Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.Br[C:20]1[S:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][N:24]=1>CN(C)C=O.C(OCC)(=O)C>[CH:3]1([N:7]2[CH2:8][CH2:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][C:20]4[S:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][N:24]=4)=[CH:14][C:11]=3[CH2:12][CH2:13]2)[CH2:6][CH2:5][CH2:4]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 150 mg, 3.66 mmol) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (530 mg, 2.43 mmol) in dimethylformamide (10 ml) at 5° C. After 0.5 hours a solution of 2-bromo-5-nitro-1,3-thiazole (1.0 g, 4.78 mmol) in dimethylformamide (5 ml) was added and the reaction mixture was allowed to warm to room temperature and stir for 2 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water, brine, dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.25:2.25:97.5) afforded the title compound (E210a); MS (ES+) m/e 346 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[CH3:19][N:20]([CH3:22])[NH2:21]>C1CCCCC1>[CH3:19][N:20]([CH3:22])[NH:21][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([C:15]([F:18])([F:17])[F:16])=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CN(C)N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: C1CCCCC1
Product: CN(C)Nc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To 20.0 g. (0.065 mole) of 2,4-dichloro-3,5-dinitrobenzotrifluoride and 300 ml. of cyclohexane in a 500 ml. round-bottom flask equipped with a stirrer and dropping funnel was added 7.86 g. (0.13 mole) of 1,1-dimethylhydrazine at ambient temperature. The addition was drop-wise over a period of about 20 minutes. Stirring was continued for 22 hours at room temperature. The resultant mixture was filtered and the insoluble solid then stirred with 300 ml. of water for one hour to dissolve the hydrazine hydrochloride. The insoluble product was isolated by filtration and washed with water. Recrystallization from 95% ethanol gave 18.3 g. (85%) of the desired product as a yellow solid, m.p. 130°-131° C.
Reaction SMILES: [CH2:1]([CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:6]=O)[CH2:2][CH2:3][CH3:4].[CH2:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.C1COCC1.CCCCCC>[Si:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=[CH2:21])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC(C=O)CCCCCO[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC(CCCC)CCCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
2-Butyl-7-(tert-butyldimethylsilyloxy)heptanaI (6.01 g, 20 mmol) in 15 ml of anhydrous THF was added dropwise to a freshly prepared solution of methylidene(triphenyl)phosphorane (22 mmol in 125 ml of anhydrous THF/hexane at 0° C. over a period of 15 min. The mixture was warmed to room temperature, stirred for 8 h, and poured into 300 ml of ice/water and extracted (3×75 ml) with ether. The combined organic extracts were washed with water and dried over anhydrous MgSO4. Solvents were removed by evaporation and pentane (250 ml) was added to the red oily residue. The mixture was chilled to 0° C. and the precipitated Ph3PO removed by filtration The precipitate was washed with ice-cold pentane and the filtrate concentrated in vacuo. The crude product was purified by PMPLC yielding 4.06 g (68%) of 8-(tert-butyldimethylsilyloxy)-3-butyloct-1-ene.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[N:36]=[CH:37][CH:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[N:36]1[N:28]2[C:27]([CH2:26][N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:40][CH:39]=3)=[O:24])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29]2)=[CH:38][CH:37]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 5 mmol of triethylamine and 3 mmol of 5,10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine. The mixture is stirred at room temperature for 5 hours and is then washed with water, NaHCO3, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid, m.p. 142°-146° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20]N(C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>>[CH2:18]([O:17][C:15]([C:14]1[C:12](=[O:13])[C:11]2[CH:10]=[C:9]3[CH:8]=[C:7]([F:24])[C:6]([F:25])=[CH:5][C:4]3=[N:3][C:2]=2[N:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Reactant: CC(C)(C)N
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc3cc(F)c(F)cc3cc2c1=O
Yield: 69.1 %

