Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1(S(N)(=O)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:14]C1C=CC=CC=1[N+]([O-])=O>>[Br:14][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2
Reactant: NS(=O)(=O)n1ccc2ccccc21
Reactant: O=[N+]([O-])c1ccccc1Br
Product: Brc1cccc2cc[nH]c12

Procedure:
Similarly, the route shown in Scheme 2 below exemplifies synthesis of certain 7-aryl(heteroaryl)-indoline(indole)-1-sulfonamide compounds of the present invention. To synthesize indole-1-sulfonamide compound (9), 1-bromo-2-nitrobenzene (6) is reduced to afford 7-bromo-1H-indole (7), which reacts with 4-methoxyphenylsulfonyl chloride to provide 7-bromo-1-(4-methoxyphenylsulfonyl)-1H-indole (8). The sulfonamide (8), is then treated with an aryl or heteroaryl boronic acid, Pd(PPh3)4, and K2CO3 in toluene/EtOH to afford final compound (9). To synthesize indoline-1-sulfonamide compound (12), 7-bromo-1H-indole (7) is further reduced (with NaCNBH3 and CH3COOH, at room temperature) to afford 7-bromoindoline (10), which reacts with a substituted phenylsulfonyl chloride to provide bromo-indoline-sulfonamide (11). The bromo-indoline-sulfonamide (11) is then treated with an aryl or heteroaryl boronic acid, Pd(PPh3)4, and K2CO3 in toluene/EtOH to afford final compound (12), which can be further modified to obtain compound (13).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:31][CH:32]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(NC(=O)c2ccccc2O)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccccc2OC(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a solution of N-(4-methoxyphenyl)-2-hydroxybenzamide (0.484 g, 2.00 mmol) in methylene chloride (35 mL) cooled to 0° C. was added 0.28 mL triethylamine (0.28 mL, 2.0 mmol), followed by the dropwise addition of a solution of 4-tert-butylbenzoyl chloride (0.393 mL, 2.00 mmol) in methylene chloride (15 mL). The reaction mixture was allowed to warm to room temperature over 16 h and washed with cold water. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. Trituration with hexane provided 0.488 g (61%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=[N:8][C:4]=2[C:3]=1[NH:35][C:36]([CH3:38])=[O:37].FC(F)(F)C(O)=O>>[NH2:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[C:21]([C:26]([OH:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=[N:8][C:4]=2[C:3]=1[NH:35][C:36]([CH3:38])=[O:37]
Reactant: CCCCc1nc2c(NC(C)=O)c(N)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(NC(C)=O)c(N)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(5-aminoacetamino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.FC(CC(O)=O)(F)F>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Agent: O=C(O)CC(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCNC1)c1sccc1Nc1ccnc2[nH]ccc12
Yield: 122.2 %

Procedure:
A solution of 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) in methylene chloride (1.0 mL) was added trifluoromethyl acetic acid (1.0 mL). After 1H the solution was concentrated in vacuo, triturated with diethylether to afford 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid pyrrolidin-3-ylamide (48 mg, 99%). LCMS (ESI) 328 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.25 (1H, s) 8.08 (1H, d, J=6.83 Hz) 8.02 (1H, d, J=5.47 Hz) 7.81 (1H, d, J=5.27 Hz) 7.48 (1H, d, J=5.47 Hz) 7.32 (1H, d, J=3.51 Hz) 6.81 (1H, d, J=5.47 Hz) 6.44 (1H, d, J=3.51 Hz) 4.32-4.51 (1H, m) 3.14 (1H, dd, J=11.62, 6.74 Hz) 3.02-3.11 (1H, m) 2.89-2.98 (1H, m) 2.86 (1H, dd, J=11.71, 5.08 Hz) 1.97-2.15 (1H, m) 1.68-1.84 (1H, m)
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)(C)=O.[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[CH2:22](O)C>CS(C)=O.C1COCC1>[F:9][C:10]([F:20])([F:21])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[CH2:22][O:17]2)=[CH:14][CH:13]=1
Reactant: CCO
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(C2CO2)cc1
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride(1.54 g, 38.46 mmol) in 35 mL of dry DMSO was added, via a solid addition funnel, trimethylsulfoxonium iodide (7.84 g, 35.61 mmol) over 5 minutes. After H2 gas evolution ceases the cloudy solution was treated with a solution of 4-trifluoromethoxybenzaldehyde (4.96 g, 25.05 mmol) in 35 mL of THF over 15 minutes. After one hour, 1 mL of ethanol was slowly added, then the THF and ethanol were removed by rotary evaporation. The DMSO solution was poured into 100 mL of water and then extracted with dichloromethane(3×75 mL). The combined organic extracts were washed with dilute brine (2×75 mL), dried (Na2SO4), filtered, evaporated and purified by flash chromatography (silica gel, 10% ethyl acetate/hexane). This procedure afforded 1.95 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:20]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Br:20])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: COc1cc(CO)ccc1OCc1ccccc1
Solvent: CCOCC
Product: COc1cc(CBr)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 192.6 %

