Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]=2[CH:11]=1
Reactant: Cc1cc(C)c2oc(=O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2oc(=O)n(CC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5,7-dimethyl-2-benzoxazolinone (200 mg, 1.23 mmol) in DMF (2 mL) was added sodium hydride (59 mg of a 60% dispersion in mineral oil, 1.47 mmol). The mixture was stirred at ambient temperature for 10 min, then tert-butyl bromoacetate (287 mg, 1.47 mmol) was added and stirring was continued for 2 h. The reaction mixture was quenched with H2O and purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=222 (M−C4H7).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=1>CCCCO>[C:14]1([C:4]2[N:3]=[C:2]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: CNS(=O)(=O)c1ccc(N)cc1
Solvent: CCCCO
Product: CNS(=O)(=O)c1ccc(Nc2cc(-c3ccccc3)nc(-c3ccccc3)n2)cc1
Temperature: 30 °C
Yield: 41.6 %

Procedure:
To a solution of 4-chloro-2,6-diphenyl-pyrimidine (0.2 g, 0.75 mmol) in n-BuOH (7 mL) was added 4-amino-N-methyl-benzenesulfonamide (0.146 g, 0.78 mmol) and the mixture was stirred at reflux temperature for 72 hours under nitrogen. The mixture was then cooled to temperature in the range of 20-40° C., the solid precipitated was filtered off and dried to give the title compound (0.13 g, 43% yield).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[C:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(C2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(C2CCNCC2)cc1)c1ccccc1-c1ccccc1
Yield: 94.8 %

Procedure:
A mixture of intermediate (18) (0.145 mol) in methanol (500 ml) was hydrogenated at 50° C. during 48 hours with Pd/C (10%, 3 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 49 g of N-[4-(4-piperidinyl)phenyl]-[1,1′-biphenyl]-2-carboxamide (intermediate 19).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][NH:11]2)=[CH:7][CH:6]=1)C=C.Cl[C:15]1[CH:20]=CC=C[C:16]=1Cl>>[CH2:20]([C:13]1[C:5]([OH:4])=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)[CH:15]=[CH2:16]
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1ccc2cn[nH]c2c1
Product: C=CCc1c(O)ccc2cn[nH]c12
Yield: 60 %

Procedure:
A solution of the product from Step A (14.2 g, 82 mmol) in 1,2-dichlorobenzene (90 mL) was fluxed for 6 h and the reaction mixture was evaporated to a residue which was purified by chromatography (silica, EtOAc) to give a tan solid (8.59 g, 60%) that was used in the next step: LC/MS (+APCI) m/z 175 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:16])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
3,4-Dichlorophenylacetic acid (76.8 g) was dissolved in dry dichloromethane (300 ml) and oxalyl chloride (52 g, 36 ml) was added to the solution obtained in one portion. The reaction mixture was protected from atmospheric moisture with a calcium chloride guard tube and stirred mechanically whilst dimethylformamide (3 drops) was added. The solution was stirred at ambient temperature for 18 hours and then evaporated under reduced pressure to give a yellow oil. Distillation in vacuo afforded 80.0 g of 3,4-dichlorophenylacetyle chloride, b.pt 97°-100°/0.6 mm, as a viscous pale yellow oil.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]#[CH:11])=[CH:4][N+:5]([O-:7])=[O:6].[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>>[N+:5]([CH:4]=[C:3]([NH:8][CH2:9][C:10]#[CH:11])[NH:21][CH2:20][CH2:19][S:18][CH2:17][C:13]1[S:12][CH:16]=[CH:15][N:14]=1)([O-:7])=[O:6]
Reactant: NCCSCc1nccs1
Reactant: C#CCNC(=C[N+](=O)[O-])SC
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
A solution of the product of Step A is treated with about an equimolar amount of 2-[(thiazol-2-yl)methylthio]ethylamine to produce, after workup, the title product.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:13][C:10]1[CH:11]=[CH:12][C:2]([O:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N)ccc1Oc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
A mixture of ethyl 2-fluoro-5-nitrobenzoate (1.07 g), phenol (565 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (20 mL) was stirred at 80° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=20:80→30:70). The object fraction was concentrated under reduced pressure and ethanol (20 mL) and 10% palladium on carbon (1.5 g) were added to the residue (1.54 g). The mixture was stirred overnight under a hydrogen stream. The catalyst was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=20:80→50:50) and recrystallized from diisopropyl ether-hexane to give the title compound (1.07 g) as a pale-brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6](OCC)=[O:7].O.[NH2:24][NH2:25]>C(O)C>[Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([NH:24][NH2:25])=[O:7]
Reactant: CCOC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(OCC(=O)NN)c(Cl)c1
Reaction time: 4 h
Yield: 76.3 %

