Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C)C=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: BrCCCCCCCBr
Reactant: COC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCCCCCCBr)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydride (3.04 g of a 50% oil dispersion, 127 mmol) is suspended in dimethylformamide (300 ml) and the suspension is cooled to 0° C. t-Butyl methyl malonate (20.08 g, 115 mmol) is added dropwise slowly and the reaction mixture is warmed to room temperature. 1,7-Dibromoheptane (29.75 g, 115 mmol) is added dropwise and the mixture is stirred for 3 hours. The mixture is partitioned between diethyl ether (500 ml) and water (1000 ml). The organic layer is washed with water (3×500 ml), brine (1×500 ml), dried (MgSO4) and the solvent is evaporated. The product is purified by silica gel chromatography (10% ethyl acetate/hexane) to give t-butyl methyl 7-bromoheptylmalonate as an oil.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11](=O)[CH3:12].O.[NH2:15][NH2:16]>C(OCC)(=O)C>[CH3:12][C:11]1[C:3]2[C:2](=[CH:7][CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[CH:4]=2)[NH:16][N:15]=1
Reactant: NN
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
A solution of 1-(2-hydroxy-5-nitrophenyl)ethanone (0.54 g, 3 mmol) in anhydrous hydrazine (2 ml) was radiated with microwaves while being stirred at 150° C. for 5 min. Water (0.5 ml) was added at 0° C. to terminate the reaction. The reaction solution was diluted with ethyl acetate (10 ml) and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated using vacuum evaporation. Recrystallization of the residue in dichloromethane produced the title compound (Yield 80%).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(CC)C(C)C)(C)C.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([C@@H:33]1[CH2:37][S:36][CH2:35][N:34]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:32])[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([O:18][C:19]([NH:21][C@H:22]([C:23]([O:25][CH2:2][C:3]#[N:4])=[O:24])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([C@@H:33]1[CH2:37][S:36][CH2:35][N:34]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:32])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C)C(=O)O
Reactant: N#CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
Bromoacetonitrile (57 μl, 0.845 mmol) and N,N-diisopropylethylamine (147 μl, 0.845 mmol) were added to a solution of (S)-2-((tert-butoxycarbonyl)amino)-6-((R)-3-(tert-butoxycarbonyl)thiazolidine-4-carboxamido)hexanoic acid (Compound tk82) (130 mg, 0.282 mmol) in acetonitrile (5 ml), and the reaction solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure using an evaporator, and the residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (R)-tert-butyl 4-(((S)-5-((tert-butoxycarbonyl)amino)-6-(cyanomethoxy)-6-oxohexyl)carbamoyl)thiazolidine-3-carboxylate (Compound tk83) (140 mg, 99%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([CH3:38])[CH2:9][CH2:10][N:11]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:14]=1.O>ClCCl>[CH3:36][CH:35]([CH3:37])[CH2:34][CH2:33][N:11]([CH2:12][C:13]1[CH:14]=[C:15]([NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:16]([NH2:19])=[CH:17][CH:18]=1)[CH2:10][CH2:9][CH:8]([CH3:7])[CH3:38]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Product: CC(C)CCN(CCC(C)C)Cc1ccc(N)c(NCCCN2CCCCC2)c1
Temperature: 0 °C

Procedure:
