Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:34])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][Si](C(C)(C)C)(C)C)[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:1][C:2]1[NH:3][C:4](=[O:34])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](CO)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Reaction time: 16 h
Yield: 86.9 %

Procedure:
To a homogeneous solution of 91 (1.2 g, 2.3 mmol) in THF (20 mL) was added 1.0 M tetrabutylammonium fluoride in THF (4.7 mL, 4.7 mmol). The reaction mixture was stirred 16 h, then concentrated and chromatographed to afford 800 mg (86%) of a white solid: 1H (400 MHz, d6-DMSO) δ 11.25 (s, 1H), 6.97 (br s, 2H), 5.95 (dd, J=5.9, 4.4 Hz, 1H), 5.89 (d, J=4.8 Hz, 1H), 5.41 (t, J=6.2 Hz, 1H), 4.90 (t, J=5.9 Hz, 1H), 4.00 (q, J=5.9 Hz, 1H), 3.48-3.64 (m, 2H), 2.06 (s, 3H), 2.04 (s, 3H); MS (+)-ES [M+H]+ m/z 401.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH2:24].[BH4-].[Na+]>CO>[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH:24][CH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][C:5]2[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=2)=[C:2]([F:1])[CH:17]=1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Reactant: CC(C)(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(F)c1
Reaction time: 8 h
Yield: 57 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.350 g, 1.14 mmol), 3,3-dimethylbutylamine (0.19 g, 1.41 mmol) and 3 Å molecular sieves in a vial. Add methanol (9.7 mL), cap and stir overnight. Add NaBH4 (0.053 g, 1.41 mmol) and stir until the gasses stop evolving. Filter the reaction mixture, then concentrate. Purify by eluting through a 40 g ISCO® column with 6% to 30% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.225 g, 49%): TOF MS ES+ 347.2 (M+H)+, HRMS calcd for C18H24N4O2F 347.1883 (M+H)+, found 347.1883, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 min, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=10.9 min, 100% purity.
Reaction SMILES: Cl.[CH2:2]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH3:13])[CH2:9][CH2:8]1)[CH2:3][C:4]#[CH:5].Br[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1CCCC1.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>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([C:5]#[C:4][CH2:3][CH2:2][NH:6][C@H:7]2[CH2:8][CH2:9][C@H:10]([CH3:13])[CH2:11][CH2:12]2)=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: C#CCCN[C@H]1CC[C@H](C)CC1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCNC1
Product: CS(=O)(=O)c1ccc(C#CCCN[C@H]2CC[C@H](C)CC2)cc1
Temperature: 50 °C

Procedure:
To a portion of the above but-3-ynyl-(trans-4-methyl-cyclohexyl)-amine hydrochloride (500 mg, 2.48 mmol) dissolved in pyrrolidine (2.5 mL) was added 1-bromo-4-methanesulfonyl-benzene (583 mg, 2.48 mmol) and the solution was degassed by bubbling nitrogen through for 10 min. Tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.025 mmol) was added and the mixture was heated at 50° C. for 16 h before the volatiles were removed by evaporation and the residue purified by HPLC to yield the intermediate [4-(4-methanesulfonyl-phenyl)-but-3-ynyl]-(trans-4-methyl-cyclohexyl)-amine.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH:14]=[O:15])=[CH:8][C:7]=1[O:16][CH3:17].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[OH:15][CH2:14][C:9]1[CH:10]=[C:11]([O:12][CH3:13])[C:6]([O:5][CH2:4][CH2:3][OH:2])=[C:7]([O:16][CH3:17])[CH:8]=1
Reactant: COC(=O)COc1c(OC)cc(C=O)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CO)cc(OC)c1OCCO
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a solution of (4-formyl-2,6-dimethoxyphenoxy)-acetate methyl ester (1.5 g, 5.9 mmol) in THF (30 mL, 0.2 M) was added LiAlH4 (403 mg, 10.6 mmol) at water temperature. The reaction mixture was stirred for 6 hours at room temperature, followed by addition of H2O, and then subjected to celite filtration. Evaporation of the resultant mixture under diminished pressure gave a white solid. Recrystallization of this solid from chloroform/hexane gave a colorless needle-like crystal (1.346 g, 100%, m.p. 26 to 28° C.).
Reaction SMILES: C(OCCCC)(=O)CC[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15]C)=[O:11].C([OH:39])CCCCCCCCCCCCCCC>O>[CH2:13]([O:12][C:10]([C:9]1[CH:4]=[CH:5][C:6]([OH:39])=[CH:7][CH:8]=1)=[O:11])[CH2:14][CH3:15]
Reactant: CCCCOC(=O)CCCCCCCCC(=O)OCCCC
Reactant: CCCCCCCCCCCCCCCCO
Solvent: O
Product: CCCOC(=O)c1ccc(O)cc1

