Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:38])[CH2:33][O:34][CH:35]([F:37])[F:36])[CH:30]=3)[C:25](O)=[O:26])=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:39][C:40]1[CH:44]=[CH:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:41]=1.N1C=CC=CC=1>C(Cl)Cl.O.C(OCC)(=O)C>[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([C:25]([NH:39][C:40]4[CH:44]=[CH:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:41]=4)=[O:26])[CH:28]=[C:29]([O:31][C@@H:32]([CH3:38])[CH2:33][O:34][CH:35]([F:37])[F:36])[CH:30]=3)=[N:19][CH:20]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)O)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Reaction time: 1 h
Yield: 27.9 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.12 mL, 0.92 mmol) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)benzoic acid (0.26 g, 0.61 mmol) in DCM (8 mL) and stirred for 1 hour. 1,1-Dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (169 mg, 0.92 mmol) then pyridine (0.1 mL, 1.23 mmol) were added and stirred for a further 20 hours. The reaction mixture was reduced in vacuo and ethyl acetate (50 mL) and water (50 mL) were added. The aqueous layer was re-extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 25-50% ethyl acetate in isohexane, to give the desired compound as a colourless oil (100 mg).
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=O.NCCCCCCO.C1(N=C=NC2CCCCC2)CCCCC1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[K+]>CN(C=O)C.C(Cl)Cl>[CH:2](=[O:1])[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: O=[Cr](=O)([O-])Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=CCCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
Biotin is conjugated to 6-aminohexanol using dicyclohexyl carbodiimide reagent in DMF solvent. The resulting alcohol is oxidized to the aldehyde using pyridinium chlorochromate, potassium acetate in methylene chloride at room temperature (according to the procedure of Ducray et al., J. Org. Chem., 1999, 64:3800-3801). The aldehyde compound is purified by silica column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:33][CH3:34])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH:26]5[CH2:30][NH:31][CH2:32][CH:25]45)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].CO.[CH2:37](Cl)Cl.C=O>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:33][CH3:34])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH:26]5[CH2:30][N:31]([CH3:37])[CH2:32][CH:25]45)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCCC2CNCC21
Reactant: ClCCl
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCCC2CN(C)CC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(octahydro-1H-pyrrolo[3,4-b]pyridin-1-yl) propoxy)quinazolin-4-amine (0.45 g) in the mixture solvent of MeOH and CH2Cl2 (1:1) was added 37% HCHO (1.00 mL) and acetic acid (0.50 mL) dropwise. The reaction mixture was stirred for 30 min at room temperature, NaB(OCOCH3)3H (1.50 g) was added in portions. The reaction mixture was stirred for another 2 h at room temperature, poured into water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (0.60 g, 70.00%), HPLC: 98.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 500.1 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.82 (m, 1H), 2.33 (m, 4H), 1.94 (m, 1H), 2.19-2.20 (m, 2H), 2.50-2.52 (m, 1H), 2.67-2.70 (m, 2H), 3.58 (s, 3H), 4.01-4.02 (m, 2H), 4.03-4.04 (m, 5H), 4.05-4.07 (m, 1H), 4.40 (s, 2H), 7.44 (s, 1H), 7.50 (t, J=4.8 Hz, 1H), 7.83-7.88 (m, 1H), 8.07-8.08 (m, 1H), 8.89-8.91 (m, 1H), 9.05 (s, 1H) ppm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=1)[CH2:11][NH:12][C:13](=[O:26])[NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][C:21](OCC)=[O:22])[N:19]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)[O-].[Na+]>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=1)[CH2:11][NH:12][C:13]([NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][CH2:21][OH:22])[N:19]=1)=[O:26]
Reactant: CCOC(=O)Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1cccc(F)c1)Nc1nc(CCO)cs1
Temperature: 25 °C

