Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1F)[C:22]#[N:23]>CN(C=O)C>[F:18][C:19]1[CH:20]=[C:21]([C:22]#[N:23])[CH:24]=[CH:25][C:26]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: Oc1ccc(NCc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(NCc3cccnc3)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(4-hydroxyphenyl)-3-pyridylmethylamine (1.0 equiv.) in DMF (0.1-0.3M) was treated with sodium hydride (1.0-1.5 equiv.)(60% dispersion in mineral oil). The reaction mixture was allowed to stir at room temperature for 30 minutes. The solution was then treated with 3,4-difluorobenzonitrile (1.6 equiv.) and allowed to stir. When complete (about 3 hours) the reaction mixture was partitioned between ethyl acetate/0.1M K2CO3, the organic layer separated, and the aqueous layer extracted 3 times with ethyl acetate. The organic layers were combined, washed with brine, and dried over MgSO4. The organic phase was concentrated in vacuo and purified by recrystallization from ethyl acetate/hexanes to give N-(4-(2-fluoro-4-cyanophenoxy)phenyl)-3-pyridylmethyl-amine 1H NMR(400 MHz, DMSO-d6): 4.29(2H, d, J=5.9 Hz), 6.40(1H, t, J=5.5 Hz), 6.63-6.65(2H, m), 6.83(1H, t, J=8.6 Hz), 6.90-6.92(2H, m), 7.33-7.36(1H, m), 7.55-7.57(1H, m), 7.74-7.76(1H, m), 7.93-7.97(1H, m), 8.43-8.44(1H, m), 8.58(1H, s). MS Found 320.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[OH:13].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:28](O)=[O:29]>O>[OH:13][C:4]1[C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][C:7]([C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:6][C:5]=1[CH:28]=[O:29]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)c1ccc(O)c(C(F)(F)F)c1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CC(C)(C)c1cc(C=O)c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 40 %

Procedure:
A mixture of 3.41 g (15.5 mmol) of 2-trifluoromethyl-4-(1,1-dimethylethyl)phenol (see E. Stokker, et al, J. Med. Chem., 23:1414 (1980) as an example of how to obtain this material) and 2.24 g (16.0 mmol) of hexamethylenetetramine was refluxed in 30 ml of trifluroacetic acid for 5 hours. The solution was cooled to ambient temperature and diluted with 200 ml of water. The aqueous residue was extracted with hexane. The organic phase was washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was chromatographed on 100 g of silica gel using hexane as eluent. There was obtained 1.54 g (6.25 mmol, 40%) of 2-hydroxy-3-trifluromethyl-5-(1,1-dimethylethyl)benzaldehyde as a white solid; mp 56°-57.5° C.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[CH3:25])[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]>C1COCC1.C(OCC)(=O)C.[Pd]>[CH3:35][C:2]([CH3:1])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[CH3:25])[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]
Reactant: CCOC(=O)/C=C/c1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of ethyl (2E)-3-(6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methylpyrimidin-4-yl)acrylate (180 mg) in THF (2.0 ml) and ethyl acetate (2.0 mL) was added 10% palladium-activated carbon (18 mg), and the mixture was stirred for 2 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (180 mg) as a pale-yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[F:8][C:9]([F:30])([F:29])[C:10]1[CH:28]=[CH:27][C:13]([O:14][C:15]2[CH:26]=[CH:25][C:18]([O:19][CH:20]([CH3:24])[C:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.[Na+].O.OP(O)(O)=O>C1(C)C(C)=CC=CC=1>[CH3:5][O:22][C:21](=[O:23])[CH:20]([O:19][C:18]1[CH:25]=[CH:26][C:15]([O:14][C:13]2[CH:12]=[CH:11][C:10]([C:9]([F:29])([F:30])[F:8])=[CH:28][CH:27]=2)=[CH:16][CH:17]=1)[CH3:24]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)[O-]
Reactant: COS(=O)(=O)OC
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