Procedure:
The SQ 30,741 and parabens are mixed with dibutyl sebacate with gentle heat, not over 50° C., and melted together and Polysorbate 60 and cetyl alcohol added. Water is heated to 80° C. to dissolve the sodium carboxymethyl cellulose forming an aqueous phase which is added with vigorous agitation to the oil phase to emulsify. Agitation is continued until the temperature drops down to 48° C. Sufficient 50° C. water is added to make 100 gm. Mixing is continued at a slow rate to congeal the mixture, until the lotion drops down to room temperature.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1.C1(N)CCCCC1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2Br)cc1
Solvent: NC1CCCCC1
Product: O=C(O)CCC(O)c1ccc(-c2ccccc2Br)cc1
Yield: 53.4 %

Procedure:
Prepared analogous to Example 25 from 4-(2'-bromo-4-biphenylyl)-4-oxo-butyric acid. Melting point of the cyclohexylamine salt: 162°-163° C.; yield: 53.4% of theory.
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].C[Si]([N:47]=[N+:48]=[N-:49])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:35]1([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2/[CH:22]=[CH:21]/[CH:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]3[NH:49][N:48]=[N:47][N:2]=3)=[CH:42][CH:41]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCc2ccccc2)Cc2ccc(C#N)cc2)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCc2ccccc2)Cc2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 295 mg (0.53 mmol) of methyl 4-((4E)-3-(4-cyanobenzyl)-5-{2-[(5-phenylpentyl)oxy]phenyl}pent-4-en-1-yl)benzoate in 20 ml of toluene is mixed with 1.05 ml (7.93 mmol) of trimethylsilyl azide and 198 mg (0.79 mmol) of di-n-butyltin oxide and heated at 80° C. for 12 hours. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: dichloromethane→dichloromethane/methanol 10:1). 284 mg (0.47 mmol, 89% of theory) of a white foam are obtained.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:5]=1[CH2:6][NH:7][C:8]([NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([O:18]CC)=O)[N:15]=1)=[NH:9].[CH:27]([NH:30]C(C)C)([CH3:29])[CH3:28]>ClCCl>[CH3:26][O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:4]([O:3][CH3:2])[C:5]=1[CH2:6][NH:7][C:8]([NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:18])[N:15]=1)=[NH:9]
Reactant: CCOC(=O)c1csc(NC(=N)NCc2c(OC)cccc2OC)n1
Reactant: CC(C)NC(C)C
Agent: [Br-]
Solvent: ClCCl
Product: COc1cccc(OC)c1CNC(=N)Nc1nc(C(=O)NC(C)C)cs1
Temperature: 60 °C
Yield: 19.7 %

