Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:12]=[C:11]([NH:13][NH2:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH3:15][C:16]([CH3:23])([CH3:22])[C:17](=O)[CH2:18][C:19]#[N:20].Cl.[OH-].[Na+]>C(O)C>[NH2:20][C:19]1[N:13]([C:11]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:3][CH3:2])[CH:12]=2)[N:14]=[C:17]([C:16]([CH3:23])([CH3:22])[CH3:15])[CH:18]=1
Reactant: COc1cc(NN)ccc1C(=O)O
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(-n2nc(C(C)(C)C)cc2N)ccc1C(=O)O
Temperature: 25 °C
Yield: 71.7 %

Procedure:
A suspension of 2-methoxy-4-hydrazinylbenzoic acid hydrochloride (1.05 g, 90% purity, 4.34 mmol) and 4,4-dimethyl-3-oxopentanenitrile (664 mg, 5.31 mmol) in ethanol (20 mL) containing conc hydrochloric acid (12 M, 0.44 mL, 5.0 mmol) was heated at reflux for 28 hr and then cooled to RT. The reaction mixture was treated with aq NaOH (2.0 M, 8.6 mL, 17 mmol) and was maintained at RT for 20 hr and then concentrated to half its original volume in vacuo. Then residue was washed with DCM (2×15 mL) and the aq layer was acidified to pH 5 with conc hydrochloric acid (12 M, 1.0 mL) and re-extracted with DCM (5×30 mL). The combined organic extracts were washed with brine (10 mL) and then dried and evaporated in vacuo to afford 4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-2-methoxybenzoic acid as a brown solid (900 mg, 61%); Rt 1.47 min (Method 2); m/z 290 (M+H)+, (ES+).
Reaction SMILES: Br[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]=[C:11]([C:14]#[N:15])[C:10](=[O:16])[C:9]=2[CH:17]=1)([CH3:4])[CH3:3].C(O)(=O)C>O>[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]=[C:11]([C:14]#[N:15])[C:10](=[O:16])[C:9]=2[CH:17]=1)([CH3:4])=[CH2:3]
Reactant: CC(C)(Br)c1ccc2occ(C#N)c(=O)c2c1
Solvent: CC(=O)O
Solvent: O
Product: C=C(C)c1ccc2occ(C#N)c(=O)c2c1
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of 6-(1-bromo-1-methylethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile (2.0 g), acetic acid (20 ml) and water (5 ml) was heated at 100° C. for one hour, which was then concentrated. The concentrate was subjected to a silica-gel (100 g) column-chromatography, eluting with chloroform-acetone-formic acid (20:1:0.1). The initial eluate was recrystallized from ethanol to give colorless crystals (600 mg) of 6-isopropenyl-4-oxo-4H-1-benzopyran-3-carbonitrile, m.p. 142°-144° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[OH:35][C:32]([C:29]1[CH:28]=[CH:27][C:26]([C:20]2[S:19][C:18]([NH:17][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[CH2:9][OH:10])[N:7]=3)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=2)=[CH:31][CH:30]=1)([CH3:34])[CH3:33]
Reactant: OCC(c1cccc(Br)n1)N1CCOCC1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)cc1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(CO)N4CCOCC4)n3)s2)cc1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (194 mg, 0.68 mmol) and 2-amino-5-[4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (190 mg, 0.69 mmol) as the starting materials.
Reaction SMILES: O[N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13]>CCO.[Pd]>[C:12]([NH:2][CH:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)C(C)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.6 %

Procedure:
To a mixture of ethyl 2-(hydroxyimino)-3-oxobutanoate (compound 8, 9.32 g, 58.5 mmol), Pd/C (400 mg, palladium on carbon, 10 wt %, support activated carbon, wet, Degussa type E101 NE/W) in EtOH was added acetic anhydride (compound 9, 11.0 mL, 117.0 mmol) at room temperature. The reaction mixture was stirred at room temperature under H2 for 15 hrs. The palladium was filtered off (filter aid, Celite 521 AW), then the filtrate was concentrated in vacuo. The crude product was purified by flash column chromatography (Biotage SP1™ FLASH Purification System was used for normal phase column chromatography with tetrahydrofuran and hexane) to provide the title compound (9.48 g, 86%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[CH2:27]([CH2:29][NH2:30])[OH:28]>N1C=CC=CC=1>[CH2:27]([CH2:29][NH2:30])[OH:28].[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:30][CH2:29][CH2:27][OH:28])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: NCCO
Solvent: c1ccncc1
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCCO)c(Cl)c32)c(F)cc1F
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 76.5 %

