Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH3:13][O:14][C:15]1[C:16]([OH:34])=[CH:17][C:18]2[CH2:19][CH2:20][C@@H:21]3[C@@H:30]([C:31]=2[CH:32]=1)[CH2:29][CH2:28][C@@:26]1([CH3:27])[C@H:22]3[CH:23]=[CH:24][C:25]1=[O:33].[C:35](OC(C)=C)(=[O:37])[CH3:36].[C:42](OC(=O)C)(=[O:44])[CH3:43]>C(Cl)Cl.CC(C)=O>[CH3:13][O:14][C:15]1[C:16]([O:34][C:42](=[O:44])[CH3:43])=[CH:17][C:18]2[CH2:19][CH2:20][C@@H:21]3[C@@H:30]([C:31]=2[CH:32]=1)[CH2:29][CH2:28][C@@:26]1([CH3:27])[C:22]3=[CH:23][CH:24]=[C:25]1[O:33][C:35](=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]12
Reactant: C=C(C)OC(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC(C)=O)CC[C@H]1C3=CC=C(OC(C)=O)[C@@]3(C)CC[C@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
Under nitrogen, toluenesulfonic acid monohydrate (0.1 g, 0.53 mmol) was added to a solution of 2-Methoxyestra-1,3,5(10),15-tetraen-3-ol-17-one prepared in Example 3 (0.25 g, 0.84 mmol), isopropenyl acetate (5 mL, 45.15 mmol) and acetic anhydride (5 mL, 53 mmol) and the mixture was heated to reflux for 6 h. At the end of that time, analysis by tlc (2% acetone in CH2Cl2) indicated a complete reaction. The reaction was cooled to room temperature, poured into ice water (˜100 mL) and stirred for 1 h. The mixture was extracted with methylene chloride (3×). The organic fractions were washed with water (1×), saturated sodium bicarbonate solution (1×) and water (1×), filtered through anhydrous sodium sulfate, combined and concentrated in vacuo. The residue was crystallized from methanol to give the pure diacetate (17) (0.259 g, 80.8%).
Reaction SMILES: [F:1][C:2]1[C:22](F)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH3:20])[CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(N(CC)CC)C>CS(C)=O>[F:1][C:2]1[C:22]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=3)[CH2:36][CH2:35]2)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH3:20])[CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCN(c5ccc(F)cc5)CC4)c(F)cc3cc2c1=O
Yield: 8.3 %

Procedure:
Ethyl 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was prepared by analogy to the method described in Example 1, from 3.2 g of ethyl 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate, 2.16 g of 4-(4-fluorophenyl)piperazine and 3.35 cm of triethylamine in 40 cm3 of dimethyl sulphoxide. After filtering off with 2 times 15 cm3 of water and 2 times 15 cm3 of ethanol, 0.4 g of ethyl 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was obtained in the form of a yellow solid melting at about 310° C.
Reaction SMILES: [Na].[CH:2]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1.O>CN1CCCC1=O>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([O:8][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:15]=1
Reactant: Brc1cncc(Br)c1
Reactant: OC1CCCCC1
Agent: [Na]
Solvent: CN1CCCC1=O
Solvent: O
Product: Brc1cncc(OC2CCCCC2)c1
Temperature: 90 °C

