Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]#[N:12].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][CH2:2][C:3]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]#[N:12])=[O:4]
Reactant: N#C[C@@H]1CCCN1
Reactant: O=C(Br)CBr
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#C[C@@H]1CCCN1C(=O)CBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
To a cold solution (−10° C.) of bromoacetyl bromide (2.0 g, 10.0 mmol) in CH2Cl2 (30 mL), a solution of (S)-pyrrolidine-2-carbonitrile (480 mg, 5.0 mmol) and pyridine (1.4 g, 210 mmol) together with a catalytic amount of DMAP (50 mg) in CH2Cl2 (10 mL) was added over a 30 minute period. After stirring for about 10 minutes, the reaction temperature was gradually increased to room temperature. Stirring at room temperature was continued overnight. The residue was diluted with CH2Cl2 (60 mL), washed with ice water and cold 10% sodium bicarbonate aqueous solution to give crude product (1.01 g; yield of 93%). Column chromatography purification of the crude product resulted in pure 1-(2-bromo-acetyl)-(S)-pyrrolidine-2-carbonitrile (892 mg; 82.6% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:34])[NH:29]2.C([BH3-])#N.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:17])([F:18])[F:19])[CH2:14][NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28](=[O:34])[NH:29]3)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)(CC(O)(CNc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1cc(F)cc2c1OCC2

Procedure:
Analogously to Example 1, the corresponding imine is produced starting from 250 mg of 4-(2,3-dihydro-5-fluoro-7-benzofuranyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 124 mg of 5-aminoquinolin-2[1H]-one. After reaction with sodium cyanoborohydride, the title compound is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:44]=[CH:43][C:6]2[CH:7]([C:17]3[C:18](=[O:42])[NH:19][C:20](=[O:41])[N:21]([C:23]4[N:28]=[C:27]([NH:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[C:26]([N+:38]([O-:40])=[O:39])=[CH:25][N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([C:3]1[CH:44]=[CH:43][C:6]2[CH:7]([C:17]3[C:18](=[O:42])[NH:19][C:20](=[O:41])[N:21]([C:23]4[N:28]=[C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])[C:26]([N+:38]([O-:40])=[O:39])=[CH:25][N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ncc([N+](=O)[O-])c(NCC(=O)OC(C)(C)C)n2)c(=O)[nH]c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ncc([N+](=O)[O-])c(NCC(=O)O)n2)c(=O)[nH]c1=O

Procedure:
A solution of the product from example 28 step (ii) (0.07 g) in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stirred overnight and evaporated. The residue was triturated with ether and filtered off. Yield 0.05 g.
Reaction SMILES: FC(F)(F)C1C=C(N[N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])C=CC=1.[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C(#N)CC#N.O.[NH2:35][NH2:36]>>[F:18][C:19]([F:27])([F:28])[C:20]1[CH:21]=[C:22]([NH:23][N:10]=[C:11]2[C:12]([NH2:13])=[N:36][N:35]=[C:14]2[NH2:15])[CH:24]=[CH:25][CH:26]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1cccc(C(F)(F)F)c1

Procedure:
4-[(3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 119 mg (0.5 mmol) of 2-[(3-trifluoromethylphenyl)hydrazono]malononitrile, which was derived from 3-(trifluoromethyl)aniline (125 μL, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed in the reaction tube approximately 10 minutes after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 43 mg (31%) of the compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([N:17]2C(=O)C3C(=CC=CC=3)[C:18]2=[O:27])[C:13](=[O:28])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.[C:31]1([C:37]2[N:42]=[CH:41][C:40](C(Cl)=O)=[CH:39][N:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([NH:17][C:18]([C:40]2[CH:41]=[N:42][C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:38][CH:39]=2)=[O:27])[C:13](=[O:28])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCN(N2C(=O)c3ccccc3C2=O)C(=O)C1
Reactant: O=C(Cl)c1cnc(-c2ccccc2)nc1
Agent: NN
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(NN1CCN(C(=O)OCc2ccccc2)CC1=O)c1cnc(-c2ccccc2)nc1
Yield: 183.8 %

