Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.F[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]([CH3:27])([CH3:26])[O:17][C:16]3=[O:28])[CH2:11][CH:10]=2)=[CH:5][C:4]=1[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.FC1[N:41]=CC(C2CC[C@@H](N3C(C4C=CC=CC=4)C(C)(C)OC3=O)CC=2)=CC=1C1N=CC=CN=1>CC(O)C.CS(C)=O>[NH2:41][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]([CH3:27])([CH3:26])[O:17][C:16]3=[O:28])[CH2:11][CH:10]=2)=[CH:5][C:4]=1[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: CC1(C)OC(=O)N([C@H]2CC=C(c3cnc(F)c(-c4ncccn4)c3)CC2)C1c1ccccc1
Reactant: CC1(C)OC(=O)N([C@@H]2CC=C(c3cnc(F)c(-c4ncccn4)c3)CC2)C1c1ccccc1
Agent: N
Solvent: CS(C)=O
Solvent: CC(C)O
Product: CC1(C)OC(=O)N(C2CC=C(c3cnc(N)c(-c4ncccn4)c3)CC2)C1c1ccccc1
Temperature: 130 °C

Procedure:
A 2-mL glass microwave reaction vessel was charged with ammonia, (2 M solution in 2-propanol) (1.806 mL, 83 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) and a mixture of 3-((S)-4-(6-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one and 3-((R)-4-(6-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (370 mg, 0.832 mmol) in DMSO (8.324 mL). The reaction mixture was stirred and heated at 130° C. for 3 days. LC-MS indicated clean and good conversion to the desired product with a small amount of starting material present. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with water and brine and dried over MgSO4. The solution was filtered and concentrated under reduced pressure. The material thus obtained was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in heptane, to provide Example 131 (3-(4-(6-amino-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one) (210 mg, 0.476 mmol, 57.1% yield) as yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.87-8.92 (m, 4H), 8.60-8.64 (m, 2H), 8.20 (d, J=2.56 Hz, 1H), 8.17 (d, J=2.46 Hz, 1H), 7.34-7.46 (m, 9H), 7.25-7.34 (m, 4H), 5.95-5.98 (m, 1H), 5.83-5.89 (m, 1H), 4.70 (s, 1H), 4.67 (s, 1H), 3.59-3.77 (m, 2H), 2.60-2.75 (m, 1H), 1.90-2.43 (m, 8H), 1.71-1.80 (m, 1H), 1.47-1.53 (m, 8H), 0.78-0.87 (m, 6H). m/z (ESI) 442.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[N:11]=[C:12]([CH2:22][C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]#[N:27])[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=3)[CH:7]=[CH:6][C:5]=12.[OH:31]O.[OH-].[Na+].Cl>CCO>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[N:11]=[C:12]([CH2:22][C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]([NH2:27])=[O:31])[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=3)[CH:7]=[CH:6][C:5]=12
Reactant: Cc1cccc(-c2[nH]c(Cc3cccc(C#N)c3)nc2-c2ccc3ncnn3c2)n1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(-c2[nH]c(Cc3cccc(C(N)=O)c3)nc2-c2ccc3ncnn3c2)n1
Temperature: 60 °C
Yield: 36.6 %

Procedure:
To a stirred solution of 3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)benzonitrile (41 mg, 0.10 mmol) in EtOH (2 mL) were added 28% H2O2 (13.9 mL, 0.11 mmol) and 1N NaOH (0.39 mL, 0.39 mmol) at room temperature. The mixture was heated to at 60° C. for 1 h and then, to it, was added 1 N HCl at 0° C. to adjust pH 7-8. After removal of the solvent, the residue was extracted with CH2Cl2 (2×15 mL). The CH2Cl2 solution was washed with water (5 mL) and brine (5 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of MeOH and CH2Cl2 (1:9 (v/v)) as eluent to give the titled compound (15 mg, 35%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.93 (br s, 1H), 8.32 (s, 1H), 7.77 (s, 1H), 7.76 (dd, 1H, overlapped, J=9.2, 1.6 Hz), 7.69 (d, 1H, J=9.2 Hz), 7.56 (d, 1H, J=8.0 Hz), 7.44 (t, 1H, J=7.6 Hz), 7.39 (d, 1H, J=7.6 Hz), 7.26 (t, 1H, J=8.0 Hz), 7.21 (d, 1H, J=7.6 Hz), 6.98 (d, 1H, J=7.6 Hz), 6.60 (br s, 1H), 6.27 (br s, 1H), 4.15 (s, 2H), 2.44 (s, 3 H); MS (ESI) m/z 410.19 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:16](I)=[C:15]([CH3:18])[O:14][N:13]=1.C([O-])(O)=O.[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[C:12]([CH3:11])=[N:13][O:14][C:15]=2[CH3:18])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Cc1noc(C)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1noc(C)c1-c1ccc(Br)cc1
Temperature: 80 °C
Yield: 85 %

