Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([CH2:14][CH:15]2[CH2:20][NH:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C:26](Cl)(=[O:28])[CH3:27].Cl>C(Cl)Cl>[C:26]([N:19]1[CH2:20][CH:15]([CH2:14][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:16][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1CNCC(CC2CCCCC2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(CC2CCCCC2)CN(C(C)=O)C1
Temperature: 25 °C

Procedure:
Triethylamine (410 μL, 2.9 mmol) was added to a solution of ethyl 5-(cyclohexylmethyl)piperidine-3-carboxylate (180 mg, 0.71 mmol) and acetyl chloride (120 mg, 1.4 mmol) in CH2Cl2 (10 mL). The reaction was maintained at room temperature for 30 min before being diluted with CH2Cl2 (20 mL) and poured into HCl (1 N, 20 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were sequentially washed with H2O (10 mL) and brine before being dried over Na2SO4. Concentration under reduced pressure and purification by silica gel chromatography (hexane→80% EtOAc/hexane) provided the title compound as a yellow oil. MS m/z: 296.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[CH:3]=1.[I:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[I:21]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Yield: 29.3 %

Procedure:
A suspension of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonitrile (9.8 g) and N-iodosuccinimide (8.87 g) was heated at reflux in carbon tetrachloride for 3.5 hours, cooled and washed with sodium bisulfite solution, NaOH solution and water. The dried (magnesium sulfate) solution was evaporated and purified by chromatography on silica gel eluting with dichloromethane to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-iodo-1H-pyrazole-3-carbonitrile (4.0 g), m.p. 212-214 ° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[O:5].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([NH:22][C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Solvent: O
Product: CCOC(=O)C=C(CC(=O)OCC)NCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.4 %

Procedure:
To 50.00 g (0.247 mol) of diethyl acetonedicarboxylate was addd dropwise 31.79 g (0.297 mol) of benzylamine at such a rate that reaction temperature was kept below 50° C. The reaction mixture was stirred at room temperature for 12 hours and poured into H2O, extracted twice with ether, dried (MgSO<) and concentrated in vacuo affording 60.00 g of a yellow-green oil. Crude was purified by HPLC using 10ethyl acetate/cyclohexane affording 46.2 g of a yellow semi solid. This was kugelrohr distilled at 53 Pa and collected at a pot temperature of 148°-150° C. to give 39.4 g (55) of enamine diester as a beige crystalline solid; mp 34°-36° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]2[O:7][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][O:10][C:5]=2[CH:4]=1)[CH3:2].C([O:22]O)(C)(C)C>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:3]1[CH:17]=[CH:16][C:6]2[O:7][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][O:10][C:5]=2[CH:4]=1)(=[O:22])[CH3:2]
Reactant: CCOC(=O)C1COc2cc(CC)ccc2O1
Reactant: CC(C)(C)OO
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)C1COc2cc(C(C)=O)ccc2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Add 2 g (8.5 mmol) of ethyl 6-ethyl-2,3-dihydro-1,4-benzodioxin-2-carboxylate dissolved in 5 cm3 of anhydrous methylene chloride to a mixture at 0° C. of 0.042 g (0.42 mmol) of chromium trioxide and 5.35 g (59.3 mmol) of 70% tert-butyl hydroperoxide in 30 cm3 of methylene chloride. Stir for 2 hours at 0° C. and then for 72 hours at room temperature. The crude product obtained by concentrating to dryness is purified by chromatography on a silica column (eluant: methylene chloride). Ethyl 6-acetyl-2,3-dihydro-1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 62%.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([C:21]3[S:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[N:23][C:22]=3[CH3:36])=[O:20])[CH2:14]2)[CH:10]=[CH:9][C:8]=1[CH3:37])C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:37][C:8]1[CH:9]=[CH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([C:21]3[S:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=4)=[N:23][C:22]=3[CH3:36])=[O:20])[CH2:14]2)=[CH:12][C:7]=1[NH:6][CH2:5][C:4]([OH:38])=[O:3]
Reactant: CCOC(=O)CNc1cc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1NCC(=O)O
Temperature: 25 °C
Yield: 110.4 %

