Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[N:8]=[C:7]([OH:16])[C:6]=1[C:17]([O:19]CC)=O)=[N+]=[N-].[H][H].C[OH:25]>CN(C)C=O.[Pd]>[Cl:15][C:11]1[CH:12]=[CH:13][C:14]2[C:5]3[C:4](=[O:25])[NH:1][C:17](=[O:19])[C:6]=3[C:7]([OH:16])=[N:8][C:9]=2[CH:10]=1
Reactant: CO
Reactant: CCOC(=O)c1c(O)nc2cc(Cl)ccc2c1CN=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c1c(O)nc1cc(Cl)ccc21

Procedure:
1.0 g (0.0032 mol) of ethyl 4-azidomethyl-7-chloro-2-hydroxy-quinoline-3-carboxylate was dissolved in a mixture of 80 ml of methanol and 20 ml of dimethylformamide and treated with 46 mg of 10% Pd/C. A hydrogen stream was conducted in slowly during 1 hr. The suspension was suction filtered and the filter cake was suspended in dimethylformamide. The suspension was filtered, concentrated, the residue was suspended in methanol and suction filtered. The substance (0.31 g) was suspended in dimethylformamide and an oxygen stream was conducted in slowly during 4 hrs. The mixture was concentrated and the product was recrystallized from dimethylformamide/methanol. Yield: 0.13 g (18%) of 7-chloro-4-hydroxy-2,3-dihydro-1H-pyrrolo[3,4-c]quinoline-1,3-dione as yellow crystals; m.p. >350° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]1([C:17]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[CH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O.O>[C:11]1([C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([N:8]3[CH2:9][CH2:10][C:5]4[CH:4]=[CH:3][O:2][C:6]=4[CH2:7]3)=[O:24])=[CH:26][CH:27]=2)=[CH2:18])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: C=C(c1ccccc1)c1ccc(C(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(c1ccccc1)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.527 g (3.302 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.74 g (3.30 mmol) of 4-(1-phenylethenyl)benzoic acid and 1.84 ml (13.2 mmol) of triethylamine in 15 ml of N,N-dimethylformamide, 0.60 ml (3.96 mmol) of diethyl cyanophosphonate was added dropwise, followed by overnight stirring at room temperature. This mixture was poured into water and extracted with diethyl ether 3 times. The combined organic layer was dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to yield 6-[4-(1-phenylethenyl)benzoyl]-4,5,6,7-tetrahydrofuro[2,3-c]pyridine.
Reaction SMILES: [NH:1]=[C:2]1[C:10]2[C:5](=[C:6]([Cl:14])[C:7]([Cl:13])=[C:8]([Cl:12])[C:9]=2[Cl:11])[C:4](=[NH:15])[NH:3]1.S([O-])([O-])(=O)=[O:17].O[NH3+].O[NH3+]>CN(C)C=O>[N:15](=[C:4]1[C:5]2[C:10](=[C:9]([Cl:11])[C:8]([Cl:12])=[C:7]([Cl:13])[C:6]=2[Cl:14])[C:2](=[NH:1])[NH:3]1)[OH:17]
Reactant: O=S(=O)([O-])[O-]
Reactant: N=C1NC(=N)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: [NH3+]O
Solvent: CN(C)C=O
Product: N=C1NC(=NO)c2c(Cl)c(Cl)c(Cl)c(Cl)c21

Procedure:
28.3 Parts, 1,3-diimino-4,5,6,7-tetrachloro-isoindoline and 8.5 parts hydroxyl-ammonium sulphate are stirred in 150 parts dimethylformamide for 1 hour at 80°. After cooling the product can be filtered and washed with dimethylformamide and water to obtain pure 1-oximino-3-imino-4,5,6,7-tetrachloroisoindoline in the form of colourless crystalls which up to 300° only darken but do not melt.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1([F:25])[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1.IC>C1COCC1>[F:13][C:14]1([F:25])[CH2:15][CH2:16][C:17]([CH3:1])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: [Li]CCCC
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CI
Product: CCOC(=O)C1(C)CCC(F)(F)CC1
Temperature: -78 °C
Yield: 107.6 %

