Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[H-].[Na+].I[CH3:14]>CN(C=O)C>[CH3:14][O:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: CI
Reactant: Oc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of sesamol (10.0 g, 0.072 mol) in DMF (50 ml) was added sodium hydride (2.08 g, 0.087 mol) at room temperature under argon. After stirring for 1 h, the mixture was treated with iodomethane (13.5 ml, 0.216 mol) and stirred for another 18 h. Upon the removal of the solvent the residue was extracted with ethyl acetate and washed with water, dried (Na2SO4) and concentrated to afford the title compound as a dark brown oil (10.5 g, 96%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]3[CH2:15][CH2:16][CH:17]([NH2:18])[CH:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][S:29](Cl)(=[O:31])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][S:29]([NH:18][C@H:17]2[C@@H:11]3[CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[N:8]=4)[CH2:14][CH2:13][N:12]3[CH2:15][CH2:16]2)(=[O:31])=[O:30])=[CH:26][CH:27]=1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Reactant: NC1CCN2CCN(c3cccc(C(F)(F)F)n3)CC12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Cc1ccc(Cl)cc1)N[C@@H]1CCN2CCN(c3cccc(C(F)(F)F)n3)C[C@@H]12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 96B (100 mg, 0.349 mmol) in dry dichloromethane (2 mL) was added (4-chlorophenyl)methanesulfonyl chloride (118 mg, 0.524 mmol) and triethylamine (212 mg, 2.096 mmol). The mixture was stirred at room temperature for 16 hours and then concentrated. The residue was purified via HPLC (Gilson®, XBridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=254 nm) to give the title compound as the first eluting diastereomer. 1H NMR (500 MHz, methanol-d4) δ 1.57-1.66 (m, 1 H), 1.91-1.99 (m, 1 H), 2.21-2.29 (m, 2 H), 2.34 (q, 1H, J=8 Hz), 2.62 (dd, 1H, J=12, 10 Hz), 2.92 (td, 1H, J=12, 3 Hz), 3.00-3.06 (m, 2 H), 3.41 (td, 1H, J=9, 6 Hz), 4.33-4.40 (m, 3 H), 4.52 (dd, 1H, J=12, 1 Hz), 6.98 (t, 2H, J=7 Hz), 7.38-7.41 (m, 2 H), 7.44-7.48 (m, 2 H), 7.66-7.72 (m, 1 H); MS (DCI) m/z 475 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[NH:19][CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1.N1C=CC=C(C2N3C=CC([C:47](C4C5C(=CC(OCC6C=CC=CC=6)=CC=5)NC=4)=[O:48])=C3CS2)C=1.[CH2:66]([CH2:68][NH2:69])[OH:67].[K+].[Br-]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([C:47](=[O:48])[NH:69][CH2:68][CH2:66][OH:67])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1
Reactant: O=C(c1ccn2c1CSC2c1cccnc1)c1c[nH]c2cc(OCc3ccccc3)ccc12
Reactant: O=C(c1ccn2c1CSC2c1cccnc1)c1c[nH]c2cc(-c3ccc(F)cc3)ccc12
Reactant: NCCO
Agent: [Br-]
Agent: [K+]
Product: O=C(c1ccn2c1CSC2c1cccnc1)c1cn(C(=O)NCCO)c2cc(-c3ccc(F)cc3)ccc12

Procedure:
The desired compound was prepared according to the method of Example 37 except substituting 3-(pyridin-3-yl)-7-[6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole, prepared as in Example 28, for 3-(Pyridin-3-yl)-7-(6-phenylmethoxyindol-3-yl)carbonyl-1H,3H-pyrrolo[1,2-c]thiazole, and substituting ethanolamine for amounts. 1H NMR (DMSO-d6, 300 MHz) δ3.32-3.42 (m, 2H), 3.60 (q, 2H, J=6Hz), 4.51 (d, 1H, J=15Hz), 4.68 (dd, 1H, J=2, 15Hz), 4.88 (t, 1H, J=6Hz), 6.79 (d, 1H, J=3Hz), 6.81 (d, 1H, J=1Hz), 7.09 (d, 1H, J=3Hz,) 7.32 (t, 2H, J=9 Hz), 7.45 (dd, 1H, J=5, 8 Hz), 7.61 (dd, 1H, J=1, 8 Hz), 7.69 (dt, 1H, J=1, 8 Hz), 7.71-7.76 (m, 2H), 8.32 (d, 1H, J=8 Hz), 8.51 (d, 1H, J=1 Hz). 8.56-8.61 (m, 3H), 8.47 (t, 1H, J=6 Hz). MS (FAB) m/e 527 (M+H)+, 440. IR (KBr) 1701, 1601, 1530, 1510, 1475, Anal calcd for C29H23FN4O3S: C, 66.15; H, 4.40; N, 10.64. Found: C, 64.93; H, 4.14; N, 10.00.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](=O)[CH2:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[C:4]([Cl:29])[CH:3]=1.Cl.[NH2:31]O>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([C:16]([F:18])([F:19])[F:17])[O:20][N:31]=3)[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[C:4]([Cl:29])[CH:3]=1
Reactant: NO
Reactant: O=C(CC(=O)C(F)(F)F)c1cn(-c2ccc(Br)cc2Cl)c(-c2ccccc2Cl)n1
Agent: Cl
Solvent: CO
Product: FC(F)(F)c1cc(-c2cn(-c3ccc(Br)cc3Cl)c(-c3ccccc3Cl)n2)no1
Yield: 87.4 %

