Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>CCOCC>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:29](=[O:30])[NH:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: Oc1ccc2c(c1)CCCN2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(Nc1ccccc1Cl)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.239 g., 1 mmol) in dry ether (10 ml) was added to a stirred suspension of sodium hydride (0.024 g., 1 mmol) in dry ether (15 ml) at −10° C. during 10 min. The reaction mixture was stirred for 20 min. Then 2-chlorophenyl isocyanate (0.184 g:, 1.2 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 2 hours during which the temperature was allowed to rise to room temperature (35° C.). The reaction mixture was quenched with water (0.2 ml), concentrated under vaccum, diluted with water (5 ml), extracted with chloroform (2×5 ml) and dried over sodium sulphate. The combined fractions of chloroform were concentrated under vaccum. The residue was chromatographed on silica gel using chloroform: hexane (20:80) as eluant to give 2i; yield: 0.25 g. (63.7%).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[C:45]([C:47]1[CH:53]=CC(N)=[CH:49][CH:48]=1)#[N:46].NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:53][C:47]([C:45]#[N:46])=[CH:48][CH:49]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: N#Cc1ccc(N)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C#N)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-cyanoaniline as the aniline component. (9%, MS=495.2 (M+H))
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])=[CH:4][CH:3]=1.[P:16]([O-:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19].CCN(CC)CC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:9][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:3][CH:4]=1
Reactant: NC(c1ccccc1)c1ccc(Br)cc1
Reactant: CCOP([O-])OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(C(N)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
To 2-b′ (9 g, 25 mmol), diethyl phosphite (10.5 g, 75 mmol) and Et3N (8.5 g, 75 mmol) in toluene was added PdCl2(dppf) (7.5 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into ethyl acetate and washed with saturated NH3Cl. The organic layer was concentrated under vacuum and the residue was purified over silica gel to provide the crude product 2-c (15 g). (M+Na)+=442.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH2:13]Cl)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[C:1]1([C:7]2[N:12]=[C:11]([CH2:13][N:25]3[CH2:26][CH2:27][CH:22]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: ClCc1ccnc(-c2ccccc2)n1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CC2CCN(Cc3ccnc(-c4ccccc4)n3)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 50 mg of 2-phenyl-4-chloromethylpyrimidine in 5 mL chloroform was added 80 mg 4-benzylpiperidine and 1 mL of N,N-diisopropylethylamine. The reaction mixture was heated at reflux temperature for 4 hr, cooled to room temperature, washed with 5 mL 1N sodium hydroxide solution and the solvent removed by evaporation under reduced pressure to yield 2-phenyl-4-[(4-benzyl-piperidin-1-yl)methyl]-pyrimidine. This material was purified by chromatography on silica gel using 5% methanol in dichloromethane as eluent. Evaporation of the solvent yielded a solid which was treated with ethereal-HCl to give 15 mg of 2-phenyl-4-[(4-benzyl-piperidin-1-yl)methyl]-pyrimidine dihydrochloride (Compound 11), mp 211-213° C.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][C:41]1[CH:42]=[C:43]([CH:47]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=2)[CH2:48][NH2:49])[CH:44]=[CH:45][CH:46]=1>C(O)(C)C>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2[NH:49][CH2:48][CH:47]([C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([CH3:40])[CH:42]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C(CN)c2cccc(C)c2)c1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Solvent: CC(C)O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4cccc(C)c4)c4cccc(C)c4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Yield: 86.5 %

Procedure:
A solution of ((2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 47) (0.6 g, 0.91 mmol) and 2,2-bis(3-methylphenyl)ethylamine (0.3 g, 1.36 mmol) in isopropanol (20 ml) was stirred at room temperature for 48 hours. Solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1, by volume) to afford the title compound as a beige foam (0.67 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O)[N:13]=[C:12]([NH2:27])[N:11]=2)[C:7]([CH3:28])=[CH:6][C:5]=1[CH3:29].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][CH2:18][NH2:19])[N:13]=[C:12]([NH2:27])[N:11]=2)[C:7]([CH3:28])=[CH:6][C:5]=1[CH3:29]
Reactant: COC(=O)c1cc(-c2cc(SCCNC(=O)OC(C)(C)C)nc(N)n2)c(C)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(-c2cc(SCCN)nc(N)n2)c(C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.3 %

