Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[O:6][C:5](=O)[CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[CH3:16][NH:17][NH2:18]>C(O)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:2]=[N:18][N:17]([CH3:16])[C:5](=[O:6])[CH:4]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C2=CC(=O)OC2O)cc1
Reactant: CNN
Solvent: CCO
Product: COc1ccc(-c2cnn(C)c(=O)c2)cc1
Temperature: 85 °C
Yield: 46 %

Procedure:
A suspension of 5-hydroxy-4-(4-methoxyphenyl)-5H-furan-2-one (2.06 g, 10 mmol) in 30 mL of ethanol was stirred as methylhydrazine (0.78 mL, 1.5 eq) was added dropwise. The reaction was heated to reflux at 85° C. for 2 h, then the solvent was reduced at reduced pressure to give a solid, which was collected and washed with cold EtOH to give 1.0 g (46%) of 5-(4-methoxy-phenyl)-2-methyl-2H-pyridazin-3-one: MS m/z 217 (M+H).
Reaction SMILES: [C:1]([NH2:7])([NH2:6])=[N:2][C:3](N)=[NH:4].[C:8]1([N:14]=[C:15]=[S:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C=O>[NH2:7][C:1]1[N:2]=[C:3]([NH2:4])[N:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:15](=[S:16])[N:6]=1
Reactant: S=C=Nc1ccccc1
Reactant: N=C(N)N=C(N)N
Solvent: CN(C)C=O
Product: Nc1nc(N)n(-c2ccccc2)c(=S)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To 25 ml of dry dimethylformamide were dissolved 2.0 g of diguanide and 2.7 g of phenyl isothiocyanate and the solution was placed at 40°~50° C. for 30 minutes. The solution was added to 200 ml of ice water to produce white precipitates, which subsequently was filtered and dried to obtain 4.05 g of the title compound having the characteristics of:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:11](OC)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH2:11][OH:12]
Reactant: COC(=O)C(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of methyl 3-(2,4-dichlorophenyl)-2-(4-chorophenyl)propionate (6.4 g, 8.6 mmol) in 50 mL ether at −40° C. was added lithium aluminum hydride (1.4 g, 37 mmol), and the reaction was allowed to warm to room temperature over 2 h. The reaction was quenched by addition of MeOH (3 mL) dropwise at −10° C., and the mixture was partitioned between 100 mL saturated ammonium chloride and EtOAc (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (400 MHz, CD3OD): δ 7.4-6.9 (m, 7H), 3.72 (m, 2H), 3.24 (dd, 1H), 3.16 (m, 1H), 2.85 (dd, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Sn]([N:53]=[N+:54]=[N-:55])(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.[F-].[K+]>C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]4[NH:55][N:54]=[N:53][N:39]=4)=[CH:36][CH:37]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(C#N)cc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.1 %

Procedure:
A mixture of 4-tert-butyl-N-{6-[2-(4-cyanophenoxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzensulfonamide (1.31 g), tributyltin azide (1.60 g) and toluene (13 ml) is refluxed under argon atmosphere for 24 hours. After cooling, ethyl acetate and 10% aqueous potassium fluoride solution are added to the reaction solution. The insoluble materials are removed by filtration, and the ethyl acetate layer is concentrated to dryness under reduced pressure. To the residue are added 10% aqueous sodium hydroxide solution and diethyl ether, and the mixture is stirred at room temperature for 20 minutes. The aqueous layer is washed with diethyl ether, and acidified with 10% hydrochloric acid under ice-cooling. The mixture is extracted with ethyl acetate, and the ethyl acetate layer is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent:chloroform:methanol=100:0~20:1), and crystallized from ethyl acetate to give 4-tert-butyl-N-{5-(4-methylphenyl)-6-[2-(4-(5-tetrazolyl)phenoxy)ethoxy]-pyrimidin-4-yl}benzensulfonamide (1.26 g).
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:30][C:31]([CH3:33])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH:31]([N:27]1[CH2:28][CH2:29][CH:24]([O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:25][CH2:26]1)([CH3:33])[CH3:30]
Reactant: CC(C)=O
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNCC3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)N1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1
Reaction time: 2 h
Yield: 52 %

