Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=O)C.[C:16](#[N:20])[CH2:17][C:18]#[N:19]>>[NH2:19][C:18]1[O:4][C:5]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=2[C:7](=[O:8])[C:17]=1[C:16]#[N:20]
Reactant: N#CCC#N
Reactant: COc1cccc(C(=O)Cl)c1OC(C)=O
Product: COc1cccc2c(=O)c(C#N)c(N)oc12

Procedure:
-- In the same way as described in Example 3, 2-acetoxy-3-methoxybenzoyl chloride and malononitrile are reacted to give a crystalline product, mp 300°C.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:6][CH:5]=1.[CH2:29](I)[CH3:30].C([O-])([O-])=O.[K+].[K+]>C(O)C>[ClH:1].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][N:13]([CH2:29][CH3:30])[CH2:12][C@H:11]2[CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)=[CH:6][CH:5]=1
Reactant: CCI
Reactant: CN(C)c1ccc([C@@H]2CCNC[C@H]2COc2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2ccc(C(F)(F)F)cc2)C1
Temperature: 60 °C
Yield: 38 %

Procedure:
Was prepared from (41) (0.35 g) and ethyl iodide (0.4 g) in abs. ethanol (30 ml). heating to 60° C. for 8 h, and subsequently at room temperature for 48 h in the presence of K2CO3 (0.4 g). Purification as described for compound (7) gave a yield of 38% of (42). M.p. 225.8°-228.1° C.
Reaction SMILES: Cl[C:2]([O:4][C:5](Cl)(Cl)Cl)=[O:3].[C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2O)[CH:14]=[CH:13][CH:12]=[CH:11]C=1.CN(C)C1C=CC=CC=1.[CH3:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C1C=CC=CC=1>[C:9]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:4][C:2]([N:35]1[CH2:36][CH2:37][CH:32]([CH3:31])[CH2:33][CH2:34]1)=[O:3]
Reactant: CC1CCNCC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Oc1ccccc1-c1ccccc1
Solvent: c1ccccc1
Solvent: CN(C)c1ccccc1
Product: CC1CCN(C(=O)Oc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 124.4 %