A lithium aluminium hydride solution (36 ml; 1N in THF) is added dropwise to a solution cooled down to 0° C. of N,N-bis(3-methylbutyl)-4-nitro-3-[(3-piperidin-1-ylpropyl)amino]benzamide (1.6 g). The mixture is returned to a temperature of 20° C. then heated under reflux for 6 hours and hydrolyzed with water cooled down to 0° C. followed by a 1N soda solution. After the addition of dichloromethane, the mixture is filtered on celite. After decantation of the filtrate and extractions, the combined organic phases are washed with 1N soda then with salt water, dried over Na2SO4 and concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (1.23 g, 85% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4][CH2:3]1.[F:19][C:20]([Si](C)(C)C)([F:22])[F:21]>[F-].[Cs+]>[OH:1][C:2]1([C:20]([F:22])([F:21])[F:19])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: O=C1CCCN(C(=O)OCc2ccccc2)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Product: O=C(OCc1ccccc1)N1CCCC(O)(C(F)(F)F)CC1
Yield: 57.7 %

Procedure:
To a solution of benzyl 4-oxoazepane-1-carboxylate (2.0 g, 8.08 mmol) in trifluoromethyltrimethylsilane (1.42 mL, 9.70 mmol) was added caesium fluoride (70.4 mg, 0.40 mmol). The reaction mixture was stirred at room temperature until complete consumption of trifluoromethyltrimethylsilane was observed by 19F NMR and quenched with a 1 M HCl solution (50 mL). The mixture was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (50 mL), separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave benzyl 4-hydroxy-4-(trifluoromethyl)azepane-1-carboxylate as a yellow oil (1.48 g). To a solution of this oil (1.3 g, 4.1 mmol) in ethanol (20 mL) was added methylcyclohexadiene (4.6 mL) and 10% palladium on carbon (0.13 g). The reaction mixture was heated at reflux for 30 min before being cooled down to room temperature, filtered through Celite®, washed with MeOH and concentrated under reduced pressure. The residue was dissolved in DMSO (10 mL) and 5-chloro-1-methyl-4-nitro-1H-pyrazole (637 mg, 3.94 mmol) and potassium fluoride (916 mg, 15.76 mmol) were added. The reaction mixture was heated at 70° C. for 16 hr, quenched with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-4-(trifluoromethyl)azepan-4-ol as a yellow solid (1.06 g, 40% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 3.78 (s, 3H), 3.71 (ddd, J=14.7, 10.5, 2.0 Hz, 1H), 3.31 (dt, J=11.8, 4.4 Hz, 1H), 3.14 (td, J=11.3, 4.6 Hz, 1H), 3.06 (ddd, J=14.7, 5.7, 2.9 Hz, 1H), 2.31-2.13 (m, 1H), 2.14-1.94 (m, 5H), 1.92-1.83 (m, 1H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:18]=[CH:17][NH:16][N:15]=3)[N:11]3[CH:19]=[CH:20][N:21]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.[CH:22]1([CH:25]=[CH:26][C:27]#[N:28])[CH2:24][CH2:23]1.C(#N)C.C1CCN2C(=NCCC2)CC1>>[CH:22]1([CH:25]([N:16]2[CH:17]=[CH:18][C:14]([C:12]3[N:11]4[CH:19]=[CH:20][N:21]=[C:10]4[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=4)[N:13]=3)=[N:15]2)[CH2:26][C:27]#[N:28])[CH2:24][CH2:23]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cc[nH]n3)n2)cn1
Reactant: N#CC=CC1CC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cn1cc(-c2cc3nccn3c(-c3ccn(C(CC#N)C4CC4)n3)n2)cn1
Temperature: 45 °C
Yield: 17.5 %

Procedure:
7-(1-Methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-3-yl)imidazo[1,2-c]pyrimidine hydrochloride (Example 129, Step C, 50.2 mg, 0.148 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 69.1 mg, 0.742 mmol) were suspended in acetonitrile (742 μL, 0.148 mmol). DBU (88.8 μL, 0.594 mmol) was added to the reaction mixture and heated at 45° C. for 15 hours. The reaction mixture was purified by reverse phase HPLC using a 0-100% acetonitrile/water gradient. The resultant solid was diluted in Et2O, sonicated, filtered and washed with Et2O to afford the title compound as a light yellow solid (9.3 mg, 17% yield). MS (apci) m/z=359.2 (M+H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[C:18]([Cl:19])=[CH:17][C:16]([S:20](Cl)(=[O:22])=[O:21])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>C(Cl)Cl>[Cl:9][C:10]1[C:18]([Cl:19])=[CH:17][C:16]([S:20]([N:4]2[CH2:5][C@H:6]([CH3:8])[CH2:7][C@H:2]([CH3:1])[CH2:3]2)(=[O:22])=[O:21])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc(Cl)c1Cl
Reactant: C[C@@H]1CNC[C@H](C)C1
Solvent: ClCCl
Product: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2cc(Cl)c(Cl)c(C(=O)O)c2)C1