Procedure:
A suspension of 3-(1-naphthylsulfonyl)-5-(piperidin-4-yloxy)-1H-indazole (71.2 mg, 0.175 mmol) in 1,2-dichloroethane was treated sequentially with acetone (0.4 mL, 5 mmol) and acetic acid (0.13 mL, 2.3 mmol), stirred for 2 hours, treated portionwise with sodium triacetoxyborohydride (255 mg, 1.20 mmol), stirred for 25 hours at ambient temperatures under nitrogen, diluted with ethyl acetate and washed with 1.0 N sodium hydroxide and brine. The organic phase was treated with methanol and chloroform, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 0.3-1.0% ammonium hydroxide/3.0-10% methanol in chloroform to afford 5-(1-isopropylpiperidin-4-yloxy)-3-(1-naphthylsulfonyl)-1H-indazole as a light orange foam, 40.9 mg (52.0% yield). The foam was dispersed in methanol and chloroform, treated with isopropanolic HCl and concentrated for 12 hours in vacuo to yield the title product as a light orange foam, 37 mg, Mass spectrum (−EI, [M−H]−) m/z 448. 1HNMR (300 MHz, DMSO-d6): δ14.11-14.15 (m*, 1H), 9.82-9.84 (m, 1H), 8.69-8.76 (m, 1H), 8.54-8.58 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.04 (m, 1H), 7.70-7.75 (m, 1H), 7.54-7.63 (m, 3H), 7.29-7.36 (m*, 1H), 7.07-7.21 (m* and dd*, 1H, J=9.15 Hz and 2.31 Hz), 4.60-4.81 (m*, 1H), 3.40-3.50 (m, 2H), 3.06-3.21 (m*, 3H), 2.10-2.20 (m, 2H), 2.00-2.08 (m, 1H), 1.80-1.95 (m, 1H), 1.22-1.28 ppm (m, 6H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[C:15](N4CCNCC4)[N:14]3[CH:25]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].NC1C=CC=CN=1.C(C1C=CC(C(=O)CCl)=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]3[CH:25]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cn3c(N4CCNCC4)cccc3n2)cc1
Agent: CC(C)(C)c1ccc(C(=O)CCl)cc1
Agent: Nc1ccccn1
Product: CC(C)(C)c1ccc(-c2cn3ccccc3n2)cc1

Procedure:
Scheme 4 provides the synthesis of a specific intermediate following the general procedures set forth in Scheme 3, which can be further elaborated to provide compounds of the Formula (IB). 2-(4-tert-Butyl-phenyl)-5-piperazin-1-yl-imidazo[1,2-a]pyridine (7) was obtained as described in Scheme 4. 2-Aminopyridine was cyclized with 4-tert-butylphenacyl chloride to afford 2-(4-tert-butyl-phenyl-imidazo[1,2-a]pyridine (5). Lithiation followed by bromination provided a ratio of three products (6a, 70.7%; 6b, 12.3%; and 6c, 17.0%). Heating the mixture with piperazine provided (7) from (6a), which was easily separated from unreactive (6b) and (6c).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH2:11])[CH:5]=1.[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[NH:11]1[C:6]2[C:7](=[CH:8][CH:9]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:5]=2)[CH:10]=[N:13]1
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
To a solution of 3-amino-4-methylbenzoic acid methyl ester (25 g, 0.15 mol) in 1 L of acetic acid cooled to 0° C. was added a solution of NaNO2 (12.5 g, 0.182 mol) in 50 ml of water and the mixture was warmed to room temperature with stirring over 4 hours. The solution was concentrated in vacuo, the residue was triturated with water, the solid was filtered and washed with water and hexane to afford 19 g (71.6%) of methyl indazole-6-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:17])=[CH:6][C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8][CH:9]=1)([O-])=O>C(O)(=O)C>[NH2:1][C:4]1[C:5]([CH3:17])=[CH:6][C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15])=[N:8][CH:9]=1
Reactant: Cc1cc(NC(=O)C(C)(C)C)ncc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Cc1cc(NC(=O)C(C)(C)C)ncc1N

