Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH2:16][C:17]([C:19]1[C:28]2[O:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:25]([CH3:35])[C:24](=[O:36])[C:23]=2[CH:22]=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].[ClH:43]>CO.CC(C)=O>[ClH:43].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][C:17]([C:19]2[C:28]3[O:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:25]([CH3:35])[C:24](=[O:36])[C:23]=3[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)CBr)cccc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(CC(=O)c2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Reaction time: 4 h

Procedure:
A solution of 11.5 g of 1-(2-methoxyphenyl)-piperazine in 30 ml of methanol was added dropwise at 20°-25° C. to a stirred mixture consisting of 21.4 g of Intermediate VI and 4.1 g of potassium carbonate in 120 ml of methanol. After 4 hours stirring at the same temperature, the reaction mixture was stripped in vacuo. The residue was extracted with chloroform and the organic solution was washed with water, dried on anhydrous sodium sulfate/calcium chloride, filtered and stripped in vacuo. The obtained crude product was dissolved in acetone and a slight excess of ethanolic hydrogen chloride was added. After collection by suction filtration and recrystallization from 95% ethanol, 16.3 g of the title compound was obtained (m.p. (189) 195°-199° C.).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15]>O1CCOCC1>[CH2:14]([N:13]([CH2:16][CH3:17])[CH:12]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3])[CH3:15]
Reactant: CCN(CC)C(OC)OC
Reactant: CC(=O)c1cccnc1
Solvent: C1COCCO1
Product: CCN(C=CC(=O)c1cccnc1)CC

Procedure:
A mixture of 0.10 mole of 3-acetylpyridine and 0.10 mole of N,N-diethylformamide dimethylacetal in 100 ml of dioxane was refluxed for 10 hours. The solvent was removed, giving 3-diethylamino-1-(3-pyridinyl)-2-propen-1-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].CS(O[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:25][CH2:24]2)=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOS(C)(=O)=O)CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 90 °C

Procedure:
A 100 mL flask was charged with 4-nitro-3-(trifluoromethyl)phenol (commercially available from Acros; 0.31 g, 1.8 mmol), tert-butyl 4-(3-(methylsulfonyloxy)propyl)-piperazine-1-carboxylate (0.64 g, 2.0 mmol), cesium carbonate (1.2 g, 3.6 mmol) and DMA. The reaction mixture was heated to 90° C. for 15 hours. The reaction mixture was allowed to cool to room temperature, extracted with ethyl acetate and 10% aqueous lithium chloride solution. The organic solvent was removed on a rotary evaporator under reduced pressure to yield tert-butyl 4-(3-(4-nitro-3-(trifluoromethyl)phenoxy)propyl)piperazine-1-carboxylate that was used without further purification. MS (EI): 434 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][C:16]([N+:19]([O-])=O)=[CH:17][CH:18]=[C:11]3[C:10]2=[O:22])[CH2:4]1)[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[NH2:19][C:16]1[CH:15]=[C:12]2[C:13](=[O:14])[N:9]([CH:5]3[CH2:6][CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4]3)[C:10](=[O:22])[C:11]2=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: CCN1CCCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCN1CCCC(N2C(=O)c3ccc(N)cc3C2=O)C1

Procedure:
2.8 Grams of 1-ethyl-3-(4-nitrophthalimido)piperidine were dissolved in 50 milliliters of hot glacial acetic acid and were hydrogenated at 50° C. and 50 p.s.i. in the presence of 0.1 grams of 5% palladium-on-charcoal catalyst until the theoretical amount of hydrogen was taken up. The hot solution was filtered and the mixture cooled and the solid formed was filtered and dried to give 1.06 grams of the title compound in the form of the monohydrochloride.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:40])C(=O)C1>C(Cl)Cl>[Br:40][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1
Reactant: COC(=O)c1ccc(CO)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)cc1C