Procedure:
A solution of n-butyl lithium (1.250 mL, 2.000 mmol) was added to a cold (−78° C.) solution of diisopropylamine (0.283 mL, 2.000 mmol) in THF under nitrogen and the mixture was stirred at −78° C. 1 h. A solution of ethyl 4,4-difluorocyclohexanecarboxylate (192 mg, 1 mmol) in THF (1 mL) was added at −78° C. The reaction mixture was stirred at −78° C. for 1 h and then gradually warm to −20° C. over 2 h. Then neat iodomethane (0.138 mL, 2.200 mmol) was added at −78° C. and the mixture was allowed to warm to rt and stirred at rt overnight. The reaction was quenched with satd. NH4Cl and extracted with EtOAc and the organic phase was washed with water, brine, dried (Na2SO4). Evaporation of the solvent afforded ethyl 4,4-difluoro-1-methylcyclohexanecarboxylate (222 mg) as a light brown oil which was dissolved in EtOH and was added a solution of KOH (112 mg, 2.000 mmol) in water (2.00 mL). The reaction mixture was heated to reflux overnight, then cooled and acidified and extracted with EtOAc to afford Cap-5 as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.26-2.17 (m, 2H), 2.07-1.95 (m, 2H), 1.94-1.83 (m, 2H), 1.63-1.54 (m, 2H), 1.31 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1.[C:13]1([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CS(C)=O>[OH:23][CH:21]([CH2:20][O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:22][NH:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: NCCCc1ccc(C(N)=O)s1
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(CCCNCC(O)COc2ccccc2)s1

Procedure:
921 mg of 5(3-aminopropyl)-2-thiophenecarboxamide and 0.68 ml of 2,3-epoxypropyl phenyl ether were heated to 90° in 15 ml of dimethylsulfoxide for 14 hours. The reaction mixture was poured into water and extracted with methylene chloride. The dried methylene chloride solutions were evaporated in vacuo and the residue was chromatographed on silica gel, whereby there were obtained 800 mg of 5-[3-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]propyl]-2-thiophenecarboxamide, m.p. 129°-130°, ε276 =12130.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:25][C:26]1[C:34]([OH:35])=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:25][C:26]1[C:34]([O:35][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Reactant: Oc1ccc2[nH]ccc2c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3F)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 95 °C
Reaction time: 3 h
Yield: 42.2 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (232 mg, 0.662 mmol), (prepared as described for the starting material in Examples 176 or 244), and 4-fluoro-5-hydroxyindole (120 mg, 0.794 mmol), (prepared as described for the starting material in Example 242), in DMF (3 ml) containing potassium carbonate (137 mg, I mmol) was stirred at 95° C. for 3 hours. After cooling, the residue was poured onto water (12 ml) and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by reversed phase C18 column chromatography eluting with methanol/ammonium carbonate (2 g of ammonium carbonate/liter saturated with CO2) (60/40 followed by 70/30). The fractions containing the expected product were combined and evaporated. The residue was dissolved in ethyl acetate, dried (MgSO4) and the volatiles were removed under vacuum. The residue was triturated with ether, filtered and dried under vacuum to give 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (130 mg, 42%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:23][F:24])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)[OH:4].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(OC(=O)C)C.O>[F:24][CH2:23][C@@H:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[N:15][C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@H](N)CF)cc2)cn1
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NS(C)(=O)=O)cc2)cn1
Yield: 49.7 %

Procedure:
To a slurry of N-((5-(4-((1R,2S)-2-amino-3-fluoro-1-hydroxypropyl)phenyl)pyridin-2-yl)methyl)methanesulfonamide (100 mg, 0.28 mmol) in ethylacetate/aqueous NaHCO3 (1:1) (2 mL) is slowly added methanesulfonyl chloride (50 mg, 0.42 mmol) over a period of 20 minutes. Reaction is diluted with water (2 mL) and extracted with ethylacetate (3×5 mL). Combined organic solution is dried over Na2SO4 and concentrated. Crude product is purified using HPLC to give the title compound (60 mg): 1H NMR (400 MHz, DMSO-d6) 2.55 (s, 3H), 2.98 (s, 3H), 3.67-3.80 (m, 1H), 4.18-4.26 (m, 0.5H), 4.31-4.40 (m, 2.5H), 4.48-4.55 (m, 0.5H), 4.60-4.67 (m, 0.5H), 4.80-4.87 (m, 1H), 5.83-5.93 (m, 1H), 7.27 (d, 1H), 7.54 (d, 2H), 7.54 (d, 1H), 7.62 (d, 1H), 7.70-7.79 (m, 3H), 8.20-8.26 (m, 1H), 8.90 (d, 1H). m/z (Cl) M+H 432.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][CH:8]([C:11]2[N:12]([CH3:19])[N:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[O:7][CH2:6][C:5]1=[O:20])=[N+:2]=[N-:3].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].O>C1COCC1>[N:1]([CH:4]1[CH2:10][CH2:9][CH:8]([C:11]2[N:12]([CH3:19])[N:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[O:7][CH2:6][CH:5]1[OH:20])=[N+:2]=[N-:3]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC(N=[N+]=[N-])C(=O)CO1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc([N+](=O)[O-])c1C1CCC(N=[N+]=[N-])C(O)CO1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 57.6 %

