Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>[Pd]>[CH2:7]([CH:2]1[CH2:3][CH2:4][CH2:5][C:1]1=[O:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC=O
Reactant: O=C1CCCC1
Agent: [Pd]
Product: CCCCCCC1CCCC1=O
Yield: 81.9 %

Procedure:
A mixture of 1008 g (12 moles) of cyclopentanone, 800 g (8 moles) of n-hexanal and 80 g of a pulverulent catalyst containing 0.5% by weight of palladium on alumina was hydrogenated in an autoclave at 140° C. and under a hydrogen pressure of 70 bar until the pressure remained constant (about 15 hours), the procedure used being similar to that described in Example 1. The catalyst was separated off and the mixture discharged from the reactor was then distilled directly. 294 g (3.5 moles) of cyclopentanone were recovered as fraction 1. 1103 g of pure 2-hexylcyclopentanone (bp. 84° C./0.35 mbar) were obtained as the main fraction; this corresponded to a selectivity of 82%, based on n-hexanal. When, as in Example 1, the molar ratio of cyclopentanone to hexanal was increased to 3:1, the selectivity increased to above 90%, as in the case of 2-heptylcyclopentanone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:13]=[C:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a mixture of (S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid (35 g, 154 mol) in DMF (155 mL) was added potassium carbonate (32 g, 1.5 eq) at room temperature. The mixture was stirred at room temperature for 1 hr before being cooled with a water bath. Methyl iodide (19.2 mL, 2 eq) was added dropwised. The mixture was stirred at room temperature for 6 hr. The reaction mixture was filtered through a pad of celite, diluted with ethyl acetate (300 mL), washed with water (200 mL). The aqueous layer was extracted with ethyl acetate (300 and 200 mL). The combined organic layers were washed with 10% Na2S2O3 solution (100 mL), water (3×200 mL) and brine, dried (Na2SO4), filtered and evaporated to dryness. The residue was passed through a silica gel (2 wt. volumes) pad with 0-15% ethyl acetate in hexanes to afford the title compound (37.06 g, quantitative yield) as a colorless oil. 1H NMR (500 MHz, CDCl3): 5.03 and 4.99 (2 br s, 2H), 4.51 (dd, J=9.5, 2.7 Hz) and 4.40 (dd, J=9.5, 3.3 Hz, 1H), 4.09 and 4.06 (2 br s, 2H), 3.73 (s, 3H), 3.01-2.92 (m, 1H), 2.65-2.60 (m, 1H), 1.47 and 1.42 (2 s, 9H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:35]=[CH:34][C:13]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]4[CH:32]=[C:31]5[C:27]([CH2:28][C:29](=[O:33])[NH:30]5)=[CH:26][CH:25]=4)[CH:18]=3)=[O:15])=[CH:12][C:11]=2[C:36]([F:39])([F:38])[F:37])[CH2:5][CH2:4]1)[CH3:2].[NH:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[CH:45]=O.N1CCCCC1>CCO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:35]=[CH:34][C:13]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]4[CH:32]=[C:31]5[C:27]([C:28](=[CH:45][C:41]6[NH:40][CH:44]=[CH:43][CH:42]=6)[C:29](=[O:33])[NH:30]5)=[CH:26][CH:25]=4)[CH:18]=3)=[O:15])=[CH:12][C:11]=2[C:36]([F:38])([F:39])[F:37])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)NC(=O)C5)c3)cc2C(F)(F)F)CC1
Reactant: O=Cc1ccc[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)NC(=O)C5=Cc4ccc[nH]4)c3)cc2C(F)(F)F)CC1
Temperature: 80 °C
Yield: 59.5 %