Reaction time: 1.5 h

Procedure:
To cis-3,5-dimethylpiperidine (374 mg.; 3.3 m moles) in 3 ml. of methylene chloride is added 192 mg. (0.66 m moles) of 2,3-dichloro-5-chlorosulfonylbenzoic acid and the mixture heated to refluxfor 1.5 hrs. The solvent is removed under reduced pressure, and the residueis partitioned between 25 ml. of 1N sodium hydroxide solution and diethyl ether. The aqueous layer is separated, acidified with 6N hydrochloric acidand the resulting precipitated product filtered and dried, 230 mg., m.p. 235°-238° C. Recrystallization from acetonitrile gave the purified product, m.p. 244°-245° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:25]([O-])([OH:27])=[O:26]>ClCCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[C:21]([O:23][CH3:24])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(c1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O2
Solvent: ClCCCl
Product: COc1cc2c(cc1[N+](=O)[O-])OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5.91 g (16.9 mmole) of {(2R)-6-methoxy-2,3-dihydro-1,4-benzodioxin-2-ylmethyl 4-methylbenzenesulfonate in 200 mL of 1,2-dichloro-ethane in an ice/water bath was added dropwise a solution of 2.50 mL (59.1 mmole) of fuming nitric acid (d 1.49) in 75 mL of 1,2-dichloroethane and the mixture was stirred for 2 hours at 0° C. After the reaction was complete, it was quenched with ice and diluted with 500 mL of methylene chloride. After the ice had melted, the organic layer was separated and washed with equal volumes of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to give 6.19 g of the (R)-enantiomer of the title compound as a light yellow solid. 1H-NMR (CDCl3): doublet 7.8 δ (2 H); multiplet 7.4 δ (3 H); singlet 6.5 δ (1 H); multiplet 4.10-4.5 δ (5 H); singlet 3.85 δ (3 H); singlet 2.5 δ (3 H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:13])[CH2:8][CH2:7][CH2:6][N:5](C(OC)=O)[CH2:4]1>O>[NH2:1][CH2:2][C:3]1([OH:13])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: COC(=O)N1CCCC(O)(CN)C1
Solvent: O
Product: NCC1(O)CCCNC1

Procedure:
5.1 g (27.1 mmol) of methyl 3-aminomethyl-3-hydroxypiperidine-1-carboxylate are heated overnight under reflux with 15.8 g of Ba(OH)2. 8H2O in 150 ml of water. The product is filtered off from BaCO3 with suction and concentrated. The residue is boiled five times using 70 ml of dioxane each time, and the dioxane solutions are concentrated and distilled.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:9][C:8]=1[NH:18]C(=O)OC(C)(C)C)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.O1CCOCC1>CO>[NH2:18][C:8]1[CH:9]=[CH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:12][C:7]=1[NH:6][C:1](=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)C(=O)Nc1cc(-c2cccs2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 0 %

Procedure:
To a stirred solution of tert-butyl (2-isobutyramido-4-(thiophen-2-yl)phenyl)carbamate (0.2 g, 0.52 mmol) in methanol (4 mL) was added 4M HCl in Dioxane (2 mL, 0.53 mmol, 1 equiv.) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. After completion the reaction was concentrated under reduced pressure then basified with a saturated aqueous solution of NaHCO3. The obtained solid was filtered and dried. The crude material was purified by column chromatography (silica gel, MeOH/CH2Cl2) to afford N-(2-amino-5-(thiophen-2-yl)phenyl)isobutyramide (0.05 mg, 36% yield). ESI+ MS: m/z 261 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 9.10 (s, 1H0, 7.5 (s, 1H0, 7.34 (d, J=4.5 Hz, 1H), 7.23-7.19 (m, 2H), 7.05-7.03 (m, 1H0, 6.75 (d, J=8.5 hz, 1H0, 5.03 (s, 2H), 2.67-2.64 (m, 1H), 1.13 (d, J=7 Hz, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:25]1[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:29][CH:30]=1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: Clc1cccc2c(C3=CCNCC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc2c(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-3-(1H-indole-4-oxy)propane (0.446 g, 2.15 mmol) and 7-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.500 g, 2.13 mmol) in the presence of 2.0 equivalents of potassium carbonate (0.593 g, 4.3 mmol) in dimethylformamide at 90° C. Yield 0.190 g (22%) of a tan foam. mp 166°-169° C. FDMS m/e=405 (M+ of free base).