Procedure:
410 mg of dimethyl 2-methylterephthalate was hydrolyzed via Procedure M and purified by ISCO Combi-Flash to afford 4-(methoxycarbonyl)-3-methylbenzoic acid. 255 mg of 4-(methoxycarbonyl)-3-methylbenzoic acid was cooled to 0° C. in 2 mL of THF before a solution of 2.6 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at ˜50% complete by TLC. The reaction was re-cooled to 0° C. and another 2.6 mL of BH3-THF was added dropwise before the ice bath was removed. Upon completion, the reaction was re-cooled to 0° C. and quenched with 3N HCl dropwise. The aqueous layer was extracted 2 times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(hydroxymethyl)-2-methylbenzoate. 220 mg of methyl 4-(hydroxymethyl)-2-methylbenzoate was cooled to 0° C. in 5 mL of DCM before adding 260 mg of Triphenylphosphine and 395 mg of NBS. The reaction was concentrated and directly purified via ISCO Combi-Flash to give pure methyl 4-(bromomethyl)-2-methylbenzoate. 255 mg of methyl 4-(bromomethyl)-2-methylbenzoate was reacted via Procedure O to give methyl 2-methyl-4-(methylsulfonylmethyl)benzoate. 250 mg of methyl 2-methyl-4-(methylsulfonylmethyl)benzoate was then hydrolyzed upon heating to 45° C. for 1 hour via Procedure M to give 2-methyl-4-(methylsulfonylmethyl)benzoic acid. 202 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-methyl-4-(methylsulfonylmethyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonylmethyl)benzamide. MS (Q1) 415 (M)+.
Reaction SMILES: O[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15]CC(C)(C)N=3)=[C:10]([CH3:21])[CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.C(O)(=[O:25])C>>[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:15])=[O:25])=[C:10]([CH3:21])[CH:9]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Cc1cc(C2(O)CCCCC2)ccc1C1=NC(C)(C)CO1
Agent: Cl
Product: Cc1cc(C2=CCCCC2)ccc1C(=O)O

Procedure:
To a solution of 2-[4-(1-hydroxy-1-cyclohexyl)-2-methylphenyl]-4,4-dimethyl-2-oxazoline (4.29 g) in acetic acid (40 ml) is added a 10% hydrochloric acid (20 ml), and the mixture is refluxed for two days. The precipitated crystals are collected by filtration, washed with water, and dried to give 4-cyclohexenyl-2-methylbenzoic acid (2.61 g) as white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[C:30]([CH2:31][CH:32]=O)=[C:29]2[C:24]([C:25](=[O:36])[CH2:26][C:27]([CH3:35])([CH3:34])[O:28]2)=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:19][O:20][C:21]1[C:30]([CH2:31][CH2:32][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=4)[CH:9]=[CH:8]3)[CH2:5][CH2:6]2)=[C:29]2[C:24]([C:25](=[O:36])[CH2:26][C:27]([CH3:35])([CH3:34])[O:28]2)=[CH:23][CH:22]=1
Reactant: NC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Reactant: COc1ccc2c(c1CC=O)OC(C)(C)CC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc2c(c1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)OC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
120 mg of 1-(piperidin-4-yl)-1H-indole-6-carboxamide and 163 mg of (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)acetaldehyde were dissolved in 10 ml of methylene chloride. Thereafter, 0.06 ml of acetic acid was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 15 minutes. Thereafter, 157 mg of sodium triacetoxyborohydride was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (methanol-ethyl acetate), followed by solidification with ethyl acetate, so as to obtain 220 mg of the subject compound.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([C:24](=[O:26])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1.[CH3:27][Mg]Br.CCOCC>O1CCCC1>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([C:24]([OH:26])([CH3:27])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C(C)(C)O)c3)ccc2o1
Reaction time: 8 h