Procedure:
To a suspension of 4-(4-ethyl-piperazin-1-ylmethyl)-N-[3-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-phenyl]-3-trifluoromethyl-benzamide (200 mg, 0.372 mmol) in EtOH (10 mL) are added pyrrole-2-carboxaldehyde (42 mg, 0.446 mmol) and piperidine (74 μL, 0.74 mmol). The mixture is heated at 80° C. for 2 hours. All the solvent is evaporated to dryness. The crude is recrystallized in EtOH to give 136 mg of the desired compound: 1H NMR (400 MHz, DMSO) δ 10.74 (s, 1 H), 10.34 (s, 1 H), 8.37 (s, 1 H), 8.18-8.24 (m, 2 H), 7.92 (d, 1 H); 7.67 (s, 1 H), 7.46-7.50 (t, 2 H), 7.24-7.28 (m, 3 H), 6.84 (d, 1 H), 6.76 (s, 1 H), 6.72 (m, 1 H), 6.67 (d, 1 H), 6.29-6.31 (m, 1 H), 3.69 (s, 2 H), 3.30 (s, 2 H), 2.30-2.48 (m, 8H), 1.00 (t, 3H); LC-MS: 615.3 (MH+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[S:24]1[CH:28]=[CH:27][C:26]([C:2]2[N:3]=[C:4]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]3[N:6]([CH:8]=[N:9][N:10]=3)[CH:7]=2)=[CH:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cn3cnnc23)CC1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccsc3)cn3cnnc23)CC1
Yield: 99.5 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(6-bromo-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate (1.0 g, 2.6 mmol), thiophen-3-ylboronic acid (0.50 g, 3.9 mmol), Pd(PPh3)4 (0.30 g, 0.26 mmol), Cs2CO3 (1.27 g, 3.9 mmol), 1,4-dioxane (25 mL) and water (25 mL). The resulting mixture was refluxed under N2 overnight. Reaction progress was monitored by TLC (EtOAc/petroleum ether=1:2). Work-up: the reaction mixture was extracted with EtOAc (50 mL). The organic solution was washed with brine (40 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 10% EtOAc in petroleum ether, to afford 1.0 g (99%) of the product as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].S(O[CH2:31][CH2:32][O:33][CH:34]([CH3:36])[CH3:35])(=O)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:31][CH2:32][O:33][CH:34]([CH3:36])[CH3:35])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: CC(C)OCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.54 g, 1.71 mmol), and sodium hydride (0.87 g, 3.48 mmol) in dimethylformamide (10 mL). After 30 minutes, add 2-(isopropoxy)ethyl mesylate (0.51 g, 5.5 mmol). Heat to 80° C. After 2 hours, cool the reaction mixture to ambient temperature and partition between dichloromethane and a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the organic layer with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: [N:1]([CH:4]([CH:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH:4]([CH:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(N=[N+]=[N-])C(Oc1ccc(F)cc1[N+](=O)[O-])c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(N)C(Oc1ccc(F)cc1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a solution of ethyl (2SR,3RS)-2-azido-3-(4-fluoro-2-nitrophenoxy)-3-phenylpropanoate (b) (2.60 g) and triphenylphosphine (2.01 g) in THF (100 ml) was added water (2 ml) and the mixture was refluxed for 1 h then stirred at RT overnight. The reaction was concentrated in vacuo and the resulting residue was purified by flash chromatography (5:2 hexane:ethyl acetate) to afford the title compound (1.55 g) as a yellow oil. 1H NMR (300 MHz, d6-DMSO) δ 1.01 (t, 3H, J=7 Hz), 1.85 (s, 2H), 3.76 (d, 1H, J=5 Hz), 3.99 (q, 2H, J=7 Hz), 5.75 (d, 1H, J=5 Hz), 6.89-7.44 (m, 7H), 7.85 (dd, 1H, J=3 Hz, J=9 Hz). MS APCI, m/z=349 (M+1). LC/MS: 1.82 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH:15](O)[CH2:16][CH3:17])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.P(Br)(Br)[Br:20]>C(Cl)(Cl)Cl.O>[Br:20][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:14][N:13]=1)[CH2:16][CH3:17]
Reactant: BrP(Br)Br
Reactant: CCC(O)c1ccc(-c2cccc(OC)c2)cn1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC(Br)c1ccc(-c2cccc(OC)c2)cn1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
To a solution of 1-(5-(3-methoxyphenyl)pyridin-2-yl)propan-1-ol (0.45 g, 1.8 mmol) in chloroform (5 mL) was added PBr3 (1.5 g, 5.55 mmol) at 0-5° C., the reaction was maintained at the same temperature for 1 h, and then the reaction was slowly warmed to rt and maintained at this temperature for 1 h. The contents were diluted with water (75 mL) and chloroform (100 mL) and the layers were separated. The organic layer was washed with bicarbonate solution (2×30 mL), dried over sodium sulphate and distilled to get the crude product. The non-polar impurity was removed by pentane washings (2×7 mL) to provide 2-(1-bromopropyl)-5-(3-methoxyphenyl)pyridine (0.45 g, crude). LC-MS m/z calcd for [M+H]+ 306.04. found 306.0.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:13][CH:14]=3)=[O:19])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc2ccncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc2ccncc2c1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-aminoisoquinoline (D96) (88 mg, 0.61 mmol) in DCM (4 ml) was added 4-biphenylcarboxylic acid (145 mg, 0.73 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (140 mg, 0.73 mmol) and the reaction stirred at ambient temperature overnight. The reaction mixture was filtered to give the title compound as a white solid. The filtrate was diluted with DCM, washed with 2M sodium hydroxide solution, dried over MgSO4 and concentrated in vacuo to give further crude product which was purified by silica SPE chromatography. Elution with an EtOAc/60-80° C. petroleum ether gradient gave a further title compound which was combined with the sample obtained from the filtration. This was dissolved in ethanol and treated with ethereal HCl and the resultant precipitate was collected to give the HCl salt of the title compound as a white solid. 1H NMR (250 MHz, DMSO) δ (ppm): 9.80 (s, 1H), 9.09 (d, 1H), 8.58 (d, 1H), 8.40 (dd, 1H), 8.33 (d, 1H), 8.28 (d, 1H), 8.16 (d, 2H), 7.90 (d, 2H), 7.79 (d, 2H), 7.54 (t, 2H), 7.45 (t, 1H)
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:23]=[C:24]([C@@H:28]2[CH2:30][O:29]2)[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>CC(O)C>[CH2:1]([N:8]([CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:30][C@@H:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=1)[OH:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc([C@@H]2CO2)c1
Reactant: c1ccc(CNCCOCc2ccccc2)cc1
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc([C@@H](O)CN(CCOCc2ccccc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 133.8 %