Procedure:
To a 50 mL flask attached with condenser was added 1-(1-(4-bromo-2-chlorophenyl)-2-(2-chlorophenyl)-1H-imidazol-4-yl)-4,4,4-trifluorobutane-1,3-dione (138 mg, 273 μmol) and MeOH (12 mL). To the solution was added hydroxylamine-HCl (190 mg, 2.73 mmol). The reaction solution was allowed to stir at reflux for 1.5 h. The solution was concentrated in vacuo and the residue was taken into EtOAc and washed with aq. NaHCO3 (50 mL×2). The EtOAc phase was partitioned, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed through a 12 g SiO2 column using a 100% hexane to 60% EtOAc gradient to yield 120 mg (86% yield) of title compound. MS (ESI) 508.3, 510.3 [M+H]+.
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.[C:12]([C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=1N)#[N:13].NC1C=CC=CC=1>CC#N>[CH2:3]([C:15]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=1[C:12]#[N:13])[CH:1]=[CH2:2]
Reactant: CC(C)(C)ON=O
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Solvent: Nc1ccccc1
Solvent: C=CCBr
Solvent: CC#N
Product: C=CCc1ccc([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 2-cyano-4-nitroaniline (489 mg, 3.0 mmol) was added during 40 minutes, while maintaining the temperature of the reaction mixture at 23-27° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 26° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 23:2) gave 367 mg (65%) of allyl-2-cyano-4-nitrobenzene as an orange oil. 1H NMR (CDCl3, 400 MHz) δ 8.51, (d, 1H, J=2.4 Hz), 8.39, (dd, 1H, J=8.6, 2.4 Hz), 7.58, (dd, 1H, J=8.6, 0.5 Hz), 6.00-5.90, (m, 1H), 5.29-5.17, (m, 2H), 3.74, (d, 2H, J=6.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 151.3, 146.8, 133.5, 131.4, 128.4,127.9, 119.6, 116.2, 114.4, 38.9; Anal HRMS Calcd. for C10H8N2O2 (M): 188.0585.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][N:10]([S:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:19])=[O:18])[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2[nH]ccc2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2nc(Cl)ccc21
Reaction time: 8 h

Procedure:
To a suspension of 5-chloro-1H-pyrrolo[3,2-b]pyridine (20. g, 130 mmol, Adesis) in DCM (200 mL) was added benzenesulfonyl chloride (20. mL, 160 mmol, Aldrich), triethylamine (27 mL, 200 mmol) and 4-dimethylaminopyridine (0.80 g, 6.6 mmol, Aldrich). The reaction mixture was stirred overnight. Water was added and the mixture was stirred for 4 h. Layers were separated and the organic phase was washed sequentially with 1 N HCl, water, saturated solution of NaHCO3, and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give an orange solid, which was triturated with MeOH (100 mL). The solid was filtered, washed with MeOH, and dried at 40° C. under high vacuum overnight. Additional product was obtained by flash chromatography of the filtrate (eluting with a gradient from 0-60% EtOAc in hexanes). Yield: (26.8 g, 95%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])C.[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].[OH-].[Na+]>O1CCOCC1.CO.O>[O:25]=[C:24]1[CH2:23][CH2:22][CH2:21][N:11]1[C:9]1[N:8]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:10]=1
Reactant: O=C(Cl)CCCBr
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1cc(N2CCCC2=O)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
700 mg (3.0 mmol) of 5-Amino-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester are dissolved in 20 ml of dioxane and added to a suspension of NaH (266 mg 60% suspension in mineral oil, 6.66 mmol) in 10 ml of dioxane. After stirring for 10 minutes at RT 4-bromobutyryl chloride (617.5 mg, 3.3 mmol) is added and the resulting mixture is stirred overnight at RT. A MeOH/H2O mixture (10 ml, 1:1) is added to destroy excess NaH and the solvent is removed in vacuo. The crude product is redissolved in 15 ml of EtOH and 8 mmol of 1M NaOH is added and the mixture is stirred overnight. The solvent is removed in vacuo and the residue subjected to HPLC chromatography: Yield: 554 mg, 68%
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4](C)[N:3]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].[OH-].[K+].[CH3:19]N(C=O)C>O>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[C:5]([CH3:19])[CH:6]=2)[S:13][C:12]=1[C:11]([O:15][CH3:16])=[O:14]
Reactant: Cc1ccc(C#N)c(Cl)n1
Reactant: COC(=O)CS
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1sc2ncc(C)cc2c1N
Yield: 79 %