Procedure:
A solution of 1.0 g of ethyl α-[2-chloro-4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetate (prepared as described in Example 5) and 0.39 g of 80% hydrazine hydrate in 10 ml of ethanol was stirred on an oil bath kept at 105° C. for 4 hours. The mixture was then cooled, after which the crystals which precipitated were collected by filtration and recrystallized from ethanol, to give 0.73 g of the title compound as white crystals melting at 252°-254° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:30]([O:32]C)=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.O.[NH2:35][NH2:36]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:18]3)(=[O:15])=[O:16])=[CH:10][CH:9]=2)=[N:4][C:3]=1[C:30]([NH:35][NH2:36])=[O:32]
Reactant: NN
Reactant: COC(=O)c1nc(-c2ccc(S(=O)(=O)C3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnc1N
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(-c3cnc(N)c(C(=O)NN)n3)cc2)C1
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 94.5 %

Procedure:
methyl 3-amino-6-[4-[(1-tert-butoxycarbonyl-3-piperidyl)sulfonyl]phenyl]pyrazine-2-carboxylate (1.65 g, 3.462 mmol) in dioxane (16.50 mL) was treated with hydrazine hydrate (866.5 mg, 842.1 μL, 17.31 mmol) and stirred at 65° C. for 2.5 hours. The reaction mixture was concentrated in vacuo. The residue was treated with water and stirred for 1 hour, filtered and washed with water, and dried overnight under high vacuum giving tert-butyl 3-[4-[5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl]phenyl]sulfonylpiperidine-1-carboxylate (1.572 g, 3.272 mmol, 93.77%) as a pale yellow powder. LC/MS m/z 421.1 [M−56+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:15]([CH2:16][CH3:17])[CH2:13][CH3:14]
Reactant: CCNCC
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCN(CC)c1ccnc2ccc(Br)cc12
Temperature: 100 °C
Reaction time: 15 h
Yield: 17.4 %

