Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C@@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C@H:11]([OH:14])[CH2:12]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:22]([N:24](CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.CN.C(O)C>ClCCl>[F:21][C:17]1[CH:16]=[C:15]([C@H:10]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[C@H:11]([OH:14])[CH2:12][NH:24][CH3:22])[CH:20]=[CH:19][CH:18]=1
Reactant: CCN(CC)CC
Reactant: OC[C@@H](O)[C@H](c1cccc(F)c1)N1CCc2ccccc21
Agent: CN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCO
Solvent: ClCCl
Product: CNC[C@@H](O)[C@H](c1cccc(F)c1)n1ccc2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol (452 mg, 1.586 mmol) in dichloromethane (3 mL) under nitrogen was added triethylamine (1.1 mL, 7.93 mmol). The mixture was cooled to 0° C., and para-toluenesulfonyl chloride (423 mg, 2.22 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 1 hour and stored at 0° C. overnight. Methylamine in absolute ethanol (8 M, 5 mL, 40 mmol) was added and the reaction mixture was sealed, and stirred overnight while warming to room temperature. All volatiles were removed under reduced pressure. The oil residue was dissolved in dichloromethane (20 mL), washed with aqueous potassium carbonate (5 mL), dried (anhydrous sodium sulfate), and concentrated. Purification by Biotage chromatography (FlasH12i, silica, 0-15% MeOH/dichloromethane/0.5% triethylamine) gave (1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol, which was dissolved dichloromethane (5 mL) and treated with a 1M ethereal solution of hydrochloric acid (1.9 mL, 1.9 mmol). To the resulting solution was added hexane until white powder formed, which was collected, washed with hexane, and dried in vacuo to yield 209 mg (44%) of (1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol hydrochloride as a white powder. MS (ES) m/z 299.0 ([M+H]+); HRMS: calcd for C18H19FN2O+H+, 299.1554; found (ESI, [M+H]+), 299.1553.
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)[CH3:3].Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:28]([NH2:30])[CH3:29])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][CH:25]([F:27])[F:26]>>[Cl:14][C:13]1[C:4]2[CH:2]([CH3:3])[N:30]([CH:28]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][CH:25]([F:26])[F:27])=[C:17]([Cl:16])[CH:18]=3)[CH3:29])[C:6](=[O:8])[C:5]=2[CH:10]=[CH:11][N:12]=1
Reactant: CC(N)c1cnc(OCC(F)F)c(Cl)c1
Reactant: COC(=O)c1ccnc(Cl)c1C(C)Br
Agent: Cl
Product: CC(c1cnc(OCC(F)F)c(Cl)c1)N1C(=O)c2ccnc(Cl)c2C1C
Yield: 17 %

Procedure:
The title compound is prepared in 17% yield (100 mg, colorless amorphous solid) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (400 mg, 1.4 mmol, Step-1 of Intermediate-6, racemate) and 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (431 mg, 1.6 mmol, Amine-16, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])=O.[CH3:9][S:10][C:11]1[N:20]=[C:19]([N:21]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)N=CC)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.Cl.O>CCOCC>[CH3:32][O:31][C:28]1[CH:27]=[C:26]2[C:25](=[CH:30][CH:29]=1)[N:21]([C:19]1[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([S:10][CH3:9])[N:20]=1)[C:2]([CH3:1])=[C:4]2[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC=NN(c1ccc(OC)cc1)c1nc(SC)nc2ccccc12
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2-c1nc(SC)nc2ccccc12