Procedure:
Lithium aluminum hydride (10.6 μL, 10.6 mmol, 1M in THF) was added dropwise to a THF (50 mL) solution of ethyl 2-(2-(3-(3-fluorobenzyl)ureido)thiazol-4-yl)acetate (1.32 g, 4.1 mmol) at −78° C. The reaction was allowed to slowly warm to ambient temperature. The mixture was stirred at ambient temperature until completion of the reaction. Sodium sulfate decahydrate (3.2 g, 10 mmol) was added carefully. It was followed by the addition of sodium bisulfate (1.8 g) and the mixture was stirred for 30 hours. An aqueous work-up with EtOAc and a recrystallization from a mixture of CH2Cl2 and hexane afforded the pure title compound. 1H NMR (400 MHz, CDCl3): 9.5 (s, 1H, br), 7.75 (s, 1H, br), 7.27 (m, 1H), 7.07 (d, 1H), 7.01 (d, 1H), 7.94 (td, 1H), 6.48 (s, 1H), 4.48 (d, 2H), 3.83 (t, 2H), 2.83 (t, 2H). MS (ES+): M/Z 338 (M+H)+.
Reaction SMILES: [S:1](CCCCCCCC)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[P:32](Cl)([Cl:35])([Cl:34])=[S:33]>>[CH2:2]([S:1][P:32]([Cl:35])([Cl:34])=[S:33])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: S=P(Cl)(Cl)Cl
Reactant: CCCCCCCCSCCCCCCCC
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: CCCCCCCCSP(=S)(Cl)Cl
Yield: 97.4 %

Procedure:
Following the procedure of the preceding Examples, 64.5 grams (0.25 mole) of (n-C8H17)2S, 18.5 grams (0.0416 mole) of P4S10 and 90 grams (0.53 mole) of PSCl3 were reacted at 190° C for 10 hours. The crude reaction mixture was distilled twice to provide 68 grams (49% yield) of n-C8H17SP(S)Cl2 having the following properties:
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>CO.C1COCC1.O>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(S(C)(=O)=O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(S(C)(=O)=O)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl 2-methyl-2-(5-methylsulfonyl-2-pyridyloxy)propionate (Step A, 0.45 g, 1.6 mol) in 5 mL MeOH, 10 mL THF and 10 mL water was added sodium hydroxide (0.19 g, 4.7 mmol). After stirring at room temperature for 3 days, the reaction mixture was partially concentrated, and was added 2 M hydrochloric acid to pH>2. The resulting mixture was extracted with EtOAc (2×20 mL), and the combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 8.60 (d, 1H), 8.16 (dd, 1H), 7.17 (d, 1H), 3.15 (s, 3H), 1.71 (s, 6H).
Reaction SMILES: C[O:2]C(=O)C1C=CC=C(O)C=1.[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:25]1([P:18](=[O:2])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
To a well-stirred solution consisting of (7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol (3.40 g, 11.83 mmol), methyl-3-hydroxybenzoate (2.70 g, 17.75 mmol), and triphenylphosphine (3.70 g, 14.20 mmol), in anhydrous tetrahydrofuran (68 ml), diethylazodicarboxylate (2.24 ml, 14.20 mmol) was added. The resulting solution was heated at 50° C. for 2 hours. The solvent was removed in vacuo, and the resulting residue was extracted into a biphasic 1N aqueous sodium hydroxide (40 ml)/methylene chloride (50 ml) mixture. The aqueous phase was twice extracted with equal volume portions of fresh methylene chloride. The combined organic extracts were dried (anhydrous magnesium sulfate), and concentrated to an amber oil. An initial flash chromatography (silica gel, 70-230 micron mesh; elution with methanol/methylene chloride=1:99 in volume) afforded partially purified product (3.3 g, contaminants: hydrazine diethylcarboxylate and triphenylphosphine oxide). A second flash chromatography of the entire sample (silica gel, 230-400 micron mesh, elution with methanol/methylene chloride=1:99) afforded the purified title compound (1.37 g, 27% yield) as a colorless amorphous solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH3:14][CH:15]1[CH:20]([CH3:21])[CH2:19][CH2:18][CH2:17][CH:16]1[NH2:22]>N1C=CC=CC=1>[CH3:14][CH:15]1[CH:20]([CH3:21])[CH2:19][CH2:18][CH2:17][CH:16]1[NH:22][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: CC1CCCC(N)C1C
Solvent: c1ccncc1
Product: CC1CCCC(NC(=O)c2cnc3ccccc3n2)C1C
Yield: 58.8 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 2,3-dimethylcyclohexylamine (115 mg, 0.90 mmol), and pyridine (5 mL) yielding 150 mg (59%) of (163): rt=10.12 min.; m/z (rel. int.) 283 (M+, 35), 212 (6), 198 (14), 175 (6), 174 (39), 158 (7), 157 (22), 131 (6), 130 (46), 129 (100), 126 (44), 109 (8), 103 (20), 103 (20), 102 (45), 76 (13), 75 (11), 67 (7), 56 (10), 55 (12), 51 (6), 43 (6), 41 (16).
Reaction SMILES: [NH2:1][C:2](=[N:5][C:6](=[O:9])[O:7][CH3:8])[O:3][CH3:4].[CH:10]([N:13]=[C:14]=[O:15])([CH3:12])[CH3:11].C(Cl)Cl.CN(C)C=O>C(N(CC)CC)C>[CH:10]([NH:13][C:14](=[O:15])[NH:1][C:2](=[N:5][C:6]([O:7][CH3:8])=[O:9])[O:3][CH3:4])([CH3:12])[CH3:11]
Reactant: CC(C)N=C=O
Reactant: COC(=O)N=C(N)OC
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N=C(NC(=O)NC(C)C)OC
Reaction time: 72 h