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=O)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C([O-])(=O)C.[NH4+:30].C(=O)(O)[O-].[Na+]>O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([NH2:30])=[O:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CCCC(N)=O
Temperature: 130 °C
Reaction time: 72 h

Procedure:
Ethyl 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate (15.9 g, 46.6 mmol, prepared as described in Parts A through C of Example 5) and ammonium acetate (35.0 g, 455 mmol) were sealed and heated in a high-pressure vessel at 130° C. for two days. An analysis by LC/NS indicated the presence of starting material, and additional ammonium acetate (15 g, 190 mmol) was added. The reaction was heated to 130° C. for several hours, allowed to cool to ambient temperature, stirred for three days, and poured into water (200 mL). Solid sodium bicarbonate was added until the solution was basic. The solution was extracted with dichloromethane (3×100 mL, 5×75 mL, and then in a continuous extractor for about 20 hours). The extracts were dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 10.3 g of 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanamide as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([CH3:15])=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N:16]1([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=2[N:30]=[CH:29][CH:28]=[CH:27]3)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH:13]([N:19]3[CH2:20][CH2:21][N:16]([C:22]4[CH:23]=[CH:24][CH:25]=[C:26]5[C:31]=4[N:30]=[CH:29][CH:28]=[CH:27]5)[CH2:17][CH2:18]3)[CH3:15])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(CC(C)=O)coc12
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cccc2c(CC(C)N3CCN(c4cccc5cccnc45)CC3)coc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred mixture of 1-(7-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 8-piperazino quinoline (213.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol) was added at room temperature. Reaction mixture was stirred at room temperature for 72 hrs. At the end, the reaction mixture was neutralized with 10% NaHCO3 and extracted with chloroform. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a yellow oil. Yield: 60 mg (14%); (M+H): 402; 1HNMR (400 MHz, CDCl3): δ 8.90˜8.14 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.13˜7.56 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.46˜6.80 (m, 8H); 4.01 (s, 3H); 3.51˜1.60 (m, 11H); 1.14(d, J=6.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([CH3:39])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([CH3:39])[CH:30]=2)[C:26]([NH:10][C:7]2[CH:8]=[CH:9][N:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)Cl)ccc1S(C)(=O)=O
Reactant: COCCn1ccc(N)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(C)c2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
In a round bottom flask was placed 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in Example 72, 30 mg, 0.21 mmol), 2,6-lutidine (34 μL, 0.29 mmol) and methylene chloride (5 mL). This solution was then cooled to 0° C. and to it was added dropwise a solution of 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionyl chloride in methylene chloride (0.096 M solution, 2 mL, 0.19 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then extracted with methylene chloride (3×10 mL). The organic extracts were then combined and washed with a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 30% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (57 mg, 65%) as