Procedure:
A mixture of laevulinic acid (7 g.), acetaldehyde N1 -(2-methylthioquinazolin-4-yl)-p-methoxyphenylhydrazone (3.5 g.) and a saturated solution of hydrogen chloride in ether (2 ml.) was heated at 95° - 100° C. for 22 hours. The mixture was poured into water (300 ml.), and the precipitated brown solid was collected by filtration and dissolved in chloroform (100 ml.). The solution was filtered and the filtrate was extracted with 2 N- ammonia solution (4 × 50 ml.). The extracts were combined and acidified to pH3 with glacial acetic acid. The mixture was filtered, and the solid crystallised from methanol to give 5-methoxy-2-methyl-1-(2-methylthioquinazolin-4-yl)indol-3-ylacetic acid, as a pale yellow crystalline solid, m.p. 175°-178° C.
Reaction SMILES: CS(O[C@H:6]1[C@@H:11]([CH3:12])[CH2:10][C@@H:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH2:19])[CH2:8][C@H:7]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[NH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[C@H:9]1[CH2:8][C@@H:7]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:6]([N:28]=[N+:29]=[N-:30])[C@@H:11]([CH3:12])[CH2:10]1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of (+/−)-(1S,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-((tert-butoxycarbonyl)amino)-6-methylcyclohexyl methanesulfonate (1.0 equiv.) in DMF (0.20 M) was added NaN3 (7.0 equiv.). The solution was submerged in a 70° C. oil bath and left stirring under Ar for 4 hrs. The solution was cooled to rt and left stirring under Ar overnight. The solution was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated to yield (+/−)-tert-butyl ((1R,2R,3S,5R)-5-(3-aminopyridin-4-yl)-2-azido-3-methyl cyclohexyl)carbamate in 87% yield. LC/MS (m/z)=347.3 (MH+), Rt=0.68 min.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH2:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:18](Cl)(Cl)=[O:19]>C1(C)C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][N:13]=[C:18]=[O:19])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)Cl
Reactant: NCc1ccccc1OCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=NCc1ccccc1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
38.5 g of 2-benzyloxybenzylamine hydrochloride are suspended in 400 ml of distilled toluene and heated at a bath temperature of 140°. Whilst stirring, phosgene is introduced and after about 50 minutes the solution becomes clear. After a further 10 minutes, the addition of phosgene is interrupted and boiling is continued for a further hour. The solution is then left to cool a little and the toluene is distilled off in vacuo. A sample of the oil remaining was distilled in a bulb tube: Boiling point, bath temperature 120°/0.06 torr.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][NH:5][C:6]([NH2:8])=[S:7].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=O.C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=2)[N:8]=1
Reactant: CC(C)CCNC(N)=S
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)CCNc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Yield: 27.3 %

Procedure:
A solution of N-(3-methylbutyl)thiourea (3.00 g, 20.5 mmol), 2-bromo-1-[4-(trifluoromethyl)phenyl]ethanone (5.45 g, 20.5 mmol) and sodium acetate (2.19 g, 26.7 mmol) in ethanol (50 mL) was stirred at 90° C. for 4 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained solid was recrystallized from dichloromethane-hexane to give the title compound (1.76 g, yield 74%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15](O)=[O:16])=[O:12].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:16])=[O:12]
Reactant: C1CCNC1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)C1CCc2ccccc2C1
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: O=C([C@@H]1CCCN1C(=O)C1CCc2ccccc2C1)N1CCCC1
Yield: 52 %

Procedure:
A colorless oil of 1-[1-(1,2,3,4-tetrahydronaphthalene-2-ylcarbonyl)-L-prolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 1-(1,2,3,4-tetrahydronaphthalen-2ylcarbonyl)-L-proline and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 52%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(4-fluorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:19][S:20]([OH:22])=[O:21].CNCCNC>CS(C)=O>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]=2[C:6]([CH3:14])=[CH:7]1)([CH3:13])[CH3:12]
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Reactant: CS(=O)O
Agent: CNCCNC
Solvent: CS(C)=O
Product: Cc1cn(C(C)C)c2cc(S(C)(=O)=O)cc(C(=O)O)c12
Temperature: 165 °C
Yield: 25.3 %