Procedure:
To a mixture of 6-bromo-4-chloro-quinoline (0.900 g, 3.71 mmol) and diethylamine (1.364 g, 18.56 mmol) in ethanol (10 mL) was added potassium carbonate (2.56 g, 18.56 mmol) at room temperature. Then, the reaction mixture was stirred for 15 h in a sealed tube. TLC analysis of the reaction mixture indicated the presence of lot of 6-bromo-4-chloro-quinoline and another 2 mL of diethylamine was added and heated to 100° C. and stirred for 15 h. After cooling to room temperature, the reaction mixture was diluted with water and the solvent was removed under the vacuum. Then, the product was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to afford 0.180 g (17.4% yield) of (6-bromo-quinolin-4-yl)-diethylamine as a light yellow oil: EI-LRMS m/e calcd for C13H15BrN2 (M+) 279.1, found 279.1.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[Na].[CH3:22][CH:23]1[O:28][CH2:27][CH2:26][N:25]([C:29]2[N:30]=[C:31]([CH2:36][C:37](O)=[O:38])[NH:32][C:33](=[O:35])[CH:34]=2)[CH2:24]1>CN(C)C=O.N1C=CC=CC=1>[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:37](=[O:38])[CH2:36][C:31]2[NH:32][C:33](=[O:35])[CH:34]=[C:29]([N:25]3[CH2:26][CH2:27][O:28][CH:23]([CH3:22])[CH2:24]3)[N:30]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC1CN(c2cc(=O)[nH]c(CC(=O)O)n2)CCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1CN(c2cc(=O)[nH]c(CC(=O)Nc3ccc(F)cc3)n2)CCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.46 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride, 6.7 ml of pyridine and 0.7 ml of 4-fluoroaniline are added to a solution of 700 mg of sodium salt of [4-(2-methylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid in 6.7 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 24 hours and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is stirred for 30 minutes. The precipitate formed is filtered off and washed with dichloromethane and with ethyl ether, so as to give 300 mg of N-(4-fluorophenyl)-2-[4-(2-methylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7].[CH3:34][S:35](Cl)(=[O:37])=[O:36].CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH3:34][S:35]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7])(=[O:37])=[O:36]
Reactant: CC(C)(C)CC1NC(C(=O)NCCCN)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCCCNS(C)(=O)=O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
A mixture of rac (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide (120 mg, 0.24 mmol), methane sulfonyl chloride (49 μL, 0.6 mmol) and dimethylaminopyridine (97.6 mg, 0.8 mmol) in CH2Cl2 (8 mL) was stirred for 5 h at rt. The mixture was then extracted with NaHCO3(s), water and the organic layer dried with MgSO4, filtered and the solvent was evaporated under reduced pressure. diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonylamino-propyl)-amide (112.1 mg, 80.5%) as an off-white powder. HRMS (ES+) m/z Calcd for C27H34Cl2N4O3S+H [(M+H)+]: 565.1802. found: 565.1800.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[CH2:9]([C:16]([C:18]([F:21])([F:20])[F:19])=O)[C:10]([C:12]([F:15])([F:14])[F:13])=O.[OH-].[NH4+]>P(=O)(O)(O)O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:10]([C:12]([F:13])([F:14])[F:15])=[CH:9][C:16]=2[C:18]([F:19])([F:21])[F:20])[N:3]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccc2c(C(F)(F)F)cc(C(F)(F)F)nc2n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A mixture of 2,6-diaminopyridine (5.2 g., 47.6 mmole), 1,1,1,5,5,5-hexafluoroacetylacetone (10.0 g., 48.0 mmole) and 85% phosphoric acid (50 ml.) are stirred for six hours in an oil-bath at 90°-95° C. then left overnight at ambient temperature. The reaction mixture is poured into ice water and neutralized with ammonium hydroxide to pH 7, the solid collected, washed with water and dried to provide 9.0 g. (67%) of product, m.p. 198-204° C. Upon recrystallization from benzene, purified product separates in the form of pale yellow needles, m.p. 204°-206° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:27]([O:31][C:32](=[O:42])[NH:33][CH2:34][CH:35]([NH2:41])[C:36]1[CH:40]=[CH:39][S:38][CH:37]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:42])[NH:33][CH2:34][CH:35]([NH:41][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[C:36]1[CH:40]=[CH:39][S:38][CH:37]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccsc1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CNC(=O)OC(C)(C)C)c5ccsc5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (200 mg, 0.536 mmol) and (2-amino-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester (from Example 74 supra) (520 mg, 2.14 mmol) was heated at 140° C., with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 10:1 to 4:1) to afford crude (2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester. (yield 150 mg). LC-MS: [M+H]+ 536.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[C@@H:23]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[S:28][C:27]2[C:38]3[C:43]([CH:44]=[CH:45][C:26]=2[N:25]([CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])[C:24]1=[O:51])=[CH:42][CH:41]=[CH:40][CH:39]=3.[ClH:52]>O1CCCC1.CC(C)=O>[ClH:52].[ClH:52].[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([C@@H:29]2[S:28][C:27]3[C:38]4[C:43]([CH:44]=[CH:45][C:26]=3[N:25]([CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])[C:24](=[O:51])[C@@H:23]2[O:8][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:31][CH:32]=1
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: O=C(O)c1cccnc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of 0.5 g (0.004 mol) of nicotinic acid and 0.7 g (0.004 mol) of 1,1'-carbonyldiimidazole in 20 ml of dry tetrahydrofuran was stirred at room temperature for 1 hour. To the solution was added 1.3 g (0.003 mol) of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-(2-(dimethylamino)ethyl]naphtho[1,2-b][1,4]thiazepin-4(5H)-one and the reaction mixture was stirred at room temperature for 17 hours. After concentrating to dryness the residue was partitioned between ethyl acetate and dilute ammonium hydroxide. The ethyl acetate solutions were washed with brine and dried (MgSO4). Removal of the solvent at reduced pressure gave 2.2 g of crude base which was dissolved in acetone and acidified with hydrogen chloride (anhydrous). The resulting crystals were separated to afford 1.9 g (99%) of (±)-cis-2,3-dihydro-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]-3-[(3-pyridinylcarbonyl)oxy]naphtho[1,2-b][1,4]thiazepin-4 (4H)-one dihydrochloride (4:5) hydrate, mp 178°-179°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[C:14]([O:35]CC3C=CC=CC=3)=[CH:15][C:16]([O:27]CC3C=CC=CC=3)=[C:17]([CH:26]=2)[C:18]([N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])=[N:11][N:10]=[C:9]1[OH:43].[H][H]>C1COCC1.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[C:14]([OH:35])=[CH:15][C:16]([OH:27])=[C:17]([CH:26]=2)[C:18]([N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])=[N:11][N:10]=[C:9]1[OH:43]
Reactant: [H][H]
Reactant: CCCCN(C)C(=O)c1cc(-c2nnc(O)n2-c2ccccc2C)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)c1cc(-c2nnc(O)n2-c2ccccc2C)c(O)cc1O
Yield: 97.6 %