a white foam: [α]31589=−29.5° (c=0.21, methylene chloride); ES-HRMS m/e calcd for C22H31N3O4S (M+H)+ 434.2108, observed 434.2108; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02-1.20 (m, 2H, CH2), 1.36-1.82 (m, 8H, 4×CH2), 2.03-2.20 (m, 1H, CH), 2.62 (s, 3H, ArCH3), 3.17 (s, 3H, SO2CH3), 3.19 (s, 3H, OCH3), 3.61 (t, J=5.2 Hz, 2H, OCH2), 3.82-3.94 (m, 1H, ArCH), 4.11 (t, J=5.2 Hz, 2H, NCH2), 6.41 (d, J=2.4 Hz, 1H, Ar), 7.41-7.47 (m, 2H, Ar), 7.54 (d, J=2.4 Hz, 1H, Ar), 7.84 (d, Jo=8.8 Hz, 1H, Ar), 10.75 (s, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:16]([CH3:18])[CH3:17])=[N:7][C:8]3[C:9](I)=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[C:21]([NH2:25])(=[O:24])[C:22]#[CH:23]>[Cu]I.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.CN(C=O)C>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:16]([CH3:18])[CH3:17])=[N:7][C:8]3[C:9]([C:23]#[C:22][C:21]([NH2:25])=[O:24])=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: C#CC(N)=O
Reactant: CC(C)c1nc2c(I)c[nH]c(=O)c2c2cc(Br)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(C#CC(N)=O)c[nH]c(=O)c2c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
9-bromo-4-iodo-6-isopropylbenzo[c]-1,6-naphthyridin-1(2H)-one (140 mg, 0.32 mmol), propynoic acid amide (26 mg, 0.38 mmol), copper (I) iodide (9.0 mg, 0.047 mmol), and Pd(Ph3P)4 (37 mg, 0.032 mmol) were added to a vial, followed by DMF (1.5 ml) and TEA (0.13 ml, 0.95 mmol). The resulting suspension was purged with argon (subsurface bubbling) for 10 min, and then stirred for 15 hr at room temperature. The reaction mixture was diluted with DMF and purified directly by reverse phase preparative HPLC using an acetonitrile/water (with 0.05% TFA as a modifier) gradient to afford 3-(9-bromo-6-isopropyl-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-4-yl)prop-2-ynamide. 1H NMR (500 MHz, DMSO-D6) δ 12.33 (br s, 1H), 10.21 (d, 1H), 8.46 (d, 1H), 8.04 (s, 1H), 7.93 (dd, 1H), 7.91 (br s, 1H), 7.58 (s, 1H), 4.07 (septet, 1H), 1.40 (d, 61-1). LRMS (ESI) calc'd for (C18H14BrN3O2) [M+H]+, 384.0; found 384.0.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9]O[C:6]=2[CH2:5][CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+:20]>CN(C)C=O>[O:1]=[C:2]1[CH2:3][CH2:4][CH2:5][C:6]2[NH:20][CH:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:7]1=2
Reactant: [NH4+]
Reactant: CCOC(=O)c1coc2c1C(=O)CCC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2c1C(=O)CCC2
Temperature: 100 °C

Procedure:
To a stirred suspension of 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (28.2 g, 157 mmol) in ethyl alcohol (500 mL) under nitrogen at ambient temperature was added acetyl chloride(56 mL, 783 mmol) dropwise. After stirring 1 h, the solution was then heated at reflux for 1 h. The solution was cooled and concentrated in vacuo. The residue was taken up into dichloromethane, washed with aqueous sodium bicarbonate, washed quickly with 1N sodium hydroxide, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford ethyl 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylate as an oil. A mixture of this ester (24.46 g, 117 mmol) and ammonium acetate (15.85 g, 206 mmol) in N,N-dimethylformamide (225 mL) was heated at 100° C. under Nitrogen for 1.25 h. The mixture was cooled, poured into ice water, and extracted two times with dichloromethane. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, concentrated in vacuo, and the residue triturated with ether to give ethyl 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate. A mixture of this ester (11.31 g, 55 mmol) in 5N sodium hydroxide (200 mL) and ethanol (20 mL) was heated at reflux for 1h. After cooling in an ice bath, the mixture was acidified with concentrated hydrochloric acid, the precipitate filtered, rinsed with ice water, and dried in vacuo to afford 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid. m.p. 269°-270° C.