Procedure:
A mixture of (2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenylamino)-acetic acid ethyl ester (19 mg, 0.035 mmol), potassium carbonate (10 mg, 0.07 mmol), methanol (5 mL) and water (1 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 20 mg (99%) of (2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenylamino)-acetic acid as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][NH:9][C@@H:10]1[C@@H:15]([OH:16])[C@H:14]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][C:26](F)(F)F)[C:21]([N+:30]([O-])=O)=[C:20]([F:33])[CH:19]=2)[CH2:13][S:12](=[O:35])(=[O:34])[CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[ClH:41].[CH3:42][OH:43]>CCOCC>[ClH:41].[ClH:41].[NH2:30][C:21]1[C:22]([O:24][CH2:25][CH2:26][O:43][CH3:42])=[CH:23][C:18]([CH2:17][C@H:14]2[C@H:15]([OH:16])[C@@H:10]([NH:9][CH2:8][C:7]3[CH:36]=[CH:37][CH:38]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)[CH2:11][S:12](=[O:35])(=[O:34])[CH2:13]2)=[CH:19][C:20]=1[F:33]
Reactant: CO
Reactant: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3cc(F)c([N+](=O)[O-])c(OCC(F)(F)F)c3)[C@@H]2O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: COCCOc1cc(C[C@@H]2CS(=O)(=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1N
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of (3R,4S,5S)-3-(3-tert-butyl-benzylamino)-5-[3-fluoro-4-nitro-5-(2,2,2-trifluoro-ethoxy)-benzyl]-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-ol (0.082 g, 0.166 mol) in MeOH (5 mL) was added NiCl2-6H2O (0.038 g, 0.155 mmol) and at 0° C. NaBH4 (0.024 g, 0.62 mmol) in two portions. After stirring for 1 h at 0-5° C. the reaction was quenched by addition of 1N aq. HCl. The reaction mixture was stirred for 0.5 h at 25° C. and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Chromatographic purification (Combi-Flash, 4 g, hexane-THF 90:10 to 10:90 containing 0.5% NEt3) provided a pure yellow oil which was converted into the hydrochloride salt with 1N HCl in Et2O to yield the title compound as a white amorphous solid: TLC (hexane-THF 2:3) Rf=0.22; HPLC RtA=1.56 min; ESIMS [M+NH4]+=509; 1H NMR (600 MHz, DMSO-d6): δ 9.89 (s, 1H), 9.08 (s, 1H), 7.67 (s, 1H), 7.43 (m, 1H), 7.38 (m, 2H), 6.62 (m, 2H), 6.18 (s, 1H), 4.24 (m, 2H), 4.14 (m, 2H), 3.82 (m, 1H), 3.3-3.7 (m, 5H), 3.29 (s, 3H), 3.24 (m, 2H), 3.03 (dd, 1H), 2.77 (m, 1H), 2.40 (dd, 1H), 2.04 (m, 1H), 1.35 (d, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:23](O)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:10]([O:9][C:7](=[O:8])[NH:14][C@@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23](=[O:24])[N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: C1CSCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCSCC1

Procedure:
Thiomorpholine (38 mmol) and Boc-L-phenylalanine (19 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) with the following work up: the reaction mixture was concentrated, diluted with ethyl acetate, then washed first with 1 N HCl three times, then with 2 N NaOH, the organic layer dried over MgSO4 and concentrated. The resulting foam was used without further purification. Yield 6.3 g, 95%.
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]([O:22][C:23]2[C:24]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:20][C:19]([N:35]=[C:36]=[O:37])=[C:18]([F:38])[CH:17]=1.Cl>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[C:18]([F:38])[C:19]([N:35]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:36]2=[O:37])=[CH:20][C:21]=1[O:22][C:23]1[C:24]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 0 °C

Procedure:
To a mixture of 1 ml of N,N-dimethylformamide and 26 mg of sodium hydride, a solution of 126 mg of ethyl 3-amino-4,4,4-trifluorocrotonate in 1 ml of N,N-dimethylformamide was added and the mixture was stirred at 0° C. Thereafter, to the reaction mixture was added a mixture of 266 mg of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl isocyanate and 1 ml of N,N-dimethylformamide at the same temperature, and the mixture was stirred over night at room temperature. The reaction solution was poured into a mixture of hydrochloric acid and ice water, and to obtain 3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH3:13][NH:14][CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:14]([CH3:13])[CH2:15][CH:16]=[O:17])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC=O)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
4-Cyanobenzenesulfonyl chloride (6 g, 0.0297 mol) in 50 ml of dry DCM was added at 0° C. to a solution of N-methylethanolamine (2.67 g, 0.0356 mol) and triethylamine (7.49 g, 0.0742 mol) in dry dichloromethane (75 ml) under nitrogen atmosphere and stirred at RT for 2 h. The reaction mixture was quenched with water and extracted with dichloromethane. Organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded crude product as solid. This solid was then washed with petroleum ether (three times) and dried under vacuum to give the sub-title compound (5.18 g) as white solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([NH:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N+:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[O-:16]
Reactant: CC(C)(C)NO
Reactant: Cc1cccc(C=O)c1O
Product: Cc1cccc(C=[N+]([O-])C(C)(C)C)c1O