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (300 mg) and ethanolamine (300 mg) were added to pyridine (1,300 mg), and the mixture was stirred at 50° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (4 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (290 mg) as a colorless powder.
Reaction SMILES: C1(C(C2C=CC=CC=2)[O:8][C:9]([C:11]2([C:14]3[C:23]([F:24])=[C:22]([F:25])[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:26])[C:15]=3[F:27])[CH2:13][CH2:12]2)=[O:10])C=CC=CC=1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:9]([C:11]1([C:14]2[C:15]([F:27])=[C:16]([F:26])[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:22]([F:25])[C:23]=2[F:24])[CH2:13][CH2:12]1)([OH:10])=[O:8]
Reactant: COC(=O)c1c(F)c(F)c(C2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c(F)c1F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(F)c(F)c(C2(C(=O)O)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
In 60 ml of anisole was dissolved 22.5 g of methyl 4-(1-diphenylmethoxycarbonylcyclopropyl)-2,3,5,6tetrafluorobenzoate. To the resulting solution was added 80 ml of trifluoroacetic acid. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. n-Hexane was added to the residue obtained. The resulting crystals were collected by filtration to obtain 12.7 g (yield: 88.8%) of methyl 4-(1-carboxycyclopropyl)-2,3,5,6tetrafluorobenzoate.
Reaction SMILES: O=[C:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[NH2:22]>C(O)C>[F:20][C:18]1[CH:19]=[C:14]2[C:15](=[CH:16][C:17]=1[F:21])[N:22]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([OH:10])=[N:13]2
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1nc2cc(F)c(F)cc2nc1O

Procedure:
A suspension of diethyl ketomalonate (1.11 mL, 7.3 mmol) and 1,2-diamino-4,5-difluorobenzene (1.0 g, 6.9 mmol) in anhydrous ethanol (20 mL) was heated at reflux under nitrogen for 3 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/methylene chloride (1:2), to provide ethyl 6,7-difluoro-3-hydroxyquinoxaline-2-carboxylate as a light yellow solid:
Reaction SMILES: [Br:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18](SC)=[N:17][C:16]3=[O:22])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Br:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[N:17][C:16]3=[O:22])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3Br)c2)S1
Reactant: CN1CCNCC1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4Br)c3)S2)CC1

Procedure:
5-[1-(2-bromo-4-chlorobenzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(2-bromo-4-chloro-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-methyl-piperazine following General Procedure C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[F:1][C:2]1[C:3]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[O:31][CH3:30])=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:20])([F:21])[F:19])=[N:13]3)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F)C(F)(F)F
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 53.5 %