Procedure:
To a 30-mL microwave tube were added methyl 6-bromo-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (490 mg, 1.580 mmol), methanesulfinic acid (212 mg, 2.054 mmol), DMSO (7 mL), N,N′-dimethyl-1,2-ethanediamine (18.10 mg, 0.205 mmol), and the mixture was degassed for 5 min by bubbling N2. Copper(I) trifluoromethanesulfonate benzene complex (63.6 mg, 0.126 mmol) was added and the tube was sealed. The mixture was heated at 165° C. overnight with stirring. The mixture was allowed to cool, filtered and purified using reverse-phase HPLC (Gemini 5u C18(2) 100A, AXIA; 30×100 mm 5 micron; 30 mL/min, 30% ACN/H2O, 0.1% formic acid to 60% ACN/H2O, 0.1% formic acid) to give the title compound (118 mg, 25%) as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.47 (d, J=8.00 Hz, 6H), 2.30-2.41 (m, 3H), 4.94 (quin, J=6.63 Hz, 1H), 7.80 (s, 1H), 7.88 (d, J=1.77 Hz, 1H), 8.24 (d, J=1.52 Hz, 1H), 13.17 (br. s., 1H). MS: (M+H)+=296.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:25][C:26]([F:34])([F:33])[CH2:27]OS(C)(=O)=O)(=O)=O>CN(C=O)C.O>[F:33][C:26]1([F:34])[CH2:27][O:13][C:11]2=[CH:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][N:10]2[CH2:25]1
Reactant: Oc1cc(-c2ccc(F)cc2)n[nH]1
Reactant: CS(=O)(=O)OCC(F)(F)COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cc3n(n2)CC(F)(F)CO3)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-pyrazol-5-ol (4 g, 22.47 mmol) in DMF (30 mL) was added K2CO3 (12.4 g, 89.88 mmol) and 2,2-difluoropropane-1,3-diyl dimethanesulfonate (9 g, 33.7 mmol) at room temperature and then stirred for 16 h at 60° C. The progress of the reaction was monitored by TLC. Thereafter, the reaction mixture was diluted with cold water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulphate and concentrated to get the crude product. Purification by column chromatography over silica gel (eluent 5-10% ethyl acetate in petrol ether) yielded 6,6-difluoro-2-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (3.2 g, 56%) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][CH2:8]2)([O-:3])=[O:2].[CH2:17](N(CC)CC)C>C(O)C.CI>[N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([CH3:17])[CH2:8]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnn2c1-c1ccccc1NC2
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CCO
Product: CN1Cn2ncc([N+](=O)[O-])c2-c2ccccc21
Reaction time: 8 h
Yield: 87 %

Procedure:
2.15 g (0.01 mole) of 1-nitro-5,6-dihydropyrazolo[1,5-c]quinazoline are dissolved in a mixture of 10 ml of ethanol and 20 ml of methyl iodide. 10 ml of triethylamine are added to the boiled mixture. The reaction mixture is boiled for 8 hours, then evaporated to dryness, the residue is dissolved in chloroform, washed with water, dried and evaporated. Thus, 2.0 g (87%) of 1-nitro-6-methyl-5,6-dihydropyrazolo[1,5-c]quinazoline are obtained. M.p.: 172°-173° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[NH:17]2)[C:13]([NH2:15])=[O:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CN(C1C=CC=CN=1)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[C:37]([N:17]1[C:18]([CH3:27])([CH3:26])[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]1=[C:12]([N:11]=[N:10][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=1)[C:13]([NH2:15])=[O:14])(=[O:39])[CH3:38]
Reactant: CC(=O)c1ccc(N=NC(C(N)=O)=C2NC(C)(C)Cc3ccccc32)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(N=NC(C(N)=O)=C2c3ccccc3CC(C)(C)N2C(C)=O)cc1
Temperature: 0 °C