Procedure:
A solution of 5-nitro-4-methyl-2-trimethylacetylaminopyridine (4.5 g, 18.97 mmol) in 50 mL of acetic acid containing 10% palladium/carbon was hydrogenated at atmospheric pressure for 48 h. The catalyst was removed by filtration and the filtrate was concentrated. The residue was coevaporated with toluene to give the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[N+:8]([O-])=[CH:7][C:6]=1[CH3:16])[CH:2]=[CH2:3].[C:17]([O:20]C(=O)C)(=[O:19])[CH3:18]>O>[C:17]([O:20][CH:10]1[C:9]2[N:8]=[CH:7][C:6]([CH3:16])=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[C:14]=2[CH2:13][CH2:12][CH2:11]1)(=[O:19])[CH3:18]
Reactant: C=CCOc1c(C)c[n+]([O-])c2c1CCCC2
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: C=CCOc1c(C)cnc2c1CCCC2OC(C)=O
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To 4.8 g of 4-allyloxy-3-methyl-5,6,7,8-tetrahydroquinoline-N-oxide was added 50 ml of acetic anhydride, and the mixture was stirred at 90° C. for 5 hours. After the reaction was completed, acetic anhydride was removed by evaporation under reduced pressure, to the residue thus obtained was added water and then extracted with chloroform. The chloroform layer was washed with an aqueous solution of sodium hydroxide and an aqueous solution saturated with sodium chloride, then dried with anhydrous magnesium sulfate. Chloroform was removed by evaporation under reduced pressure to obtain 5.0 g of 8-acetoxy-4-allyloxy-3-methyl-5,6,7,8-tetrahydroquinoline in the form of brown oily substance.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:32][CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:34])([F:1])[F:33])=[O:6])[CH:13]=[CH:12][CH:11]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[C:29]([N:39]1[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]1)=[O:30]
Reactant: CN1CCNCC1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Product: CC(C(=O)N1CCN(C)CC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 1-methylpiperazine. LCMS (M+H)+: m/z=556.3.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=O)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[NH2:23][C:24]1[CH:25]=[CH:26][C:27]2[N:28]([CH2:37][CH3:38])[C:29]3[C:34]([C:35]=2[CH:36]=1)=[CH:33][CH:32]=[CH:31][CH:30]=3.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C.CCCCCC.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([NH:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([CH2:37][CH3:38])[C:29]4[C:34]([C:35]=3[CH:36]=2)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:16])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2]
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CC(=O)Nc3ccc(C#N)c(C(F)(F)F)c3)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 39.2 %

Procedure:
To a solution of the compound obtained in Step 1 (300 mg, 0.95 mmol), 3-amino-9-ethylcarbazole (241 mg, 1.15 mmol) and DIEA (0.500 mL, 2.86 mmol) in DMF (6 mL) was added HATU (544 mg, 1.43 mmol), and the mixture was stirred at room temperature for 14 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 75% ethyl acetate/hexane), and then NH-silica gel column chromatography (solvent gradient; 5 to 100% ethyl acetate/hexane) to give the title compound (189 mg, 0.372 mmol, 39.0%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)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>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH3:17])[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:20]=[CH:21][C:2]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(CNC(=O)c2ccc(Br)nc2)cc1OC
Reactant: OB(O)c1ccccc1
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: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2ccc(-c3ccccc3)nc2)cc1OC
Temperature: 90 °C
Yield: 40.6 %