63 g of dimethyl sulfate are added within 5 minutes and at 130° C. to 348 g of anhydrous sodium-2-[4'-(4"-trifluoromethyl-phenoxy)-phenoxy]-propionate, suspended in 1,000 ml of xylene. After the addition, stirring of the mixture is continued for 1 hour, the mixture is cooled at 85° C., at said temperature 200 ml of water and 0.5 ml of H3PO4 are added and, for the separation of the inorganic salts, the mixture is stirred for 10 minutes. After separation of the water phase, the xylene is distilled off. 340 g of methyl-2-[4'-(4"-trifluoromethyl-phenoxy)-phenoxy]-propionate are obtained melting at 142° C. under 0.05 torr. According to gas chromatogram the content of pure final product is 99.4%, the residual content of unreacted acid is 0.6%, which corresponds to a yield of 99.4%.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:35])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:34])([CH3:33])[CH2:4]1.[CH2:36]([O:38][C:39]([C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=1)=[O:40])[CH3:37]>C1OCCC1>[CH2:36]([O:38][C:39](=[O:40])[C:41]1[CH:48]=[CH:47][C:44](/[CH:45]=[C:12](/[C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:3]([CH3:35])([CH3:2])[CH2:4][C:5]3([CH3:33])[CH3:34])\[CH3:13])=[CH:43][CH:42]=1)[CH3:37]
Reactant: CCOC(=O)c1ccc(C=O)cc1
Reactant: CC(c1ccc2c(c1)C(C)(C)CC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CC3(C)C)cc1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
300 ml of butylene oxide are added to 30.5 g of [1-(1,1,3,3-tetramethyl-5-indanyl)ethyl]-triphenylphosphonium bromide and 8 g of 4-ethoxycarbonylbenzaldehyde and the mixture is then stirred at 65° C. for 12 hours in an inert gas atmosphere. The resulting clear solution is cooled, introduced into ca 500 ml of ice/water and extracted twice with hexane. The organic extract is extracted three times with methanol/water, dried over sodium sulphate and concentreated under reduced pressure. The residue is purified by adsorption on silica gel using hexane/ether (19:1) for the elution. The p-[(E)-2-(1,1,3,3-tetramethyl-5-indanyl)propenyl]-benzoic acid ethyl ester obtained from the eluate melts at 70°-71° C. after recrystallization from ether/hexane.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]=[CH:19][CH:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)=[CH:12][CH:11]=2)=[C:6]([F:27])[C:5]=1[F:28])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]=[CH:19][CH:20]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]3)=[CH:12][CH:11]=2)=[C:6]([F:27])[C:5]=1[F:28])[CH3:2]
Reactant: CCOc1ccc(-c2ccc(CCC=CC3CCC(O)CC3)cc2)c(F)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOc1ccc(-c2ccc(CCC=CC3CCC(=O)CC3)cc2)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
The compound (s55) (7.4 g) and methylene chloride (100 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to 0° C. Dess-Martin periodinane (DMP; 9.7 g) was added in the temperature range of 0° C. to 5° C. After 1 hour of stirring at 0° C., the reaction mixture was allowed to come to room temperature, and the stirring was continued for another 8 hours. Celite was added to the reaction mixture, and unnecessary materials were removed. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder to give 4-(4-(4′-ethoxy-2′,3′-difluoro-1,1′-biphenyl-4-yl)but-1-en-1-yl)cyclohexanone (s56) (7.2 g). The yield based on the compound (s55) was 97.8%.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:13]1([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:25]2[CH:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:28][CH:27]=3)[CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][C:16]([O:41]CCCCCCCC)=[CH:17][CH:18]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>ClCCl>[CH2:50]([C:13]1([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:14]2[CH:15]=[C:16]([OH:41])[CH:17]=[CH:18][C:19]=2[C:20]2[C:25]1=[CH:24][C:23]([C:26]1[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:30][CH:31]=1)=[CH:22][CH:21]=2)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]