Procedure:
To a solution of 4-azido-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-3-one (Intermediate 55) (1 g, 3.57 mmol) in dry THF (25 mL) under nitrogen cooled to −78° C. was added L-selectride (1 M in THF, 4.3 mL, 4.3 mmol) and the mixture was stirred at −78° C. for 45 min. The mixture was allowed to warm to room temperature and water (10 mL) was added. The solvents were removed under reduced pressure and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with water (40 mL) and brine (40 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave racemic 4-azido-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-3-ol (relative stereochemistry as shown above) as a yellow oil (580 mg, 58%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 5.63 (dd, J=10.6, 3.5 Hz, 1H), 4.21-4.14 (m, 3H), 4.01 (s, 3H), 3.69-3.58 (m, 1H), 2.45-2.33 (m, 1H), 2.27-2.08 (m, 2H), 2.01-1.84 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][OH:8])[N:3]=1.CCO/[CH:12]=[C:13](/[CH:15]=O)\[CH3:14]>C(O)(=O)C>[CH3:15][C:13]1[CH:12]=[N:1][C:2]2[N:6]([N:5]=[C:4]([CH2:7][OH:8])[N:3]=2)[CH:14]=1
Reactant: CCO/C=C(\C)C=O
Reactant: Nc1nc(CO)n[nH]1
Solvent: CC(=O)O
Product: Cc1cnc2nc(CO)nn2c1
Temperature: 80 °C

Procedure:
To a slurry of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol (16.6 g, 87.6 mmol) from step 6 of example A(1) in acetic acid was added 3-ethoxymethacrolein (10 g, 87.6 mmol). The mixture was heated to 80° C. for 4 hours. Upon cooling of the reaction, the product cyrstallized out of solution. The collected product was a white solid (14 g, 92%). 1H NMR (300 MHz, DMSO-d6): δ 2.38 (s, 3 H), 4.63 (s, 2 H), 5.52 (s, 1 H), 8.75 (s, 1 H), 9.21 (s, 1 H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(CCCCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 5-phenylpentanoic acid (257 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (413 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (471 mg, 69%).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:6][CH:5]=1.Cl>CC(O)=O.O>[O:16]=[C:14]1[NH:13][C:12](=[O:17])[CH:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:18])=[O:2])=[CH:5][CH:6]=2)[S:15]1
Reactant: COC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(C(=O)O)cc2)S1
Temperature: 120 °C
Yield: 41.5 %

Procedure:
A solution of methyl ester 351 (250 mg, 0.94 mmol) in AcOH (10 ml) was treated with conc. HCl (5 ml) and the reaction mixture was heated at 120° C. for 2 hrs, cooled and evaporated to produce a solid residue which was re-suspended in water and collected by filtration to afford the title compound (98 mg, 41% yield). LRMS: 251.3 (calcd.), 250.1 [M−H]− (found).
Reaction SMILES: F[C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[CH2:12]([C:14]1[NH:15][CH:16]=[CH:17][N:18]=1)[CH3:13].[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>[Pd]>[CH2:12]([C:14]1[N:18]2[C:2]3[CH:3]=[N:4][CH:5]=[CH:6][C:7]=3[NH:8][C:19](=[O:20])[C:17]2=[CH:16][N:15]=1)[CH3:13]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCc1ncc[nH]1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Agent: [Pd]
Product: CCc1ncc2c(=O)[nH]c3ccncc3n12