Procedure:
A solution of 23 parts of methyl N-(1-amino-1-methoxymethylene)-carbamate, 16 parts of isopropyl isocyanate 60 parts of methylene chloride, and a catalytic amount of dimethylformamide and triethylamine is allowed to stand at room temperature for 3 days. The solvent is evaporated to afford 33 parts of crude methyl 4-isopropyl-N-methoxycarbonyl-allophanimidate, an oil, ND25 1.4823.
Reaction SMILES: O.[SH-].[Na+].[CH3:4][C:5]1([CH3:15])[O:9][N:8]=[C:7]([S:10]([CH2:13][CH3:14])(=O)=O)[CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+].BrCC1[C:31]([CH:37]([F:39])[F:38])=[N:32][N:33]([CH3:36])[C:34]=1[Cl:35]>CN(C)C=O.O>[Cl:35][C:34]1[N:33]([CH3:36])[N:32]=[C:31]([CH:37]([F:39])[F:38])[C:14]=1[CH2:13][S:10][C:7]1[CH2:6][C:5]([CH3:15])([CH3:4])[O:9][N:8]=1
Reactant: Cn1nc(C(F)F)c(CBr)c1Cl
Reactant: CCS(=O)(=O)C1=NOC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(F)F)c(CSC2=NOC(C)(C)C2)c1Cl
Reaction time: 2 h
Yield: 67.8 %