Procedure:
To a solution of 4-(benzyloxy)-3-methoxybenzyl alcohol (9.0 g, 36.84 mmol) in anhydrous diethyl ether (150 mL) was slowly added PBr3 (4.99 g, 18.42 mmol) via syringe, and the resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with diethyl ether (100 mL) and washed with saturated aqueous NaHCO3 (2×75 mL) and brine (2×75 mL). The organic layer was dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to afford 4-(benzyloxy)-3-methoxybenzyl bromide (10.9 g, 96%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[C:21]4[CH:22]=[C:23]([C:26]([NH2:28])=O)[CH:24]=[CH:25][C:20]=4[N:19]=[CH:18]3)[CH:14]=[N:13][CH:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)(Cl)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[C:21]4[CH:22]=[C:23]([C:26]#[N:28])[CH:24]=[CH:25][C:20]=4[N:19]=[CH:18]3)[CH:14]=[N:13][CH:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Nc1cncc(-n2cnc3ccc(C(N)=O)cc32)n1)c1cccc(F)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(Nc1cncc(-n2cnc3ccc(C#N)cc32)n1)c1cccc(F)c1
Yield: 79.7 %

Procedure:
In an analogous procedure to that reported in Example 4, 1-(6-{[1-(3-fluorophenyl)ethyl]amino}pyrazin-2-yl)-1H-benzimidazole-6-carboxamide (83 mg 0.21 mmol) was reacted with phosphorus oxychloride to afford the product as a pale yellow solid (60 mg, 80%).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]5[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][N:39]([CH2:41][C:42](OCC)=[O:43])[CH:40]=2)O1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(N1C(C2SC3CCOC4C=C(C5C=NN(CCO)C=5)C=CC=4C=3N=2)=NC=N1)(C)C>>[N:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:15]2[C:14]([C:8]3[S:9][C:10]4[CH2:11][CH2:12][O:13][C:4]5[CH:3]=[C:2]([C:36]6[CH:37]=[N:38][N:39]([CH2:41][CH2:42][OH:43])[CH:40]=6)[CH:27]=[CH:26][C:5]=5[C:6]=4[N:7]=3)=[N:18][CH:17]=[N:16]2)=[CH:25][CH:24]=1
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3Cc3ccncc3)nc1-2
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCO)c3)ccc1-2
Agent: [Al+3]
Agent: [H-]
Product: OCCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4Cc4ccncc4)nc2-3)cn1