Procedure:
2-Chloro-3-cyano-6-methyl pyridine (1.5 g, 9.8 mmol) and methyl thioglycolate (0.88 mL, 9.8 mmol) were dissolved in DMF (7 mL). To the solution was added 1.0 g KOH in 5 mL H2O over 30 min. The reaction was then quenched by the addition of ice water, and the product collected by filtration to yield 1.72 g (79%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 2.88 (s, 3H), 3.91 (s, 3H), 5.90 (br s, 2H), 7.17 (d, 1H), 7.82 (d, 1H),
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[CH:16][C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.C(O)C.[Pd]>[C:22]1([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:20][CH2:21][NH:8][CH2:9][CH2:10][C:11]=4[NH:12][C:13]=3[CH:14]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCc3[nH]c4cc(-c5ccccc5)ccc4c3CC2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc(-c2ccc3c4c([nH]c3c2)CCNCC4)cc1
Yield: 50.8 %

Procedure:
A mixture of 3-benzyl-8-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.07 g, 3.0 mmol), glacial acetic acid (2 drops) and Pd/C (10%, 0.6 g) in ethanol (150 mL) was reacted in a manner similar to Example 8 to give 0.40 g (51%) of the title compound as a tan crystalline solid: mp 220-222° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.41, 7.61-7.59, 7.46, 7.42-7.38, 7.28-7.22, 3.04-3.01, 2.96-2.94, 2.87-2.84; 13C NMR (100 MHz, DMSO-d6) δ 142.4, 138:2, 135.3, 133.0, 128.5, 128.4, 126.8, 126.0, 117.9, 117.5, 111.8, 108.8, 50.5, 48.8, 32.5, 28.0; IR (drift) 3305, 2929, 2918, 2893, 2827, 1468, 1324, 1242, 869, 814, 787, 762, 753, 743, 700 cm−1; MS (EI) m/z 262 (M+); HRMS (FAB) calcd for C18H18N2+H: 263.1548, found: 263.1543; Anal. Calcd for C18H18N2.0.1 C2H4O2: C, 81.46; H, 6.91; N, 10.44. Found: C, 81.11; H, 7.01; N, 10.35.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].[F:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O>CCOCC.O>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][C:5]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[CH3:14])[CH2:24][CH2:23]2)=[O:21])=[CH:28][CH:29]=1
Reactant: Cc1[nH]c2ccccc2c1CCCBr
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c2ccccc2c1CCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 50 °C