Procedure:
1.2 g of sodium hydrosulfide hydrate (purity: 70%, 15.0 mmoles) was added to a solution of 1.9 g (10.0 mmoles) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline dissolved in 30 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. Thereto were added 2.1 g (15.0 mmoles) of anhydrous potassium carbonate, 2.3 g (15.0 mmoles) of Rongalit and 2.6 g (10.0 mmoles) of 4-bromomethyl-5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 15 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 2.1 g (yield: 68.0%) of 3-(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as a colorless viscous liquid (nD20=1.5183).
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][NH:28][CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[N:32]1[C:41]2[C:36](=[CH:37][C:38]([CH:42]=O)=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C.CC(O)=O>CN(C=O)C>[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][N:28]([CH2:42][C:38]6[CH:37]=[C:36]7[C:41](=[CH:40][CH:39]=6)[N:32]=[CH:33][CH:34]=[CH:35]7)[CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: O=Cc1ccc2ncccc2c1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccc5ncccc5c3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) in DMF (1 mL), was added quinoline-6-carbaldehyde (31 mg, 198 μmol), DIPEA (34 mg, 46 μL, 264 μmol) and AcOH (11.8 mg, 11 μL, 198 μmol). The reaction mixture was stirred at room temperature for 1 hour. STAB (42 mg, 198 μmol) was added and stirring was continued for 18 hours. The reaction mixture was partitioned between EtOAc (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 ml). The organic layer was washed with further saturated aqueous sodium hydrogen carbonate solution (2×10 mL), dried over magnesium sulfate and concentrated in vacuo to furnish a brown oil. The crude material was purified by HPLC Method A to afford 20.6 mg of the title compound.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12]C=1.[C-:16]1([CH2:21][N:22]2[C:26](=[O:27])[NH:25][NH:24][C:23]2=[O:28])[CH:20]=[CH:19][CH:18]=[CH:17]1.[CH-]1C=CC=C1.[Fe+2:34]>O1CCCC1>[C-:16]1([CH2:21][N:22]2[C:23](=[O:28])[N:24]=[N:25][C:26]2=[O:27])[CH:17]=[CH:18][CH:19]=[CH:20]1.[CH-:12]1[CH:13]=[CH:14][CH:15]=[CH:10]1.[Fe+2:34]
Reactant: Ic1ccccc1
Reactant: O=c1[nH][nH]c(=O)n1C[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1N=NC(=O)N1C[c-]1cccc1
Reaction time: 2 h

Procedure:
With reference to EXAMPLE 1-1, 5 mg (0.016 mmol) of iodobenzene diacetate was added to a mixture of 5 mg (0.017 mmol) of 4-(ferrocenylmethyl)urazole and 0.25 mL of tetrahydrofuran at room temperature. The mixture was stirred for 2 hours to give the tetrahydrofuran solution of 4-(ferrocenylmethyl)-1,2,4-triazoline-3,5-dione. A tetrahydrofuran (0.25 mL) solution of 1 mg (0.0025 mmol) of alfacalcidol prepared in accordance with the method described in Japanese Patent Publication (KOKAI) No. 48-62750, Tetrahedron Lett., 1973, 2339 and Tetrahedron, 30, 2701 (1974) was added to the resulting solution, followed by stirring at room temperature for an hour. The resulting mixture was concentrated under reduced pressure and the residue obtained was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:2) to give 1 mg (57%) of the titled alfacalcidol/4-(ferrocenylmethyl)-1,2,4-triazoline-3,5-dione adduct (ALF-FMTAD) as a yellow oily substance.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CON(C)[C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]1[C:22]([O:25][CH3:26])=[N:23][N:24]=[C:17]1[C:16]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:15]2)=[O:11].O.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[CH:28]([NH:27][C:16]1[C:17]2[N:18]([C:22]([O:25][CH3:26])=[N:23][N:24]=2)[C:19]2[C:14]([N:15]=1)=[CH:13][C:12]([CH:10]=[O:11])=[CH:21][CH:20]=2)([CH3:30])[CH3:29]
Reactant: COc1nnc2c(NC(C)C)nc3cc(C(=O)N(C)OC)ccc3n12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1nnc2c(NC(C)C)nc3cc(C=O)ccc3n12
Temperature: 23 °C
Reaction time: 1.33 h

Procedure:
Solid LAH (8 mg) was added to a solution of 4-isopropylamino-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid-methoxy-methyl-amide (50 mg) in THF at −78° C. After 80 min., the solution was warmed to 23° C. Portions of water (40 μL), 15% aqueous sodium hydroxide solution (40 μL), and water (180 μL) were added sequentially. The resulting mixture was diluted with EtOAc, and was then dried over sodium sulfate and filtered. Concentration afforded 4-isopropylamino-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carbaldehyde as a white solid. MS (M+H)+=286.4.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[C-:11]#[N:12].[K+].CCOC(C)=O>CN(C=O)C.O>[C:11]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])#[N:12]
Reactant: N#Cc1cccc(CBr)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cccc(C#N)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
3-Bromomethyl-benzonitrile (150 mg, 0.76 mmol) was dissolved in DMF (2 ml). KCN (55 mg, 0.84 mmol) was dissolved in the minimum amount of water and was added to the reaction. The resulting solution was stirred at 85° C. overnight. The reaction mixture was allowed to cool to room temperature, EtOAc (5 ml) was added, and the solution was washed with saturated NaHCO3 (4×10 ml). The organic layer was dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].Cl.Cl[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>O.COCCOCCOC>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: COc1cc(N2CCNCC2)cc(OC)c1OC
Yield: 14.5 %