Procedure:
A mixture of 4-bromophenylboronic acid (1 g, 5 mmol), 3,5-dimethyl-4-iodoisoxazole (0.93 g, 4.2 mmol), bis(triphenylphospine)palladium(II) chloride (59 mg, 2 mol %), NaHCO3 (1.06 g, 12.6 mmol) in DME (5 mL) and H2O (5 mL) was heated to 80° C. under N2 for 18 h. The reaction mixture was partitioned between 1 N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (5% EtOAc in hexanes) to give the title compound as a white solid (0.9 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16]3[C:19]([S:30]([CH3:33])(=[O:32])=[O:31])=[N:20][N:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[C:15]=3[C:14]2=[O:34])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].N.C(O)[CH2:38][OH:39]>>[OH:39][CH2:38][CH2:1][O:2][C:3](=[O:35])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16]3[C:19]([S:30]([CH3:33])(=[O:32])=[O:31])=[N:20][N:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[C:15]=3[C:14]2=[O:34])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc(N2CCc3c(S(C)(=O)=O)nn(-c4ccc(OC)cc4)c3C2=O)cc1
Reactant: OCCO
Agent: N
Product: COc1ccc(-n2nc(S(C)(=O)=O)c3c2C(=O)N(c2ccc(C(C)(C)C(=O)OCCO)cc2)CC3)cc1
Temperature: 80 °C
Yield: 33 %

Procedure:
2-{4-[3-Methanesulfonyl-1-(4-methoxyphenyl)-7-oxo-1,4,5,7-tetrahydropyrazolo[3,4-c]pyridin-6-yl]phenyl}-2-methylproprionic acid methyl ester (0.077 g, 0.15 mmol) was placed in a sealed tube containing 10% ammonia in ethylene glycol (3 mL) and heated 80° C. for 2 h. The reaction was cooled, quenched with H2O, extracted with EtOAc, and dried (MgSO4). Purification by chromatography on silica (1:1 hexanes/ethyl acetate) and then HPLC purification afforded 27 mg (33%) title compound. High Resolution Mass Spec (M+H)+ for C26H30N3O7S 528.1776.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].C(N(CC)C(C)C)(C)C.[F:19][C:20]([F:48])([F:47])[C:21]1[CH:22]=[C:23]([CH:44]=[CH:45][CH:46]=1)[CH2:24][NH:25][C:26](=[O:43])[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2[CH:38]=[C:37](F)[CH:36]=[CH:35][C:34]=2[N+:40]([O-:42])=[O:41])[CH:28]=1>CN(C)C=O.O>[F:47][C:20]([F:19])([F:48])[C:21]1[CH:22]=[C:23]([CH:44]=[CH:45][CH:46]=1)[CH2:24][NH:25][C:26](=[O:43])[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2[CH:38]=[C:37]([N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:4][CH2:3][O:2][CH3:1])[CH:36]=[CH:35][C:34]=2[N+:40]([O-:42])=[O:41])[CH:28]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Reactant: COCCNCCOC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(CCOC)c1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Into a 10-mL vial, was placed a solution of bis(2-methoxyethyl)amine (285.6 mg, 2.15 mmol, 3.00 equiv) in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (277 mg, 2.14 mmol, 2.99 equiv). This was followed by the addition of a solution of N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide (300 mg, 0.72 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL). The resulting solution was stirred for 48 h at 80° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×70 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5˜1). The product was obtained as 270 mg (71%) of a yellow to green oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:6])[CH:2]=[CH2:3].Cl.C(=O)(O)[O-].[Na+]>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1ccccn1
Reaction time: 5 h
Yield: 72.4 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(2-pyridylmethyl)pyrrolidine (4.88 g) in acetonitrile (50 ml) was added dropwise conc. hydrochloric acid (3.3 ml) at room temperature. The reaction mixture was stirred for 5 hours, then neutralized with saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-pyridylmethyl) pyrrolidine (2.46 g). On the other hand the aqueous layer was extracted five times with chloroform. The combined chloroform layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-pyridylmethyl) pyrrolidine (0.23 g).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]3[CH2:16][CH2:15][CH2:14][S:13]3)[C:6]=2[NH:5][C:4]2=[CH:17][C:18]([C:20](O)=[O:21])=[N:19][N:3]12.CO.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:38][C:39]1[NH:43][N:42]=[N:41][N:40]=1>CN(C=O)C>[O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]3[CH2:16][CH2:15][CH2:14][S:13]3)[C:6]=2[NH:5][C:4]2=[CH:17][C:18]([C:20]([NH:38][C:39]3[NH:43][N:42]=[N:41][N:40]=3)=[O:21])=[N:19][N:3]12
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cc2[nH]c3c(C4CCCS4)cccc3c(=O)n2n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1nnn[nH]1)c1cc2[nH]c3c(C4CCCS4)cccc3c(=O)n2n1

