Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:14]1[CH:19]=[N:18][C:17]2N(O)N=[N:22][C:16]=2[CH:15]=1.CCN=C=NCCCN(C)C.Cl.Cl.NC1C=NC=CC=1>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH2:10][C:11](=[O:13])[NH:22][C:16]1[CH:17]=[N:18][CH:19]=[CH:14][CH:15]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TEA (2.2 ml, 16 mmol) is added to a stirred solution of BOC-β-alanine (2.4 g, 12.7 mmol), HOAt (0.68 g, 5.0 mmol), EDCl.HCl (2.43 g, 12.7 mmol) in DCM and stirred at room temperature. After 1 hour, 3-aminopyridine (1.0 g, 10.6 mmol) is added and the mixture is stirred at room temperature for a further 3 hours. The mixture is then diluted with DCM (200 ml) and washed with 0.1 M HCl followed by 1M NaOH. The organic portion is dried (MgSO4) and concentrated in vacuo to afford the title compound as a white crystalline solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:24]=1.Cl>O1CCCC1>[CH2:19]([O:18][C:13](=[O:17])[C:14]([CH3:16])([CH3:15])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:24]=1)[CH3:20]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: CCOC(=O)C(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)Cc1ccc(CC(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
To a solution of diisopropylamine (13.11 mmol, 1.8 mL) in anhydrous tetrahydrofuran (40 mL) cooled to −78° C. under a nitrogen atmosphere was added 2.5M n-BuLi in hexanes (13.11 mmol, 5.24 mL). The resulting solution was allowed to stir at −78° C. for 20 minutes, warmed to room temperature for 10 minutes, then cooled back to −78° C. for 10 minutes. The mixture was added to a solution of ethyl isobutyrate (13.11 mmol, 1.76 mL) dissolved in anhydrous tetrahydrofuran (20 mL) cooled to −78° C. The resulting solution was allowed to stir at −78° C. for 1 h. (4-Bromomethyl-phenyl)-acetic acid (1 g, 4.37 mmol) in anhydrous tetrahydrofuran (10 mL) was added to the solution dropwise. The solution was warmed to room temperature and was allowed to stir for 20 minutes. The reaction mixture was poured over a dilute HCl solution (1 N). The aqueous layer was isolated and extracted with diethyl ether (1×). The organic layers were combined, washed with 2N HCl (2×), brine (1×), dried over anhydrous sodium sulfate, and concentrated to a crude oil. The oil was chromatographed on silica gel (Merck silica gel 60, art#9385-3) eluting with 10% methanol/methylene chloride to give 3-(4-carboxymethyl-phenyl)-2,2-dimethyl-propionic acid ethyl ester as a white solid (0.97 g, 84%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:22]([C:25]1[N:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S:43](=[O:46])(=[O:45])[NH2:44])=[CH:33][CH:32]=2)[C:28]2[CH:47]=[C:48]([C:52]3[N:56]([CH3:57])[C:55]4[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=4[N:53]=3)[CH:49]=[C:50]([CH3:51])[C:27]=2[N:26]=1)[CH2:23][CH3:24].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[CH2:22]([C:25]1[N:29]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S:43]([NH:44][C:1](=[O:9])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:45])=[O:46])=[CH:35][CH:36]=2)[C:28]2[CH:47]=[C:48]([C:52]3[N:56]([CH3:57])[C:55]4[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=4[N:53]=3)[CH:49]=[C:50]([CH3:51])[C:27]=2[N:26]=1)[CH2:23][CH3:24]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Temperature: 55 °C

Procedure:
145 mg of benzoic acid and 192 mg of carbonyldiimidazole are stirred in 1 ml of tetrahydrofuran for 2 hours at 50° C. To this is added a solution of 163 mg of 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-sulphamoyl-biphenyl, 0.133 ml of 1,8-diazabicyclo-[5.4.0]undec-7-ene and 1 ml of tetrahydrofuran and the mixture is maintained at 55° C. for 2.5 hours. Then 50 ml of ethyl acetate and 20 ml of 5% citric acid are added. The organic phase is dried with sodium sulphate and evaporated down. The residue obtained is chromatographed over silica gel with dichloromethane/ethanol (95:5).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C)C.CO>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][OH:11])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
To a solution (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (26.1 g, 0.1 mol) in THF (500 mL), BH3.Me2S (80 mL, 0.8 mmol) was added dropwise at −78° C., then stirred at rt for 3 hrs. The reaction was stopped by careful addition of methanol. After evaporation and three distillations of methanol, the residue was dissolved in EtOAc, washed with 1 M NaHCO3, and brine. (S)-methyl 4-(tert-butoxycarbonylamino)-5-hydroxypentanoate (12 g, yield 49%) was obtained as an oil that was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH:4]=[C:5]([CH3:7])[CH3:6].[CH3:10][C:11]([CH3:15])=[CH:12]CO.[N+](C1C=C([N+]([O-])=O)C=CC=1O)([O-])=O>>[CH3:1][O:2][CH:3]([O:8][CH2:9][CH:10]=[C:11]([CH3:15])[CH3:12])[CH:4]=[C:5]([CH3:7])[CH3:6]
Reactant: COC(C=C(C)C)OC
Reactant: CC(C)=CCO
Agent: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Product: COC(C=C(C)C)OCC=C(C)C
Temperature: 25 °C
Reaction time: 76 h