Procedure:
3-Ethoxycarbonyl-7,8-difluoro-4-oxo-1-tert-butyl-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions described in Example 10, but starting with 4 g of ethyl 2-(2-chloro-6,7-difluoro-3-quinolylcarbonyl)-3(dimethylamino)acrylate and 0.87 g of tert-butylamine. 2.7 g of 3-ethoxycarbonyl-7,8-difluoro-4-oxo-1-tert-butyl-1,4dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 206° C., which is used without further purification for the subsequent steps.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:28])[C:6]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C@@H:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH:18]=O)[CH2:10]2.[CH3:29][NH2:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:28])[C:6]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C@@H:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH2:18][NH:30][CH3:29])[CH2:10]2
Reactant: CN
Reactant: Cn1ncc(Cl)c1-c1ccc2c(c1)CN([C@H](C=O)Cc1cccc(F)c1)C2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC[C@H](Cc1cccc(F)c1)N1Cc2cc(-c3c(Cl)cnn3C)ccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2S)-2-[5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]-3-(3-fluorophenyl)propanal (40.0 mg, 0.100 mmol), methylamine (20.3 μL, 0.151 mmol) and sodium triacetoxyborohydride (42.6 mg, 0.201 mmol) in tetrahydrofuran (1 mL) was stirred at room temperature overnight. Direct purification on prep.—HPLC (pH=10) gave the desired product as white solid. LC-MS found: 413.1 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[C:26]([F:29])([F:28])[F:27])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:31]>O>[NH2:31][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[C:26]([F:27])([F:28])[F:29])=[O:9])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(c1ccc(F)cc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: [OH-]
Solvent: O
Product: Nc1ccc(C(=O)c2cnc3c(C(F)(F)F)cccc3c2-c2ccccc2)cc1
Temperature: 150 °C

Procedure:
(4-Fluorophenyl)[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone (0.631 g, 1.60 mmol) and ammonium hydroxide (9 mL) are heated in a steel pressure vessel at 150° C. overnight. The cooled reaction is poured into water, extracted with methylene chloride, and concentrated in vacuo. The resulting solid into DMSO (2 mL) and ammonium hydroxide (8 mL) is heated in the steel bomb at 150° C. overnight and worked up as above. The product is purified by chromatography eluting with 30:70 ethyl acetate:hexane to yield the title compound as a solid (0.344 g). MS (ESI) m/z 393; HRMS: calcd for C23H15F3N2O—H, 391.10582; found (ESI, [M−H]−), 391.1054.
Reaction SMILES: O[C@@H:2]1[CH2:7][N:6]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[CH2:44]([O:51][NH:52][C@H:2]1[CH2:7][N:6]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:3]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](O)CN1C(=O)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Temperature: 0 °C
Yield: 84.5 %

Procedure:
After a solution of 10.22 g (34.38 mmol) of (2S,5S)-tert-butyl 5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate in dehydrated acetonitrile (113 mL) was cooled from −30 to −40° C. under argon atmosphere, 4.4 mL (37.78 mmol) of 2,6-lutidine was added, and then 5.92 mL (36.09 mmol) of trifluoromethanesulfonic acid anhydride was added dropwise over 10 minutes, followed by further allowing to react at −30° C. for 15 minutes. To this reaction mixture was added 8.46 g (68.73 mmol) of benzyloxyamine (washed with acetonitrile (5 mL)), followed by raising the temperature to 0° C. within 30 minutes, and further 4.4 mL (37.78 mmol) of 2,6-lutidine was added, followed by allowing to react at 0 to 5° C. for 3.5 days. This reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate (200 mL) and washed sequentially with water (200 mL), 10% aqueous citric acid solution (200 mL×3 times), 6.5% aqueous sodium hydrogencarbonate solution (100 mL) and saturated brine (100 mL). Each aqueous layer was back-extracted with ethyl acetate (100 mL), the organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was applied to silica gel column chromatography (hexane/ethyl acetate=4/1) to afford 11.69 g of the title compound as a colorless oil (yield 85%). Enantiomeric excess: 99.0% ee (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, hexane/ethanol=9/1, flow rate 1 mL/min., retention time 4.5 min.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:10]([OH:16])[C:11]([O:13]CC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].OO.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:10]([OH:16])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](O)[C@@H](CCCc1ccccc1)NC(=O)OC(C)(C)C
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCc1ccccc1)[C@H](O)C(=O)O

Procedure:
A solution of Example 9C (0.316 g, 0.90 mmol), 30% hydrogen peroxide (0.40 mL, 3.5 mmol), and lithium hydroxide monohydrate (0.076 g, 1.8 mmol) in 3:1 tetrahydrofuran/water (8 mL) was stirred at 0° C. for 3 hours and concentrated. The concentrate was dissolved in water and the pH adjusted to 10 with 1M NaOH. The solution was washed twice with diethyl ether, adjusted to pH 2 with 1M HCl, and extracted twice with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 324 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl.[OH:24][C:25]1[C:34]([N:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:34]([N:35]([CH3:37])[CH3:36])[C:25]=4[OH:24])[CH2:30]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Reactant: CN(C)c1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: CN(C)c1ccc(-c2nc(C(=O)N3CCc4c(ccc(N(C)C)c4O)C3)c3ccccc3n2)cc1
Yield: 10 %