Procedure:
5-[2-Amino-6-(2-tert-butoxycarbonylaminoethylsulfanyl)pyrimidin-4-yl]-2,4-dimethylbenzoic acid methyl ester (531 mg, 1.23 mmol) obtained in Step 1 above was dissolved in dichloromethane (3.0 ml). Trifluoroacetic acid (1.5 ml) was added to the solution, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, and then a saturated aqueous sodium bicarbonate solution was added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined together, and sequentially washed with water and a saturated aqueous sodium chloride solution. The ethyl acetate solution was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to yield the crude product of 5-[2-amino-6-(2-aminoethylsulfanyl)pyrimidin-4-yl]-2,4-dimethylbenzoic acid methyl ester (443 mg) as a white solid material.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]2[CH:17]([C:18](O)=[O:19])[CH2:16][N:15]([CH3:21])[C:14](=[O:22])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:31])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]2[CH:17]([C:18]([Cl:31])=[O:19])[CH2:16][N:15]([CH3:21])[C:14](=[O:22])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-benzyloxy-2-ethoxycarbonyl-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-7-carboxylic acid (250 mg, 0.670 mmol) in anhydrous CH2Cl2 at 0° C. were added 2M oxalyl chloride in CH2Cl2 (1.339 mL, 2.678 mmol) and DMF (1 drop). The reaction was stirred at 0° C. for 30 minutes and allowed to warm to room temperature for 1 hour. The mixture was concentrated in vacuo and azeotroped twice with anhydrous CH2Cl2 to afford the title product. ES MS (M+H)=392.
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][C:29]([O:31]CC)=[O:30])[C:20]3=[O:34])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[OH-].[Na+].O.Cl>C(O)C>[C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][C:29]([OH:31])=[O:30])[C:20]3=[O:34])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CCOC(=O)Cn1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
Ethyl (R)-2-{3-[1-(acenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo-benzoimidazol-1-yl}acetate (2.6 g, 5.8 mmol) was dissolved in ethanol (10 ml), 2N-aqueous sodium hydroxide solution (10 ml) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, 1N-hydrochloric acid was added for neutralization, and the mixture was extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained solid was washed with ethyl acetate to give the title compound (2.4 g) as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9]N(C)C)=O.Cl.[F:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26]([NH2:28])=[NH:27].C[O-].[Na+]>CO>[F:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26]1[N:28]=[C:6]([C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=2)[C:8]([S:13]([CH3:16])(=[O:14])=[O:15])=[CH:9][N:27]=1
Reactant: CN(C)C=C(C(=O)c1cccc(C(F)(F)F)c1)S(C)(=O)=O
Reactant: N=C(N)c1ccc(F)cc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1cnc(-c2ccc(F)cc2F)nc1-c1cccc(C(F)(F)F)c1
Yield: 77.5 %

Procedure:
6 g of 1-(3-trifluoromethylbenzoyl)-l-methanesulfonyl-2-(N,N-dimethylamino)ethene and 4.6 g of 2,4-difluorobenzamidine hydrochloride were dissolved in 30 ml of methanol at room temperature and 1.2 g of sodium methoxide was added thereto. The resulting mixture was heated under reflux for an hour. The solvent was distilled away under reduced pressure. The residue was washed with water and then dried to obtain 6 g of 2-(2,4-difluorophenyl)-4-(3-trifluoromethylphenyl)-5-methanesulfonylpyrimidine (Compound 147).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][OH:9].C([O-])(O)=O.[Na+].Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O>C(Cl)Cl>[OH:9][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:16](=[O:17])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccccc1NO
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1N(O)C(=O)Oc1ccccc1
Temperature: -10 °C
Yield: 72 %