Procedure:
In a 50 ml. one-neck flask was placed 5.5 g. (0.0422 mol.) of 1,1-dimethoxy-3-methyl-2-butene and 10.0 g. (0.116 mol.) of prenol and 0.40 g. (0.002 mol.) of 2,4-dinitrophenol. The resulting solution was degassed with nitrogen and sealed with a serum cap and stirred at room temperature for 76 hours. The reaction solution was then diluted with 100 ml. of hexane and washed with 3 × 100 ml. of 1.0 N aqueous NaOH solution and 2 × 100 ml. of saturated aqueous NaCl solution. The combined water washings were back with extracted 1 × 50 ml. of hexane. The combined hexane solutions were dried (Na2SO4) and concentrated to give 9.0 g. of crude product. Distillation of 8.3 g. at 20 mmHg and a bath temperature of 55°-60° gave 1.48 g. of prenol. Continued distillation initially at 0.20 mmHg gave 2.43 g. of 1-methoxy-1-(3-methylbut-2-enoxy)-3-methyl-2-butene (b.p. 40°-45° at 0.02 mmHg) and finally at 0.050 mmHg gave 3.29 g. of 1,1-bis-(3-methylbut-2-enoxy)-3-metylbut-2-ene (b.p. 70°-75° at 0.050 mmHg).
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)=[C:6]([N+:23]([O-])=O)[CH:5]=1)(=[O:3])[CH3:2].C(OCC)C>C(O)C.ClCCl.[Pd]>[C:1]([C:4]1[CH:22]=[CH:21][C:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)=[C:6]([CH:5]=1)[NH2:23])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Nc2cccc(-c3cccnc3)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)c1ccc(Nc2cccc(-c3cccnc3)c2)c(N)c1
Yield: 80.2 %

Procedure:
4-acetyl-2-nitro-N-(3-(3-pyridyl)-phenyl)-aniline (2 g, 6 mmol) is suspended in a mixture of ethanol (50 ml) and dichloromethane (10 ml) and is hydrogenated at ambient pressure using palladium (5% on activated carbon) as the catalyst. Filtration of the resulting solution through celite followed by evaporation of solvent leaves an oil which upon trituration with a mixture of diethylether and petroleumether (1:1) affords 1.46 g pure 5-acetyl-2-(3-(3-pyridyl)phenylamino)aniline (80%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1.[CH2:18]([Sn](CCCC)(CCCC)CCCC)[CH:19]=[CH2:20].C(OCC)(=O)C.[F-].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:20]([C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1)[CH:19]=[CH2:18]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(Cl)nnc1Oc1ccccc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1cc(OC)c(Oc2ccccc2C)nn1
Reaction time: 8 h
Yield: 30.5 %

Procedure:
In toluene (4 mL) was dissolved 200 mg (0.797 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1), 305 mg (0.921 mmol) of allyl(tributyl)tin, and then, 96.8 mg (0.0838 mmol) of tetrakis(triphenylphosphine)palladium were successively added to the solution at room temperature, and the resulting mixture was refluxed for 3 hours and 20 minutes. The reaction mixture was allowed to stand at room temperature overnight, and then, ethyl acetate, water and sodium fluoride were added to the mixture and the resulting mixture was stirred for 2 hours. The mixture was filtered through Celite, ethyl acetate was added to the filtrate, then the organic layer was separated, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 62.1 mg (0.243 mmol, Yield: 30.5%) of 6-allyl-4-methoxy-3-(2-methylphenoxy)pyridazine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([OH:38])[CH:34]=[C:35]([Br:37])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.CC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:38][C:33]2[CH:32]=[C:31]([Br:30])[CH:36]=[C:35]([Br:37])[CH:34]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(Br)c2)c1CCC(=O)OCC
Temperature: 25 °C
Yield: 99 %