Procedure:
From 4,9-dihydro-9-oxo-5-(tetrahydro-2-thienyl)pyrazolo[5,1-b]quinazoline-2-carboxylic acid, compound with methanol (1:1) (0.40 g; 1.3 mmole), DMF (20 ml); 1,1' carbonyl-diimidazole (0.5 g; 3.1 mmole) and 5-amino-1H-tetrazole, monohydrate (0.131 g; 1.3 mmole), following the procedure of Example 3, there is obtained 4,9-dihydro-9-oxo-5-(tetrahydro-2-thienyl)-N-1H-tetrazol-5-yl-pyrazolo[5,1-b]quinazoline-2-carboxamide (70 mg); mp>230° (d).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[C:21]1([CH:27]([NH:29][CH2:30][C:31]([CH:36]=[CH2:37])=[CH:32][CH:33]=[CH:34]C)[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:30]([N:29]([CH:27]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:28])[C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:37][CH:36]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: C=CC(=CC=CC)CNC(C)c1ccccc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N(Cc2ccccc2)C(C)c2ccccc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and (1-phenyl-ethyl)-(2-vinyl-hexa-2,4-dienyl)-amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C27H29NO5 [M+H]+: 448.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH:21]=1)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:21]=[C:20]([CH:19]=[C:4]([CH:5]=[C:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH:3]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cc(Br)cc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Oc2cc(Br)cc(C=C3CCNCC3)c2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 119.4 %

Procedure:
To a solution of tert-butyl 4-(3-bromo-5-(5-(trifluoromethyl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (1.2 g, 2.33 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (1.79 mL, 23.37 mmol) at 0° C. The reaction mixture was stirred for 30 min at 0° C. and at RT for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 three times. The organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness to give the title compound (1.15 g, 100%). 1H NMR (500 MHz, CDCl3): δ 8.43 (s, 1H), 7.93 (d, J=6.75 Hz, 1H), 7.23 (s, 1H), 7.20 (s, 1H), 7.05 (d, J=8.45 Hz, 1H), 6.89 (s, 1H), 6.39 (s, 1H), 3.23 (m, 2H), 3.12 (m, 2H), 2.75 (m, 2H), 2.64 (m, 2H); m/z (413.2, 415.2, M+ H+).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3S[CH:16]=[CH:17][N:18]=3)[S:13][C:6]=12.ClC1C=CN=C2C=C(CN3CC[O:40][CH2:39][CH2:38]3)SC=12>>[F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([CH2:14][N:18]3[CH2:38][CH2:39][O:40][CH2:16][CH2:17]3)[S:13][C:6]=12
Reactant: Clc1ccnc2cc(CN3CCOCC3)sc12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(CN4CCOCC4)sc23)c(F)c1

Procedure:
Following the procedure described above for the synthesis of compound 11 (example 12, step 3, scheme 2) but substituting compound 10 for compound 131, title compound 132 was obtained as a yellow solid (110 mg, 69% yield). MS (m/z) 390.1 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[N-:8]=[N+:9]=[N-:10].[Na+].[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:13]>N1C(C)=CC=CC=1C>[CH2:17]([O:16][C:14]([C:12]1[NH:13][N:10]=[N:9][N:8]=1)=[O:15])[CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C#N
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nnn[nH]1
Temperature: 0 °C
Reaction time: 6 h
Yield: 52.6 %