Procedure:
A mixture of 3-(3-bromopropyl)-2-methylindole (13.8 g), 4-(4-fluorobenzoyl)piperidine (6.0 g), K2CO3 (4.0 g) and dimethylformamide (DMF) (100 ml) is stirred and heated at 50° C. under N2 for 16 hours. The mixture is poured into H2O, and the aqueous mixture extracted with benzene, the benzene extract is washed with H2O, dried (Na2SO4), and the solvent evaporated to leave an oil. The oil is taken up in ether and HCl (g) is bubbled into it to precipitate 10.6 g of a hydrochloride salt. The salt is converted to the free base (an oil). Upon trituration of the oil with ether 4.2 g of a solid is collected. The solid is recrystallized from EtOH-H2O (charcoal treatment), and then twice from isopropanol to yield 1.9 g (15%), m.p. 135°-137° of 3-{3-[4-(4-fluorobenzoyl)piperidyl]propyl} 2-methylindole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7]2[CH:15]=[C:14]([C:16](O)=[O:17])[CH:13]=[CH:12][C:8]=2[S:9][C:10]=1[CH3:11].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH2:35]([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:36][CH2:37][CH2:38][CH3:39].N12CCCN=C1CCCCC2.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7]2[CH:15]=[C:14]([C:16](=[O:17])[NH:43][S:40]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])[CH:13]=[CH:12][C:8]=2[S:9][C:10]=1[CH3:11]
Reactant: CCCCCS(N)(=O)=O
Reactant: Cc1sc2ccc(C(=O)O)cc2c1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2sc(C)c(Cc3ccc(Cl)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
3-(3,4-Dichlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylic acid (160 mg) was dissolved in dry dimethylformamide (2 ml). Carbonyl-diimidazole (111 mg) was added and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added n-pentanesulfonamide (108 mg) and 1,8-diazabicyclo[5,4,0]undec-7-ene (122 mg) and the mixture was stirred at 100° C. for 1.5 hr. The reaction mixture was cooled in ice, and the pH thereof was adjusted to pH 4 with 1N hydrochloric acid. The mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was eluted by silica gel column chromatography (hexane:ethyl acetate=1:1). The resulting residue was crystallized from hexane-ethyl acetate to give 3-(3,4-dichlorobenzyl)-2-methyl-5-(n-pentanesulfonyl-carbamoyl)benzo[b]thiophene (118 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:17].[C:31]([C:35]1[CH:43]=[CH:42][C:38]([CH:39]=[N:40][OH:41])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>CC(C)=O>[C:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:22]=[CH:23][C:18]([C:16]([NH:15][C:5]2[CH:6]=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:41]/[N:40]=[CH:39]/[C:38]3[CH:37]=[CH:36][C:35]([C:31]([CH3:34])([CH3:32])[CH3:33])=[CH:43][CH:42]=3)[CH:8]=[CH:9][C:4]=2[C:3]([OH:30])=[O:2])=[O:17])=[CH:19][CH:20]=1.[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:41]/[N:40]=[CH:39]/[C:38]2[CH:42]=[CH:43][C:35]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:36][CH:37]=2)=[CH:6][C:5]=1[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)c1ccc(C=NO)cc1
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(/C=N/OCCCOc2ccc(C(=O)O)c(NC(=O)c3ccc(-c4ccccc4)cc3)c2)cc1
Product: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(C)(C)C)cc2)cc1NC(=O)c1ccc(-c2ccccc2)cc1
Yield: 131.7 %

Procedure:
The desired product was prepared using a procedure similar to Step 6 of example 34. Thus, 2-[(biphenyl-4-carbonyl)-amino]-4-(3-bromo-propoxy)-benzoic acid methyl ester (0.325 g, 0.694 mmol) was reacted with Cs2Co3 (0.475 g, 1.457 mmol) and 4-tert-Butyl-benzaldehyde oxime (0.135 g, 0.763 mmol) in acetone (30 ml) to give 2-[(1,1′-biphenyl-4-ylcarbonyl)amino]-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid methyl ester (0.258 g, 0.457 mmol, 66%) as a viscous yellow oil. 1H NMR (DMSO-d6) δ 1.20 (s, 9H), 2.05-2.18 (m, 2H), 3.85 (s, 3H), 4.18 (t, 2H), 4.23 (t, 2H), 6.79 (d, 1H), 7.32-7.50 (m, 7H), 7.73 (d, 2H), 7.85 (d, 2H), 7.95-8.02 (m, 3H), 8.18 (s, 1H), 8.39 (s, 1H), 11.98 (s, 1H), mass spectrum [ES(+)], m/z 565 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Br)([CH3:12])[CH3:11]>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a flame-dried flask under an argon atmosphere is added 1.85 g of commercially available 4-bromobenzaldehyde and charged with 30 mL of tetrahydrofuran. The solution is cooled to 0 ° C. and slowly treated with 7.0 mL of isopropylmagnesium bromide. After stirring overnight at room temperature the reaction mixture is concentrated under reduced pressure. The residue is partioned between diethyl ether and saturated ammonium chloride; the aqueous layer is then extracted with diethyl ether. The combined organic phases are dried (magnesium sulfate), and the volatiles are removed. The residue is flash column chromatographed using 30% to 60% diethyl ether in hexane to afford 1.25 g of the title product as a viscous, tan oil.
Reaction SMILES: [N:1]1([C:7](=[O:9])[CH3:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:10]([O-])([O-])=O.[K+].[K+].Br[C:17]([Br:20])([CH3:19])C>>[Br:20][CH2:17][CH2:19][CH2:10][N:4]1[CH2:5][CH2:6][N:1]([C:7](=[O:9])[CH3:8])[CH2:2][CH2:3]1
Reactant: CC(C)(Br)Br
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N1CCNCC1
Agent: [K+]
Product: CC(=O)N1CCN(CCCBr)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32 %