Procedure:
Trichloromethyl chloroformate (3.54 mL, 29.4 mmol) is added dropwise under a nitrogen atmosphere to a solution of 2-phenylphenol (10.0 g, 58.8 mmol) in 150 mL of benzene at room temperature. After the addition, dimethylaniline (7.45 mL, 58.8 mmol) is added dropwise at such a rate that the temperature of the reaction mixture is maintained between 20°-25° C. The resulting mixture is stirred at room temperature for 3 hours. A solution of 4-methylpiperidine (6.95 mL, 58.8 mmol) and dimethylaniline (7.45 mL, 58.8 mmol) in 50 mL of benzene is then added dropwise. After the addition the reaction is stirred at room temperature overnight. The reaction mixture is washed with 1N HCl, 5% NaHCO3, dried (MgSO4) and the solvent removed under reduced pressure. Purification of the crude reaction product by HPLC (hexane-methylene chloride) followed by recrystallization from diisopropyl ether gives the title compound as a white crystalline solid (10.8 g, 62), mp 85° -86° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:28]([NH2:30])=[S:29])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1>C(OCC)C>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:30]=[C:28]([NH:27][C:17]2[CH:18]=[CH:19][C:20]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:15]([O:14][CH3:13])[CH:16]=2)[S:29][CH:2]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Solvent: CCOCC
Product: COc1cc(Nc2nc(-c3ccc(Cl)cc3Cl)cs2)ccc1-n1cnc(C)c1
Yield: 98.9 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 90 mg (0.33 mmol) 2-bromo-2′,4′-dichloroacetophenon and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude reaction was diluted with diethyl ether and the precipitate was filtered off and dried to yield 128 mg (99%) [4-(2,4-dichloro-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light yellow solid. MS ISP (m/e): 431.1/433.2 (100/65) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.78 (s, 1H), 9.28 (s, 1H), 7.99 (s, 1H), 7.97 (d, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.55 (d, 1H), 7.53 (s, 1H), 7.50 (d, 1H), 7.25 (d, 1H), 3.88 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [Mg].[CH3:2][C:3]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1Br)([CH3:5])[CH3:4].[CH2:17]1[O:19][CH2:18]1>O1CCCC1>[CH3:2][C:3]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[CH2:17][CH2:18][OH:19])([CH3:5])[CH3:4]
Reactant: C1CO1
Reactant: CC(C)(C)c1ccc(Br)c(C(C)(C)C)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCO)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 243 mg (10 mmoles) of magnesium turnings in 10 ml of tetrahydrofuran is added dropwise a solution of 2.69 grams (10 mmoles) of the title product of Example 9 in 5 ml of tetrahydrofuran. After the addition is complete, the mixture is refluxed for one hour. Ethylene oxide (440 mg, 10 mmoles) is then added, and refluxing continued for one hour. The mixture is cooled to room temperature and partitioned between saturated ammonium chloride and diethyl ether. The aqueous layer is further extracted with ether, the combined organic extracts washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate and hexane as eluents gives the title compound.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:5])=O.O.ON1C2C=CC=CC=2N=N1.[NH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.CN(C)C=O>[OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:3]([NH:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:5]
Reactant: NN1CCOCC1
Reactant: O=C(O)C(O)(c1ccccc1)c1cccnc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(NN1CCOCC1)C(O)(c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
A mixture of 2-hydroxy-2-phenyl-2-(3-pyridinyl)acetic acid (3.48 g, 0.015 mole), 1-hyrdoxybenzotriazole hydrate (4.10 g, 0.03 mole), 1,3-Dicyclohexycarbodiimide (3.09 g, 0.015 mole), 4-aminomorpholine (1.45 ml, 0.015 mole), sodium bicarbonate (1.26 g, 0.015 mole), N,N-dimethyformamide (36 ml) and dioxane (36 ml) were stirred at room temperature overnight. The volatiles were removed in vacuo, dichloromethane (170 ml) was added and following filtration, the organic layer was washed with saturated sodium bicarbonate and brine. After drying, filtration and concentration, the residue was purified by column chromatography using 10% methanol in chloroform to give 3.92 g of the product as a white foam. High Res. Mass Spec. Calcd. for C17H19N3O3 : 314.1505 (M+H). Found: 314.1501.
Reaction SMILES: [O:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19]12([C:29](Cl)=[O:30])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[C:19]12([C:29]([N:4]3[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]([C:29]([C:19]45[CH2:28][CH:23]6[CH2:22][CH:21]([CH2:27][CH:25]([CH2:24]6)[CH2:26]4)[CH2:20]5)=[O:30])[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:1][CH2:2][CH2:3]3)=[O:30])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: C1COCCOCCNCCOCCOCCN1
Product: O=C(N1CCOCCOCCN(C(=O)C23CC4CC(CC(C4)C2)C3)CCOCCOCC1)C12CC3CC(CC(C3)C1)C2

Procedure:
Analogously to Example 2 from 1,7,10,16-tetraoxa-4,13-diazacyclooctadecane and 1-adamantylcarbonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([SH:11])[S:9][CH:10]=1)[CH3:2].[C:13]([O:17][C:18](=[O:21])[CH2:19]Br)([CH3:16])([CH3:15])[CH3:14]>>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([S:11][CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:21])[S:9][CH:10]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)Cc1csc(S)n1
Product: CCOC(=O)Cc1csc(SCC(=O)OC(C)(C)C)n1

Procedure:
The title compound was obtained by an operation similar to that of Example 2 and using (2-mercapto-1,3-thiazol-4-yl)acetic acid ethyl ester synthesized in Example 1 and bromoacetic acid tert-butyl ester to give {2-[(2-tert-butoxy-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid ethyl ester, followed by sequential operations similar to those of Examples 3, 4 and 34.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=1.CO.C(Cl)Cl>COCCO>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:13]=[CH:12][C:5]3[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCCNC2=O
Solvent: ClCCl
Solvent: CO
Solvent: COCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCNC3=O)ncc1Cl
Temperature: 120 °C
Yield: 25 %

