Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl-].[Al+3].[Cl-].[Cl-].O>[N+](C)([O-])=O>[CH:13]1([C:18]([C:8]2[O:9][C:5]3[C:4]([F:12])=[CH:3][C:2]([F:1])=[CH:11][C:6]=3[C:7]=2[CH3:10])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1coc2c(F)cc(F)cc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Cc1c(C(=O)C2CCCC2)oc2c(F)cc(F)cc12
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of 5,7-difluoro-3-methyl-1-benzofuran (1.0 g) synthesized above, and cyclopentanecarbonylchloride (867 mg) in nitromethane (20 mL) was added aluminum chloride (anhydrous) (1.19 g) at 0° C., and the mixture was stirred for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-95:5, v/v) to give the title compound (1.25 g, 80%) as a colorless solid.
Reaction SMILES: [Na].[C:2]1([O:9][CH3:10])[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:11]([O:13][C:14](=[O:22])[CH:15](Cl)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:12]>C(O)C>[CH2:11]([O:13][C:14](=[O:22])[CH:15]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[O:9][CH3:10])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:12]
Reactant: COc1ccccc1O
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Oc1ccccc1OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 6.9 g (0.3 mole) of sodium pellets dissolved in 400 ml of absolute ethanol was successively added a solution of 37.9 g (0.305 mole) of guaiacol in 50 ml of ethanol followed by a solution of 68.1 g(0.35 mole) of diethylchloromalonate in 50 ml of ethanol. The mixture was heated at reflux for 28 hr and then stirred at ambient temperature for 3 days. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between salt water and ethyl ether. The layers were separated and the aqueous layer was extracted twice with 150 ml portions of ethyl ether. The combined organic layers were washed with brine, dried (sodium sulfate) and concentrated to give a yellow oil. The oil was subjected to vacuum distillation and 66.6 g (79%) of the title compound was collected as a clear oil, bp 136°-153° C. at 0.3 mm.
Reaction SMILES: [CH3:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([OH:12])=[O:11])([CH2:6][CH2:7]1)[CH:4]=[CH:3]2.[H][H]>[Pd].C(O)C>[CH3:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([OH:12])=[O:11])([CH2:4][CH2:3]1)[CH2:6][CH2:7]2
Reactant: [H][H]
Reactant: CC12C=CC(C(=O)O)(CC1)CC2
Agent: [Pd]
Solvent: CCO
Product: CC12CCC(C(=O)O)(CC1)CC2

Procedure:
In this preparation a mixture containing 0.1 mole of 4-methylbicyclo[2.2.2]oct-2-ene-1-yl carboxylic acid and 1 g. of 5% palladium on carbon catalyst in 300 ml. of ethanol is stirred under hydrogen, at room temperature, until no more hydrogen is absorbed (about 2.4 liters are absorbed). The catalyst is then filtered off and the solvent removed from the filtrate by evaporation, under vacuum, affording 4-methylbicyclo[2.2.2]oct-1-yl carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:13]([O:28][CH3:29])[CH:12]=3)=[CH:9][N:8]([CH:30]3[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[C:13]([O:28][CH3:29])[CH:12]=3)=[CH:9][N:8]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)[CH2:32][CH2:31]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(-c2cn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Reaction time: 20 h

Procedure:
To a solution of 92% pure N1-{4-[4-amino-7-(4-oxocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-3-phenylpropanamide (1.0 g, 2.1 mmol), N-methylpiperazine (0.63 g, 6.3 mmol), acetic acid (0.38 g, 6.3 mmol) in dichloroethane (100 mL) was added sodium triacetoxyborohydride (0.67 g, 3.15 mmol) portionwise under nitrogen. The solution was stirred for 20 hr and then quenched by the addition of saturated aqueous sodium bicarbonate solution (50 mL). The aqueous layer was extracted with dichloromethane (3×50 mL), dried (sodium sulphate), filtered and evaporated to leave a sludge which was purified by flash silica gel column chromatography using dichloromethane to 50% MeOH/dichloromethane in 10% increments. F84-96 were combined and evaporated to leave cis-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)-3-phenylpropanamide (0.26 g) as a cream foamy glass. HPLC: (5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) tr=12.65 min, 95.2%.1H NMR (d6 DMSO, 400 MHz): 9.17(1H, s), 8.14(1H, s), 8.05(1H, d), 7.28(5H, m), 7.18(1H, m), 7.10(1H, s), 6.99(1H, d), 6.11(2H, bs), 4.67(1H, m), 3.88(3H, s), 2.90(2H, m), 2.73(2H, m), 2.50(7H, m), 2.28(3H, s), 2.06(3H, m), 1.71(2H, m), 1.55(2H, m). F121-138 were combined and evaporated to leave trans-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)-3-phenylpropanamide (0.11 g) as a white solid. HPLC: (5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) tr=12.61 min, 96.2%. 1H NMR (d6 DMSO, 400 MHz): 9.16(1H, s), 8.13 (1H, s), 8.04(1H, d), 7.44(1H, s), 7.29 (4H, m), 7.18(1H, m), 7.09(1H, s), 6.97 (1H, d), 6.11(2H bs), 4.53(1H, m), 3.88 (3H, s), 2.93(2H, m), 2.71(2H, m), 2.50 (4H, m), 2.30(5H, m), 2.14(3H, s), 1.89(6H, m), 1.46(2H, m).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][CH:15]([OH:24])[CH2:16][NH:17][CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C(Cl)Cl>[Si:30]([O:24][CH:15]([CH2:14][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:16][NH:17][CH2:18][C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC(CNCc1ccco1)Cn1c2ccccc2c2ccccc21
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(CNCc1ccco1)Cn1c2ccccc2c2ccccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a stirred solution of 1-(9H-carbazol-9-yl)-3-((furan-2-ylmethyl)amino)propan-2-ol (1.80 g, 5.6 mmol) and imidazole (1.912 g, 28.1 mmol) in anhydrous methylene chloride (50 mL) was added tert-butyldimethylsilyl chloride (2.117 g, 14.0 mmol). The reaction mixture was stirred overnight at 70° C. The reaction mixture was washed with saturated aqueous sodium chloride and saturated aqueous sodium carbonate, dried (anhydrous sodium sulfate), filtered, and concentrated. The residue was purified by silica gel column chromatography (0-40% ethyl acetate in hexanes) to afford the product as a thick oil (2.4 g, 98%). 1H NMR (300 MHz, CDCl3) δ 8.08 (d, 2H, J=7.8 Hz), 7.53-7.40 (m, 4H), 7.37 (d, 1H, J=1.5 Hz), 7.22 (t, 2H, J=7.2 Hz), 6.32 (dd, 1H, J=3.3, 1.8 Hz), 6.16 (d, 1H, J=3.3 Hz), 4.56 (dd, 1H, J=14.4, 6.0 Hz), 4.41-4.22 (m, 2H), 3.85 and 3.75 (dd, 2H, J=14.4, 14.4 Hz), 2.74 (dd, 1H, J=12.0, 4.5 Hz), 2.61 (dd, 1H, J=12.0, 3.6 Hz), 1.60 (br s, 2H), 0.80 (s, 9H), −0.13 (s, 3H), −0.42 (s, 3H). ESI m/z: 435.2 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16]I>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([CH3:16])[C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2ccc(Br)cc2)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CCC1c1ccc(Br)cc1
Reaction time: 0.33 h
Yield: 67 %

Procedure:
A solution of 5-(4-bromophenyl)-2-pyrrolidinone (preparation described in WO00/21958) (200 mg, 0.83 mmol) in dimethylformamide (5 ml) was treated with a solid suspension of sodium hydride (60% in mineral oil, 35 mg, 0.88 mmol). The reaction mix was allowed to stir for 20 minutes, then methyl iodide (124 mg, 0.88 mmol) was added and the whole mix stirred for a further 18 hours. The reaction mixture was quenched with a few drops of water then partitioned between dichloromethane (15 ml), and water (60 ml), the organic layer was removed and washed with water again (2×10 ml), then reduced to minimum volume under reduced pressure to give the title compound as a brown oil (141 mg, 67%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([NH:11][C:12]2[CH:13]=[N:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH:23]([C:26]1[N:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[O:28][N:27]=1)([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:23]([C:26]1[N:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([C:2]3[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([NH:11][C:12]4[CH:13]=[N:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=4)[N:5]=[CH:4][N:3]=3)[CH2:33][CH2:32]2)[O:28][N:27]=1)([CH3:25])[CH3:24]