Procedure:
Under an argon atmosphere, sodium (750 mg, 31.75 mmol) was added to refluxing cyclohexanol (15 mL). The mixture was refluxed until complete consumption of sodium. The remaining cyclohexanol was removed by a stream of argon to give a white solid, which was dissolved in N-methyl-pyrrolidinone (16 mL). After addition of 3,5-dibromopyridine (3 g, 12.66 mmol), the mixture was stirred and heated at 90° C. for 1 h, then cooled to room temperature, poured into cold (5° C.) water (60 mL), and extracted with diethyl ether (3×50 mL). The combined organic phases were washed with water (25 mL) and then brine (25 mL), then dried (MgSO4), filtered and concentrated by rotary evaporation to give 6.2 g of an orange oil, which was purified by column chromatography, eluting with cyclohexane/ethyl acetate (95/5, v/v). Selected fractions containing the product were concentrated via rotary evaporation to give 1.6 g (50%) of a light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[C:17]([CH3:23])=[N:18][O:19][C:20]=2[CH2:21][OH:22])=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>O>[CH3:34][S:35]([O:22][CH2:21][C:20]1[O:19][N:18]=[C:17]([CH3:23])[C:16]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8](=[O:9])[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1noc(CO)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1noc(COS(C)(=O)=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a round bottomed flask was added crude (4-chlorophenyl)(2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)phenyl)methanone (24.9 mg, 0.076 mmol), DCM (2 mL), and Et3N (21.18 μl, 0.152 mmol). This solution was cooled to 0° C. before addition of MsCl (7.10 μl, 0.091 mmol) and the reaction stirred at 0° C. for 30 min before diluting with water and extracting with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated to afford crude (4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methyl methanesulfonate.
Reaction SMILES: C(C(C)(CCCCCO)C)#N.[OH:12][C:13]1[C:20](O)=[C:19](CC)[CH:18]=[CH:17][C:14]=1[CH:15]=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O:52][CH2:53][CH3:54])=O)=NC(OCC)=O>C1COCC1>[CH2:19]([C:18]1[C:53]([OH:52])=[CH:54][C:15]([OH:16])=[C:14]([CH:17]=1)[CH:13]=[O:12])[CH3:20]
Reactant: CCc1ccc(C=O)c(O)c1O
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: CC(C)(C#N)CCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(C=O)c(O)cc1O
Temperature: 25 °C

Procedure:
A 50 mL dry THF solution of the above prepare 2-cyano-2-methyl-7-hydroxyheptane and 2,3-dihydroxy-4-ethylbenzaldehyde was stirred at room temp. To this solution added triphenylphosphine (17.91 g, 68.3 mmol) and finally diethyl azodicarboxylate (11.89 g, 68.3 mmol). The reaction was stirred at room temp for 2 h 15 min. and then quenched with saturated NH4Cl solution. The THF was removed under vacuum and the resulting residue was dissolved in EtOAc and the EtOAc solution was washed with brine. The organic layer was dried over MgSO4. Filtration and solvent removal gave an orange solid. The product was purified by Waters Prep 500 chromatography using silica gel as a solid support and eluting with a gradient of 10% to 30% EtOAc/Hexane over 50 min. The desired product was obtained as a yellow oil (10.50 g, 51%).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][CH:16]1[CH2:21][NH:20][CH2:19][CH2:18][N:17]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CCN(C(C)C)C(C)C>CCO>[CH3:15][CH:16]1[CH2:21][N:20]([C:2]2[N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:19][CH2:18][N:17]1[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23]
Reactant: O=[N+]([O-])c1cnn(CC(F)(F)F)c1Br
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC1CN(c2c([N+](=O)[O-])cnn2CC(F)(F)F)CCN1C(=O)OC(C)(C)C
Yield: 47.7 %

Procedure:
A solution of Intermediate 39, 5-bromo-4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole (550 mg, 2.01 mmol), (±) tert-butyl 2-methylpiperazine-1-carboxylate (403 mg, 2.01 mmol), DIPEA (2 mL) in EtOH (6 mL) was stirred at 130° C. for 2 hours in a microwave oven. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using PE:EtOAc (1:1) as eluting solvents to afford tert-butyl (±)-2-methyl-4-(4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)piperazine-1-carboxylate as yellow solid (377 mg, 48%). MS (ESI) m/z: 394 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[Cu][C:14]#[N:15]>CN(C=O)C.C(OCC)(=O)C>[C:14]([C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8])#[N:15]
Reactant: N#C[Cu]
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(CC(=O)O)ccc1F
Temperature: 130 °C
Yield: 65 %