Procedure:
A mixture of 350 g (purity about 80%; 2.3 mol; prepared by a similar method to Bamberger et al., Ann. Chem. 316 (1901), 278) of N-(2-methylphenyl)hydroxylamine and 286.8 g (3.4 mol) of NaHCO3 in 700 ml of CH2Cl2 is treated with 447 g (2.85 mol) of phenyl chloroformate with vigorous stirring at about -10° C. The mixture is stirred for about 1 hour at -10° C. and 600 ml of water are then added dropwise, the temperature of the reaction mixture increasing to 5-10° C. and a vigorous evolution of gas occurring. The aqueous phase is then separated off and extracted once more with CH2Cl2. The combined organic phases are extracted with water, dried over MgSO4 and concentrated. The residue crystallizes and is stirred with cyclohexane. 407 g (72%) of the title compound are obtained as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[C:12]([CH2:25][O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])=[N:13][N:14]([CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:15]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Cl:39][C:40]([Cl:47])([Cl:46])[CH2:41][O:42][C:43](Cl)=[O:44]>CCOC(C)=O.O>[Cl:39][C:40]([Cl:47])([Cl:46])[CH2:41][O:42][C:43](=[O:44])[NH:10][C:8]1[N:7]([C:11]2[C:12]([CH2:25][O:26][Si:27]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:29])[CH3:30])[CH:34]([CH3:36])[CH3:35])=[N:13][N:14]([CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:15]=2)[N:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:9]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)[Si](OCc1nn(CCOC2CCCCO2)cc1-n1nc(C(C)(C)C)cc1N)(C(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[Si](OCc1nn(CCOC2CCCCO2)cc1-n1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a solution of Intermediate 74f (0.44 g, 0.85 mmol) in EtOAc (5 mL) was added 1N aqueous NaOH solution (1.7 mL, 1.7 mmol) followed by 2,2,2-trichloroethylchloroformate (0.13 mL, 0.93 mmol). The reaction was stirred at RT for 4 h then treated with another portion of 2,2,2-trichloroethylchloroformate (35 μL, 0.25 mmol) and stirred over the weekend. The reaction was treated with another portion of 2,2,2-trichloroethylchloroformate (35 μL, 0.25 mmol) and stirred for 1 h then diluted with EtOAc and water and the layers were separated. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-4% MeOH in DCM, to give the title compound (0.47 g, 80%). 1H NMR (300 MHz, CDCl3): 0.96 (18H, d, J=6.8 Hz), 1.01-1.17 (3H, m), 1.25 (9H, s), 1.38-1.51 (4H, m), 1.54-1.75 (2H, m), 3.36-3.45 (1H, m), 3.58-3.68 (1H, m), 3.68-3.77 (1H, m), 3.97-4.07 (1H, m), 4.24 (2H, t, J=4.7 Hz), 4.51 (1H, t, J=3.2 Hz), 4.59 (2H, s), 4.69-4.73 (2H, m), 6.26 (1H, s), 7.63 (1H, s), 7.74 (1H, s).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:12]2[C:11]([C:18]([F:19])([F:21])[F:20])=[CH:10][C:9]3[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C2=Nc3cc(N4CCC4)c(C(F)(F)F)cc3NC(=O)C2)ccn1

Procedure:
The title compound was prepared from {5-azetidin-1-yl-2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M52) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an orange solid (51 mg).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[OH:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1cccc(Br)n1
Temperature: 25 °C

Procedure:
To a chilled (−10° C.) solution of 6-bromopyridine-2-carboxaldehyde (5.0 g, 27 mmol) in THF (108 mL) is added a 1 M solution of 4-fluorophenylmagnesium bromide in THF (30 mL, 30 mmol). The temperature is allowed to slowly warm to room temperature over 30 minutes and then the reaction mixture is quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers are dried over Na2SO4 and concentrated. The crude material is purified by silica gel chromatography eluting with 15% EtOAc-hexanes to afford (6-bromopyridin-2-yl)-(4-fluorophenyl)-methanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([O:53][CH3:54])[C:39]=1[OH:55]>>[NH2:29][CH:26]1[CH2:27][CH2:28][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:41]=[C:40]([O:53][CH3:54])[C:39]([OH:55])=[C:38]([Cl:37])[CH:43]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][N:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(Nc4cnc(N5CCC(N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 20.9 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyrimidin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (77 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (20 mg, 21% over 2 steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.35 (s, 1H), 8.48 (s, 2H), 8.29 (dd, J=8.8, 1.9 Hz, 1H), 8.21 (s, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.09 (s, 1H), 6.89 (s, 1H), 4.04 (m, 2H), 3.94 (s, 3H), 3.89 (m, 1H), 3.79 (m, 2H), 2.82 (s, 1H), 2.52 (ddd, J=14.8, 12.7, 6.4 Hz, 1H), 2.23 (dt, J=11.6, 6.2 Hz, 1H), 1.21 (s, 4H); ESI MS m/z 531 [C28H27ClN6O3+H]+; HPLC 99.9% (AUC), tR=10.11 min.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[N:18][C:19](=[O:30])[N:20]([CH2:22][CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[CH:21]=4)[S:15][C:8]=23)=[C:4]([F:33])[CH:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:48])[CH2:44][C:45](O)=[O:46].C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C.C(Cl)CCl>[F:33][C:4]1[CH:3]=[C:2]([NH:1][C:45](=[O:46])[CH2:44][C:43]([NH:42][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][CH3:34])=[O:48])[CH:32]=[CH:31][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[N:18][C:19](=[O:30])[N:20]([CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:21]=3)[S:15][C:8]=12
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: Nc1ccc(Oc2ccnc3cc(-c4cnc(=O)n(CCN5CCOCC5)c4)sc23)c(F)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cnc(=O)n(CCN5CCOCC5)c4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.3 %