Procedure:
A solution of 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-oxo-piperazine-1-carboxylic acid benzyl ester (53 mg, 0.14 mmol) in MeOH (10 mL) is treated with anhydrous hydrazine (0.3 mL, 9.56 mmol). The reaction mixture is stirred at reflux under N2 for 3.5 h. The reaction mixture is concentrated. The residue is dissolved in a mixture of DMF (2 mL) and DCM (2 mL), and treated with 2-phenyl-pyrimidine-5-carbonyl chloride (32 mg, 0.15 mmol). The mixture is stirred under N2 for 16 h, and then diluted with EtOAc (35 mL). The mixture is washed successively with saturated aqueous KHCO3, (15 mL), water (2×15 mL), and saturated aqueous NaCl (15 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue is purified by flash silica gel chromatography (80:20 to 0:100 heptane:EtOAc gradient elution) to afford 3-oxo-4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-piperazine-1-carboxylic acid benzyl ester as an oil (111 mg, 18%). MS: 432 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.70-10.10 (br, 1H), 9.06 (s, 2H), 8.46 (dd, J=7.8, 1.7 Hz, 2H), 7.44-7.60 (m, 3H), 7.25-7.40 (m, 5H), 5.18 (s, 2H), 4.36 (s, 2H), 3.93 (t, J=5.1 Hz, 2H), 3.69-3.81 (br s, 2H). IC50=103.5 nM.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[NH:11][NH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([CH:7]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[NH:11][NH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCCCCCCCN1NNN=C1C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCCCN1NNN=C1C(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 92.9 %

Procedure:
A mixture of methyl 5-(diphenylmethyl)-2H-tetrazole-1-nonanoate (5.00 g, 12 mmol), 5N NaOH solution (7.40 mL, 36 mmol) and methanol (100 mL) was heated to reflux on a steam bath. After 20 minutes, the mixture was concentrated, diluted with water and 2N HCl solution and a white solid collected by filtration. Recrystallization from a mixture of CH2Cl2 and hexanes gave 5-(diphenylmethyl)-2H-tetrazole-1-nonanoic acid (4.40 g, 90%), mp 68°-70° C.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[NH:6][C:7](=[O:14])[C:8]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[N:4]2[N:3]=1.CI.[CH3:18]N(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1[CH:15]=[C:5]2[N:6]([CH3:18])[C:7](=[O:14])[C:8]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[N:4]2[N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc2[nH]c(=O)c3cnccc3n2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: Cc1cc2n(C)c(=O)c3cnccc3n2n1
Temperature: 25 °C

Procedure:
2 g. of 2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin5(4H)-one are treated with 2 g. of methyl iodide in 20 ml. of dimethylformamide in the presence of 2 g. of potassium carbonate at 70° with stirring for 12 hours. The mixture is cooled to room temperature, 20 ml. of water are added and the precipitated 2,4-dimethylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5(4H)-one is filtered off, yield: 1.5 g. (70%); m.p. > 300° (DMF).
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=1.O>CN(C)C=O>[CH3:21][O:20][C:13]1[CH:12]=[C:11]([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18]
Reactant: Sc1ccccc1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
Using the procedure reported in Chem. Pharm. Bull. 40(2), 351-6, 1992, sodium hydride (60% suspension in mineral oil, 1.26 g, 44 mmol) was added to 40 mL of dimethyl formamide (DMF) at 0° C., and a solution of benzenethiol (2.25 g, 22 mmol) in 5 mL of DMF was added dropwise over five minutes, followed by stirring for 30 minutes. A solution of 4-chloro-2-methoxy-1-nitro-benzene (3.25 g, 20 mmol) in 25 mL of DMF was then added dropwise to the reaction mixture over 30 minutes, after which stirring was continued for another hour. Sixty mL of water was added to the reaction mixture, and a solid precipitated and was collected and dried under vacuum to yield 4.63 g (17.7 mmol, 89%) of 2-methoxy-1-nitro-4-phenylsulfanyl-benzene. MS: 262 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].F[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.O>CN(C)C=O>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[CH3:1][C:2]1[N:3]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:4]=[CH:5][CH:6]=1
Reactant: Fc1cccnc1
Reactant: Cc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccn(-c2cccnc2)n1
Product: Cc1ccnn1-c1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 6 %
Yield: 51.2 %