Procedure:
Reaction of 2-(4-(dimethylamino)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 35 (10% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 2.56 and 2.60 (2s, 6H), 2.73 and 2.89 (2t, 2H), 3.03 and 3.04 (2s, 6H), 3.47 and 4.03 (2t, 2H), 4.38 and 4.91 (2s, 2H), 6.76-7.02 (m, 4H), 7.56-8.01 (m, 5H), 8.31-8.39 (m, 2H); MS (ESI) m/z 468 ([M+H]+).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[N:28]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[N:28]2)(=[O:3])[CH3:2]
Reactant: Nc1cccc2ncccc12
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3ncccc23)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 60 mg (0.417 mmol) of 5-aminoquinoline was added. The resulting mixture was stirred at room temperature for four hours and the final product was collected by filtration and washed with diethylether to yield the title compound (80 mg, 74.8% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)([CH3:4])([CH3:3])[CH3:2].[C:24]1([NH:30][NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[C:24]1([NH:30][N:31]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:18]([OH:19])=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)c1cc(C(=O)c2ccccc2)cc(C(C)(C)C)c1O
Reactant: NNc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)c1cc(C(=NNc2ccccc2)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
One gram of 3,5-di-t-butyl-4-hydroxybenzophenone and 880 mg of phenylhydrazine were refluxed under heating in 30 ml of benzene in the presence of 20 mg of p-toluenesulfonic acid for 3.5 hours. The reaction mixture was poured into water and extracted with benzene. The extract was chromatographed on a silica gel column, and recrystallized from diethyl ether/n-hexane to give 3,5-di-t-butyl-4-hydroxybenzophenone phenylhydrazone as colorless needles.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=O)=[C:9]([O:16][CH3:17])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:18].[H-].[Na+].[CH3:21][N:22]1[CH:26]=[C:25]([C:27]2[C:32]3[N:33]=C(S(C)(=O)=O)[N:35]=[CH:36][C:31]=3[CH:30]=[CH:29][N:28]=2)[CH:24]=[N:23]1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:35]=[CH:36][C:31]4[CH:30]=[CH:29][N:28]=[C:27]([C:25]5[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=5)[C:32]=4[N:33]=3)=[C:9]([O:16][CH3:17])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:18]
Reactant: COc1cc(-c2cnc(C)n2C)ccc1NC=O
Reactant: Cn1cc(-c2nccc3cnc(S(C)(=O)=O)nc23)cn1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(-c2cnc(C)n2C)ccc1Nc1ncc2ccnc(-c3cnn(C)c3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 14 %

Procedure:
A solution of N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)formamide (Preparation 55, 37 mg, 0.151 mmol) in THF (1 mL) was treated with sodium hydride (10 mg, 0.250 mmol) at 0° C. After stirring for 20 minutes at room temperature, the mixture was cooled to 0° C. and 8-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 35, 50 mg, 0.173 mmol) was added. The reaction was allowed to reach room temperature and stirred for 18 hours. Aqueous NaOH (2M, 0.5 mL) and MeOH (0.5 mL) were added and the resulting mixture stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine, dried and evaporated. The residue was purified by silica gel column chromatography eluting with 0 to 10% MeOH in EtOAc to give the title compound (9 mg, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:15]N(C=O)C.IC.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: CN(C)C=O
Reactant: Cc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a stirred solution of 5-chloro-2-methyl-3-nitrobenzoic acid (1 equiv.) in DMF (3 ml per 1 mmol), iodomethane (4 equiv.) and sodium carbonate (4 equiv.) were added. The resulting reaction mixture was stirred at 60° C. for 8 h. On completion, the reaction mixture was filtered and the inorganic solid residue washed with ethyl acetate. The combined filtrate was concentrated under vacuum till dryness. The residue was re-dissolved in ethyl acetate and washed with 5% sodium bicarbonate solution followed by 5M HCl solution. Organic layer was finally washed with brine, dried over sodium sulfate and concentrated to afford pure methyl 5-chloro-2-methyl-3-nitrobenzoate (90-95%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH:8]=O)#[N:2].[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH:8]=[N:13][NH:14][C:15]([NH2:17])=[S:16])#[N:2]
Reactant: N#Cc1cccc(C=CC=O)c1
Reactant: NNC(N)=S
Product: N#Cc1cccc(C=CC=NNC(N)=S)c1
Yield: 46 %