Procedure:
Prepare by reaction of 3-fluoro-4-nitropyridine-N-oxide with 2-ethylimidazole followed by hydrogenation with Pd-C and cyclization with carbonyldiimidazole to provide the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[C:21](Cl)=[O:22]>CCOCC>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]2[O:9][C:20](=[O:24])[C:21](=[O:22])[O:12][C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(O)c(O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCc1ccc2oc(=O)c(=O)oc2c1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A mixture of 4.16 g (25 mM) of 4-n-butylcatechol, 5.06 g (50 mM) of triethylamine and ml of dry ether was cooled in an ice water bath so as to maintain the temperature at 5° C. or below. The mixture was added dropwise over 2 hours under stirring with a solution of 3.50 g (28 mM) of oxalyl chloride in 10 ml of dry ether. After completing the dropwise addition, the temperature of the reaction mixture was gradually raised to the room temperature and then aging was conducted for an hour. The resultant mixture was heated under reflux for 3 hours in order to complete the aging. The separated crystals of triethyl ammonium chloride was filtered. After thoroughly washing the crystals with ether, the ether solution was collected and dried with anhydrous sodium sulfate. After distilling off ether, the reaction product was recrystallized from a solvent mixture of carbontetrachloride and petroleum benzine to obtain 5.26 g (23 mM) of 6-n-butyl-1,4-benzodioxine-2,3-dione 2/5 hydrate as colorless crystals having a melting point of 88°-93° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:34]/[C:35](/[CH3:41])=[CH:36]\[C:37]([O:39][CH3:40])=[O:38].[ClH:42]>C(O)(C)C.O1CCOCC1>[ClH:42].[CH3:16][C:14]1[NH:34][C:35]([CH3:41])=[C:36]([C:37]([O:39][CH3:40])=[O:38])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:13]=1[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:17]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCN1CCN(c2ccc(F)cc2)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(c3ccc(F)cc3)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 76.4 %

Procedure:
A mixture of m-nitrobenzaldehyde, 2-[4-(4-fluorophenyl)-1-piperazinyl]ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1, and the product obtained was further treated with a dioxane solution of hydrogen chloride to give 2-[4-(4-fluorophenyl)-1-piperazinyl]ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride as a light yellow powder, m.p. 108°-110° C. Yield 76.4%. NMR(DMSO-d6) δ: 2.30(3H,s, ##STR27## 2.38(3H,s, ##STR28## 3.60(3H,s,COOCH3), 4.48(2H,m,--COOCH2CH2 --), 5.03(1H,s,C(4) --H).
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[CH2:9][CH2:8]1)(C)(C)C.[OH-].[Na+]>Cl.CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH:10]2[CH2:11][CH2:12][CH:7]([OH:6])[CH2:8][CH2:9]2)=[C:15]([NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[CH:16]=1
Reactant: Cc1ccnc2c(C(=O)Nc3cc(Cl)ccc3OC3CCC(O[Si](C)(C)C(C)(C)C)CC3)cnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccnc2c(C(=O)Nc3cc(Cl)ccc3OC3CCC(O)CC3)cnn12
Temperature: 80 °C
Yield: 31.8 %