Procedure:
Similarly to as described in General Procedure C: 8-Bromo-2-(2-pyridin-4-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate. The crude ester was reduced with lithium aluminum hydride as described for 2-{-4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethanol. The product was purified by HPLC to give 302 as a colorless solid (32 mg). LCMS: 472.1.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16](C(OC(C)(C)C)=O)[N:15]=[C:14]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:13]=1.[F:36][CH:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44]2[CH:53]=[CH:52][C:47]([C:48](OC)=[O:49])=[CH:46][CH:45]=2)[CH2:39][CH2:38]1>C1COCC1>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:14]2[CH:13]=[C:12]([NH:11][C:48](=[O:49])[C:47]3[CH:46]=[CH:45][C:44]([CH2:43][N:40]4[CH2:39][CH2:38][CH:37]([F:36])[CH2:42][CH2:41]4)=[CH:53][CH:52]=3)[NH:16][N:15]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COC(=O)c1ccc(CN2CCC(F)CC2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(CN4CCC(F)CC4)cc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
A solution of NaHMDS in THF (1 M, 0.65 ml, 0.65 mmol, 1.5 eq) was added dropwise at ambient temperature to a mixture of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl) ethyl]pyrazole-1-carboxylate (150 mg, 0.43 mmol, 1 eq) and methyl 4-[(4-fluoropiperidin-1-yl)methyl]benzoate (131 mg, 0.52 mmol, 1.2 eq) in THF (0.5 ml). The reaction mixture was stirred at ambient temperature for 1 h. It was then concentrated and the crude product was purified by reverse-phase prep. HPLC (basic) using a 39-49% gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were taken and evaporated to afford the title compound as a colourless solid (33 mg, 16% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:4]=1[OH:12].O.C(=O)(O)[O-].[Na+].[Br:19][C@H:20]([CH:24]([CH3:26])[CH3:25])[C:21](Cl)=[O:22]>C(OCC)(=O)C>[Br:19][C@H:20]([CH:24]([CH3:26])[CH3:25])[C:21]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:10])[CH3:11])[C:4]=1[OH:12])=[O:22]
Reactant: CC(C)c1cccc(N)c1O
Reactant: CC(C)[C@@H](Br)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(NC(=O)[C@H](Br)C(C)C)c1O
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a stirred, ice-cooled mixture of 2-amino-6-isopropylphenol hydrochloride (15.0 g), ethyl acetate (200 ml), water (100 ml), and sodium bicarbonate (20.0 g), was added dropwise a solution of (R)-2-bromo-3methylbutyryl chloride (16.0 g) in ethyl acetate (30 ml). The whole was stirred for 30 minutes, and the ethyl acetate layer was separated, washed with water and dried over MgSO4. Removal of the solvent gave (R)-2-(2-bromo-3-methylbutyryl)amino-6-isopropylphenol as crystals (19.1 g, 76.1%). Recrystallization from isopropyl ether afforded colorless needles, mp 108°-109° C. [α]D23 +44.8° (c=0.82, MeOH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH:10]=[CH:9]2.Br[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([O:29][CH3:30])=[N:21][CH:20]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.O1CCOCC1>[CH3:30][O:29][C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH3:16])[C:11](=[O:17])[CH:10]=[CH:9]3)=[CH:20][N:21]=1
Reactant: COc1ncc(Br)c2ccccc12
Reactant: Cn1c(=O)ccc2cc(OCCCN)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(NCCCOc2ccc3c(ccc(=O)n3C)c2)c2ccccc12
Temperature: 80 °C
Yield: 25.5 %