Procedure:
The product from Example 136C (87 mg, 0.25 mmol) was dissolved into tetrahydrofuran (5 mL), treated with 3 M methylmagnesium bromide in ether (0.3 mL, 0.9 mmol), stirred overnight, quenched with 0.5 M aqueous dipotassium hydrogen phosphate, and diluted with EtOAc and a little CH2Cl2. The resulting emulsion was sonicated, and the aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, dried (Na2SO4), concentrated, and chromatographed on silica with a gradient of 2 to 10% MeOH/20% MeCN/CH2Cl2 followed by 10% MeOH/CH2Cl2 to provide the title compound as an orange resin (˜33% yield). 1HNMR (300 MHz, CD3OD) δ 1.20 (d, 3H), 1.42-1.58 (m, 1H), 1.58 (s, 6H), 1.76-1.90 (m, 2H), 1.96-2.12 (m, 1H), 2.3-2.7 (m, 3H), 2.97-3.13 (m, 2H), 3.22-3.4 (m, 2H), 6.62 (s, 1H), 7.38 (dd, 1H), 7.40-7.46 (m, 2H), 7.46-7.48 (m, 2H), 7.72 (dd, 1H), 7.76 (dd, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:6]([CH3:15])=[CH:5][C:4]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[C:20]([CH3:30])=[CH:19][N:18]=1.[F:31][C:32]([F:37])([F:36])[C@@H:33]1[CH2:35][O:34]1>CN(C=O)C>[CH3:15][C:6]1[CH:5]=[C:4]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[C:20]([CH3:30])=[CH:19][N:18]=2)[C:3]([CH3:2])=[CH:8][C:7]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:35][C@H:33]([OH:34])[C:32]([F:37])([F:36])[F:31])[CH2:11][CH2:10]1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2C)n[nH]1
Reactant: FC(F)(F)[C@@H]1CO1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C[C@H](O)C(F)(F)F)CC4)cc3C)ncc2C)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-5-methyl-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine hydrochloride (36.0 mg, 0.084 mmol) in DMF (0.5 mL) were added TEA (23.4 μL, 0.168 mmol) and (S)-2-(trifluoromethyl) oxirane (72.8 μL, 0.84 mmol). The reaction mixture was stirred at room temperature overnight, and purified by preparative RP-HPLC to provide (S)-3-(4-(2,5-dimethyl-4-(5-methyl-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)phenyl)piperidin-1-yl)-1,1,1-trifluoropropan-2-ol; ESMS m/z 504.3 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:46]=[CH:45][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:26]=4[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:20][C:19]=3[N:36](C)[C:37](=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:47].O1CCOCC1>>[ClH:47].[C:32]([C:26]1[CH:27]=[C:28]([OH:31])[CH:29]=[CH:30][C:25]=1[O:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]=[C:15]([CH2:14][O:13][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][CH:4]4[S:3][C:2](=[O:1])[NH:6][C:5]4=[O:7])=[CH:46][CH:45]=3)[N:36]([CH3:37])[C:19]=2[CH:20]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2C(C)(C)C)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(O)cc3C(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of t-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetylamino]-5-(2-t-butyl-4-hydroxyphenoxy)phenyl}-N-methylcarbamate (1.24 g) and 4N hydrogen chloride/dioxane (20 ml) was stirred at room temperature for 14 hours. The solvent of the reaction mixture was evaporated to dryness and to the residue was added ethyl acetate and insoluble product was isolated by filtration and washed with ethyl acetate to give the title compound (0.75 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:12][C:13](N)=[O:14]>>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:13](=[O:14])[NH:12][C:4]2=[O:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: NC(N)=O
Product: O=c1[nH]c(=O)c2cc(I)ccc2[nH]1

