, and was extracted with DCM (2×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. Compound 19b was obtained as a yellow solid (40.0 mg, 64% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C35H38N8O3: 619.3 (M+H). found: 619.3.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[N-:22][N:21]=1
Reactant: Cc1cc(C)[nH]n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C)[n-]n1
Reaction time: 0.5 h

Procedure:
N-Benzyloxycarbonyl-DL-proline (4.98 g) was dissolved in dry dichloromethane (100 ml) and 3,5-dimethylpyrazole (2.12 g) and dicyclohexylcarbodiimide (4.5 g) were added to the solution at -20° C. After 30 min the temperature was elevated to room temperature and the solution was stirred for 20 h. After the completion of the reaction, 0.3 ml of acetic acid was added to the reaction mixture and an insoluble matter was removed by filtration. After the solvent was distilled off, the residue was dissolved in a small amount of ethyl acetate. An insoluble matter was removed by filtration and the filtrate was evaporated to dryness under reduced pressure to give 6.0 g of N-benzyloxycarbonyl-DL-proline-3,5-dimethylpyrazolide (yield: 91.7%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][NH2:10])=[CH:4][N:3]=1.[C:11](=[O:13])=[O:12].C([OH:17])(C)C>>[C:11](=[O:17])([OH:13])[OH:12].[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][NH2:10])=[CH:4][N:3]=1
Reactant: O=C=O
Reactant: CC(C)O
Agent: Cc1ncc(CN)c(N)n1
Product: O=C(O)O
Temperature: 10 °C

Procedure:
Into the same four-necked flask as used in Example 1 was charged a solution of 30.0 g (purity: 96.2%, 0.209 mole) of crude 2-methyl-4-amino-5-aminomethylpyrimidine dissolved in 300 g of isopropanol, followed by maintaining the temperature of the solution at 10° C. Subsequently, 44 g (1 mole) of carbon dioxide was blown into the solution over about 2 hours and the reaction was carried out to precipitate a white crystal of 2-methyl-4-amino-5-aminomethylpyrimidine carbonate with extreme easiness. Then, the resulting crystal was filtered off, washed with a small amount of isopropanol, and dried in vacuo at 20° C. until it may have constant weight to obtain 37.8 g of 2-methyl-4-amino-5-aminomethylpyrimidine carbonate.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:18]1[C:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32](OC)=O)=[CH:27][CH:26]=2)=[N:21][N:20]=[N:19]1>C(O)C>[CH:2]1([N:7]2[C:11]3=[N:12][C:32]([CH2:31][C:28]4[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:22]5[NH:18][N:19]=[N:20][N:21]=5)=[CH:30][CH:29]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: COC(=O)Cc1ccc(OCc2nnn[nH]2)cc1
Agent: [Na]
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc(OCc4nnn[nH]4)cc3)nc(=O)c1-2
Yield: 13.5 %

Procedure:
Sodium (0.253 g) was dissolved in ethanol (15 ml) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.813 g, 3.7 mmol) and methyl 4-(5-tetrazolylmethoxy)phenylacetate (17 g, 7.3 mmol) were added. The reaction mixture was refluxed for about 2 days, cooled, and then the solvent was removed in vacuo. The residue was treated with water and acetic acid and the precipitate which formed was collected by filtration and dried at 60° C. under vacuum. The product was then dissolved in ethyl acetate, extracted with Na2CO3 (4×200 ml) and the aqueous layer was acidified to pH 2.5 with concentrated HCl. The aqueous layer was then extracted with ethyl acetate (2×300 ml) and the organic layer was dried over MgSO4, filtered and concentrated in vacuo. The solid residue was recrystallized from ethyl acetate to afford 0.21 g of 1-cyclopentyl-3-ethyl-6-[4-(5-tetrazolylmethoxy)phenylmethyl]pyrazolo[3,4-d]pyrimidin-4-one.2/5 hydrate, m.p. 240-242° C.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:8][CH:9]1[CH2:14][CH2:13][C:12]([F:16])([F:15])[CH2:11][CH2:10]1)(=O)=O.[CH3:25][NH2:26]>CCOC(C)=O>[F:15][C:12]1([F:16])[CH2:13][CH2:14][CH:9]([CH2:8][C@H:7]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:6][NH:26][CH3:25])[CH2:10][CH2:11]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCC(F)(F)CC1
Solvent: CCOC(C)=O
Product: CNC[C@H](CC1CCC(F)(F)CC1)NC(=O)OC(C)(C)C
Temperature: 55 °C
Yield: 34.4 %

Procedure:
(S)-2-(tert-butoxycarbonylamino)-3-(4,4-difluorocyclohexyl)propyl methanesulfonate (28.8 g, 0.077 mol) was dissolved in alcoholic of methylamine solution (350 mL) and the reaction was warmed at 50-60° C. overnight. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure to give an oil, which was dissolved into EtOAc, washed with water twice and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to afford (S)-tert-butyl 1-(4,4-difluorocyclohexyl)-3-(methylamino)propan-2-ylcarbamate (8.1 g, 34.4%). 1H NMR (400 MHz, CDCl3): 5.12 (m, 1H), 4.97 (m, 1H), 3.82 (m, 1H), 3.63 (dd, J=14.4&4.4 Hz, 1H), 3.45 (dd, J=14.4&9.2 Hz, 1H), 2.76&2.74 (s, 1H), 2.20-1.20 (m, 11H), 1.44 (s, 9H); MS (E/Z): 307 (M+H+).
Reaction SMILES: [C:1](=[O:47])([O:16][C:17]1[C:18]([CH3:46])=[C:19]2[C:24](=[C:25]([CH3:28])[C:26]=1[CH3:27])[O:23][C:22]([CH3:45])([CH2:29][CH2:30][CH2:31][CH:32]([CH3:44])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:43])[CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:21][CH2:20]2)[O:2][CH2:3][CH:4]1[O:15][CH:5]1[CH2:6][O:7]CC1C=CC=CC=1.C(O)C.[H][H]>[C].[Pd].C(O)(=O)C>[C:1](=[O:47])([O:16][C:17]1[C:18]([CH3:46])=[C:19]2[C:24](=[C:25]([CH3:28])[C:26]=1[CH3:27])[O:23][C:22]([CH3:45])([CH2:29][CH2:30][CH2:31][CH:32]([CH3:44])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:43])[CH2:37][CH2:38][CH2:39][CH:40]([CH3:41])[CH3:42])[CH2:21][CH2:20]2)[O:2][CH2:3][CH:4]1[O:15][CH:5]1[CH2:6][OH:7]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)OCC1OC1COCc1ccccc1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1OC(=O)OCC1OC1CO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Yield: 80.2 %

Procedure:
A mixture comprising 6.5 g (0.01 mol) of 4-benzyloxy-2,3-epoxybutyl 2,5,7,8-tetramethyl-2-(4',8', 12'-trimethyltridecyl)-6-chromanyl carbonate, 1 g of 5% palladium carbon, 150 ml of ethanol and 5 ml of acetic acid was catalytically reduced with hydrogen at an initial pressure of 4 kg/cm2 until no hydrogen was absorbed any more (approximately 6 hours). After filtering off the catalyst, the filtrate was concentrated to thereby reduce the amount to 1/3, poured into water and extracted with ether. Then the extract was successively washed with an aqueous solution of sodium hydrogencarbonate and water, and dried. After distilling off the solvent, the obtained oily residue was purifed by column chromatography (silica gel, hexane/ethyl acetate) to thereby give 4.5 g of the title compound as a colorless oily product.