Procedure:
To a solution of 3-methyl-1H-pyrazole (10.99 g, 134 mmol) in N,N-dimethylformamide (100 ml) at 0° C. was added sodium hydride (3.71 g, 154 mmol, 60% dispersion). The reaction was stirred at 0° C. for 2 hours. 3-Fluoropyridine (10.0 g, 103 mmol) was added, and the reaction was stirred at 100° C. overnight. The reaction was cooled to room temperature and water was added slowly. The mixture was extracted with dichloromethane and the combined organic phases were washed with brine, concentrated and chromatographed (0-100% ethyl acetate/hexanes) to afford 3-(3-methyl-1H-pyrazol-1-yl)pyridine (8.4 g, 52.77 mmol, 51.2%) and 3-(5-methyl-1H-pyrazol-1-yl)pyridine (1.0 g, 6%). Analytical data of both products is consistent with that reported under Example 6, Step 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][N:17]=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.CCO.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(C(C)(C)C)ncc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a stirring suspension of ethyl 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-tert-butylpyrimidine-5-carboxylate (0.49 g, 1.24 mmol) in 1:1:1 THF/EtOH/H2O (9 ml) at RT was added LiOH.H2O (120 mg, 4.94 mmol) and the mixture was stirred overnight at RT. The reaction mixture was checked by LC-MS and the completed reaction was concentrated to an aqueous residue, acidified (pH 3-4) with 3M HCl and the solution was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried (MgSO4), filtered and concentration. The crude was dissolved in isopropanol and the solid (LiCl and NaCl) was filtered and washed with isopropanol. The filtrate was concentrated to obtain the desired product 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-tert-butylpyrimidine-5-carboxylic acid (0.36 g, 80% yield). MS (ESI) m/z: 365.0 (M+H+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([C:40]([NH:42][CH3:43])=[O:41])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:45].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:45].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[CH:36]=[C:35]([O:38][CH3:39])[CH:34]=[C:33]([C:40]([NH:42][CH3:43])=[O:41])[C:32]=5[CH:31]=[CH:30][C:29]4=[O:44])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CNC(=O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5 mL of an ethyl acetate solution containing 369 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-5-((methylamino)carbonyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 9 mL of 4 mol/L hydrogen chloride/ethyl acetate was added and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, ethyl acetate was added to the residue thus obtained, and the resulting solid was filtered to give 205 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinoline-5-carboxamide hydrochloride as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[N:15]=[C:14]([Cl:16])[N:13]=[C:12]([N:17]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[CH:18]2[CH3:26])[CH:11]=1>CN(C)C=O>[ClH:16].[CH3:9][C:10]1[N:15]=[C:14]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=[C:12]([N:17]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[CH:18]2[CH3:26])[CH:11]=1
Reactant: Cc1cc(N2CCc3ccsc3C2C)nc(Cl)n1
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cc1cc(N2CCc3ccsc3C2C)nc(Nc2ccc(F)cc2)n1
Product: Cl
Yield: 71.6 %

Procedure:
After 4-fluoroaniline(0.4 ml, 3.7 mmol) was added to a mixture solution of 6-methyl-4-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl)-2-chloropyrimidine(0.7 g, 2.5 mmol) and dimethylformamide(10 ml), 0.7 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>CO>[CH:14]([N:6]1[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]1[CH2:4][C:3]([OH:17])=[O:2])([CH3:16])[CH3:15]
Reactant: COC(=O)CC1c2ccccc2CN1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1Cc2ccccc2C1CC(=O)O
Reaction time: 48 h
Yield: 85.3 %

Procedure:
To the compound of Step B (0.53 g., 2.30 mmol) in MeOH (5.1 mL) was added 1.0N NaOH (2.53 mL, 2.53 mmol). After two days, the solution was concentrated to dryness. The resulting residue was diluted with 1.0N HCl and water was loaded onto a strong cation exchange resin. The resin was washed with water, THF/water (1:1) and then water. The product was then eluted from the resin with pyridine/water (1:9). The eluent was concentrated to dryness to afford about 0.43 g (85%) of the final compound. EIS-MS 220 [M+1].
Reaction SMILES: [H-].[Na+].C(=O)=O.[N:6]1([CH2:11][CH:12]([OH:25])[CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:10]=[CH:9][N:8]=[CH:7]1.[Cl:26][C:27]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:28]=1[CH2:29]Cl>C(COC)OC.O.CC(C)=O>[Cl:26][C:27]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:28]=1[CH2:29][O:25][CH:12]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)[CH2:11][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)c1ccc(SCC(O)Cn2ccnc2)cc1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(SCC(Cn2ccnc2)OCc2ccc(Cl)cc2Cl)cc1
Temperature: -20 °C