Procedure:
The title compound was prepared according to the procedure described in Example 9 using 2-hydroxy-3-methylbenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 94% yield as a yellow crystalline solid, m.p. 59.2° C. (Rf=0.71 on a silica gel plate using 1:1 hexanes/EtOAc as an eluant).
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([O-])(=[O:19])=[O:18])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>O>[Cl:24][S:17]([CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:8]2[CH:21]=[CH:22][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)=[CH:11][CH:12]=1)(=[O:19])=[O:18]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)[O-])cc2)cc1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)Cl)cc2)cc1
Temperature: 90 °C
Yield: 27.8 %

Procedure:
4-(4-Nitrobenzyl)-phenylmethanesulfonic acid sodium salt (2.29 g) was combined with phosphorus pentachloride (1.45 g). The mixture was heated to 90° C. for 5 minutes, poured into water, and extracted with dichloromethane (3x 20 mL). Solvents were evaporated to give 4-(4-chlorosulfonylmethylbenzyl)-nitrobenzene as an impure yellow solid (0.63 g). This product was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[NH2:7].[C:9]([CH:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13](OC)=[O:14])(=O)[CH3:10]>C1(C)C(C)=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[C:3]([CH3:8])=[N:4][N:5]2[C:13]([OH:14])=[C:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:9]([CH3:10])=[N:7][C:6]=12
Reactant: Cc1n[nH]c(N)c1Cl
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)Cc1c(C)nc2c(Cl)c(C)nn2c1O
Yield: 57.5 %

Procedure:
To a solution of 4-chloro-3-methyl-1H-pyrazol-5-amine (0.263 g, 2 mmol) and dimethyl 2-acetylsuccinate (1.3 g, 6 mmol) in xylene (50 mL) was added p-toluenesulfonic acid monohydrate (4 mg, 0.02 mmol). The reaction mixture was heated at reflux under a Dean-Stark trap for 2 hrs. The solid was filtered and washed by hexanes to afford (0.31 g, 58%) of the title compound. 1H-NMR (500 MHz, DMSO-d6) δ ppm 2.28 (s, 3H), 2.33 (s, 3H), 3.54 (s, 2H), 3.61 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]([NH:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=1)=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]1[O:24][C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=2)=[N:7][N:6]=1
Reactant: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Cl)ccc2Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Cl)ccc3Cl)o2)cc1
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Into a 250 ml flask fitted with a mechanical stirrer and thermometer was introduced 30 g (0.0686 mol) 2,5-dichloro-N′-[4-(octyloxy)benzoyl]benzohydrazide and 181 ml phosphorus oxychloride. This was refluxed and stirred for 8 hrs. About 100 ml of phosphorus oxychloride was distilled off under reduced pressure. The cooled residue was poured onto water and crushed ice with manual stirring and allowed to stand until the ice had melted. The precipitated white solid was collected by filtration, dried and recrystallized from ethanol. There was obtained 25.7 g (89% yield, mp 86° C.) of 2-(2,5-dichlorophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole (2). The structure was confirmed unambiguously by 1D and 2D NMR techniques and gave the following: 1H-NMR (500 MHz, CDCl3) 0.89 (3H, t), 1.31 (8H, m), 1.46 (2H, q), 1.79 (2H, q), 6.97 (2H, d), 7.38 (1H, dd), 7.44 (1H, d), 8.01 (2H, d), 8.06 (1H, d); 13C-NMR (500 MHz, CDCl3) 13.90 (C-28), 22.44, 25.79, 28.91, 29.01, 29.13, 31.59, 68.08 (C-21), 114.78 (C14 and C-16), 115.37 (C-12), 124.27 (C-6), 128.58 (C-13 and C-17), 130.23 (C-11), 130.87 (C-7), 131.75, 132.20, 132.87 (C-10), 161.03, 161.98 (C-15), 164.95 (C-5).
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[NH2:9][CH2:10][CH2:11][C:12]([O:14][C@H:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[CH:17]([C:18](=O)[CH2:19][C@@H:20]3[C@@H:29]2[CH2:28][CH2:27][C@@:25]2([CH3:26])[C@H:21]3[CH2:22][CH2:23][C:24]2=[O:34])[CH2:16]1)=[O:13].[ClH:36].[NH2:37][OH:38]>>[ClH:36].[NH2:9][CH2:10][CH2:11][C:12]([O:14][C@H:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[CH:17](/[C:18](=[N:37]/[OH:38])/[CH2:19][C@@H:20]3[C@@H:29]2[CH2:28][CH2:27][C@@:25]2([CH3:26])[C@H:21]3[CH2:22][CH2:23][C:24]2=[O:34])[CH2:16]1)=[O:13]
Reactant: NO
Reactant: C[C@]12CC[C@H](OC(=O)CCN)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Product: C[C@]12CC[C@H](OC(=O)CCN)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
Following the procedure described in Example 1 and starting from 3β-(3-aminopropionyloxy)androstane-6,17-dione fumarate (Prepn. 69, 260 mg) and hydroxylamine hydrochloride (41 mg), the title compound I-dm was obtained (168 mg, 75%), after purification by flash chromatography (SiO2; CH2Cl2:MeOH 9:1). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.42 (1H, s), 8.13 (3H, bb), 4.63 (1H, m), 3.27 (1H, m), 2.98 (2H, t), 2.64 (2H, t), 2.45-0.95 (19H, m), 0.77 (3H, s), 0.69 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=O)[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:14].P(Cl)(Cl)(Cl)=O>>[Cl:14][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][N:5]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cc([N+](=O)[O-])c[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc([N+](=O)[O-])cnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Methoxy-5-nitro-2-pyridone (5.7 g, 0.034 mole) was added to a combination of phosphorus pentachloride (5.0 g) and phosphorus oxychloride (40 ml); the reaction mixture was refluxed for 2.5 hours, cooled, poured over ice/water (300 ml) and stirred for 30 minutes. The resulting solid was collected by filtration, washed with water and air dried; yield, 1.72 g (27 percent), m.p. 40° to 41° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[C:22]([Cl:34])=[CH:21][N:20]=1>>[Cl:34][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Reactant: COc1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccccc4OC)n3)c(OC)cc21
Yield: 35.9 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (51 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-phenyl)-amine (53 mgs) was converted to the title compound (33 mgs, 35%) as a white foam. 1H-NMR (CDCl3): δ 8.42 (d, J=7.9 Hz, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.54 (s, 1H), 7.13-7.09 (1, 2H), 7.01-6.94 (d, 2H), 6.72 (s, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 2.70-2.60 (m, 2H), 2.30-2.19 (m, 4H), 1.17 (t, J=7.3 Hz, 3H). LC/MS: found (M+H)+=468.24; MP: 78-80° C.
Reaction SMILES: C(O[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])C.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[NH:30][NH2:31]>C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([N:8]1[CH2:9][CH2:10][C:11]2[NH:31][N:30]([C:21]3[CH:22]=[N:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20]=3)[C:4](=[O:5])[C:6]=2[CH2:7]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: NNc1cnc2ccccc2n1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2[nH]n(-c3cnc4ccccc4n3)c(=O)c2C1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (500 mg, 1.84 mmol; Tetrahedron 1994, 50, 515) in toluene (10 mL) was added quinoxalin-2-yl-hydrazine (295 mg, 1.85 mmol; Heterocycles 1985, 23, 2603). This mixture was stirred at reflux overnight, cooled to room temperature, concentrated, and purified by flash column chromatography (25→75% ethyl acetate/hexanes) to give 600 mg (89%) of the title compound of Example 75, Step A as a light orange solid. 1H NMR (CDCl3, 250 MHz, 5:1 mixture of tautomers) δ 11.94 (br s, 0.83H), 10.16 (s, 0.17H), 9.57 (s, 0.83H), 8.13 (dd, 1H), 7.91-7.69 (c, 3H), 4.45 (s, 1.66H), 4.33 (s, 0.34H), 3.79-3.72 (c, 2H), 2.82-2.72 (c, 2H), 1.52 (s, 9H); MS (APCI) 368 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:30]([O-])([N+]([O-])=O)=[O:31]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:30]=[O:31])[C:5]([N:7]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CC(C)CCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)CCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 68.7 %