Procedure:
7-Amino-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (21 mg, 0.12 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (36 mg, 0.12 mmol) were suspended in 2-methoxyethanol (1 ml), and heated to 120° C. for 5 hours. Concentration afforded a yellow solid. Preparative TLC (5% MeOH/CH2Cl2) gave the title compound the desired as a white solid, 13 mg. (25% yield) 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 9.68 (s, 1H), 8.68-8.77 (m, 2H), 8.30 (s, 1H), 7.80-7.86 (m, 1H), 7.71-7.78 (m, 1H), 7.59 (s, 2H), 7.43-7.51 (m, 1H), 7.34-7.39 (m, 1H), 7.12-7.18 (m, 1H), 2.85-2.97 (m, 2H), 2.79 (s, 3H), 2.60-2.71 (m, 2H), 1.80-1.90 (m, 2H); MS (m/e) 437 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]1.CCN(CC)CC>C1COCC1.CCOC(C)=O>[O:40]=[S:37]1(=[O:41])[CH2:38][CH2:39][N:34]([S:20]([C:16]2[CH:15]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][CH:25]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:22])=[O:21])[CH2:35][CH2:36]1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCS(=O)(=O)CC4)c3)n2)n1
Yield: 47.2 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.300 g, 0.613 mmol) by treatment with commercially available thiomorpholine-1,1-dioxide (0.166 g, 1.226 mmol) and Et3N (0.260 mL, 1.84 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.170 g, 47%) as a white solid. MS (ISP) 588.1 [(M+H)+]; mp 230° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][P:9]2(=[O:14])[O:13][CH2:12][CH2:11][O:10]2)=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].CO>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][P:9]2(=[O:14])[O:10][CH2:11][CH2:12][O:13]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CP2(=O)OCCO2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CP2(=O)OCCO2)cc1
Yield: 56.6 %

Procedure:
A mixture of 2-(4-nitrobenzyl)-1,3,2-dioxaphospholane-2-oxide (8.56 g), palladium-carbon (5%, 50% wet, 4.0 g) and methanol (300 ml) was subjected to a catalytic hydrogenation at room temperature and under 1 atm. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to yield 2-(4-aminobenzyl)-1,3,2-dioxaphospholane-2-oxide (4.25 g, 57%), which was then recrystallized from ethanol-hexane to yield colorless prisms having a melting point of 183° to 184° C.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3C[CH2:12][CH:13]=[CH:14][C:8]=3N=CCC=2[S:3][CH:2]=1.[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19].C([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])C>C(Cl)Cl>[S:3]1[C:40]2[CH2:39][N:36]([C:25]([C:24]3[CH:28]=[CH:29][C:21]([NH:20][C:18](=[O:19])[C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=4[CH3:15])=[CH:22][CH:23]=3)=[O:26])[C:37]3[CH:38]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:9][C:10]=2[CH:1]=[CH:2]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: C1=CC2=C(CC1)c1ccsc1CC=N2
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3sccc3Cc3ccccc32)cc1