Reactant: CCCCCCCCCc1ccc(-c2ccc3c(c2)C(CCCCCCCC)(CCCCCCCC)c2cc(OCCCCCCCC)ccc2-3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCCCCCc1ccc(-c2ccc3c(c2)C(CCCCCCCC)(CCCCCCCC)c2cc(O)ccc2-3)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 1 M solution of boron tribromide in dichloromethane, (0.55 cm3, 0.00581 mol) was added dropwise to a stirred solution of 9,9-dioctyl-2-(4-nonylphenyl)-7-octyloxyfluorene (2.79 g, 0.00388 mol) and dichloromethane (100 cm3) at 0° C. The temperature was allowed to rise to RT overnight and the solution added to ice-water (200 cm3) with vigorous stirring. The product was extracted into diethyl ether (2×200 cm3). The combined organic extracts were washed with saturated aqueous sodium carbonate solution (150 cm3), dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography [silica gel, dichloromethane:hexane: 20:80] (yield 2.2 g, 93.4%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N:12]1([C:17]2[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1>ClCCCl>[OH:23][C:19]1[CH:18]=[C:17]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:22]=[CH:21][C:20]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: Oc1cccc(N2CCCC2)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)c1ccc(N2CCCC2)cc1O
Temperature: 60 °C
Yield: 36.3 %

Procedure:
A mixture of 14.8 g (0.1 mole) of phthalic anhydride, 16.3 g (0.1 mole) of 100 percent 3-pyrrolidinophenol and 50.0 ml of 1,2-dichloroethane was maintained at approximately 40° C. for approximately twenty-four hours, at approximately 60° C. for approximately twenty-four hours and at reflux temperature for approximately twelve hours. After cooling the reaction mixture to ambient temperature, the solid which precipitated was collected by filtration and washed with 500.0 ml of 1,2-dichloroethane. The solid was dissolved in dilute aqueous soduim hydroxide, the resulting mixture was filtered to remove insolubles. The filtrate was adjusted to pH 7.0 with the addition of glacial acetic acid and the solid tar-like material which formed was collected by filtration. To the filtrate an additional amount of glacial acetic acid was added. The solid which precipitated was collected by filtration, washed with water and dried to obtain 11.3 g of 2-(2-hydroxy-4-pyrrolidinophenyl)carbonylbenzoic acid, a pale pink-colored solid which melted at 190°-192° C. To the filtrate there was added an additional portion of glacial acetic acid and the solid which was collected by filtration, washed with water and dried to obtain 0.3 g a pale yellow-colored crystals of the desired product which melted at 193°-195° C. The infrared spectra of the two solids were identical having significant maxima at 1100 cm-1 (C=O;m). The nuclear magnetic spectra were consistent with the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)([O-:3])=[O:2].[NH2:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]([OH:31])([CH3:30])[CH3:29])[CH2:24][CH2:23]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[OH:31][C:28]([CH:25]1[CH2:26][CH2:27][CH:22]([CH2:21][NH:20][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[N:16][C:8]=2[O:7][C:6]2[CH:17]=[CH:18][CH:19]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:23][CH2:24]1)([CH3:30])[CH3:29]
Reactant: O=C(O)c1cccnc1Oc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(O)[C@H]1CC[C@H](CN)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)C1CCC(CNC(=O)c2cccnc2Oc2cccc([N+](=O)[O-])c2)CC1

Procedure:
A solution of 2-(3-nitro-phenoxy)-nicotinic acid (86.9 mg, 0.33 mmol), trans-2-(4-Aminomethyl-cyclohexyl)-propan-2-ol (57.2 mg, 0.33 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (148 mg, 0.33 mmol), and diisopropylethyl amine (0.29 mL, 1.67 mmol) in 10 mL of dry DMF was stirred overnight. The solution was then diluted with ethyl acetate and washed with water, 5% citric acid, saturated sodium bicarbonate, and brine, dried over magnesium sulfate and concentrated to an oil. Purified through a pad of silica eluted with ethyl acetate to give a clear oil (120 mg.) 1HNMR (CDCl3) δ1.04 (4H, dd), 1.14 (6H, s), 1.55 (2 s), 1.88 (4. m), 3.37 (2H, t) 7.23 (1H, m), 7.51 (1H, d), 7.64 (1H, t), 8.07 (1H, t), 8.16 (2H, m), 8.63 (1H, dd); MS: m/e 414 (M++1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:12]([OH:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:9]=1)=[O:7])[CH3:4].[CH2:28](Br)[CH:29]=[CH2:30].C(OCC)(=O)C>CS(C)=O>[CH2:3]([O:5][C:6]([C:8]1[C:12]([O:13][CH2:30][CH:29]=[CH2:28])=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:9]=1)=[O:7])[CH3:4]
Reactant: C=CCBr