Procedure:
11.9 g of 3,4,5-trimethoxyaniline, 11.6 g of bis(2-chloroethyl)amine hydrochloride, 9 g of anhydrous potassium carbonate, and 48 ml of diglyme were mixed and refluxed under heating for 28 hours. The reaction mixture was cooled, and was added into 100 ml of water. A concentrated aqueous potassium hydroxide solution was added to the aqueous mixture until the mixture had pH 12. The aqueous solution was then extracted with ethyl acetate. The ethyl acetate portion was washed with water, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill offthe solvent. The residue was purified by silica gel column chromatography to give 2.37 g of the desired compound as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Br[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[N:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:5][N:4]([C:16]2[CH:21]=[N:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:3]1=[O:14]
Reactant: COc1ccc(Br)cn1
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(N2CC(C(=O)OC(C)(C)C)N(C)C2=O)cn1
Yield: 44.3 %

Procedure:
To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 1.998 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 5-bromo-2-(methyloxy)pyridine (0.259 ml, 1.998 mmol) in 1,4-dioxane (20 ml) was added cesium carbonate (2604 mg, 7.99 mmol), Xantphos™ (87 mg, 0.150 mmol) and tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.100 mmol) and the reaction was stirred at reflux overnight. After cooling the solvent was removed under vacuum and the residue was partitioned between dichloromethane and water. The organic layer was separated, washed with saturated sodium hydrogen carbonate solution, water and then brine and passed through a hydrophobic frit. The organic layer was reduced under vacuum and the residue was purified by Flashmaster automated silica gel chromatography eluting with 0-30% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxylate (272 mg, 43.4% yield). LC/MS [M+H]+=308. (ii) Trifluoroacetic acid (1 ml) was added to a solution of 1,1-dimethylethyl 3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxylate (270 mg, 0.878 mmol) in dichloromethane (2 ml) and the solution was stirred at room temperature overnight. The reaction mixture reduced to dryness under vacuum azeotroping with toluene and then dried under heated vacuum overnight to give 3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜0.88 mmol). LC/MS [M+H]+=252.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH3:14])[CH2:7][C:6]2([CH3:16])[CH3:15].[C-]#N.[Na+].C#N.Cl>CS(C)=O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH3:14])[CH2:7][C:6]2([CH3:15])[CH3:16]
Reactant: COc1ccc2c(c1)C(C)(C)CC(C)C2=O
Agent: C#N
Agent: Cl
Agent: [C-]#N
Solvent: CS(C)=O
Product: CC1CC(C)(C)c2cc(O)ccc2C1=O
Temperature: 25 °C

Procedure:
A solution 6-methoxy-2,4,4-trimethyl-3,4-dihydro-2H-naphthalen-1-one (described in Journal of Pharmaceutival Sciences, 1970, 59(6), p 869-870, Floyd et al. incorporated herein by reference; 1.2 g, 5.5 mmol) and sodium cyanide (2 g, 41 mmol) in anhydrous dimethylsulfoxide (15 mL) was heated at 230° C. for 24 h under argon. The reaction mixture was then cooled to ambient temperature, poured into ice and acidified (Caution! Hydrogen cyanide evolution!) with dilute hydrochloric acid and extracted with ethyl acetate (×2). The combined organic extract was washed with brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound, which was used as such for the next step (1 g, 89%).