Procedure:
A mixture of 400 mg of 9,10-dihydro-4H-thieno[2,3-d][1]benzazepine and 600 mg of 4-[(2-methylbenzoyl)amino]benzoyl chloride is stirred in 30 ml of methylene chloride in the presence of 3 ml of triethylamine for 8 hours. The volatiles are removed in vacuo to give a residue which is partitioned between water and chloroform. The organic layer is dried (Na2 SO4) and the filtrate evaporated in vacuo to give a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 518 mg of the desired product. M+1=439.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:21])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([Li])CCC.[C:27](=[O:29])=[O:28].Cl>C1COCC1.O>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[C:4]([CH3:21])=[CH:3][C:2]([C:27]([OH:29])=[O:28])=[CH:7][N:6]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
Under an argon atmosphere, a solution of tert-butyl 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylate (400 mg) in THF (8 ml) was cooled to −78° C., and 1.63 M n-butyl lithium (0.9 ml) was added dropwise thereto, followed by stirring at the same temperature for 1 hour. Crushed dry ice was put into another flask, and THF (30 ml) was poured thereinto. The mixture to which n-BuLi had been added dropwise immediately before was added thereto, followed by stirring as it was for 1 hour. To the reaction mixture was added water and 1 M hydrochloric acid, and the pH of the aqueous layer was adjusted to around 5.0. The aqueous layer was extracted with EtOAc, the organic layer was separated, and then the aqueous layer was extracted with CHCl3 again. These organic layers were combined and dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 6-[4-(tert-butoxycarbonyl)piperazine-1-yl]-5-methylnicotinic acid (169 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH3:19])=[C:13]([NH:15][C:16]([NH2:18])=[S:17])[CH:14]=2)[CH:4]=1.[ClH:20].[C:21](OCC)(=O)[CH3:22]>CN(C)C=O.O1CCOCC1.ICC>[ClH:20].[ClH:20].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH3:19])=[C:13]([NH:15][C:16](=[NH:18])[S:17][CH2:21][CH3:22])[CH:14]=2)[CH:4]=1
Reactant: CCOC(C)=O
Reactant: COc1ccnc(-c2ccc(C)c(NC(N)=S)c2)c1
Agent: Cl
Solvent: CCI
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCSC(=N)Nc1cc(-c2cc(OC)ccn2)ccc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of N-(5-(4-methoxypyridin-2-yl)-2-methylphenyl)-thiourea (0.15 g) in N,N-dimethylformamide (3 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.274 ml) and iodoethane (0.22 ml), and the mixture was stirred at ambient temperature for 5 hours. Ethyl acetate (100 ml) was added to the mixture, and the mixture was cooled. The precipitate was collected by filtration. The precipitate was dissolved in water, and to the solution was added a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and to the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.5 ml). The precipitate was collected by filtration and dried under reduced pressure to give N-(5-(4-methoxypyridin-2-yl)-2-methylphenyl)-S-ethylisothiourea dihydrochloride (168 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](/[C:10](/[C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)=[CH:11]/[C@@H:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])[C:15](=[O:28])[CH2:14][CH2:13]2)=[N:6][C:7]=1[O:8][CH3:9].C([Li])CCC.[C:44]1(=[O:48])[CH2:47][CH2:46][CH2:45]1.[Cl-].[NH4+]>O1CCCC1>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([C:10]([C:5]2[CH:4]=[CH:3][C:2]([C:44]3([OH:48])[CH2:47][CH2:46][CH2:45]3)=[C:7]([O:8][CH3:9])[N:6]=2)=[CH:11][CH:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])[C:15](=[O:28])[CH2:14][CH2:13]2)=[CH:34][CH:33]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: O=C1CCC1
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(Br)c(OC)n2)c(OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CCC2C=C(c2ccc(C(C)(C)C)cc2)c2ccc(C3(O)CCC3)c(OC)n2)c(OC)c1
Reaction time: 0.5 h