Procedure:
6-(3-Amino-propoxy)-1-methyl-1H-quinolin-2-one (232 mg), 4-bromo-1-methoxy-isoquinoline (286 mg), palladium acetate (II) (22 mg), xantphos (558 mg), and sodium t-butoxide (192 mg) were added to dioxane (10 ml). The mixture was heated at 80° C. for overnight under argon atmosphere. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture, and followed by celite filtration. The filtrate was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1→1:0). The purified product was condensed under reduced pressure to give the title compound (99 mg) as a brown amorphous solid.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])[CH:13]=2)[C:8]=1[Br:32])C.[OH-].[K+].Cl>C1COCC1.O>[Br:32][C:8]1[C:9]2[C:14](=[CH:13][C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:5][C:4]([OH:33])=[O:3]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)OCC)ccc3c2)sc2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)O)ccc3c2)sc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
A mixture of [1-bromo-6-(3-pentanoyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester (0.0932 g, 0.177 mmol) and potassium hydroxide (0.063 gm 1.1 mmol) in THF (5 mL) and water (5 mL) was stirred at ambient temperature for two hours. It was then poured in excess water and acidified with 2N hydrochloric acid. This was then extracted with ethyl acetate and washed with water and brine. The organic phase was dried with anhydrous magnesium sulfate, filtered, solvent evaporated and dried in vacuo at 64° C. for 25 hours to yield [1-bromo-6-(3-pentanoyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid as a light yellow solid (0.0662 g, 75.2%): MP: 164–5° C.; mass spectrum (+EI, [M+H]+) m/z 497/499. 1H NMR (500 MHz, DMSO-d6): δ13.0–13.2 (br, 1H), 8.24 (d, 1H, J=8.70 Hz), 8.07–8.13 (m, 3H), 7.95–7.97 (m, 1H), 7.76 (dd, 1H, J=8.78 Hz and 1.91 Hz), 7.45–7.51 (m, 3H), 5.02 (s, 2H), 2.42 (t, 2H, J=7.22 Hz), 1.40–1.46 (m, 2H), 0.97–1.04 (m, 2H), 0.58 ppm (t, 3H, J=7.41 Hz). Elemental Analysis for C25H21BrO4S: Calcd: C, 60.37; H, 4.26; N, 0.00; Found: C, 60.23; H, 4.35; N, 0.00.
Reaction SMILES: [F:1][C:2]([C:11]1[CH:12]=[C:13]([NH2:18])[C:14]([NH2:17])=[CH:15][CH:16]=1)([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[CH2:19]([S:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=O)[CH3:20].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.N1C=CC=CC=1>[CH2:19]([S:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]1[NH:17][C:14]2[CH:15]=[CH:16][C:11]([C:2]([F:1])([C:7]([F:8])([F:9])[F:10])[C:3]([F:6])([F:5])[F:4])=[CH:12][C:13]=2[N:18]=1)[CH3:20]
Reactant: CCSc1ccccc1C(=O)O
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(C(F)(C(F)(F)F)C(F)(F)F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 11.5 %

Procedure:
To a mixture of 4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzene-1,2-diamine (552 mg), 2-ethylsulfanylbenzoic acid (401 mg), and pyridine (27 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (422 mg) and 1-hydroxybenzotriazole (27 mg) were added at room temperature. The reaction mixture was stirred at room temperature for 5 hours, diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in a mixed solution of DMF (7.5 mL) and toluene (30 mL), and then p-toluenesulfonic acid (837 mg) was added at room temperature. The mixture was stirred with heating at 130° C. for 8 hours, and allowed to stand to cool to room temperature. Into the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 97 mg of 2-(2-ethylsulfanyl-phenyl)-5-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-1H-benzimidazole (hereinafter, Present Compound 346).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26](O)=[O:27])=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.[NH:35]1[CH2:39][CH2:38][C@@H:37]([OH:40])[CH2:36]1>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26]([N:35]3[CH2:39][CH2:38][C@@H:37]([OH:40])[CH2:36]3)=[O:27])=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)=[CH:13][N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CCC(=O)O)c3n2)cn1
Reactant: O[C@@H]1CCNC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CCC(=O)N4CC[C@@H](O)C4)c3n2)cn1