Procedure:
3.5 g of 1-(2-chloroethyl)-3-isopentyl-3-D-galactopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.6 g of 1-(2-chloroethyl)-1-nitroso-3-isopentyl-3-D-galactopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].[H-].[Na+].I[CH3:25]>CN(C)C=O>[CH3:25][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reaction time: 0.25 h
Yield: 102.3 %

Procedure:
To a stirred solution of 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.06 g, 0.20 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added sodium hydride (60% in mineral oil, 0.20 g, 0.50 mmol) at ambient temperature. The mixture was stirred for 15 min, and iodomethane (0.14 g, 1.0 mmol) was added in one portion. The reaction mixture was stirred at ambient temperature for 1 h, and then concentrated to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (0% to 30% gradient) to afford 1′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.06 g, 88%): mp 187-190° C.; 1H NMR (300 MHz, CDCl3) δ7.32 (dd, J=7.4, 7.4 Hz, 1H), 7.17 (d, J=7.4 Hz, 1H), 7.06 (t, J=7.4 Hz, 1H), 6.91 (d, J=7.4 Hz, 1H), 6.49 (s, 1H), 6.40 (s, 1H), 4.79 (ABq, 2H), 4.52 (t, J=8.5 Hz, 2H), 3.28 (s, 3H), 2.98 (t, J=8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 177.7, 161.6, 161.1, 142.9, 132.7, 128.6, 123.6, 123.2, 120.0, 119.7, 118.8, 108.1, 93.0, 80.4, 72.2, 57.6, 28.9, 26.6; MS (ES+) m/z 294.1 (M+1).