Procedure:
Prepared according to general method B from 2-amino-5-iodobenzoic acid (5.0 g) and urea (11.4 g). Yield: 5.34 g (98%) of a solid. 1H-NMR (DMSO-δ6) δ (ppm) 8.04 (d, J=2.0 Hz, 1H), 7.77 (dd, J=2.1 Hz, J=8.6 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[CH:5][C:6]([N+:17]([O-:19])=[O:18])=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=1.[CH:24]([C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31](B(O)O)[CH:32]=1)([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1>[CH:24]([C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31]([C:7]2[CH:8]=[C:3]([O:2][CH3:1])[C:4]([C:20]([F:23])([F:22])[F:21])=[CH:5][C:6]=2[N+:17]([O-:19])=[O:18])[CH:32]=1)([CH3:26])[CH3:25]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1cc(OC)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
Trifluoromethanesulfonic acid 5-methoxy-2-nitro-4-trifluoromethyl-phenyl ester (2.6 g) is dissolved in 1,4-dioxane (20 ml) and thereto is added 5-isopropyl-2-methoxybenzene boronic acid (1.5 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (575 mg) and cesium carbonate (3.44 g), and the mixture is stirred under nitrogen atmosphere at 80° C. overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a saturated aqueous sodium bicarbonate solution, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=49:1→17:3) to give 5′-isopropyl-5,2′-dimethoxy-2-nitro-4-trifluoromethyl-biphenyl (2.35 g). MS (m/z): 370 [M+H]+
Reaction SMILES: [K].[CH3:2][N:3]([CH3:37])[C:4]1[CH:33]=[C:32]([N:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:5]=1[CH:6]([C:18]1[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:8]=1>>[CH3:37][N:3]([CH3:2])[C:4]1[CH:33]=[C:32]([N:34]([CH3:35])[CH3:36])[CH:31]=[CH:30][C:5]=1[C:6]1([C:7]2[CH:8]=[CH:9][C:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:11][CH:12]=2)[C:18]2[C:19](=[CH:23][C:24]([N:27]([CH3:28])[CH3:29])=[CH:25][CH:26]=2)[C:20](=[O:22])[O:21]1
Reactant: CCN(CC)c1ccc(C(c2ccc(N(C)C)cc2C(=O)O)c2ccc(N(C)C)cc2N(C)C)cc1
Agent: [K]
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3cc(N(C)C)ccc32)cc1

Procedure:
Employing a procedure similar to that described in Example 1, part C above, the potassium salt of 2-[2,4-bis(dimethylamino)-4'-diethylaminobenzhydryl]-5-dimethylaminobenzoic acid from A was oxidized to obtain 11.4 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(4-diethylaminophenyl)-6-dimethylaminophthalide (Formula I: R=CH3 ; X=H; Y=4-(C2H5)2NC6H4 ; Z=2,4-[(CH3)2N]2C6H3) as a tan solid melting at 123°-125° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].[CH3:13][N:14](P(N(C)C)(N(C)C)=O)[CH3:15].CNC>O>[F:9][CH:8]([F:10])[C:4]1[C:3]([CH:11]=[O:12])=[C:2]([N:14]([CH3:15])[CH3:13])[N:6]([CH3:7])[N:5]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Agent: CNC
Solvent: O
Product: CN(C)c1c(C=O)c(C(F)F)nn1C
Temperature: 50 °C
Reaction time: 12 h
Yield: 51.6 %

Procedure:
To mixture of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (34 g, 0.17 mol) and HMPA (50 mL) was added a 40% aqueous solution of dimethylamine (66.3 mL). The reaction mixture was stirred for at 50° C. for 12 h, diluted with water (1 L), and the product was extracted with dichloromethane (2×100 mL). The combined organic layers were dried with sodium sulfate and evaporated. The liquid residue was purified chromatographically on silica gel using dichloromethane/ethyl acetate as eluent (1:3, Rf=0.25) to give 17.81 g (51.6%) of the title product. Satisfactory C,H,N-analysis was obtained. 1H NMR (400 MHz, DMSO-d6): δ 2.93 (s, 6H), 3.72 (s, 6H), 7.07 (t, J=56 Hz, 1H), 9.94 (s, 1H). GC-MS calcd for C8H11F2N3O: 203.09, found (M+): 203 m/z.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[C:12]([CH3:29])[CH:11]=1)(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:29][C:12]1[CH:11]=[C:10]([S:7]([NH:6][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)(=[O:8])=[O:9])[CH:15]=[CH:14][C:13]=1[O:16][C@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3ccnn3C)c(C)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)ccc1O[C@H]1CCCC[C@@H]1c1ccnn1C
Yield: 81.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (79 mg, 0.14 mmol) prepared in Example 54a, triethylsilane (0.1 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (4.0 mL), to yield the title compound (49 mg, 84%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Product: Cc1cc(N2CCCC2)c2ccc(OCc3ccc(C#N)cc3)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 4-bromomethyl benzonitrile whereby the product was isolated as free base, 4-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile as a brown solid. ISP mass spectrum, m/e: 344.4 (M+1 calculated for C22H21N3O: 344).
Reaction SMILES: C([O:4][C:5]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C@@H:9]1[CH2:11][O:10]1)C=C.[C:24]1(C)[CH:29]=C(C)C=C(C)[CH:25]=1>>[CH2:29]([C:15]1[C:5]2[O:4][CH:9]([CH2:11][OH:10])[CH2:8][O:7][C:6]=2[CH:12]=[CH:13][C:14]=1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:24]=[CH2:25]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1cc(OCc2ccccc2)ccc1OC[C@@H]1CO1
Product: C=CCc1c(OCc2ccccc2)ccc2c1OC(CO)CO2
Reaction time: 15 h