Procedure:
A solution of 1.1 kg of 5-[4-(2-methylphenyl)-3-hydroxy-4H-1,2,4-triazol-5-yl]-2,4-bisbenzyloxy-N-methyl-N-butylbenzamide, 5% Pd/C (50.5% of water) and 85 l of hydrogen in 10 l of THF is treated at 23° C. for 7 h in an autoclave. The resultant solution is subsequently evaporated and crystallised from ethanol, giving 738 g (95%) of 5-[4-(2-methylphenyl)-3-hydroxy-4H-1,2,4-triazol-5-yl]-2,4-dihydroxy-N-methyl-N-butylbenzamide (“C1”); MW 396.5.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M7) (350 mg, 0.63 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (207 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][C@H:26]1[CH2:30][CH2:29][CH2:28][O:27]1>>[CH3:23][N:24]([CH2:25][C@H:26]1[CH2:30][CH2:29][CH2:28][O:27]1)[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: CNC[C@H]1CCCO1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN(C[C@H]1CCCO1)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)—N-methyl-1(tetrahydrofuran-2-yl)methanamine (1.2 equiv) to give 174 (18.4 mg, M+1 411.1)
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[C:26]([C:30]([O:32]CC)=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1.[OH-].[Na+].Cl>CO>[CH3:1][S:2][C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:13][CH:14]=2)[C:6]2[C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1
Reactant: CCOC(=O)c1cccc2nc(SC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 90.4 %

Procedure:
A solution of ethyl 2-methylthio-1-[[2′-(1H-tetrazol-5yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate (0.2 g) in a methanol (5 ml) solution containing 1N NaOH (1.3 ml) was heated under reflux for 2 hours. The reaction mixture was adjusted to about pH 4 with dilute hydrochloric acid to give crystals. The crystals were collected by filtration, and recrystallized from ethyl acetate-hexane to give colorless crystals (0.17 g, 81%), m.p. 223-225° C. (decomp.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH3:22].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH3:22])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:31])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C=NC1CCCCC1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: c1ccncc1
Product: CCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)NC1CCCCC1
Reaction time: 1 h
Yield: 66 %

Procedure:
A solution of the compound of Example 46, 1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.67 mmol) in 30 mL of pyridine was chilled in an ice water bath. With vigorous stirring, the solution was treated with cyclohexyl isocyanate (0.340 mL, 2.67 mmol). After 1 h, the reaction was concentrated to yield an off white solid. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) gave 748 mg of N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-cyclohexylurea as a white solid.