Procedure:
0.157 g (0.35 mmol) ethyl 2-{[[(2,6-dimethoxybenzyl)amino](imino)methyl]amino}-1,3-thiazole-4-carboxylate bromide were combined with 1.50 ml (17.28 mmol) diisopropylamine and were heated in the microwave at 50 to 70° C. (150 Watt) for 2 hours. In this example, complete reaction was achieved only after further heating in the microwave at 70° C. (150 Watt) by “heating by cooling” after 4.5 hours. The reaction mixture was diluted with 20 ml dichlormethane and was washed with water (3×30 ml). After drying over MgSO4, filtration and removal of the organic solvent under vacuum, the mixture was purified on preparative HPLC (Merck: Chromolith RP-18E, 100-25; eluent water/acetonitrile/0.1 molar acetic acid). 26 mg of 2-{[[(2,6-dimethoxybenzyl)amino](imino)methyl]amino}-N-isopropyl-1,3-thiazole-4-carboxamide were isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
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: COCCOC
Solvent: O
Product: N#Cc1cccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 51.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 3-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.036 g (51%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-2-carboxamide as a white solid.
Reaction SMILES: N.C(OC([O:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Cl:25])=[O:17])=[CH:10][CH:9]=1)=O)C>CC(C)=O.N1C=CC=CC=1>[OH:7][C:8]1[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Cl:25])=[O:17])=[CH:12][CH:13]=1
Reactant: CCOC(=O)Oc1ccc(/C=C/C(=O)OCCCCCCCl)cc1
Agent: N
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(/C=C/c1ccc(O)cc1)OCCCCCCCl
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.2 %

Procedure:
A 25% NH3 solution diluted in 780 mL of acetone is added dropwise to a solution of 89.3 g (247 mmol) of 6-chlorohexyl(2E)-3-{4-[(ethoxycarbonyl)oxy]phenyl}prop-2-enoate in 752 mL of pyridine. The mixture is allowed to stir for 20 hours at room temperature. The reaction mixture is then partitioned between ethylacetate and water. The organic phase is then washed repeatedly with water, dried over sodium sulfate, filtered off and concentrated by rotary evaporation. The solid is dried under vacuum to yield 70 g (100%) of pure 6-chlorohexyl(2E)-3-(4-hydroxyphenyl)prop-2-enoate as a white powder.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.C(OC([NH:15][C@@H:16]([CH2:20][CH3:21])[C:17](O)=[O:18])=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC.C(Cl)[Cl:53]>O1CCCC1>[ClH:53].[NH2:15][C@@H:16]([CH2:20][CH3:21])[C:17]([N:3]([CH3:4])[CH3:1])=[O:18]
Reactant: ClCCl
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC[C@H](N)C(=O)N(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (201.9 μL, 1.500 mmol) was added to a solution of (2S)-2-[(tert-butoxycarbonyl)amino]butanoic acid (101.6 mg, 0.500 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (221.1 mg, 0.500 mmol) in DCM (5 mL), followed by addition of 2.0 M of dimethylamine in tetrahydrofuran (0.500 mL). The mixture was stirred at RT for 4 h. The organic layer was separated. The aqueous layer was extracted with DCM (3×5 mL). The combined organic layers were washed with NaHCO3 (7.5%), and brine, dried over Na2SO4, filtered, and concentrated. The residue was treated with HCl in dioxane (4 M, 1.0 mL) at RT for 4 h. The volatiles were evaporated under reduced pressure. The residue was washed with ether and dried in-vacuo to give the desired product which was directly used in the next step without further purification. Analytical LCMS: (M+H)+=131.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16].C(N(CC)CC)C>C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:11][NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)NO
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)NOC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
4-Chlorobenzoyl chloride (1.10 mL, 8.57 mmol) is added slowly to a solution of ethyl hydroxycarbamate 6 (1.00 g, 9.52 mmol) and triethylamine (1.19 mL, 8.57 mmol) in diethyl ether (30 mL) at 0° C. then stirred at room temperature for 30 min. The reaction is quenched with HCl (1 M; 10 mL) then water (100 mL) is added and extracted with diethyl ether (100 mL). The organic layer is washed with sat. NaHCO3 (50 mL), water (50 mL), dried with MgSO4 and concentrated. The residue is purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate 9:1 then 8:2) to yield 7 (1.54 g) as an off-white solid. M.p. 79° C. (determined by differential scanning calorimetry, sharp onset); FTIR (neat, cm−1) 3210, 3094, 2990, 1765, 1708, 1588, 1495, 1487, 1473, 1443, 1401, 1368, 1298, 1283, 1249, 1235, 1177, 1121, 1107, 1090, 1054, 1016, 996, 876, 852, 771, 747, 728, 681; 1H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 8.02 (dt, J=2.1, 8.7 Hz, 2H), 7.46 (dt, J=2.1, 8.7 Hz, 2H), 4.28 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 165.1, 156.6, 140.9, 131.3, 129.1, 125.2, 63.0, 14.3; HRMS (ES+) m/z calcd for C10H10ClNO4 (M+Na)+ 266.0191, found 266.0199.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:12]([NH2:15])[CH2:13][NH2:14].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)=[C:20]2[C:33]#N.[OH-].[Na+]>O>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)=[C:20]2[C:33]1[NH:14][CH2:13][CH2:12][N:15]=1
Reactant: N#Cc1c(-c2cccc(F)c2)[nH]c2ccc(Cl)cc12
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc(-c2[nH]c3ccc(Cl)cc3c2C2=NCCN2)c1