Procedure:
Hydrochloric acid (concentrated, 5 drops) was added to a solution of 7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-amide (ca. 0.22 mmol) in methanol (3 mL) and the resulting mixture was heated at 80° C. for 30 minutes. The resulting mixture was cooled, basified by addition of an aqueous solution of sodium hydroxide (4 M, few drops) and evaporated under reduced pressure. The crude residue was purified by flash chromatography to give 28 mg of 7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide (off-white solid). MS=401 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24](Cl)[C:23]4[C:18](=[C:19]([Br:29])[CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH3:32]>O1CCCC1>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24]([N:31]([CH3:32])[CH3:30])[C:23]4[C:18](=[C:19]([Br:29])[CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CNC
Reactant: COc1cc(Br)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(Cl)c2c1
Solvent: C1CCOC1
Product: COc1cc(Br)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(N(C)C)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 8-bromo-4-chloro-6-methoxy-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (Reference Example 28a) (0.1512 g, 0.317 mmol) in 100 mL 2.0 M dimethyl amine in tetrahydrofuran was heated at 100° C. in a Parr bomb. The initial pressure was 75–80 psi and then remained at approximately 60 psi. After 18 hours, the reaction was cooled to room temperature, concentrated and dried to afford the crude product as a brown solid. Purification on silica gel using a gradient of 100:0 to 95:5 methylene chloride:methanol afforded the clean product (0.142 g; 92%). 1H NMR (300 MHz, DMSO, d6) δ 10.20 (s, 1 H, C(O)NH), 7.90 (d, 1 H, Jm=2.7 Hz, ArH5), 7.69 (d, 2 H, Jo=9.0 Hz, ArH2′ & H6′), 7.60 (s, 1 H, ArH3), 7.41 (d, 1 H, Jm=2.7 Hz, ArH7), 7.01 (d, 2 H, Jo=9.0 Hz, ArH3′ & H5′), 3.96 (s, 3 H, OCH3), 3.75 (t, 4 H, J=4.8 Hz, OCH2CH2N), 3.10 (t, 4 H, J=4.8 Hz, OCH2CH2N), 3.08 (s, 6 H, N(CH3)2); Mass Spec.: calc. for [C21H19BrClN3O3+H]+ Theor. m/z=485, 487; Obs.=485, 487
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.Cl.[NH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=1)=[O:36]>C1COCC1>[O:36]=[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:45])[F:46])[CH:38]=1)[CH2:34][NH:33][C:21]([CH:18]1[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[CH2:20][CH2:19]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2cccc(C(F)(F)F)c2)CC1
Reaction time: 0.08 h
Yield: 60.1 %

Procedure:
Add N-methylmorpholine (13.0 mL, 118 mmol) to a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (11.2 g, 48.8 mmol) in THF (400 mL) at −10° C. and stir for 5 min. Add isobutyl chloroformate (5.1 mL, 38.8 mmol) and continue stirring at −10° C. for 2 h. Add 2-amino-1-(3-(trifluoromethyl)phenyl)ethanone hydrochloride (9.35 g, 39.0 mmol) and continue stirring for 1 h. Add methylene chloride (500 mL) to the mixture and filter. Wash the filtrate with sat. aqueous sodium bicarbonate (400 mL) and concentrate in vacuo. Purify the residue by silica gel chromatography (330 g RediSep column, eluting with a gradient of 0% to 100% ethyl acetate:hexane, 6.0 L) to provide tert-butyl 4-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethylcarbamoyl)piperidine-1-carboxylate (9.72 g, 60%).
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][C:15]#[CH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CC)CC)C>C(#N)C.[Cu]I>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][C:15]#[C:16][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Brc1ccccn1
Reactant: C#CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc2c(c1)c1c(n2CC#Cc2ccccn2)CCN(C)C1
Temperature: 80 °C
Yield: 57.1 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(prop-2-ynyl)-1H-pyrido[4,3-b]indole [(p-tolylhydrazine hydrochloride (600 mg, 3.7 mmol), propargyl bromide (80 wt % solution in toluene, 0.34 mL, 3.7 mmol), triethyl amine (1.5 mL, 11.3 mmol) and N-methyl-4-piperidone hydrochloride (316 mg, 2.1 mmol) were taken in ethanol (15 mL) to obtain 80 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(prop-2-ynyl)-1H-pyrido[4,3-b]indole after purification on silica gel (230-400 mesh) chromatography eluting with MeOH-DCM gradient) (150 mg, 0.6 mmol)], 2-bromopyridine (0.06 mL, 0.6 mmol), dichlorobis(triphenylphosphine) palladium (8 mg, 0.012 mmol), CuI (1 mg, 0.006 mmol), and triethylamine (0.01 mL 0.071 mmol) in acetonitrile (5 mL) was heated at 80° C. for 1.5 h to obtain 108 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)prop-2-ynyl)-1H-pyrido[4,3-b]indole after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL). 1H NMR (DMSO-d6, TFA salt) δ (ppm): 8.45-8.40 (d, 1H), 7.80-7.70 (t, 1H), 7.45-7.40 (m, 1H), 7.30-7.25 (t, 1H), 7.25 (s, 2H), 7.10-7.00 (d, 1H), 5.60 (s, 2H), 4.60-4.55 (d, 1H), 4.25-4.20 (d, 2H), 3.85-3.75 (d, 1H), 3.65-3.40 (m, 2H), 3.00 (s, 3H), 2.30 (s, 3H).