Reactant: CC(=O)c1c(Cl)ncnc1Nc1ccc(S(C)(=O)=O)nc1
Reactant: CC(C)c1noc(C2CCNCC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(Nc2ccc(S(C)(=O)=O)nc2)ncnc1N1CCC(c2nc(C(C)C)no2)CC1
Yield: 30.4 %

Procedure:
To a solution of 1-[4-chloro-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-5-yl]-ethanone (0.21 mmol, 70 mg) and 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine hydrochloride (0.21 mmol, 49 mg) in N,N-dimethyl formamide (500 uL) was added potassium carbonate (0.21 mmol, 29 mg). The mixture was microwaved at 100° C. for 150 seconds. Its progress was monitored by thin layer chromatography and LCMS. The reaction was treated with water and the desired compound was extracted in ethyl acetate. Organic layer was evaporated in vacuo. Purification by HPLC provided Compound B139 as a white solid (31 mg, 31%). 1H-NMR (400 MHz, CDCl3) δ(ppm): 10.9 (s, 1H); 8.90 (d, 1H); 8.58 (d, 1H); 8.32 (s, 1H); 8.05 (d, 1H); 4.09 (m, 2H); 3.41 (m, 2H); 3.29 (h, 1H); 3.23 (s, 3H); 3.09 (h, 1H); 2.48 (s, 3H), 2.18 (m, 2H), 2.02 (m, 2H), 1.35 (d, 6H) LCMS (ESI), m/z 486.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[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](=[O:31])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1.[C:33]([C:37]1[CH:45]=[CH:44][C:40]([CH:41]=[N:42][OH:43])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:43]/[N:42]=[CH:41]/[C:40]2[CH:44]=[CH:45][C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:38][CH:39]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)c1ccc(C=NO)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(C)(C)C)cc2)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
To a solution of 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-(3-bromo-propoxy)-benzoic acid methyl ester (0.53 g, 1.00 mmol) and 4-tert-butyl-benzaldehyde oxime (0.20 g, 1.10 mmol) in acetone (35 mL) was added cesium carbonate (1.30 g, 4.00 mmol). The mixture was heated to reflux overnight and then allowed to cool back to room temperature. The mixture was partitioned between ethyl acetate and brine and the layers were then separated. The aqueous layer was extracted with two additional portions of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was purified by flash chromatography through silica gel using diethyl ether/hexanes (0/100 gradient to 5/95) to give 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid methyl ester (0.30 g, 48%) as an off-white solid. 1H NMR (400 MHz, CDCl3); δ 12.52 (s, 1H), 8.51 (d, 1H), 8.48 (s, 2H), 8.06 (s, 1H), 8.04 (s, 1H), 7.99 (d, 1H), 7.47-7.35 (AA′BB′, 4H), 6.67 (dd, 1H), 4.34 (t, 2H), 4.22 (t, 2H), 3.92 (s, 3H), 2.23 (m, 2H), 1.28 (s, 9H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(N(CC)CC)C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>ClCCl.[Cu]I.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>[CH3:17][Si:18]([CH3:20])([CH3:19])[C:21]#[C:22][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(C#N)c1
Temperature: 25 °C

Procedure:
To a solution of commercially available 3-iodobenzonitrile (25 g, 0.109 mol), copper (I) iodide (2.08 g, 0.0109 mol), PdCl2(PPh3)2 (3.82 g, 0.0054 mol) and triethylamine (45.7 ml, 0.327 mol) in 250 of dry dichloromethane was added 12.8 g (0.131 mol) of trimethylsilylacetylene drop wise at 0° C. over a period of 10 min. The reaction mixture was stirred at RT over night. The reaction mixture was diluted with additional dichloromethane, filtered over Celite and the filtrate was concentrated. The crude material was purified by silica gel (60-120) column chromatography using 95:5 petrolium ether/ethyl acetate as eluent. A2.1 (20 g, 92%) was obtained as a brown solid 1H NMR, 400 MHz, CDCl3: 7.79 (s, 1H), 7.67 (d, 1H), 7.59 (d, 1H), 7.43 (t, 1H), 0.26 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:5][CH:4]=1.Cl>CO.CCOCC>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2=CCNC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: FC(F)(F)c1ccc(C2CCNC2)cc1
Reaction time: 0.08 h
Yield: 64 %

Procedure:
0.08 mmol 3-(4-Trifluoromethyl-phenyl)-2,5-dihydro-1H-pyrrole was dissolved in MeOH and HCl in ether was added until pH 1. After 5 minutes stirring, the solvents were evaporated. To a solution of this salt in 0.7 ml methanol under argon was added 2 mg Pd/C 10% and the mixture was hydrogenated under atmospheric pressure of hydrogen at room temperature for 4 h. The mixture was cooled, flushed with argon, diluted with methanol, filtered and the solvent was removed in vacuo to yield the title compound (64%) as an oil MS (m/e): 216.3 ([M+1], 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:7][C:6]=2[CH:16]=1.CCN(CC)CC.[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH:10]3[CH2:11][CH2:12][N:13]([S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[CH2:14][CH2:15]3)[CH2:7][C:6]=2[CH:16]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Brc1ccc2c(c1)CC(C1CCNCC1)O2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of 4-(5-bromo-2,3-dihydrobenzofuran-2-yl)piperidine (Compound 9A, 185 mg, 0.656 mmol) and Et3N (0.18 mL, 1.311 mmol) in CH2Cl2 (6 mL) at 0° C. was added propane-1-sulfonyl chloride (140 mg, 0.983 mmol). Upon completion of addition, the reaction mixture was warmed to room temperature, where it stirred for 2 hours. After this time, the reaction mixture was diluted with CH2Cl2 (5 mL) and washed with aqueous NaHCO3 (saturated, 5 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 50% EtOAc) to afford Compound 10A as a white solid (213 mg, 0.549 mmol, 84% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.27-7.25 (m, 1 H), 7.21 (dd, J=8.4, 2.1 Hz, 1 H), 6.63 (d, J=8.3 Hz, 1 H), 4.63-4.53 (m, 1 H), 3.93-3.84 (m, 2 H), 3.22 (dd, J=15.7, 9.1 Hz, 1 H), 2.96 (dd, J=15.8, 8.1 Hz, 1 H), 2.91-2.86 (m, 2 H), 2.80-2.71 (m, 2 H), 2.05-1.99 (m, 1 H), 1.90-1.81 (m, 2 H), 1.80-1.71 (m, 2 H), 1.53-1.41 (m, 2 H), 1.07 (t, J=7.4 Hz, 3 H). LC/MS (m/z)=389 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C@@H:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][C:31]([N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42]Cl)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:26]([O:30][C:31]([N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42][N:14]([C@H:11]1[CH2:12][CH2:13][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:25])[CH2:9][CH2:10]1)[CH:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][CH2:16]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N[C@H]2CCCc3cccnc32)CC1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N(Cc2nc3ccccc3n2C(=O)OC(C)(C)C)C2CCCc3cccnc32)CC1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a suspension of [4-((S)-5,6,7,8-tetrahydro-quinolin-8-ylamino)-trans-cyclohexyl]-carbamic acid tert-butyl ester (1.95 g, 5.64 mmol) in dry acetonitrile (60 mL) was added 2-chloromethyl-benzoimidazole-1-carboxylic acid tert-butyl ester (1.65 g, 6.20 mmol), diisopropylethylamine (2.0 mL, 11.4 mmol) and potassium iodide (100 mg, 0.60 mmol). The mixture was warmed to 60° C. and stirred for 2 days under nitrogen. The mixture was concentrated, dissolved in methylene chloride (80 mL) and washed with brine (50 mL). The aqueous layer was extracted with methylene chloride (3×50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude mixture was purified by column chromatography on silica gel (80 g) with methanol/methylene chloride (4:96) to afford 2-{[(4-tert-butoxycarbonylamino-trans-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester as a white solid (1.82 g, 56%). 