Procedure:
2-(4-acetyl-phenylazo)-2-(3,3-dimethyl-3,4-dihydro-2H-isoquinoline-1-ylidene)-acetamide (Asinex Corp., Russia) and dimethylaminopyridine are dissolved in pyridine on the ice bath, and acetic anhydride is added. After the reaction is stopped, the solvent after the reaction as described above is poured on ice water to extract the reaction product by adding dichloromethane. The reaction product is dried by using anhydrous sodium sulfate and filtered and, then, the solvent is removed by reducing the pressure. The residue containing the reaction product is purified by column chromatography to obtain the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[CH2:18]([N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:30](=[O:32])[CH3:31])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(=O)Cl
Reactant: CCCCCN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCN1CCN(c2cccc3c2C[C@H](NC(C)=O)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-pentylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (170 mg, 0.57 mmol) and triethylamine (86 μL, 0.86 mmol) in methylene chloride (30 mL) was added dropwise acetyl chloride (41 μL, 0.57 mmol) in methylene chloride (10 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The methylene chloride phase was dried (Na2SO4), filtered and evaporated in vacuo. The residue crystallized from diethyl ether/hexane. This gave 120 mg (62% yield) of the title compound as white crystals: mp 119-120° C.; [α]21D +25° (c 0.97, chloroform); EIMS (70 eV) m/z (relative intensity) 343 (49, M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](O)[CH3:13]>>[N+:8]([C:6]1[CH:7]=[C:12]([C:13]2[O:11][C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[N:1]=2)[CH:3]=[CH:4][CH:5]=1)([O-:10])=[O:9]
Reactant: CCO
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Product: O=[N+]([O-])c1cccc(-c2nc3cc([N+](=O)[O-])ccc3o2)c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
To 11.5 grams (0.05 mole) of 3-nitrophenylchloroxime are added 150 milliliters of ethanol. To the mixture are added 23.1 grams (0.15 moles) of 2-amino-4-nitrophenol. The mixture is stirred under nitrogen at about 30° C. overnight and filtered to yield 2-(m-nitrophenyl)-5-nitrobenzoxazole.
Reaction SMILES: Cl.[S:2]1[C:6]([NH2:7])=[CH:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]1=2.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)#[N:13]>N1C=CC=CC=1.C(Cl)Cl>[S:2]1[C:6]([NH:7][S:20]([C:17]2[CH:16]=[CH:15][C:14]([C:12]#[N:13])=[CH:19][CH:18]=2)(=[O:22])=[O:21])=[CH:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]1=2
Reactant: Nc1cc2ccccc2s1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)Nc2cc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.6 %

Procedure:
To a stirred solution of compound 1-C (0.927 g, 5.0 mmol) in pyridine (10 mL) and methylene chloride (5 mL), cooled on an ice bath, was added 4-cyanobenzene-1-sulfonyl chloride (1.01 g, 5.0 mmol) portion-wise over 3 min. The reaction was allowed to warm slowly to ambient temperature and allowed to stir for 72 h. The reaction mixture was concentrated under reduced pressure, the crude residue was partitioned between EtOAc (100 mL) and 1N HCl (25 mL), the layers separated, the organic phase washed with brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2) eluting with an EtOAc-heptane gradient to afford 1.22 g of compound 389-A as a tan-brown powder. 1H-NMR (DMSO-d6): δ 6.91 (s, 1H), 7.33-7.21 (m, 2H), 7.69-7.64 (m, 1H), 7.82-7.76 (m, 1H), 7.99-7.93 (m, 2H), 8.11-8.05 (m, 2H), 11.49 (br s, 1H); MS: m/z 313.1 (M-H)−.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)[CH3:2].C(=O)(O)O.[NH2:23][NH:24][C:25]([NH2:27])=[NH:26]>C(O)(C)C.Cl>[C:13]1([C:5]2[NH:6][C:7]3[C:12]([C:4]=2[C:1](=[N:23][NH:24][C:25](=[NH:26])[NH2:27])[CH3:2])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: CC(C)O
Product: CC(=NNC(=N)N)c1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 80 °C
Yield: 36 %