Procedure:
N-Benzyl-2-(benzyloxy)ethane amine (13.6532 g) which can be prepared according to the method described in Reference example 56, etc. was added with (R)-2-(3-nitrophenyl)oxirane (20.21 g) and 2-propanol (205 mL), followed by stirring for 36 hours at reflux. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. Toluene (100 mL) was added to the residue and the mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (“COLUMN-D”; n-hexane:ethyl acetate=85:15→80:20) to obtain the title compound (30.761 g).
Reaction SMILES: [C@@H:1]([NH:5][C:6]1[C:7](=[O:20])[NH:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].N1C=CC=CC=1.[O:27](S(C(F)(F)F)(=O)=O)[S:28]([C:31]([F:34])([F:33])[F:32])(=O)=[O:29]>ClCCl>[C@@H:1]([NH:5][C:6]1[C:7]([O:20][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:27])=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2[nH]c1=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
To a solution of (S)-methyl 3-(sec-butylamino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (300 mg, 1.10 mmol) in dichloromethane (40 mL) was added pyridine (344 mg, 4.36 mmol). Tf2O (615 mg, 2.18 mmol) was added drop-wise with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature and then washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford (S)-methyl 3-(sec-butylamino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (390 mg, crude).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][CH:14]=[C:4]2[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=1.Cl>CCO>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:2]2[CH:7]=[C:6]([NH:8][CH:9]3[CH2:11][CH2:10]3)[N:5]3[N:12]=[CH:13][CH:14]=[C:4]3[N:3]=2)[CH:21]=[CH:20][C:19]=1[OH:22]
Reactant: Clc1cc(NC2CC2)n2nccc2n1
Reactant: Nc1ccc(O)c(Cl)c1
Agent: Cl
Solvent: CCO
Product: Oc1ccc(Nc2cc(NC3CC3)n3nccc3n2)cc1Cl
Yield: 76.9 %