Procedure:
The compound is prepared according to the method described in Example 1A from 3-cyanocinnamaldehyde (2.54 mmol) and from thiosemicarbazide (2.54 mmol). Yield 46%.
Reaction SMILES: C(S([O:8][N+:9]([O-])=[O:10])(=O)=O)(F)(F)F.[CH2:12]([O:14][C:15]([N:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[C@H:20]([N:28]([CH2:33][C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=2)[C:29]([O:31][CH3:32])=[O:30])[CH2:19][C@@H:18]1[CH3:48])=[O:16])[CH3:13].O>ClCCl>[CH2:12]([O:14][C:15]([N:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][C:25]=2[N+:9]([O-:10])=[O:8])[C@H:20]([N:28]([CH2:33][C:34]2[CH:35]=[C:36]([C:44]([F:47])([F:45])[F:46])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=2)[C:29]([O:31][CH3:32])=[O:30])[CH2:19][C@@H:18]1[CH3:48])=[O:16])[CH3:13]
Reactant: O=[N+]([O-])OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)N1c2ccc(Cl)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1c2c(cc(Cl)cc2[N+](=O)[O-])[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
To a pre-dried flask under nitrogen atmosphere was prepared a slurry of F3CSO3NO2 (2.6 mmol) in 9 mL of dichloromethane [ref. J. Org. Chem. 1973, 38 (25), 4243]. The solution was cooled to −78° C. and a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 32) (0.72 g, 1.3 mmol) in anhydrous dichloromethane (5 mL) was added. The reaction was stirred at −78° C. for 1.5 h, then warmed to 0° C. and stirred for 1 h and 40 min. Water (30 mL) was then added, and the mixture was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title product (0.75 g, 96%). MS m/z 598 (M++H); 1H NMR (CDCl3) δ 7.85 (bs, 1H), 7.8 (bs, 1H), 7.7 (bs, 1H), 7.65 (bs, 1H), 7.1 (bs, 1H), 3.80 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][NH2:21]>ClCCl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:21][O:20][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)=[O:13])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1ccc(O)cc1
Reactant: NOC1CCCCO1
Solvent: ClCCl
Product: O=C(CCCc1ccc(O)cc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
A mixture of 4-(4-Hydroxyphenyl)butanoic acid (0.90 g, 5 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.59 g, 5 mmol) and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (1.15 g, 6 mmol) in 50 mL dichloromethane was stirred at room temperature for 2 h (monitored by TLC). The mixture was extracted with water and dried over magnesium sulfate. The residue was purified by chromatography (MeOH:DCM=1:50) to give the title compound (0.84 g, 65%). NMR (400 MHz in DMSO, Bruker AVANCE-400): δ 1.50 (m, 3H, OTHP), 1.71 (m, 3H, OTHP), 1.73 (m, 2H, CH2), 1.96 (m, 2H, CH2), 2.44 (m, 2H, CH2), 3.48 (t, 1H, J=5.0 Hz, OTHP), 3.91 (t, 1H, J=10.0 Hz, OTHP), 4.80 (s, 1H, OTHP), 6.65 (d, 2H, J=5.0 Hz, Ar—H), 6.95 (d, 2H, J=10.0 Hz, Ar—H), 9.10 (s, 1H, NH), 10.87 (s, 1H, OH).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[O:22][CH2:21][C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[NH:13][C:12]4=[O:20])[C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Br[CH2:46][C:47]1[O:48][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:50][CH:51]=1.ClCC1C=NC(OC)=NC=1>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[O:22][CH2:21][C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]([CH2:46][C:47]5[O:48][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:50][CH:51]=5)[C:12]4=[O:20])[C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)Nc2ccccc21
Agent: COc1ncc(CCl)cn1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using 3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 5-(chloromethyl)-2-methoxypyrimidine, 3-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione was obtained (59%) as a colorless solid: mp 198-199° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 7.37-7.30 (m, 1H), 7.23-7.18 (m, 3H), 7.12-7.03 (m, 2H), 6.77 (s, 1H), 6.56 (s, 1H), 5.17-4.99 (m, 2H), 4.91-4.75 (m, 2H), 3.31 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ176.2, 156.8, 154.3, 152.9, 141.5, 136.1, 132.9, 131.4, 128.9, 123.6, 123.3, 121.5, 114.0 (2C), 109.8, 109.2, 104.2, 92.4, 79.3, 57.2, 36.4, 28.1; MS (ES+) m/z 456.4 (M+1).