Procedure:
Ethylendiamine tosylate (929 mg, 4.0 mmol) and 5-chloro-3-cyano-2-(3-fluorophenyl)-1H-indole (0.27 g, 1.0 mmol) were thoroughly mixed in a mortar and heated with melting at 320° C. for 10 min. After cooling it was stirred with a small amount of water, and the mixture was brought to pH9 with 2N sodium hydroxide. The precipitate was collected by filtration, washed with water, and dried in vacuo. The title imidazoline was isolated by chromatography on silica gel with dichloromethane/10% ethanolic ammonia 9:1 and recrystallized from methanol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[O:12][CH2:11]1.[OH-].[K+]>CO>[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[CH:15][CH2:14]2)[O:12][CH2:11]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Yield: 93.2 %

Procedure:
Indole (45.3 g, 0.38 mol), 1,4-cyclohexanedione monoethylene ketal (45.5 g, 0.29 mol) and potassium hydroxide (9.12 g, 0.16 mol) are heated to reflux in 100 mL of methanol for 18 hours. The reaction is cooled and the product is isolated by filtration and washed with water to give a white solid (69.0 g).
Reaction SMILES: CCN(C1C=CC2C3(C4C(OC=2C=1)=CC(C)=C(NC1C=CC=CC=1)C=4)OC(=[O:20])C1C3=CC=CC=1)CC.P([O-])([O-])([O-])=O.[CH3:42][C@@H:43]([C@@H:50]1[C@@:54]2([CH3:70])[CH2:55][CH2:56][CH2:57]/[C:58](=[CH:59]\[CH:60]=[C:61]3\[CH2:62][C@@H:63]([OH:69])[CH2:64][C@H:65]([OH:68])[C:66]\3=[CH2:67])/[C@@H:53]2[CH2:52][CH2:51]1)[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48].C(Cl)Cl>C(O)C>[CH3:42][C@@H:43]([C@@H:50]1[C@@:54]2([CH3:70])[CH2:55][CH2:56][CH2:57]/[C:58](=[CH:59]\[CH:60]=[C:61]3\[CH2:62][C@@H:63]([OH:69])[CH2:64][C@H:65]([OH:68])[C:66]\3=[CH2:67])/[C@@H:53]2[CH2:52][CH2:51]1)[CH2:44][CH2:45][CH2:46][C:47]([OH:20])([CH3:48])[CH3:49]
Reactant: CCN(CC)c1ccc2c(c1)Oc1cc(C)c(Nc3ccccc3)cc1C21OC(=O)c2ccccc21
Reactant: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: 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
Reaction time: 48 h