Procedure:
Trifluoroacetic acid (24.47 g, 0.21M) was added dropwise over 0.5 hr under nitrogen to a stirred suspension of sodium azide (12.59 g, 0.19M) in 2,6lutidine (100 ml) at 8° to 12°. After stirring for 7 minutes ethyl cyanoformate (20.4 g, 0.20M) was added in one portion. The mixture was heated and stirred at 75° for 6 hours and then, after cooling, stirred at 20° for 16 hr. After cooling to 10° the mixture was added to ice (250 g) and 11 molar hydrochloric add (100 ml) keeping the temperature below 20°. The product was extracted into ethyl acetate (1×250, 1×200, 2×100 ml) and the combined extracts dried over magnesium sulphate. After evaporation of the solvent under reduced pressure the oily product (38.22 g) was taken up in ether (50 ml) and hexane (25 ml) added. Storage at 4° for 2-3 days produced crystalline ethyl-1H-tetrazole-5-carboxylate that was filtered off, washed with chilled ether, and air dried, 14.12 g (52.6% yield), m.p. 88°-93°.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=S)[N:3]1[CH:12]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13]([O:15][CH3:16])=[O:14].C(Cl)Cl.CC[O:28]C(C)=O>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:28])[N:3]1[CH:12]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCC(C(=O)OC)N1C(=O)c2ccccc2C1=S
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CCC(C(=O)OC)N1C(=O)c2ccccc2C1=O

Procedure:
Dimethyl 2-(1,3-dihydro-1-oxo-3-thioxo-2H-isoindol-2-yl) -pentanedioate (208) and Dimethyl 2-(1,3-dihydro-1,3-dithioxo-2H-isoindol-2-yl)-pentanedioate (209). A mixture of compound 207 (144 mg, 0.47 mmol) and LR (191 mg, 0.47 mmol) in toluene was stirred in a 110° C. oil bath for 10 h. The solvent was then evaporated and the residue was purified by column chromatography, (silica gel) using CH2Cl2 as the eluent, to obtain compound 209 (17 mg, 11%) as a dark red oil. Thereafter, using CH2Cl2:EtOAc (10:1) as the eluent the more polar component 208 (105 mg, 70%) was obtained as a red oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:24])([F:23])[C@:9]([NH:13][C@H:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][OH:16])([CH3:12])[C:10]#[N:11].O.[OH-].[K+]>O1CCCC1>[NH2:11][CH2:10][C@@:9]([NH:13][C@H:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:15][OH:16])([CH3:12])[C:8]([F:23])([F:24])[F:7]
Reactant: C[C@@](C#N)(N[C@@H](CO)c1ccccc1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@](CN)(N[C@@H](CO)c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
65.10 mL (65.10 mmol) of a 1 M solution of lithium aluminum hydride in tetrahydrofuran are added to a solution, cooled to 2° C., of 16.80 g (65.10 mmol) of (S)-3,3,3-trifluoro-2-((R)-2-hydroxy-1-phenylethylamino)-2-methylpropionitrile in 50 mL of anhydrous tetrahydrofuran in a three-necked flask under argon. At the end of the addition, the reaction mixture is allowed to warm to room temperature and is then stirred overnight. The mixture obtained is cooled to 0° C., followed by very slow dropwise addition of 12 mL of water. Substantial evolution of gas and a temperature rise to 4° C. are observed. 12 mL of 15% potassium hydroxide and then 25 mL of water are added to the resulting mixture, maintained at 0° C. The white precipitate formed is filtered off and the filtrate obtained is dried over magnesium sulfate and then concentrated under reduced pressure to give 10.50 g of (R)-2-((S)-1-aminomethyl-2,2,2-trifluoro-1-methylethylamino)-2-phenylethanol, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](O)[C:8]([CH3:13])=[N:7]2.P(Cl)(Cl)([Cl:16])=O>[NH4+].[OH-]>[Cl:16][C:9]1[C:8]([CH3:13])=[N:7][C:6]2[C:11]([N:10]=1)=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2cccc(Cl)c2nc1O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc2cccc(Cl)c2nc1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 8-chloro-3-methylquinoxalin-2-ol (1.0765 g, 5.5314 mmol) and phosphorous oxychloride (10.127 mL, 110.63 mmol) was stirred at 100° C. After 3 h, the mixture was cooled to room temperature. The mixture was poured into ice (˜100 mL) with stirring and neutralized with NH4OH (30 mL) and ice with stirring. The resulting precipitate was collected by filtration, rinsed with water (200 mL), and dried to give 3,5-dichloro-2-methylquinoxaline as a pink solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98-8.07 (2 H, m), 7.84 (1 H, dd, J=8.3, 7.7 Hz), 2.79 (3 H, s); LC-MS (ESI) m/z 213.0 [M+H]+. The pink solid was carried on crude without purification for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[C:6]([F:8])[CH:7]=1.[CH:11](O)=O>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]2[NH:9][CH:11]=[N:10][C:4]=2[CH:3]=1
Reactant: O=CO
Reactant: Nc1cc(Br)cc(F)c1N
Product: Fc1cc(Br)cc2nc[nH]c12
Yield: 92 %