Procedure:
To 5-chloro-N-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (500 mg, 2.396 mmol) in EtOH (10 mL) was added 4-amino-2-chlorophenol (516 mg, 3.59 mmol) followed by concentrated HCl (0.218 mL, 2.64 mmol). The reaction mixture was stirred at reflux temperature for 4 days. Removed 5 mL of EtOH on rotavap followed by addition of 5 mL of diethyl ether. The resulting solid was filtered off and rinsed with diethyl ether. Dried under nitrogen to provide 582 mg (77%) of 2-chloro-4-(7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)phenol as the HCl salt. LCMS (ES): >95% pure, m/z 316 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 73.8 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (36.2 mg, 0.0881 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with piperidine (0.035 mL, 0.35 mmol), acetic acid (0.101 mL, 1.76 mmol) and sodium triacetoxyborohydride (93 mg, 0.44 mmol), followed by purification by preparative thin-layer chromatography (hexane/ethyl acetate=1/2) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (31.2 mg, yield 74%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])=[N:5][N:6]2[CH3:11].C[O-].[Na+].CO.C(O)(=O)C[C:23](CC(O)=O)(C(O)=O)[OH:24]>CS(C)=O>[CH3:23][O:24][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])=[N:5][N:6]2[CH3:11]
Reactant: Cn1nc(S(N)(=O)=O)c2c(F)cccc21
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1cccc2c1c(S(N)(=O)=O)nn2C
Temperature: 130 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
A solution containing 5 g (21.8 mmol) of 4-fluoro-1-methyl-1H-indazole-3-sulfonamide and 12.6 g of sodium methoxide (a 28% methanol solution) (65 mmol) in DMSO (50 ml), was stirred at 130° C. for one hour. After confirming the disappearance of the starting material by thin layer chromatography (TLC), the mixture was poured into ice water and acidified with citric acid. Formed crystals were collected by filtration and washed with water and IPE to obtain 3.2 g (yield: 60.9%) of the desired product. Melting point: 268°-270° C.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[CH3:17][CH:18](O)[CH3:19]>>[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([O:14][CH:18]([CH3:19])[CH3:17])=[O:13]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: CC(C)O
Agent: CS(=O)(=O)O
Product: CC(C)OC(=O)c1cc(N)ccc1Cl
Reaction time: 6 h
Yield: 75 %