Procedure:
Nocardia autotrophica N-102 in the same BG medium (100 ml/500 ml-Erlenmeyer flask) as used in Example 1 was cultured at 28° C. under the aerobic conditions for 48 hours. To the culture medium were added 10 ml of a 5% PMCD solution (0.01 M phosphate buffer, pH 7.0) and a solution of 0.1% 1α-hydroxyvitamin D3 in 1 ml of ethanol (in the amount of 140 mol of PMCD relative to 1 mol of 1α-hydroxytvitamin D3). After cultivation for a further 2 hours, methylene chloride was added to the flask, and analysis was carried out according to the method as described in Example 3. The peak fraction having a retention time of 12 minutes was collected, concentrated at 40° C. or below under reduced pressure and applied to HPLC on Zorbax ODS column (4.6 mm×25 cm, made by Du Pont Co., USA) with water-methanol (1:9) as a mobile phase at a flow rate of 1.0 ml/min. After elution, the peak fraction having a retention time of 5.6 minutes was collected and concentrated to dryness at 40° C. or below under reduced pressure with a nitrogen gas replacement to give 650 μg (65% of the conversion ratio from the material) of 1α,25-dihydroxyvitamin D3. On the other hand, following the same procedure as above but without PMCD, the amount of 25-hydroxyvitamin D3 obtained was 350 μg/ml (35% of the conversion ratio from the material).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=S)[NH:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]2=3)=[CH:4][CH:3]=1.[C:21]([NH:24][NH2:25])(=O)[CH3:22]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12]3=[N:25][N:24]=[C:21]([CH3:22])[N:11]3[C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]2=3)=[CH:4][CH:3]=1
Reactant: O=C1CC(=S)Nc2ccccc2N1c1ccc(Cl)cc1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2
Yield: 40.1 %

Procedure:
A solution of 1-(4-chlorophenyl)-4-thioxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (1.0 g, 3.3 mmol) and acetohydrazide (1.23 g, 16.6 mmol) in n-butanol (20 ml) was refluxed for 24 h under N2 atmosphere. The solvent was evaporated in vacuo and partitioned between DCM (100 mL) and water (50 mL). The organic phase was dried over Na2SO4 and the solvent was evaporated in vacuo to afford a residue. The residue was purified by column chromatography (silica-gel, DCM:MEOH=30:1) to give 6-(4-chlorophenyl)-1-methyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one (430.0 mg, 40%). LRMS (M+H+) m/z: calcd 324.08. found 324. 1H NMR (300 MHz, CD3OD): δ 2.72 (s, 3H), 3.94 (q, J=14.1 Hz, 2H), 7.15-7.24 (m, 3H), 7.40-7.52 (m, 4H), 7.70-7.73 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[O:6][C:7]=1[NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)#[N:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>CCOC(C)=O>[F:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:5]1[O:6][C:7]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:59]3[CH2:64][CH2:63][O:62][CH2:61][CH2:60]3)=[O:15])=[CH:11][CH:10]=2)=[C:3]([C:1]#[N:2])[N:4]=1
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Nc1ccc(C(=O)O)cc1
Reactant: C1COCCN1
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: CCOC(C)=O
Product: N#Cc1nc(-c2c(F)cccc2F)oc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.3 %

Procedure:
To a solution of 4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid (0.020 g, 0.059 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.022 g, 0.059 mmol), and diisopropylethylamine (0.020 mL, 0.117 mmol) in N,N-dimethylformide (2 mL) was added morpholine (0.005 mL, 0.059 mmol) and the reaction mixture stirred at room temperature for 16 hours. The reaction was then diluted with EtOAc washed with 1M HCl, water and brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-(morpholine-4-carbonyl)phenylamino)oxazole-4-carbonitrile (0.009 g, 0.022 mmol, 37%) as a yellow solid. LCMS (2) Rt: 2.38 min; m/z (ES+) 411.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[SH:28][C:29]1[S:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([S:28][C:29]3[S:30][CH:31]=[C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:33]=3)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCCC(O)c1ccc(COc2ccc(CCC(=O)OCC)c(F)c2)cc1
Reactant: Sc1nc(-c2ccccc2)cs1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCC(Sc1nc(-c2ccccc2)cs1)c1ccc(COc2ccc(CCC(=O)OCC)c(F)c2)cc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{[4-(1-hydroxybutyl)benzyl]oxy}phenyl)propanoate (0.500 g, 1.34 mmol), 2-mercapto-4-phenylthiazole (0.284 g, 1.47 mmol) and triphenylphosphine (0.700 g, 2.67 mmol) in toluene (10 mL) was added diethyl azodicarboxylate (40% toluene solution, 1.21 mL, 2.67 mmol) with stirring at room temperature, and the mixture was stirred at the same temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-20:80) to give the title compound (0.555 g, yield 76%) as a colorless oil.