Procedure:
(5R)-5-[(E)-2-(5-Bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-42(1) (100 mg) was dissolved in tetrahydrofuran (5 mL), and n-butyllithium was added at −78° C. After stirring for 30 minutes, cyclobutanone was added dropwise. The mixture was stirred for further 30 minutes and then an ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give 5-{2-(4-tert-butylphenyl)-2-[5-(1-hydroxycyclobutyl)-6-methoxypyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (EZ mixture) (35 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:28][C:29]([NH2:31])=[O:30].[N-:36]=[N+:37]=[N-:38].[Na+].CCCCCC>CN(C)C=O>[N:36]([CH2:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:11]2[N:10]=[CH:9][C:8]([CH2:28][C:29]([NH2:31])=[O:30])=[C:7]([NH:6][CH2:5][C:4]3[CH:32]=[C:33]([F:35])[CH:34]=[C:2]([F:1])[CH:3]=3)[CH:12]=2)=[CH:19][CH:18]=1)=[N+:37]=[N-:38]
Reactant: CS(=O)(=O)OCCCc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: [N-]=[N+]=NCCCc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
268 mg of 4-[(3,5-difluorobenzyl)amino]-6-{[4-(3-methanesulfonyloxypropyl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 199) was dissolved in 1.5 mL of N,N-dimethylformamide, to which 71 mg of sodium azide was added and stirred at 80° C. for 30 minutes. After cooling, hexane was added to the reaction mixture, and the deposit was filtered. The filtered product was dissolved in chloroform, washed with water and saturated saline, and dried on anhydrous sodium sulfate. By evaporating the solvent, 229 mg (94%) of the title compound was obtained as a slight yellow crystalline powder.
Reaction SMILES: C([O:9][C@@H:10]1[C@@:43]2([CH3:44])[C:14](=[CH:15][CH:16]=[C:17]3[C@@H:42]2[CH2:41][CH2:40][C@@:39]2([CH3:45])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:38])[CH2:23][CH2:24][CH:25]([O:29]C(=O)C2C=CC=CC=2)[CH:26]([CH3:28])[CH3:27])[CH2:13][C@@H:12]([O:46]C(=O)C2C=CC=CC=2)[CH2:11]1)(=O)C1C=CC=CC=1.C1C=CC=CC=1>O>[CH3:38][C@@H:22]([C@@H:21]1[C@@:39]2([CH3:45])[CH2:40][CH2:41][CH2:42]/[C:17](=[CH:16]\[CH:15]=[C:14]3\[CH2:13][C@@H:12]([OH:46])[CH2:11][C@H:10]([OH:9])[C:43]\3=[CH2:44])/[C@@H:18]2[CH2:19][CH2:20]1)[CH2:23][CH2:24][CH:25]([OH:29])[CH:26]([CH3:27])[CH3:28]
Reactant: CC(C)C(CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)c5ccccc5)C[C@H](OC(=O)c5ccccc5)[C@]4(C)[C@H]3CC[C@]12C)OC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCC(O)C(C)C)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.1 %

Procedure:
30 mg of 1α,3β,24-tribenzoyloxycholesta-5,7-diene was dissolved in 500 ml. of benzene, and the resulting solution was irradiated with ultraviolet rays in an atmosphere of argon at 10° C. for 2 minutes. After the reaction, isomerization was carried out for 2 hours in the argon atmosphere under reflux of benzene. After the reaction, most of the benzene was evaporated off at reduced pressure, and 2 ml. of 5% potassium hydroxide-methanol and 2 ml. of benzene were added to the residue. The mixture was maintained at room temperature for 28 hours in an atmosphere of argon to perform hydrolysis. The reaction product was diluted with water, and extracted with ethyl acetate. The ethyl acetate layer was repeatedly washed with water, and dried. The ethyl acetate was evaporated off at reduced pressure. The residue was subjected to the same separating and purifying procedure as in Example 20 to afford 1.9 mg of 1α,24-dihydroxycholecalciferol having the same properties as the product obtained in Example 20.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH:9]([NH:16][CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[OH:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.C[CH2:27][O:28]CC.[OH-].[Na+].ClC(OC(Cl)(Cl)Cl)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][CH:9]([N:16]2[CH2:17][CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:19][C:27]2=[O:28])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:6]1
Reactant: OC(CNC(CCN1CCOCC1)c1ccccc1)c1ccccc1
Reactant: CCOCC
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1OC(c2ccccc2)CN1C(CCN1CCOCC1)c1ccccc1
Yield: 16.5 %

Procedure:
2-(3-Morpholino-1-phenylpropyl)amino-1-phenylethanol (2.2 g, 6.46 mmol) prepared in the above (1), ether (100 ml) and 10% NaOH (50 ml) were mixed and stirred. To the obtained mixture, 20% toluene solution of trichloromethyl chloroformate [14 ml (14 mmol)] was dropwise added slowly for a period of 1 hour. After stirring at room temperature for 1 hour, ethyl acetate (200 ml) was added to the resulting solution, and then the ethyl acetate portion was collected. The obtained portion was washed with saturated aqueous sodium chloride (100 ml) and then dried over anhydrous sodium sulfate. After the solvent was removed by distillation under reduced pressure, the residue was purified by medium pressure silica gel column chromatography (chloroform/methanol=50/1) to obtain 510 mg of diastereoruer A (yield: 21.5%) and 390 mg of diastereomer B (yield: 16.5%) of the titled compound as oily products, provided that the diastereoisomers showing the Rf values of about 0.6 and 0.5 in TLC (chloroform/methanol=10/1) were referred to as diastereoisomers A and B, respectively.