1H NMR (CDCl3) δ 1.09 (bs, 2H), 1.43 (s, 9H), 1.68 (s, 9H), 1.83-2.14 (m, 6H), 2.47-2.63 (m, 1H), 2.65-2.79 (m, 1H), 2.79-2.95 (m, 1H), 3.32 (bs, 1H), 4.30 (bs, 2H), 4.46 (s, 2H), 6.75-6.89 (m, 1H), 7.00-7.13 (m, 1H), 7.61-7.70 (m, 1H), 7.70-7.79 (m, 1H), 8.32 (bs, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10]C)=[O:9])[C:4]([O:12][CH2:13][C:14]2[O:18][N:17]=[C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:15]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4]([O:12][CH2:13][C:14]2[O:18][N:17]=[C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:15]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1OCc1cc(OCc2ccc3ccccc3n2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1cc(CC(=O)O)c(OCc2cc(OCc3ccc4ccccc4n3)no2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A mixture of methyl [1-methyl-3-[3-(2-quinolylmethoxy)-5-isoxazolylmethoxy]-1H-pyrazol-4-yl]acetate (674 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-methyl-3-[3-(2-quinolylmethoxy)-5-isoxazolylmethoxy]-1H-pyrazol-4-yl]acetic acid (532 mg, yield 82%), which was then recrystallized from tetrahydrofuran-hexane. melting point: 124–125° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([CH3:21])=[N:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.[Cl-].[Na+]>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH:15]([CH3:21])[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)CCN=C2C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1OCc1ccccc1)CCNC2C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.3 %

Procedure:
To a solution of 249 (949 mg, 3.4 mmol) in EtOH (15 ml) at 0° C. was added sodium borohydride (256 mg, 6.8 mmol) portionwise. The reaction mixture was stirred at rt for 1.5 h. Water (100 ml) was added and the aqueous layer was neutralised. The aqueous layer was saturated with sodium chloride and extracted with EtOAc (3×100 ml). The combined organic layers were washed with sat. aq. sodium hydrogen C(Ar)bonate (100 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound (600 mg, 63%) a yellow oil. 1H NMR (400 MHz; DMSO-d6) 1.58 (3H, d, J=6.4 Hz, CH3CH), 2.50 (2H, s, CH2), 2.82-2.95 (2H, m, CH2), 3.76 (3H, s, OCH3), 4.42 (1H, q, J=6.4 Hz, CH3CH), 5.06 (2H, s, CH2Ph), 6.86 (1H, s, CH), 6.88 (1H, s, CH), 7.31-7.44 (5H, m, 5×CH, phenyl), 9.40 (1H, brs, NH). LC/MS (ES+) tr=0.73 min, m/z 284.13 (M++H).
Reaction SMILES: [OH:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O.C1(C)C=CC=CC=1>[Pt].C(O)C>[NH2:15][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:5]=1[NH:4][CH2:3][C:2]([OH:1])([CH3:18])[CH3:19])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(O)CNc1c(N)cnc2ccccc12

Procedure:
Using the method of Example 16, 7.0 g (0.027 mole) of 4-(2-hydroxy-2-methylpropylamino)-3-nitroquinoline, 1 g of platinum on charcoal, 200 ml of toluene and 150 ml of ethanol was hydrogenated on a Paar apparatus. The solution was filtered, then evaporated to dryness to provide 3-amino-4-(2-hydroxy-2-methylpropylamino)quinoline as a solid residue. To the residue was added 50 ml of triethyl orthoformate and 5 drops of formic acid. The solution was heated at 135° to 140° C. for one hour, then allowed to stand for about 16 hours. The product was separated by filtration, dissolved in hydrochloric acid and reprecipitated with sodium hydroxide solution. The product was recrystallized from ethanol to provide 1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline hydrate, m.p. 169°-170° C. Analysis: Calculated for C14H15N3O. H2O: % C, 64.8; % H, 6.6; % N, 16.2; Found: % C, 65.1: % H, 6.6; % N, 16.4.