Procedure:
A solution of (2S)-2-{[2-(allyloxy)-4-(benzyloxy)phenoxy]methyl}oxirane (28.5 g, 91.3 mmole) in 1 L of mesitylene was refluxed under nitrogen for 2 days. The solvent was then removed in vacuum and replaced with 500 mL of ethanol. Sodium bicarbonate (25.0 g) was added and the mixture was stirred under nitrogen for 15 hours. The mixture was filtered, the ethanol was removed in vacuum and 500 mL of methylene chloride added. This solution was washed with 500 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum to a dark oil. This was column chromatographed on silica gel with methylene chloride as eluant to give 15.6 g of the (S)-enantiomer of the title compound as a tan oil. 1H-NMR (CDCl3): multiplet 7.4 δ (5H); doublet 6.7 δ (1H); doublet 6.5 δ (1H); multiplet 6.0 δ (1H); singlet 5.05 δ (2H); multiplet 5.0 δ (2H); multiplet 4.3 δ (2H); doublet of doublets 4.1 δ (1H); doublet of doublets 3.8 δ (2H); multiplet 3.5 δ (2H), broad singlet 1.9 δ (1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:5][C:6]1[C:7]([CH2:15][CH3:16])=[N:8][N:9]([CH2:13][OH:14])[C:10]=1[CH2:11][CH3:12].ClC(Cl)(Cl)[C:23]([N:25]=C=O)=[O:24]>ClCCl>[C:23](=[O:24])([O:14][CH2:13][N:9]1[C:10]([CH2:11][CH3:12])=[C:6]([CH2:5][C:4]2[CH:17]=[C:18]([Cl:20])[CH:19]=[C:2]([Cl:1])[CH:3]=2)[C:7]([CH2:15][CH3:16])=[N:8]1)[NH2:25]
Reactant: CCc1nn(CO)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1nn(COC(N)=O)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
A solution of the alcohol of Example 41 (280 mg, 0.90 mmol) in dichloromethane (5 ml) was cooled to 0° C., treated with trichloroacetyl isocyanate (128 μl, 1.1 mmol) and stirred at 0° C. for 30 minutes. The solution was soaked into a pad of alumina (neutral, activity II, Brockmann), washed with dichloromethane and then extracted with ethyl acetate. The organic extract was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a solvent gradient of cyclohexane:ethyl acetate (2:1, by volume) gradually changing to cyclohexane:ethyl acetate (1:1, by volume) to afford the title compound (238 mg) as a solid, m.p. 153–155° C.
Reaction SMILES: [CH2:1]=O.[CH2:3]([NH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)=[O:23])=[C:17]2[OH:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:11][C:12]2[C:21]3=[C:16]([C:17](=[O:33])[C:18]([C:22]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)=[O:23])=[CH:19][N:20]3[CH2:1]1)[CH:15]=[C:14]([CH2:34][N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1)[CH:13]=2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(CNCc3ccccc3)cc(CN3CCOCC3)cc2c1O
Reactant: C=O
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(CN4CCOCC4)cc3c1=O)CN(Cc1ccccc1)C2

Procedure:
Aqueous formaldehyde (0.25 ml, 37% solution) is added to a solution of 8-((benzylamino)methyl)-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (Preparation 29, 60 mg) in methanol (2.5 mL) at 50° C. The solution is allowed to cool and the resulting precipitate is filtered and washed with methanol to give 38 mg of the title compound. Physical characteristics: M.p. 203-205° C.; 1H NMR (DMSO-d6) δ2.38, 3.57, 3.73, 4.20, 4.57, 5.29, 7.2-7.4, 7.51, 8.08, 8.74, 10.4. Anal. Found: C, 68.50; H, 5.72; N, 10.29.