Procedure:
To a mixture of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (14.54 g, 30.84 mmol), 3,5-dibromophenol (8.55 g, 33.92 mmol), and potassium carbonate (8.53 g, 61.68 mmol) were added N,N-dimethylformamide (210 mL) and acetone (420 mL) at room temperature. The resulting suspension was heated to reflux for 2 days. Then, the reaction mixture was cooled to room temperature and diluted with water (200 mL). The organic compound was extracted into ethyl acetate (2×200 mL) and the combined organic extracts were washed with brine solution (200 mL). The organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the crude product which was purified by using a Biotage column chromatography (FLASH 40L, Silica), eluting with 10% ethyl acetate/hexanes to obtain 4-{3-[6-(3,5-dibromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (19.61 g, 99%) as a colorless oil: ES(+)-HRMS m/e calculated for C29H38O6Br2 (M+H)+ 641.1108, found 641.1101.
Reaction SMILES: [F:1][C:2]1([F:27])[C:4]2([C:11]3[N:16]=[C:15]4[N:17]([CH3:26])[C:18](=[O:25])[N:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]4=[CH:13][CH:12]=3)[CH2:5][CH:6]3[CH:10]([CH:3]12)[CH2:9][NH:8][CH2:7]3.[O:28]1[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[N:29]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:27][C:2]1([F:1])[C:4]2([C:11]3[N:16]=[C:15]4[N:17]([CH3:26])[C:18](=[O:25])[N:19]([CH2:20][C:21]([CH3:24])([CH3:22])[CH3:23])[C:14]4=[CH:13][CH:12]=3)[CH2:5][CH:6]3[CH:10]([CH:3]12)[CH2:9][N:8]([C:33]([C:30]1[CH:31]=[CH:32][O:28][N:29]=1)=[O:34])[CH2:7]3
Reactant: O=C(O)c1ccon1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C34CC5CNCC5C3C4(F)F)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C34CC5CN(C(=O)c6ccon6)CC5C3C4(F)F)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(4,4-Difluorooctahydro-4aH-cyclopropa[3,4]cyclopenta[1,2-c]pyrrol-4a-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (30-3, 50 mg, 0.14 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 22.5 mg, 0.20 mmol, 1.5 equiv), DIPEA (0.070 mL, 0.40 mmol, 3.0 equiv) and HATU (76 mg, 0.20 mmol, 1.5 equiv) were added to anhydrous acetonitrile (1 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 30-4 as a white solid. MS m/z (M+H): calculated=472.2155; observed=472.2153.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[CH:8][N:9]2[CH2:13][CH2:14][F:15])=[CH:4][N:3]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][N:9]2[CH2:13][CH2:14][F:15])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn(CCF)c2c(Cl)c(Cl)ncc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(CCF)c2c(Cl)c(Cl)ncc2c1=O
Temperature: 0 °C