Procedure:
Trifluoromethanesulfonic acid 2-fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenyl ester (30.0 mg, 0.068 mmol) was coupled to 2-methoxyphenyl-boronic acid (13.5 mg, 0.089 mmol) as described in Example 35 part c), affording 5-(6-fluoro-2′-methoxybiphenyl-3-yl)-2-trifluoromethyl[1,8]-naphthyridine (14.5 mg, 53%). δH (360 MHz, CDCl3) 3.86 (3H, s), 7.03-7.09 (2H, m), 7.32-7.48 (4H, m), 7.55 (1H, dd, J 2.5 and 6.7), 7.60 (1H, d, J 4.6), 7.83 (1H, d, J 8.4), 8.66 (1H, d, J 8.4), 9.27 (1H, d, J 4.6). m/z (ES+) 399 [MH]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:53])([CH3:52])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25](/[CH:28]=[C:29]3\[C:30](=[O:50])[NH:31][C:32]4[C:37]\3=[CH:36][C:35]([S:38]([CH2:41][C:42]3[C:47]([Cl:48])=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:49])(=[O:40])=[O:39])=[CH:34][CH:33]=4)[NH:24][C:23]=2[CH3:51])=[O:21])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.Cl>C(Cl)Cl.C(OCC)(=O)C>[NH2:7][C:8]([CH3:53])([CH3:52])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25](/[CH:28]=[C:29]3\[C:30](=[O:50])[NH:31][C:32]4[C:37]\3=[CH:36][C:35]([S:38]([CH2:41][C:42]3[C:43]([Cl:49])=[CH:44][CH:45]=[CH:46][C:47]=3[Cl:48])(=[O:40])=[O:39])=[CH:34][CH:33]=4)[NH:24][C:23]=2[CH3:51])=[O:21])[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCN(C(=O)C(C)(C)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCN(C(=O)C(C)(C)N)CC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a mixture of (2-{4-[2-({5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-ethyl]-piperazin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (from the above reaction) in DCM (3 mL) was added 6N HCl in ethyl acetate. The mixture was stirred at 40° C. for 3 hours. The reaction was concentrated, basified to pH 7-8 with 2N NaOH, extracted with DCM and concentrated. The residue was purified on a silica gel column to give 40 mg the titled compound as a red solid.
Reaction SMILES: [C:1]([C:4]1[CH:38]=[CH:37][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:20][C:21]([C:23]3[N:27](CC4C=CC(OC)=CC=4)[N:26]=[N:25][N:24]=3)=[O:22])[C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:6]([CH2:39][CH2:40][C:41]([F:44])([F:43])[F:42])[C:5]=1[OH:45])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:38]=[CH:37][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:20][C:21]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[O:22])[C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:6]([CH2:39][CH2:40][C:41]([F:42])([F:44])[F:43])[C:5]=1[OH:45])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2C(=O)Nc2cc(OCCCOc3ccc(C(C)=O)c(O)c3CCC(F)(F)F)ccc2C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)c1ccc(OCCCOc2ccc(C)c(NC(=O)c3nnn[nH]3)c2)c(CCC(F)(F)F)c1O

Procedure:
A solution of 2.84 g (4.5 mmol) of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-6-methyl-phenyl}}-1-(4-methoxybenzyl)-tetrazole-5-carboxamide in 90 ml of trifluoroacetic acid and 9 ml of anisole is refluxed for 60 minutes. The reaction mixture is concentrated under reduced pressure, about 150 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off. The N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-6-methyl-phenyl}}-1H-tetrazole-5-carboxamide thus obtained, of melting point 236°-238° C. (decomposition), is dissolved in 50 ml of tetrahydrofuran, and one equivalent of sodium, dissolved in 5 ml of methanol, is added. After addition of ether, crystallizations starts. The sodium salt of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-6-methyl-phenyl}}-1H-tetrazole-5-carboxamide of melting point 115°-125° C. (decomposition) is thus obtained.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[S:7][S:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][S:17][S:18]Cl>ClCCCl>[C:1]([NH:5][S:7][S:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][S:17][S:18][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: ClSSSCCCCCCSSSCl
Solvent: ClCCCl
Product: CC(C)(C)NSSSCCCCCCSSSNC(C)(C)C

Procedure:
70.0 ml (736 mmol) of tert-butylamine are used as initial charge in 1,2-dichloroethane in an inertized three-necked flask with dropping funnel, reflux condenser with hose coupling at its upper end, a tap with hose coupling and a Teflon stirrer bar, in a countercurrent of argon. 10.2 g (29.3 mmol) of 1,6-bis(chlorotrisulphanyl)hexane in 50 ml of 1,2-dichloroethane are then added dropwise, with stirring. The reaction mixture is stirred at room temperature for 4 hours. The resultant salt is filtered off, and the organic phase is washed three times with water and dried over sodium sulphate. After removal of the solvent on a rotary evaporator and drying in the vacuum generated by a rotary-vane pump, 1,6-bis(tert-butylaminotrisulphanyl)hexane precipitates in the form of a yellow oil. The crude yield is 11.9 g (97%). Elemental analysis was carried out on the crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH:20][C:21]1[CH:22]=[CH:23][C:24]2[O:29][CH2:28][CH:27]([C:30](O)=[O:31])[O:26][C:25]=2[CH:33]=1>>[OH:20][C:21]1[CH:22]=[CH:23][C:24]2[O:29][CH2:28][CH:27]([C:30]([N:9]3[CH2:10][CH2:11][N:6]([CH2:5][C:4]4[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([O:16][CH3:17])[C:3]=4[O:2][CH3:1])[CH2:7][CH2:8]3)=[O:31])[O:26][C:25]=2[CH:33]=1
Reactant: COc1ccc(CN2CCNCC2)c(OC)c1OC
Reactant: O=C(O)C1COc2ccc(O)cc2O1
Product: COc1ccc(CN2CCN(C(=O)C3COc4ccc(O)cc4O3)CC2)c(OC)c1OC
Yield: 65 %