Procedure:
To a solution of (3-bromo-4-fluoro-phenyl)-acetic acid (10 g, 42.9 mmol) in DMF (65 mL) was added copper (I) cyanide (7.7 g, 85.8 mmol) and heated at 130° C. for 24 hrs. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (250 mL). The organic layer was washed with water (5×50 mL), brine (50 mL), dried over sodium filtered and concentrated under reduced pressure. The crude material was re-crystallized from diethyl ether and hexane to afford the title compound as a yellow solid in 65% yield, 5 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][CH2:22][CH2:23][C@H:24]([NH:28][CH2:29][CH:30]([O:33][CH3:34])[O:31][CH3:32])[CH2:25][O:26][CH3:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:11](=[O:13])[N:28]([C@H:24]([CH2:25][O:26][CH3:27])[CH2:23][CH2:22][O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:29][CH:30]([O:31][CH3:32])[O:33][CH3:34])[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC[C@H](CCOCc1ccccc1)NCC(OC)OC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC[C@H](CCOCc1ccccc1)N(CC(OC)OC)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 87.3 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-alanine (1.12 g, 5.92 mmol) and ((S)-3-benzyloxy-1-methoxymethyl-propyl)-(2,2-dimethoxy-ethyl)-amine (1.60 g, 5.38 mmol) in N,N-dimethylformamide (16 mL) were added 4-methylmorpholine (1.63 g, 16.1 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (3.07 g, 8.06 mmol) at room temperature. The reaction mixture was stirred at room temperature was stirred at room temperature for 16 h, then partitioned between water and heptane/ethyl acetate 1:1. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) furnished the title compound (2.20 g, 87%). Colorless oil, MS (ISP)=469.4 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:22]S(C3C=CC(C)=CC=3)(=O)=O)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[C:38]([CH2:39]O)=[N:37][CH:36]=[N:35]1.[H-].[Na+].O>CN(C=O)C>[CH:1]1([C:6]2[C:7]([O:22][CH2:39][C:38]3[N:34]([CH3:33])[N:35]=[CH:36][N:37]=3)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4)nnc(C)c3c2C2CCCC2)cc1
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccccc2)n2nc(OCc3ncnn3C)c(C3CCCC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-cyclopentyl-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (Example 5, step a; 300 mg, 0.67 mmol) and (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (90.4 mg, 1.2-molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (29.5 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (90 ml) was added then the solution was extracted with diethyl ether (4×50 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-Cyclopentyl-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-phenylpyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether (152 mg, mp=159° C.). 1H NMR (360 MHz, CDCl3) δ 1.66-1.96 (8H, m), 2.86 (3H, s), 3.44 (1H, m), 3.87 (3H, s), 5.54 (2H, s), 7.61-7.58 (3H, m), 7.90 (1H, s), 8.24-8.26 (2H, m); MS (ES+) m/e 389 [MH]+. Anal. Found C, 65.02; H, 5.97; N, 25.31%. C21H23N7O requires C, 64.76; H, 5.95; N, 25.18%.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH:9]=2)[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[C:43]1(=[O:53])[N:47]([CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH:9]=3)[CH:4]=2)[C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12
Reactant: CCCN(CCC)CCCCc1ccc2cc(CO)ccc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCN(CCC)CCCCc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
The compound (70.0 mg) obtained in Example 124-2 was added with triphenylphosphine (76.1 mg) and phthalimide (36.1 mg), and then dissolved in anhydrous THF (1.0 ml). Subsequently, the solution was added with a 40% diethyl azodicarboxylate/toluene solution (0.132 ml) in an ice bath and stirred at room temperature for 3 hours under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off and the residue was then purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (75.0 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.N[CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1.C([N:25](CC)CC)C>C(Cl)Cl>[CH:15]1([NH:25][N:9]2[CH:8]([CH3:12])[C:4]3[N:5]=[CH:6][N:7]=[CH:2][C:3]=3[N:10]2[CH3:11])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH2:14]1
Reactant: CCN(CC)CC
Reactant: Cc1nn(C)c2c(Cl)ncnc12
Reactant: NC1Cc2ccccc2C1
Solvent: ClCCl
Product: CC1c2ncncc2N(C)N1NC1CCc2ccccc21
Yield: 62 %