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C=CCOc1c(C(=O)OCC)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 0.75 h

Procedure:
To a slurry of sodium hydride (39 mg of 60% in oil) in DMSO (2.4 ml) was added 5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester I-1d (300 mg, 0.8 mmol) and the mixture was agitated for 45 minutes. Allyl bromide (0.1 ml, 1.2 mmol) was added and stirring was continued for 4.5 hours. The reaction solution was diluted into ethyl acetate, washed with water (2×), brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound (I-1e) as an orange oil, 340 mg. This material was taken onto the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Cl.[CH2:11]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O>[CH2:11]([N:18]([C:7]1[CH:6]=[N:5][N:4]([CH3:9])[C:3](=[O:10])[C:2]=1[Cl:1])[CH2:19][CH2:20][CH2:21][OH:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Reactant: OCCCNCc1ccccc1
Agent: Cl
Solvent: O
Product: Cn1ncc(N(CCCO)Cc2ccccc2)c(Cl)c1=O
Reaction time: 8 h
Yield: 53.7 %

Procedure:
A solution of 11.48 g (64,1 mmol) of 4,5-dichloro-2-methyl-3(2H)-pyridazinone and 31.84 g (193.0 mmol) of 3-(N-benzylamino)propanol in 250 ml of water is boiled for 25 hours while stirring. The mixture is cooled, its pH is set with concentrated hydrochloric acid to 3 and it is extracted with 2×400 ml of ethyl acetate. The organic phase is dried and evaporated, 10 ml of ethyl acetate are added to the evaporation residue, then it is left to stand overnight at −10° C. The precipitated crystals are filtered and washed with ethyl acetate and then with diethyl ether. In this way 10.60 g (54%) of the title compound are obtained with a melting point of 94-95° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[CH:18]2.[N:24]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[NH:20]1[C:21]2[C:17](=[CH:16][C:15]([NH:14][C:5]3[C:4]4[C:9](=[CH:10][N:11]=[C:2]([NH:32][CH2:31][CH2:30][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]#[N:13])=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: NCCN1CCOCC1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc2[nH]ccc2c1
Product: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1ccc2[nH]ccc2c1
Yield: 55 %

Procedure:
Following the procedure described above in Example 34, 6-fluoro-4-(1H-indol-5-ylamino)-1,7-naphthyridine-3-carbonitrile was reacted with 2-morpholin-4-yl-ethylamine. The crude product was purified by flash column chromatography (2 to 10% methanol in methylene chloride) to give a yellow solid (0.103 g, 55%). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.4 (m, 4 H) 2.6 (t, J=6.8 Hz, 2 H) 3.4 (m, 2 H) 3.6 (m, 4 H) 6.5 (m, 2 H) 7.1 (dd, J=8.5, 1.9 Hz, 1 H) 7.2 (s, 1 H) 7.4 (m, 1 H) 7.4 (d, J=8.6 Hz, 1 H) 7.5 (d, J=1.8 Hz, 1 H) 8.1 (s, 1 H) 8.8 (s, 1 H) 9.7 (s, 1 H) 11.2 (s, 1 H).
Reaction SMILES: [S:1]1(=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].[C:13]1(C)C=CC=CC=1.S(OC)(OC)(=O)=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:13][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1](=[O:10])[CH2:2]1
Reactant: O=S1C=Nc2ccccc21
Reactant: Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CN1CS(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Benzothiazolone (3.78 g, 0.025 mole) was dissolved in a solution of sodium hydroxide (1.60 g, 0.0375 mole) in water (100 c.c.), and tetra-n-butylammonium bromide (0.24 g, 7.5×10-4 mole) and toluene (40 c.c.) were added thereto. Dimethyl sulfate (4.70 g, 0.0375 mole) was added dropwise thereto at room temperature, and the mixture was stirred at room temperature for 1 hour, followed by phase-separation. The toluene layer was washed once with water, and the solvent was removed under reduced pressure to obtain 4.14 g of N-methylbenzothiazolone as white crystals. Yield 100%, purity 97.7%, m.p. 70°-73.5° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[CH:22]([C@@H:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:33]#[N:34])[CH:30]=2)[CH2:25]1)=O>>[OH:21][C:18]([C:9]1[N:8]([C@@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][CH2:22][C@@H:24]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:33]#[N:34])[CH:30]=4)[CH2:25]3)[CH2:7][CH2:6]2)[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=1)([CH3:19])[CH3:20]