Procedure:
To a solution of the amine 416 (0.16 mmol) in DMF (1 mL) was added acid 27 (38 mg, 0.18 mmol), HOBT (24 mg, 0.18 mmol) and EDC×HCl (46 mg, 0.24 mmol). The mixture was stirred at room temperature for 16 h. The solvent was evaporated, then the residue was purified by flash chromatography with gradient of methanol (0-5%) in dichloromethane, followed by preparative HPLC purification with gradient of methanol (20-100%) in water to give title compound 412 (14 mg, 13% yield). MS (m/z): 659.1 (M+H). 1H NMR (DMSO-d6) δ (ppm): 10.59 (s, 1H), 9.64 (s, 1H), 9.16 (d, J=3.3 Hz, 1H), 8.69 (d, J=3.3 Hz, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.07 (d, J=7.4 Hz, 1H), 7.98 (s, 1H), 7.88 (dd, J=13.2.3 Hz, 1H), 7.51 (t, J=9.0 Hz, 1H), 7.43 (dd, J=8.8, 1.6 Hz, 1H), 7.11-7.05 (m, 2H), 6.94-6.90 (m, 1H), 6.67 (d, J=4.7 Hz, 1H), 4.05 (t, J=6.5 Hz, 2H), 3.86 (s, 3H), 3.64 (s, 2H), 3.55-3.50 (m, 4H), 2.63 (t, J=5.5 Hz, 2H), 2.46-2.42 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C@@H:8]1[CH2:13][CH2:12][C@H:11]([O:14]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:10][CH2:9]1.O.C([O-])([O-])=O.[K+].[K+]>CO>[OH:14][C@@H:11]1[CH2:10][CH2:9][C@H:8]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]2=[O:1])[CH2:13][CH2:12]1
Reactant: O=C(O[C@H]1CC[C@@H](N2CCCCC2=O)CC1)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1CCCCN1[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve cis-4-nitro-benzoic acid-4-(2-oxo-piperidin-1-yl)-cyclohexyl-ester (5.0 g, 14.4 mmol) in methanol (150 mL), add water (20 mL), K2CO3 (8.7 g, 0.06 mol) and stir the reaction mixture at room temperature for 18 hours. Extract the reaction mixture with DCM (2×100 mL), dry the organic layer over Na2SO4 and remove the solvent to obtain cis-1-(4-hydroxy-cyclohexyl)-piperidin-2-one as clear oil (6.0 g). Combine cis-1-(4-hydroxy-cyclohexyl)-piperidin-2-one (6.0 g, 0.03 mol), imidazole (3.1 g, 0.05 mol), tert-butyl chloro dimethyl silane (6.9 g, 0.05 mol) and stir at room temperature for 18 hours. Wash the reaction mixture with water (150 mL) and dry the organic layer over Na2SO4. Remove the solvent and purify the residue by chromatography over silica gel (eluting with 0 to 50% EtOAc in hexane) to obtain the title compound as a clear oil (3.4 g, 76%): MS (ES+) m/z=312 (M+H)+.
Reaction SMILES: C([N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:21])[CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][CH2:6]1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[C:15]1([CH2:14][CH2:13][CH2:12][C:11]([N:8]2[CH2:7][CH2:6][NH:5][CH2:10][CH2:9]2)=[O:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)N1CCN(C(=O)CCCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCc1ccccc1)N1CCNCC1
Reaction time: 1 h

Procedure:
1-tert-Butyl-4-(4-phenylbutanoyl)piperazine (A, 2.64 g) was dissolved in trifluoroacetic acid (10 mL)—dichloromethane (10 mL). After siring for 1 hr, the reaction mixture was evaporated in vacuo. Toluene and methanol were added to the residue, then evaporated in vacuo to give the titled compound (1.63 g) as a colorless solid.