Procedure:
3-(2-(2-(Tert-butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)propanoic acid (50 mg) was reacted with (R)-pyrrolidin-3-ol via General Procedure F followed by Boc deprotection via General Procedure E to give 10.9 mg 109 as white solid following reverse phase purification. MS (Q1) 440.2 (M)+
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH3:22])=[CH:16][CH:15]=[C:14]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:13]=2.C(N(CC)CC)C>ClCCl>[CH2:33]([O:32][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:19]([CH2:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH3:22])[C:5]([CH2:4][O:3][CH2:1][CH3:2])=[N:8][C:9]=3[CH:10]=[N:11][C:12]=2[CH:13]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(CNc1c(N)cnc2cc(OCc3ccccc3)ccc12)NC(=O)OC(C)(C)C
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
Ethoxyacetyl chloride (1.82 mL, 16.60 mmol) was added to a chilled (0° C.) solution of tert-butyl [2-(3-amino-7-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]carbamate (6.04 g, 13.8 mmol) and triethylamine (3.86 mL, 27.68 mmol) in 150 mL of anhydrous dichloromethane. After stirring for 30 minutes, the cooling bath was removed and the reaction was stirred for 24 hours at ambient temperature. The volatiles were removed under reduced pressure and the resulting residue was dissolved in ethanol, followed by the addition of 3.86 mL of trietylamine. The reaction was heated at reflux for 2.5 days and then cooled to ambient temperature. The solvent was removed under reduced pressure and dichloromethane was added. The solution was sequentially washed with aqueous sodium bicarbonate followed by brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure. The residue was purified using flash column chromatography on silica gel, eluting with 5% methanol in dichloromethane. Clean fractions were concentrated; while fractions containing both the product and the starting material were resubmitted to the reaction conditions and repurified as described above. The combined lots provided a total of 5.07 g of tert-butyl [2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carbamate was obtained as an orange foam.
Reaction SMILES: C([C:3]1[N:4]([CH:21]2[CH2:23][CH2:22]2)[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[CH:9][C:8]([F:17])=[C:7]([F:18])[C:6]=2[O:19][CH3:20])C.Cl>C(O)(=O)C>[CH:21]1([N:4]2[C:5]3[C:10](=[CH:9][C:8]([F:17])=[C:7]([F:18])[C:6]=3[O:19][CH3:20])[C:11](=[O:16])[C:12]([C:13]([OH:15])=[O:14])=[CH:3]2)[CH2:22][CH2:23]1
Reactant: CCc1c(C(=O)O)c(=O)c2cc(F)c(F)c(OC)c2n1C1CC1
Agent: Cl
Solvent: CC(=O)O
Product: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C
Yield: 91.8 %

Procedure:
A mixture of ethyl-1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid (500 mg, 1.55 mmol), glacial acetic acid (5 mL), and 1N hydrochloric acid (1 mL) was allowed to reflux for 2 hours and was poured into ice water. The resulting precipitate was collected by suction filtration and washed with distilled water and diethyl ether to give 420 mg, 91% yield of a white solid, m.p. 187°-189° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.B.Cl.[OH-].[Na+]>C1COCC1>[NH2:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][C:14]2[CH:24]=[CH:25][C:11]([CH2:10][CH2:9][NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)=[N:17][CH:18]=1
Reactant: N#Cc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Product: NCc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Temperature: 25 °C
Yield: 21.5 %

Procedure:
Dissolve 6-[4-(2-benzylaminoethyl)phenoxy]nicotinonitrile 0.0650 g, 0.197 mmol) in THF (2.0 mL). Beat to 65° C. before adding borane-dimethyl sulfide (0.0211 mL, 0.217 mmol). Continue heating for about 2 hours. Then add 5.0 N HCl (0.30 mL). Beat at reflux for 1 hour 20 minutes before cooling to room temperature. Add 1.0 N NaOH until the solution is basic. Extract with ether (3×25 mL). Concentrate the organic layer before purifying by flash chromatography, eluting with 10% (2.0 M NH3 in methanol), 10% methanol and 80% ethyl acetate. Load the product onto a 1 g SCX column with methanol. Wash with methanol and elute with 2.0 M NH3 in methanol. Run a second flash 40 column eluting with 10% (2.0 M NH3 in methanol), 5% methanol and 85% ethyl acetate. Load the product onto a 5 g SCX column with methanol. Wash the column with methanol (4×10 mL) and 25% (2.0 M NH3 in methanol) in methanol (1×10 mL). Then elute with 50% (2.0 M NH3 in methanol) in methanol to give the title compound (0.0141 g, 21.7%): MS ES+ 334.0 (M+H)+, base peak ES+ 227.0 (M-NHCH2C6H5)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=4.8 min. 91.2% purity.