Procedure:
A solution of 5-bromo-2,3-diaminofluorobenzene (Apollo, 3 g; 14.63 mmol) in formic acid (75 mL) was heated at reflux overnight after which the reaction mixture was concentrated under vacuum to give a brown oil. It was extracted with EtOAc from a saturated aqueous solution of NaHCO3, dried over MgSO4 and evaporated under vacuum to give the title compound as a light pink solid (2.91 g, 92%). 1H NMR (DMSO-d6): δ 8.30 (s, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.27 (dd, J=10.3, 1.5 Hz, 2H), 3.32 (bs, 2H). HPLC (Method A), Rt: 2.09 min (purity: 97.4%). LC/MS (Method B): 216.9 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([CH2:14][CH2:15][CH:16]=O)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:16][CH2:15][CH2:14][C:12]2[O:11][N:10]=[C:9]([CH:8]=[CH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:13]=2)[CH2:28][CH2:27]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCCc1cc(C=Cc2ccccc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCc2cc(C=Cc3ccccc3)no2)CC1
Yield: 58.9 %

Procedure:
About 2 min after dissolving 3-[3-(2-phenylvinyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-(2-methoxyphenyl)piperazine (17 mg, 0.09 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (28 mg, 0.13 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 18.5 hr and followed the same processes as in Example 1 to obtain 9.5 mg (53.5%) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:21]/[O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])/[C:8]([O:10]CC2C=CC([N+]([O-])=O)=CC=2)=[O:9])[N:6]=1.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:21]/[O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(N)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(N)n1
Temperature: 5 °C
Yield: 80.3 %

Procedure:
In 1.2 l of tetrahydrofuran is dissolved 20 g (45.9 mmol) of p-nitrobenzyl (Z)-2-(2-amino-4-thiazolyl)-2-(t-butoxycarbonylmethoxyimino)acetate and, after addition of 20 g of 10% palladium-on-carbon, hydrogen gas is bubbled into the solution. After completion of the reaction, the catalyst is filtered off, and the filtrate is poured into 300 ml of water. The mixture is adjusted to about pH 8 with 5% aqueous sodium bicarbonate and washed with three 200-ml portions of ethyl acetate. The aqueous layer is adjusted to pH about 2 with 10% HCl and cooled to 5° C. or lower. The resulting crystalline precipitate is collected by filtration, washed with water and dried under reduced pressure to give 11.1 g of (Z)-2-(2-amino-4-thiazolyl)-2-(t-butoxycarbonylmethoxyimino)acetic acid.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.CC(C)([O-])C.[K+].C([O:31][N+:32]([O-])=[O:33])(C)C>CC(C)=O.CCCCCC>[OH:11][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:5]([CH2:4][CH2:3][C@:2]12[CH3:1])[C@:20]1([CH3:21])[C:14](=[C:15]([N+:32]([O-:33])=[O:31])[C:16](=[O:17])[CH2:18][CH2:19]1)[CH2:13][CH2:12]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: CC(C)O[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C([N+](=O)[O-])C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O

Procedure:
By the method of example 1, testosterone (2.88 g, 10 mM), potassium tert-butoxide (3.40 g, 30 mM) and isopropylnitrate (1.01 ml) are reacted to yield 17β-hydroxy-4-nitroandrost-4-en-3-one, m.p. 158-160° C. (acetone-hexane)