Procedure:
A dry 250-ml round bottom flask equipped with stir bar, addition funnel and N2 inlet was charged with dry dimethoxyethane (25 ml) and sodium hydride [60% (0.79 g, 0.0265 moles)]. The resulting slurry was cooled to -35° C. (with an external dry ice and acetone bath); then 1-(1-imidazolyl)-3-(4-tert-butylphenylthio)-propan-2-ol, 5.0 g (0.0172 moles), in 10 ml dry dimethoxyethane was added dropwise. After the addition was complete, the reaction mixture was allowed to warm to about -20° to -10° C. and was stirred at that temperature until no more H2 evolution was apparent. The reaction mixture was then cooled to -20° C. and 3.7 g (0.0189 mole) 2,4-dichlorobenzyl chloride were added very slowly. After the addition was complete, the reaction mixture was allowed to come to room temperature and was allowed to stir overnight. The reaction mixture was poured into water and ice and then extracted with ethyl acetate (twice). The ethyl acetate extracts were combined and washed with water until neutral. The ethyl acetate phase was dried, filtered, and then concentrated to give an oil which was chromatographed to give 2.0 g of the above-identified product.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[F:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:22]1[C:21]2[C:25](=[CH:26][C:18]([F:17])=[CH:19][CH:20]=2)[NH:24][C:23]1=[O:27])([CH3:3])[CH3:2]
Reactant: O=C1Cc2ccc(F)cc2N1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(F)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-fluoro-2-oxindole to give 0.3 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-6-fluoro-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][CH2:11][N:12]1[C:20]2[N:19]=[CH:18][NH:17][C:16]=2[C:15](=[O:21])[NH:14][C:13]1=[S:22].C(N(CC)CC)C.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([CH:40]=O)=[CH:32][CH:31]=1.C([BH3-])#N.[Na+]>>[CH3:8][N:9]([CH2:40][C:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:30]=[CH:31][CH:32]=1)[CH2:10][CH2:11][N:12]1[C:20]2[N:19]=[CH:18][NH:17][C:16]=2[C:15](=[O:21])[NH:14][C:13]1=[S:22]
Reactant: O=Cc1ccnc2ccccc12
Reactant: CNCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN(CCn1c(=S)[nH]c(=O)c2[nH]cnc21)Cc1ccnc2ccccc12
Yield: 14.1 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 26(c) by using 3-[2-(methylamino)ethyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate (0.10 g, 0.29 mmol, obtained from Example 28(c)), triethylamine (0.032 mL, 0.32 mmol), 4-quinoline carboxaldehyde (0.060 g, 0.38 mmol) and sodium cyanoborohydride (0.028 g, 0.44 mmol) which yielded 0.015 g (14% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:32](=[O:33])[NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1nc(C2CCNCC2)c2ccccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1nc(C2CCN(C(=O)Nc3ccccc3)CC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of 2-amino-4-(4-piperidinyl)quinazoline (100 mg, 0.44 mmol) obtained in Example 11(1) and triethylamine (133 mg, 1.3 mmol) in dichloromethane (50 ml) was added phenyl isocyanate (50 mg, 0.42 mmol) under a nitrogen atmosphere. The mixture was stirred for about 3 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was purified by silicagel column chromatography (chloroform:methanol=99:1) to give the titled compound (127 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[CH:8][CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:36])=[C:31]([CH2:33][CH2:34]O)[N:32]=2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][CH2:34][CH2:33][C:31]2[N:32]=[C:28]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[O:29][C:30]=2[CH3:36])=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(O)c2ccccc12)OC
Reactant: COc1ccc(-c2nc(CCO)c(C)o2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(OC)cc3)oc2C)c2ccccc12)OC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-3-(4-hydroxy-naphthalen-1-yl)-2-methoxy-propionic acid methyl ester was reacted with 2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethanol [J. Med. Chem. (1998), 41(25), 5037-5054] in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-methoxy-3-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-methoxy-3-(4-{2-[2-(4-methoxy-phenyl-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-propionic acid as colorless solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.[CH3:26][O:27][C:28](=[O:34])[CH:29](O)[CH:30]([CH3:32])[CH3:31].CO>C(OCC)(=O)C>[CH3:26][O:27][C:28](=[O:34])[CH:29]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH:30]([CH3:32])[CH3:31]
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Reactant: COC(=O)C(O)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(C)C

Procedure:
Following the procedures of Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol and 2-hydroxy-3-methyl-butyric acid methyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give racemic 3-Methyl-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyric acid methyl ester as a yellow oil contaminated with triphenylphosphine oxide. LCMS: RT=3.70 min, [M+H]+=466