Procedure:
7-chloro-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidine (28 mg, 0.15 mmol) (see J. Med. Chem. 31, 454 (1988)), 2-aminoindan (66 mg, 0.50 mmol), and triethylamine (30 μl, 0.2 mmol) in dry methylene chloride (1 ml) were heated to reflux for 2 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=1:4) to obtain the title compound (26 mg, 0.093 mmol) having the following physical properties:
Reaction SMILES: C(O)C.[CH3:4][C@@H:5]([C@@H:13]1[C@@:17]2([CH3:33])[CH2:18][CH2:19][CH2:20]/[C:21](=[CH:22]\[CH:23]=[C:24]3\[CH2:25][C@@H:26]([OH:32])[CH2:27][C@H:28](O)[C:29]\3=[CH2:30])/[C@@H:16]2[CH2:15][CH2:14]1)[CH2:6][CH2:7][CH2:8][C:9]([OH:12])([CH3:11])[CH3:10].CC(C)=O>CS(C)=O>[CH3:4][C@@H:5]([C@@H:13]1[C@@:17]2([CH3:33])[CH2:18][CH2:19][CH2:20]/[C:21](=[CH:22]\[CH:23]=[C:24]3\[CH2:25][C@@H:26]([OH:32])[CH2:27][CH2:28][C:29]\3=[CH2:30])/[C@@H:16]2[CH2:15][CH2:14]1)[CH2:6][CH2:7][CH2:8][C:9]([OH:12])([CH3:10])[CH3:11]
Reactant: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Solvent: CCO
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@@H]12

Procedure:
As a result, as noted in Table 8, ethanol showed a calcitriol production yield of 48.45 mg/L, and acetone and DMSO showed calcitriol production yields of 74.87 mg/L and 70.85 mg/L, respectively, and calcifediol production yields of 156.37 mg/L and 141.81 mg/L, respectively. Especially, methanol showed a calcitriol production yield of 90.12 mg/L, and a calcifediol production yield of 166.87 mg/L.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.[C:23]([Cl:31])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C(Cl)(Cl)Cl>[ClH:31].[C:23]([O:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cl
Product: O=C(OCC1CNCCO1)c1ccccc1

Procedure:
4-Benzyl-2-hydroxymethylmorpholine (prepared by the method disclosed in Synthetic Communication, Vol. 10, pages 59-73, 1980) (200 g) and triethylamine (122 g) are dissolved in chloroform (1.5 liter), and thereto is added dropwise benzoyl chloride (135 g) with stirring under ice cooling. The mixture is stirred at room temperature for 16 hours and thereafter to the mixture is added water. The chloroform layer is separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous saline solution in this order, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue is dissolved in ethyl acetate (150 ml) and thereto is added 4N hydrogen chloride/ethyl acetate (250 ml) with stirring under ice cooling, and the precipitated crystals are separated by filtration, washed with ethyl acetate and acetone in this order to give the title compound (240 g) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[C:27]([CH2:28][OH:29])=[CH:26][C:25]([F:30])=[C:24](Cl)[N:23]=1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CS(C)=O>[CH:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][N:7]=[C:4]2[CH2:3][CH2:2][N:1]([C:24]3[C:25]([F:30])=[CH:26][C:27]([CH2:28][OH:29])=[C:22]([Cl:21])[N:23]=3)[CH2:6][CH2:5]2)[CH2:14][CH2:13]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Reactant: OCc1cc(F)c(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3nc(Cl)c(CO)cc3F)CC2)CC1
Temperature: 130 °C
Yield: 29.2 %