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCC(N)CC1
Reactant: N#Cc1ccc2c(c1)C[C@@H](C=O)C2
Product: Cc1ccc2c(c1)nc(C(C)(C)O)n2[C@H]1CC[C@@H](NC[C@H]2Cc3ccc(C#N)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of 2-[1-(4-amino-cyclohexyl)-5-methyl-1H-benzoimidazol-2-yl]-propan-2-ol (prepared as cis/trans-isomer mixture) and (S)-2-formyl-indan-5-carbonitrile through the same reductive amination method described previously. The crude mixture was separated through flash column chromatography using methylene chloride and methanol (20:1 to 10:1). The fraction with less retention time (higher Rf) gave cis-(S)-2-({4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-benzoimidazole-1-yl]-cyclohexylamino}-methyl)-indan-5-carbonitrile. The analysis of the 1H-NMR confirmed the cis-conformation of the cyclohexane. LC-MS showed a single peak, C28H34N4O (m/e) calcd 442.2733, obsd 443.3 (M+H). 1H-NMR (CD3OD) □ 7.82 (d, 1H), 7.55 (s, 1H), 7.49 (d, 1H), 7.41 (s, 1H), 7.38 (d, 1H), 7.03 (d, 1H), 5.30 (m, 1H), 3.23 (m, 2H), 2.71-2.93 (m, 8H), 2.43 (s, 3H), 1.98 (br d, 2H), 1.72 (s, 6H), 1.64 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:10]=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22].OO.S([O-])([O-])=[O:30].[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:21])[CH:10]=[N+:11]([O-:30])[C:12]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]1=[O:22]
Reactant: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c2c(c(O)c[n+]1[O-])C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 100 °C

Procedure:
A mixture of ethyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (22 g, 58 mol), glacial acetic acid (500 mL), and hydrogen peroxide (65.8 mL, 30% by weight in water) was heated at 100° C. for four hours. The resultant solution was cooled in an ice bath to 25° C. and treated with saturated aqueous sodium sulfite solution while keeping the reaction mixture below 40° C. When starch paper test showed complete consumption of residual peroxide, the solution was concentrated to two third of its volume, pH was adjusted to ˜3 with aqueous HCl and the solution was extracted with dichloromethane (3 times). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title product as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[Al](C)C.[N:14]1([CH2:20][C:21]2[CH:22]=[C:23]3[C:32]4[N:31]([CH:33]=2)[C:30](=[O:34])[C:29]([C:35](OCC)=[O:36])=[CH:28][C:27]=4[CH2:26][CH2:25][CH2:24]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:35]([C:29]2[C:30](=[O:34])[N:31]3[CH:33]=[C:21]([CH2:20][N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)[CH:22]=[C:23]4[CH2:24][CH2:25][CH2:26][C:27]([CH:28]=2)=[C:32]34)=[O:36])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c3c(cc(CN4CCOCC4)cn3c1=O)CCC2
Reactant: NCc1ccc(Cl)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cc2c3c(cc(CN4CCOCC4)cn3c1=O)CCC2
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 4-chlorobenzylamine (142 mg, delivered as a 1M methylene chloride solution) in anhydrous CH2Cl2 (3 mL), is added trimethylaluminum (482 μL, 2 M solution in heptane). After two hours at room temperature, ethyl 6-(morpholin-4-ylmethyl)-3-oxo-9,10-dihydro-3H,8H-pyrido[3,2,1-ij]quinoline-2-carboxylate (Preparation 18, 327 mg) is added as a solid in one portion. Stirring is continued for 2.5 hours before quenching with 10 mL of a 35% aqueous solution of Rochelle's salt. This biphasic, gelatinous mixture is stirred for two hours before separating the layers and extracting the aqueous layer five times with CH2Cl2. The resulting solution is concentrated in vacuo to give a bright yellow solid which is recrystallized from acetone (reflux, 62 mL/g) to afford 251 mg (73%) of the title compound as a canary yellow solid. Physical characteristics: M.p. 200-201° C.; 1H NMR (CDCl3); δ10.2, 9.07, 8.54, 7.41, 7.33, 7.28, 4.67, 3.71, 3.53, 3.02, 2.48, 2.02; 13C NMR (CDCl3): δ165.5, 157.5, 140.6, 138.6, 137.7, 134.7, 132.7, 130.9, 129.0, 128.6, 127.1, 125.2, 113.1, 109.2, 66.8, 60.4, 53.6, 42.9, 30.4, 28.7, 21.3; HRMS m/z 452.1747 (C25H26ClN3O3+H).