Procedure:
Methanesulfonic acid (99%, 318 g, 3.3 mole) was added slowly to a stirred mixture of 5-amino-2-chlorobenzoic acid (85%, 215 g, 1.1 mole) in 2-propanol (about 1100 ml). The mixture was heated under reflux with stirring for 6 hours, then the excess 2-propanol was evaporated under reduced pressure. Water (about 1000 ml) was added to the residue and the mixture was neutralized with solid sodium bicarbonate and extracted with methylene chloride (about 1200 ml). The extract was washed twice with water, dried over magnesium sulfate and evaporated to give a purple oil, which crystallized on seeding. The product was reprecipitated from dilute hydrochloric acid solution by slowly basifying with concentrated ammonium hydroxide and seeding. The resulting crystals after drying melted at 50.5°-52° C. (170 g, 75% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@@H:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=3[OH:26])[CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH4+].[Cl-].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[OH:26][C:20]1[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=1[C@@H:16]1[CH2:15][CH2:14][C@H:13]([NH:12][S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]3[NH:31][N:30]=[N:29][N:2]=3)[CH:4]=2)(=[O:11])=[O:10])[CH2:18][CH2:17]1
Reactant: N#Cc1cccc(S(=O)(=O)N[C@H]2CC[C@@H](c3ccc(O)cc3O)CC2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(N[C@H]1CC[C@@H](c2ccc(O)cc2O)CC1)c1cccc(-c2nnn[nH]2)c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
A solution of Example 9 (20 mg, 54 μmol) in DMF (2 ml) was treated with NH4Cl (17 mg, 323 μmol) and NaN3 (21 mg, 323 μmol). The mixture was heated under reflux for 6 hr, then stirred for 18 hr at 20° C., before being partitioned between EtOAc (30 ml) and H2O (5 ml). The aqueous phase was extracted with EtOAc (3×15 ml) and the combined organic extracts were washed with brine (30 ml) and dried (MgSO4). Filtration, solvent evaporation under reduced pressure, and FCC (EtOH-EtOAc, 1:3) afforded the title compound (16 mg, 72%) as a pale yellow solid. δH ((CD3)2CO) 1.30–1.88 (m, 8H), 2.60–2.71 (m, 1H), 3.62–3.69 (m, 1H), 4.23–4.30 (m, 1H), 6.20 (dd, 1H), 6.44 (d, 1H), 6.50 (d, 1H), 6.87 (d, 1H), 7.55 (t, 1H), 7.63–7.68 (m, 1H), 7.72–7.76 (m, 1H), 7.80 (d, 1H), 8.30 (d, 1H), 8.73 (s, 1H); m/z (ES−) 414 [M−H]−.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:12]([NH:13][C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16](O)=O)=[CH:11][CH:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+].[OH-].O=P(Cl)(Cl)[Cl:27]>>[C:1]1([CH2:7][N:8]2[C:12]3=[N:13][C:14]4[C:15]([C:16]([Cl:27])=[C:11]3[CH:10]=[N:9]2)=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccccc1Nc1ccnn1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Clc1c2ccccc2nc2c1cnn2Cc1ccccc1

Procedure:
A mixture of N-(1-phenylmethylpyrazol-5-yl) anthranilic acid (6 g) and POCl3 (60 ml) is heated on a steam bath overnight. The reaction mixture is poured into ice waterl, neutralized with NH4OH, and the precipitate which forms is collected by filtration,washed with water and dried to afford 5 g of 1-phenylmethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline, as a light brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: NCc1ccccc1
Reactant: O=C(O)Cc1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1Br)NCc1ccccc1
Reaction time: 2 h

Procedure:
To a stirring solution of 2-bromophenylacetic acid in dichloromethane (0.2 M) was added benzylamine (1.2 eq), triethylamine (1.5 eq), and EDAC (1.5 eq). After 2 hrs, the solution was washed with water, 10% HCl, 10% sodium carbonate, and water, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a colorless solid. EI-MS m/z 304/306 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[CH2:6][C@H:7](OC)[B:8]([OH:10])[O:9][C:4]=2[C:3]=1[C:15]([OH:17])=[O:16].[CH3:18][N:19]1[CH:23]=[N:22][N:21]=[C:20]1[SH:24]>>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[CH2:6][C@H:7]([S:24][C:20]3[N:19]([CH3:18])[CH:23]=[N:22][N:21]=3)[B:8]([OH:10])[O:9][C:4]=2[C:3]=1[C:15]([OH:17])=[O:16]
Reactant: Cn1cnnc1S
Reactant: CO[C@H]1Cc2ccc(F)c(C(=O)O)c2OB1O
Product: Cn1cnnc1S[C@H]1Cc2ccc(F)c(C(=O)O)c2OB1O

Procedure:
Compound 24 was prepared from Compound 19G (example 19) following methods described in steps 5 and 6 of Example 1 utilizing 4-methyl-3-mercapto-1,2,4-triazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][Br:12])[C:5]([OH:7])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc(CBr)c(Br)c1
Yield: 43.9 %

Procedure:
3-Bromo-4-methylbenzoic acid (10 g), N-bromosuccinimide (8.7 g) and 2,2′-azobisisobutyronitrile (0.4 g) were suspended in carbon tetrachloride (50 ml) and then heated to reflux for 2 hours. The mixture was returned to room temperature and added a 15% aqueous solution of citric acid (20 ml), and stirred for some time. Resulting crystals were filtered and washed with the 15% aqueous solution of citric acid (20 ml), and then dried, to obtain 3-bromo-4-(bromomethyl)benzoic acid (6 g).