Procedure:
2d (0.48 g, 1.7 mmol), 55a (0.36 g, 1.86 mmol) and diisopropylethylamine (0.31 mL, 1.9 mmol) were combined in 5 mL of DMSO and heated at 130° C. for 2 days. The mixture was cooled, poured into ethyl acetate (15 mL), washed with water (10 mL) and brine (10 mL), dried and concentrated. The residue was purified by flash chromatography (eluent: 10 to 50% ethyl acetate+0.1% triethylamine in hexane) to afford 55b as a yellow oil (0.22 g, 30% yield): LC-MS 425.1 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:3][CH2:2]1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:1]1([C:4]2[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:28]4[CH2:29][CH2:30][O:26][C:27]4=[O:31])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C2CC2)c1
Reactant: O=C1NCCO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3)CC2)c(C2CC2)c1
Yield: 27.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-(2-cyclopropyl-4-methylphenyl)piperazin-1-yl](4-iodophenyl)methanone (280 mg) described in Preparation Example 17 and oxazolidin-2-one (313 mg), the title compound (69 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:16]1[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CN1CCNCC1
Solvent: CC#N
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of 3,4-difluoronitrobenzene (12.00 g, 75.4 mmol) (Aldrich) and N-methylpiperazine (18.89 g, 188.6 mmol) in acetonitrile (150 mL) was heated at reflux for 3 h. The reaction mixture was allowed to stand overnight at room temperature, then the solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate (200 mL each). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the combined organic layers were then washed with water and brine (200 mL each), dried (MgSO4), filtered, and evaporated under reduced pressure to give 1-(2-fluoro-4-nitrophenyl)-4-methylpiperazine as a pale brown solid (17.5 g, 97%, mp 68-70° C.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O:19][C:20](=[O:41])[CH2:21][CH2:22][NH:23][C:24](=[O:40])[C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH2:38]O)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:26]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:38][CH:31]([C:28]3[CH:27]=[CH:26][C:25]([C:24]([NH:23][CH2:22][CH2:21][C:20]([OH:41])=[O:19])=[O:40])=[CH:30][CH:29]=3)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCC(CO)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: CC(C)(C)c1ccc(-c2ccc(O)cc2)cc1
Product: CCCCCCC(COc1ccc(-c2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound is prepared by essentially following the procedures as described in Example 8, using 4′-tert-butyl-biphenyl-4-ol and 3-[4-(1-hydroxymethyl-heptyl)-benzoylamino]-propionic acid methyl ester as starting materials. MS (ES): 528.3 [M+H]−.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([OH:14])[CH:10]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:14][C:11]1[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[O:13][N:12]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1cc(-c2cccc(Cl)c2Cl)on1
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2cccc(Cl)c2Cl)on1
Yield: 76 %

Procedure:
5-(2,3-Dichlorophenyl)-3-hydroxyisoxazole (0.3 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.23 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.37 g, 77%) as a colorless powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]N1C(=O)CCC1=O.[CH2:28]([O:35][CH2:36][CH2:37]O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:28]([O:35][CH2:36][CH2:37][Br:20])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCOCc1ccccc1
Reaction time: 12 h
Yield: 85 %

Procedure:
A solution of triphenyl phosphine (2.1 g, 7.9 mmol) in dry methylene chloride (16 mL) was added dropwise over 10 min to a stirred mixture of N-bromosuccinimide (1.4 g, 7.9 mmol) in dry methylene chloride (23 mL) at -78° C. The reaction was kept in the dark and stirring was continued until all the N-bromosuccinimide had dissolved (10 min). A solution of 2-(benzyloxy)ethanol in dry methylene chloride (10 mL) was added dropwise. The cooling bath was removed and stirring was continued for 12 h at rt. The organic layer was then concentrated in vacuo and passed through a silica plug with 1:1 hexane:methylene chloride to afford 2-(benzyloxy)bromoethane (1.20 g, 85%).