Procedure:
3.33 g (0.01 mol) of ethyl 7,8-dichloro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylate are heated at reflux in a mixture of 13 ml of acetic acid, 13 ml of water and 1.3 ml of concentrated sulphuric acid for two hours. The cooled mixture is put into ice-water, and the product is isolated and washed with water.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][C:6](=[NH:10])[O:7][CH2:8][CH3:9].N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl.CCOC(C)=O>[CH2:21]([O:20][C:18]([N:10]=[C:6]([O:7][CH2:8][CH3:9])[CH2:5][CH2:4][O:3][CH3:2])=[O:19])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=N)CCOC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)N=C(CCOC)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Ethyl 3-methoxypropanimidate hydrochloride (1.0 g, 6.0 mmol) was suspended in DCM (12 mL) and cooled to 0° C. Pyridine (2 mL, 24.7 mmol) was added dropwise and the mixture was stirred for 15 min. Ethyl chloroformate (0.97 g, 9.0 mmol) was added dropwise and the mixture was diluted with DCM (20 mL), allowed to warm to RT, and stirred for 12 h. The mixture was diluted with a mixture of EtOAc and hexanes (1:1, 200 mL) and the solids were removed by filtration through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to afford ethyl N-ethoxycarbonyl-3-methoxy-propanimidate (1.0 g, 83%) as a light green solid. 1H NMR (400 MHz, DMSO-d6): δ 4.08 (q, J=7.0 Hz, 2H), 4.05 (q, J=7.0 Hz, 2H), 3.50 (t, J=6.4 Hz, 2H), 3.19 (s, 3H), 2.57 (t, J=6.4 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H), 1.19 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[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:19](O)(=O)[CH3:20].[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].[Na+]>ClCCCl.CO.CC(C)=O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH:19]([CH3:20])[CH3:23])[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: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)O
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(C)=O
Solvent: CO
Product: CCOCc1nc2cnc3ccccc3c2n1NC(C)C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A solution of 2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-amine (2.50 g, 10.3 mmol) in 250 mL of 1,2-dichloroethane was treated with acetone (0.83 mL, 11.3 mmol), acetic acid (0.65 mL, 11.3 mmol) and sodium triacetoxyborohydride (2.39 g, 11.3 mL). After stirring overnight, additional acetone (5 mL), acetic acid (0.65 mL, 11.3 mmol) and sodium triacetoxyborohydride (2.39 g, 11.3 mL) were added. After 2 d, the reaction was carefully quenched by addition of saturated NaHCO3 solution. The layers were separated and the aqueous portion was extracted with additional CH2Cl2. The combined organic layers were washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to give a brown oil. Some isopropylidene intermediate was still present, so the material was dissolved in 50 mL of MeOH and treated with NaBH4 (1.0 g). After 2 h, the reaction was quenched by the addition of H2O and the reaction mixture was concentrated under reduced pressure. The residue was partitioned between saturated NaHCO3 solution and CH2Cl2. The layers were separated and the organic portion was washed with saturated NaHCO3, H2O and brine. The organic portion was dried over Na2SO4, filtered, and concentrated under reduced pressure. Chromatography (SiO2, 4% MeOH/CHCl3) gave N-(2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (0.98 g) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:11]/[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])/[C:9]#[N:10])=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(/C=C(\C#N)c2ccc(F)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])c(CC(C#N)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a cooled solution of (Z)-2-(4-fluorophenyl)-3-(5-methyl-2-nitrophenyl)acrylonitrile (3.0 g, 0.0106 mol) in THF (25 mL) and MeOH (75 mL) was added sodium borohydride (0.808 g, 0.0212 mol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 2 h at RT. After completion of reaction (monitored by TLC), the mixture was diluted with water (100 mL), and extracted with EtOAc (3×150 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain product as a yellow colored solid (3 g, 99% yield).
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.Cl.[CH2:13]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=1[C:30]([NH:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1)=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.CNC.C(N(CC)CC)C>O1CCCC1.O>[CH2:13]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:3]([CH3:4])[CH3:2])=[O:26])=[CH:23][C:22]=1[C:30]([NH:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1)=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: CNC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.7 %

Procedure:
WSC.HCl (95 mg, 0.50 mmol) was added to a solution of 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid (242 mg, 0.50 mmol), dimethylamine hydrochloride (41 mg, 0.50 mmol) and triethylamine (51 mg, 0.50 mmol) in tetrahydrofuran (5 mL) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with diluted hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=1:4) to give the title compound (165 mg, 64.9%) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:29](=[O:30])[C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: CN
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Product: CNC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Yield: 86 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (210 mg, 0.46 mmol) was reacted with methylamine to give the title compound as a white solid (181 mg, 86%); NMR Spectrum 1.66 (d, 3H), 2.68 (d, 3H), 5.16 (q, 1H), 6.04 (s, 2H), 7.01 (d, 1H), 7.37 (d, 1H), 7.66 (s, 1H), 7.72-7.80 (m, 4H), 8.21 (s, 1H), 8.39 (m, 1H), 8.54 (s, 1H), 8.56 (s, 1H), 10.70 (br s, 1H); Mass spectrum MH+ 460.
Reaction SMILES: [CH:1]12B[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[O:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-:15].[Na+].OO.Cl>O1CCCC1.C(O)C>[CH2:12]1[C:1]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:13][CH2:14][O:10][C:11]1=[O:15]
Reactant: B1C2CCCC1CCC2
Reactant: [OH-]
Reactant: C1CCOC1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: O=C1CC2(CCCCCCC2)CCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of methyl (1-vinylcyclooctyl) acetate (1.33 g) in tetrahydofuran (6 mL) was added 0.5M 9-borabicyclo[3.3.1]nonane/tetrahydrofuran (25.3 mL) dropwise over 15 minutes. The reaction solution was then allowed for its temperature to rise to room temperature and it was stirred for additional 2 hours. The reaction solution was again ice-cooled, and ethanol (8 mL), a 6N aqueous sodium hydroxide solution (11 mL) and 30% hydrogen peroxide (11 mL) were successively to the solution. The reaction solution was allowed for its temperature to rise to room temperature and it was stirred for additional 75 minutes. The reaction solution was again ice-cooled. After addition of conc. hydrochloric acid (8 mL), the solution was stirred for additional 30 minutes. The reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, hexane-ethyl acetate (9:1)] to give the title compound (0.74 g).