Procedure:
That compound is obtained in a yield of 65% starting from 1-(2,3,4-trimethoxy benzyl)piperazine and 7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]/[C:13]1[CH:21]=[C:20]2[C:16]([C:17](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[N:18][N:19]2COCC[Si](C)(C)C)=[CH:15][CH:14]=1>CO.CCO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]/[C:13]1[CH:21]=[C:20]2[C:16]([C:17](/[CH:30]=[CH:31]/[C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)=[N:18][NH:19]2)=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(/C=C3/C(=O)Nc4ccc(Br)cc43)cc21
Solvent: CCO
Solvent: CO
Product: O=C1Nc2ccc(Br)cc2/C1=C\c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Temperature: 80 °C

Procedure:
A solution of (E)-5-bromo-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one (75 mg, 0.131 mmol) in 12 mL of a 2:1:1 mixture of MeOH/EtOH/4M HCl was heated to 80° C. for 24 hours. LC-MS indicated a mixture of the title compound plus a partially deprotected methoxymethyl indazole compound (see Example A63). The solvents were removed and the mixture was purified by prep-HPLC to give 7.3 mg (13%) of the title compound as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.87 (s, 1H), 10.82 (s, 1H), 8.76 (d, J=5.78 Hz, 2H), 8.45 (d, J=8.00 Hz, 1H), 8.23-8.13 (m, 3H), 8.04 (s, 1H), 7.96 (s, 1H), 7.73 (d, J=16.6 Hz, 1H), 7.64 (s, 1H), 7.60 (d, J=7.81 Hz, 1H), 7.43 (d, J=7.31 Hz, 1H), 6.87 (d, J=8.11 Hz, 1H); MS ESI 443.3 [M+H]+, calcd for [C23H15BrN4O+H]+ 443.05.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][NH:3]1.Cl.[CH3:15]O>>[OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:15])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: O=C(O)c1ccc2c(=O)[nH][nH]c2c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2c(O)n[nH]c2c1
Yield: 100 %

Procedure:
3-Oxo-2,3-dihydro-1H-indazole-6-carboxylic acid (1.5 g, 8.4 mmol) was suspended in methanol (17 mL). Concentrated hydrochloric acid (3.1 mL, 101 mmol) was added and the reaction was heated to reflux for 24 hours. The reaction was concentrated to give the title compound (1.6 g, 100%). +ESI (M+H) 193.1; 1H NMR (400 MHz, DMSO-d6, δ): 11.98 (br. s., 1H), 7.89 (s, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.50 (dd, J=8.5, 1.3 Hz, 1H), 3.85 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].O[C:10]1[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[C:12]=2[N:13]=[N:14][N:15]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:10]1[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[C:12]=2[N:13]=[N:14][N:15]=1
Reactant: NCc1ccccn1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: NC(=O)c1cccc2c(NCc3ccccn3)nnnc12