Procedure:
To a mixture consisting of 6-bromo-N-(3,4-dimethoxybenzyl)nicotinamide (1.11 g), phenylboronic acid (0.77 g), and tetrakis(triphenylphosphine)palladium(0) (0.365 g) in N,N-dimethylformamide (20 mL) under a nitrogen atmosphere was added a 2 M aqueous cesium carbonate (6 mL). The stirring mixture was heated to 90° C. for two hours and was subsequently partitioned between ethyl acetate (200 mL) and water (200 mL). The phases were separated and the organic phase was washed twice with fresh portions of water (2×200 mL) and brine solution (150 mL), was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide an orange solid. The solid was triturated with 1:1 v/v hexanes-ethyl acetate and collected by filtration to afford the title compound as a solid (0.447 g, 40.6% yield); 1H-NMR (300 MHz; CDCl3) δ 9.06 (d, 1H, J=2.1 Hz), 8.20 (dd, 1H, J=8.4, 2.4 Hz), 8.05-8.01 (m, 2H), 7.81 (dd, 1H, J=8.4, 0.6 Hz), 7.51-7.47 (m, 3H), 6.92-6.84 (m, 3H), 6.51 (broad t, 1H), 4.62 (d, 2H, J=5.7 Hz), 3.891 (s, 3H), 3.888 (s, 3H); Rf 0.17 with 7:3 v/v hexanes-ethyl acetate; MS (APCl+) m/z 349 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:38])C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH:32]1([CH2:31][CH2:30][O:29][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:39])=[O:3])=[C:8]([CH3:38])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:17]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCCC3CCCCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(OCCC3CCCCC3)c2)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
{4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.36 mmol) was dissolved in THF (2 mL) and ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 30 min. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 107 mg (57%). HPLC-MS: m/z: 523.9 (M)+; Rt: 2.06 min.
Reaction SMILES: [OH-:1].[K+].[NH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1>CC(O)(C)C>[NH2:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([C:4]([NH2:3])=[O:1])=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(CN)cc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: NCc1ccc(C(N)=O)cc1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
Powdered potassium hydroxide (340 mg, 6 mmol) was added in one portion to a stirred solution of 4-(aminomethyl)benzonitrile (200 mg, 1.5 mmol) in 2-methyl-2-propanol (20 ml) at reflux under nitrogen. The reaction was heated at reflux for 30 minutes and cooled to room temperature. The mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5, by volume) to provide the title compound (150 mg) as a white solid.
Reaction SMILES: C[C@@H]([C@@H]1[C@@]2(C)CCC/C(=C\C=C3\C[C@@H](O)C[C@H](O)C\3=C)/[C@@H]2CC1)/C=C/[C@@H](C(C)C)C.O1[C@H:33]2[C:34](=[O:60])[CH:35]=[C:36]3[C@:57]([CH3:58])([C@@H:32]12)[C@@H:56]1[C@H:39]([C@H:40]2[C@:53]([CH3:59])([CH2:54][CH2:55]1)[C@@H:43]([C@H:44]([CH3:52])[CH:45]=[CH:46][C@H:47]([CH3:51])[CH:48]([CH3:50])[CH3:49])[CH2:42][CH2:41]2)[CH:38]=[CH:37]3>>[CH3:52][C@@H:44]([C@@H:43]1[C:53]2([CH3:59])[CH2:54][CH2:55][CH:56]3[C:57]4([CH3:58])[C:36](=[CH:35][C:34]([CH2:33][CH2:32]4)=[O:60])[CH:37]=[CH:38][CH:39]3[CH:40]2[CH2:41][CH2:42]1)/[CH:45]=[CH:46]/[C@@H:47]([CH:48]([CH3:49])[CH3:50])[CH3:51]
Reactant: CC(C)[C@@H](C)C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)/C=C/[C@H](C)C(C)C)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Product: CC(C)[C@@H](C)/C=C/[C@@H](C)[C@H]1CCC2C3C=CC4=CC(=O)CCC4(C)C3CCC21C