Procedure:
A mixture of 1-(1-piperazinyl)-1-ethanone (6.7 g, 0.052 mol), dibromopropane (330 mL, excess) and K2CO3 (10.2 g, 0.079 mol) was stirred at rt for 4 h. The mixture was washed with 4×100 mL of water, and the organic phase (diluted with DCM) was acidified with aqueous hydrobromic acid (7 mL of 62% HBr dissolved in 150 mL of water). The organic layer was separated and washed with water (2×50 mL). The combined water layers were extracted with ether, neutralised (to pH 7) with 13 mL of 10 M NaOH, and then extracted with DCM. The combined organic layers were dried and concentrated in vacuo to give 4.1 g (32%) of the title compound.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:17]3[CH:18]=[CH:19][C:20]([O:22][C:23]4[S:24][C:25]5[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=5[N:27]=4)=[CH:21][C:16]=3[O:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[K+].Cl>CC(O)C>[CH:4]([OH:5])=[O:3].[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[O:22][C:20]1[CH:19]=[CH:18][C:17]2[C:13]([CH2:12][N:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)=[CH:14][O:15][C:16]=2[CH:21]=1
Reactant: CCOC(=O)C1CCN(Cc2coc3cc(Oc4nc5ccccc5s4)ccc23)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(O)C1CCN(Cc2coc3cc(Oc4nc5ccccc5s4)ccc23)CC1
Product: O=CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
To a solution 1-[6-(benzothiazol-2-yloxy)-benzofuran-3-ylmethyl]-piperidine-4-carboxylic acid ethyl ester (342 mg, 0.783 mmol) in IPA (8 mL) was added 2 M KOH (3.9 mL, 7.8 mmol) and stirred (rt, 2 h). The pH of the reaction mixture was adjusted to pH 8 with 1 M HCl (1.7 mL) and partitioned with DCM (30 mL). The aqueous phase was extracted with DCM (3×30 mL). The organic layers were combined, dried, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to provide the title compound as a colorless solid (86 mg, 24%). MS (ESI): mass calcd. for C22H20N2O4S, 408.1; m/z found, 408.9 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.78-7.64 (m, 4H), 7.56 (d, J=2.0, 1H), 7.41-7.35 (m, 1H), 7.31-7.27 (m, 1H), 3.90 (5, 2H), 3.61 (5, J=135.2, 1H), 3.17 (d, J=11.3, 3H), 2.36 (t, J=10.9, 3H), 2.11-1.77 (m, 4H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH:34]=[CH:35][CH:36]=1)[CH2:13][C:14]1[C:15]([C:19]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:20])=[CH:16][S:17][CH:18]=1.C(Cl)Cl.CC(O)=O>C([O-])(O)=O.[Na+]>[Br:1][C:18]1[S:17][CH:16]=[C:15]([C:19]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:20])[C:14]=1[CH2:13][C:12]1[CH:34]=[CH:35][CH:36]=[C:10]([Cl:9])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cscc2Cc2cccc(Cl)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2csc(Br)c2Cc2cccc(Cl)c2)cc1
Reaction time: 16 h

Procedure:
N-Bromosuccinimide (43.0 mg, 0.242 mmol) was added to methyl 4-[(1S)-1-({[4-(3-chlorobenzyl)-3-thienyl]carbonyl}amino)ethyl]benzoate from Example 3, Step 4 (50.0 mg, 0.121 mmol) in 1:1 CH2Cl2/AcOH (1.2 mL). After 16 h, the reaction was slowly poured in 5% aq. NaHCO3. The aqueous layer was extracted with CHCl3 and the combined organics were washed with 5% aq. NaHCO3, sat. Na2S2O3 and brine, dried (Na2SO4) and concentrated. The crude product was purified by Combi Flash chromatography system (0-2% EtOAc/CHCl3 in 15 min.) to afford the desired product as a brown solid.
Reaction SMILES: [NH2:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH3:20])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][CH3:20])[C:4]([CH2:3][C:2]([NH:1][C:23](=[O:26])[CH2:24][CH3:25])([CH3:21])[CH3:22])=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCC(=O)Cl
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)CC
Yield: 77.1 %

Procedure:
Using the method of Example 68, 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 595 mg, 2.00 mmol) was reacted with propionyl chloride (463 mg, 5.00 mmol). The crude product was purified by IFC (silica gel eluting with a gradient of 15 to 25% CMA in chloroform) followed by recrystallization from ethyl acetate/hexanes to provide 545 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]propionamide as a white solid, mp 158-159° C. MS (APCI) m/z 354 (M+H)+; Anal. Calcd for C20H27N5O: C, 67.96; H, 7.70; N, 19.81. Found: C, 67.80; H, 8.08; N, 19.77