Procedure:
A mixture of 2-phenylindole (193.3 mg, 1.0 mmol) and acetyl chloride (92 μL, 1.3 mmol) in CH2Cl2 is treated with tin tetrachloride (97.4 μL, 1.9 mmol) at room temperature, shaken for 6 h, quenched with saturated NaHCO3 and extracted with ethyl acetate. The extracts are combined and concentrated in vacuo to afford the 3-acetyl-2-phenylindole intermediate. A suspension of the thus-obtained 3-acetyl-2-phenylindole (47 mg, 0.2 mmol) in isopropanol and concentrated HCl (5 μL) is treated with aminoguanidine bicarbonate, heated at 80° C. for 2 h, cooled to room temperature and concentrated in vacuo. The resultant residue is purified by HPLC to afford the title product, 21.0 mg (36% yield), identified by HPLC1 and mass spectral analyses, (M+H) 292, retention time 3.9 min.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:2]1C=CC=CC=1.[C:20](OC[C@H]1OC1)(=[O:24])CCC>>[OH:24][CH2:20][C@H:1]1[O:8][C:9](=[O:19])[N:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH2:2]1
Reactant: CCCC(=O)OC[C@@H]1CO1
Reactant: COc1ccc(NC(=O)OCc2ccccc2)cc1
Product: COc1ccc(N2C[C@@H](CO)OC2=O)cc1

Procedure:
Starting from (4-methoxy-phenyl)-carbamic acid benzyl ester (prepared from 4-methoxy-aniline and CbzCl according to procedure C) and (S)-glycidyl butyrate and following the procedure described for the preparation of intermediate 1.iii), the title compound was obtained as a grey solid (469 mg, 54%).
Reaction SMILES: [OH:1][CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:25]O)=[CH:20][CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[CH2:25][O:1][CH:2]2[C:14]3[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=3)=[CH:22][CH:23]=1
Reactant: O=c1[nH]c2c([nH]c1=O)C(O)c1ccccc1-2
Reactant: OCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: O=c1[nH]c2c([nH]c1=O)C(OCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1)c1ccccc1-2
Yield: 17.5 %

Procedure:
A suspension of 9-hydroxy-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione. 1H2O (0.50 g, 2.13 mmol) in acetic acid (30 ml), 2,2-bis(4-chlorophenyl)ethanol (2.84 g, 10.65 mmol) and p-toluensulfonic acid (20 mg) was refluxed for 21 hours. The reaction mixture was evaporated in vacuo to dryness, the residue was suspended in ethanol (40 ml) and the precipitate was filtered off and washed with ethanol and dried to give 0.39 g of the crude product, which was recrystallized from ethanol to yield 0.174 g (17.5%) of the title compound. M.p. 234°-237° C. 1 -NMR (DMSO-d6, δ): 3.68 (t, 1H), 4.0 (t, 1H), 4.27 (t, 1H), 5.23 (s, 1H), 7.1-7.5 (m, 12H), 11.98 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:10])[CH2:8]Br)[N:6]=1.O[CH2:12][CH2:13][NH:14][CH:15]([CH3:29])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1.C(=O)([O-])O.[K+].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>CC(C)=O>[C:25]([CH2:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH:15]([N:14]2[CH2:13][CH2:12][O:10][CH:7]([C:5]3[N:6]=[C:2]([Cl:1])[S:3][CH:4]=3)[CH2:8]2)[CH3:29])=[CH:18][CH:19]=1)([O:27][CH3:28])=[O:26]
Reactant: O=C(CBr)c1csc(Cl)n1
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(Cl)n3)C2)cc1

Procedure:
Prepared by analogy to Example 32 by reaction of 5 g (0.0208 mol) of 2-chloro-4-bromoacetyl-thiazole with 5.6 g (0.021 mol) of N-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine in 200 ml of acetone and 6.3 g (0.063 mol) of potassium hydrogen carbonate over 20 hours at room temperature. The reduction is carried out in 41 ml of trifluoroacetic acid using 3.5 g (0.029 mol) of triethylsilane for 24 hours. The crude product is purified on a silica gel column using methylene chloride/methanol=20:1 as eluant.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>CN(C=O)C.O>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[C:27]([F:28])([F:29])[F:30])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To 4-hydroxy-N-(t-butoxycarbonyl)piperidine (10.0 g) in DMF was added NaH (2.2 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours. 4-Flouro-3-trifluoromethyl-1-nitrobenzene (5.3 mL) was added and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with aqueous NaHCO3 and aqueous HCl, dried over sodium sulfate, concentrated and purified on silica gel column (hexane/ethyl acetate, gradient) to afford a compound of formula (C), 4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-1-nitrobenzene in 80% yield.