Procedure:
1α-Hydroxy vitamin D2 exhibiting strong vitamin D activity is disclosed in U.S. Pat. No. 3,907,843. A synthetic route to 1α-hydroxy vitamin D2 disclosed therein is shown in the following reaction scheme I, which includes conversion of isoergosterone (compound 1) prepared from ergosterol to ergosta-1,4,6,22-tetraen-3-one (compound 2) followed by reaction with hydrogen peroxide to give 1α,2α-epoxy-ergosta-4,6,22-trien-3-one (compound 3), reaction of this compound with liquid ammonia and metal lithium to give 1α-hydroxy-7,8-dihydroergosterol (compound 4) followed by acetylation to give 1α-acetoxy-7,8-dihydroergosteryl acetate (compound 5), dehydrogenation of this compound to 1α-hydroxyergosteryl diacetate (1α,3β-diacetoxy-ergosta-5,7,22-trien)(compound 6), irradiation of this compound with light, causing cleavage of the ring to give 1α,3β-diacetoxy previtamin D2 (compound 7) and thermal isomerization and deacetylation of this compound to give 1α-hydroxy vitamin D2 (compound 8). The synthesis of 1α-hydroxy vitamin D2 by the above processes, however, gives rise to a number of problems. The reaction yield of the compounds is low including 16% yield in the formation of compound 5 from compound 3 and less than 10% yield in the formation of compound 6 from compound 5, and hence the overall yield through the synthesis of compound 6 from compound 1 amounts to less than 0.4%. In the conversion of compound 3 into compound 4, use of liquid ammonia and metal lithium is highly dangerous. In the conversion of compound 5 into compound 6, there is formed as by-products an isomeric compound 9 (1α,3β-diacetoxy ergosta-4,6,22-trien) which is difficult to separate and is responsible for reducing the purity of 1α-hydroxy vitamin D2. In view of the foregoing problems, the prior processes are not satisfactory for the production of 1α-hydroxy vitamin D2 in industrial scale. ##STR1##
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C([O-])([O-])=O.[K+].[K+].[NH2:12][C:13]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[C:14]=1[C:15]#[N:16]>C(Cl)(Cl)Cl>[C:15]([C:14]1[C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:13]=1[NH:12][C:2](=[O:3])[O:4][CH3:5])#[N:16]
Reactant: COc1ccc(N)c(C#N)c1OC
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1ccc(OC)c(OC)c1C#N
Yield: 99.7 %

Procedure:
Methyl chloroformate (18.6 g, 19.7 mmol) was added to a suspension of K2CO3 (2.71 g, 19.6 mmol) and 2-amino-5,6-dimethoxybenzonitrile (7.0 g, 39.3 mmol) in 70 ml of CHCl3. The resulting mixture was heated at reflux for 2 hours before being filtered and evaporated to a residual solid. Recrystallization of the crude material from MeOH yielded 4.64 g (50.2%) of product in good purity.
Reaction SMILES: C([O-])(O)=O.[Na+].O.O.[Sn](Cl)Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[C:28]([N+:40]([O-])=O)[CH:27]=3)=[N:22][CH:23]=2)=[CH:14][CH:13]=1.CO>CCOC(C)=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39]4)=[C:28]([NH2:40])[CH:27]=3)=[N:22][CH:23]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Nc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
200 mg (2.5 mmol) NaHCO3 and 300 mg (1.1 mmol) tin-(II)-chloride dihydrate are added to a solution of 100 mg (0.22 mmol) 5-(4-chloro-phenyl)-2-[3-nitro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine (Example 3.13) in 10 mL EtOAc and the reaction mixture is refluxed for 2 h. To complete the reaction a further 200 mg (2.5 mmol) NaHCO3, 300 mg (1.1 mmol) tin-(II)-chloride dihydrate and 1 mL MeOH are added and the mixture is refluxed for a further 2 h. After cooling, 4 g of silica gel are added, the solvent is eliminated i.vac. and the residue is purified by chromatography (silica gel, DCM/MeOH/NH3 8:2:0.2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][CH:28]=[C:29]([C:31](O)=[O:32])[N:30]=2)=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:31]([C:29]1[N:30]=[C:26]([C:23]2[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=2)[S:27][CH:28]=1)=[O:32]
Reactant: O=C(O)c1csc(-c2ccncc2)n1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1csc(-c2ccncc2)n1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2-pyridin-4-yl-thiazole-4-carboxylic acid. MS: 448.2 (M+H).