Procedure:
Compound 5 was prepared following general synthetic scheme 7 wherein pyridin-2-ylmethanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [281 (M+1)], 1H NMR (400 MHz, DMSO-d): δ 9.40 (s, 2H), 8.56-8.51 (m, 3H), 8.04 (s, 1H), 8.00 (t, 1H), 7.76-7.72 (m, 1H), 7.40 (d, 1H), 7.29-7.26 (m, 1H), 4.99 (d, 2H).
Reaction SMILES: O1CCCC1.B.CO.[Br:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12]([C:20](O)=[O:21])([CH2:13]3)[CH2:11]1)[CH2:17]2>O1CCCC1>[Br:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12]([CH2:20][OH:21])([CH2:13]3)[CH2:11]1)[CH2:17]2
Reactant: O=C(O)C12CC3CC(CC(Br)(C3)C1)C2
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: OCC12CC3CC(CC(Br)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 ml round-bottomed flask, 3-bromoadamantane-1-carboxylic acid (7.89 g) was dissolved in tetrahydrofuran (30 mL). Borane tetrahydrofuran complex (1M in hexane, 60 mL) was added slowly. The mixture was stirred at room temperature overnight. Methanol (20 mL) was added to the solution slowly. After removal of the solvents, methanol (5 mL) was added to the oily residue. Removal of the solvent provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][N:13]1[C:18]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27]O)[CH2:21][CH2:20]2)=[CH:17][C:16](=[O:29])[N:15]([CH3:30])[C:14]1=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:12][N:13]1[C:18]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][O:11][C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[Cl:1])[CH2:21][CH2:20]2)=[CH:17][C:16](=[O:29])[N:15]([CH3:30])[C:14]1=[O:31]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: Cn1c(N2CCN(CCCO)CC2)cc(=O)n(C)c1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(N2CCN(CCCOc3ccc([N+](=O)[O-])cc3Cl)CC2)cc(=O)n(C)c1=O
Yield: 47.7 %

Procedure:
In 70 ml of anhydrous tetrahydrofuran were suspended 2.4 g of 2-chloro-4-nitrophenol, 3.38 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound a) and 3.62 g of triphenylphosphine, and 2.4 g of diethyl azodicarboxylate was added to the resultant suspension. Afterward, the resultant mixture was treated in the same manner as in Reference Example 4 to obtain 2.5 g of light yellow crystals. The crystals were recrystallized from ethanol to obtain 2.07 g of crystalline 1,3-dimethyl-6-[4-(3-[2-chloro-4-nitrophenyloxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound u).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[CH2:12][N:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][C:17]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:19]=2)[C:14]1=[O:27])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[CH2:12][N:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][C:17]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:19]=2)[C:14]1=[O:27]
Reactant: COC(=O)c1ccc2ccn(Cc3cccc(NC(=O)OC(C)(C)C)c3)c(=O)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2ccn(Cc3cccc(N)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-{3-[(tert-butoxycarbonyl)amino]benzyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.23 g, 0.57 mmol) in methylene chloride (5 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (7 mL, 28 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated to dryness to afford methyl 2-(3-aminobenzyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate.HCl (0.20 g, quant.). LC-MS: (FA) ES+ 309.
Reaction SMILES: [Br:1][C:2]1[C:21](Br)=[CH:20][CH:19]=[C:4]2[C:5]([N:7]([C:10]3([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6].C(O)(=O)C.C([O-])(=O)C.[Na+].[H][H]>[Pd]>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:4]2[C:5]([N:7]([C:10]3([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: [H][H]
Reactant: NC(=O)C1(N2C(=O)c3ccc(Br)c(Br)c3C2=O)CCCCC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)C1(N2C(=O)c3cccc(Br)c3C2=O)CCCCC1

Procedure:
A solution of 1-(3,4-dibromophthalimido)cyclohexanecarboxamide in acetic acid containing one equivalent of sodium acetate is reduced with hydrogen in the presence of palladium on carbon to give the product 1-(3-bromophthalimido) cyclohexanecarboxamide, m.p. 199°-200° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][CH2:37][CH:38]([NH2:40])[CH3:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:40][CH:38]([CH3:39])[CH2:37][O:36][CH3:35])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[O:21])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCOCC2)c1=O
Reactant: COCC(C)N
Product: COCC(C)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[2-(4-morpholinyl)-2-oxoethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (±)-1-(methyloxy)-2-propanamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as an off-white rigid foam: 1H NMR (CDCl3) δ 10.01 (1H, d, J=8 Hz), 8.57 (1H, s), 7.15 (2H, dd, J=8.6, 5.5 Hz), 7.03 (3H, m), 4.98 (1H, d, J=17 Hz), 4.91 (1H, d, J=17 Hz), 4.34 (1H, m), 4.12 (2H, s), 3.73 (2H, m), 3.68 (2H, m), 3.56 (4H, m), 3.45 (2H, d, J=5 Hz), 3.39 (3H, s), 1.29 (3H, d, J=7 Hz); HRMS calcd for C26H29FN4O6+H+: 513.2149. Found: 513.2145.