Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][CH2:26][CH2:27][OH:28]>CN(C)C=O>[OH:28][CH2:27][CH2:26][CH2:25][N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17]
Reactant: O=c1[nH]cc(-c2ccccc2)c2ccccc12
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2c(-c2ccccc2)cn1CCCO
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A mixture of 22.1 g of 4-phenyl-1(2H)-isoquinolone, 20 g of anhydrous potassium carbonate and 100 ml of dimethylformamide was stirred for 2 hours at 100° C. Then, 11 g of 3-chloropropanol was added to the resulting solution and the mixture was stirred at 110° C. for 5 hours. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in dichloromethane. Water was added to the resulting solution and, after thoroughly stirring, the dichloromethane layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 23 g of 2-(3-hydroxypropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 84° C. as colorless prisms.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[CH2:20][CH2:19][CH2:18]2.Cl[Si:27]([CH3:30])([CH3:29])[CH3:28]>C1COCC1.O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21]([O:25][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][CH2:19][CH2:18]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC=C2O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of diisopropylamine (2.42 mL, 17.1 mmol) in THF (50 mL) at 0° C. is added n-BuLi (6.84 mL, 17.1 mmol, 2.5 M in hexane) dropwise. After 40 min, 6-methoxy-1-tetralone (3.0 g, 17.1 mmol) in THF (15 mL) is added at −78° C. It is then stirred at −78° C. for 2.5 h before chloro trimethylsilane (3.2 mL, 25.7 mmol) is added. It is then warmed to RT and stirred for 18 h. Water is added and the reaction mixture is extracted with EtOAc, washed with sat. NH4Cl solution, dried with MgSO4 and concentrated to give the title compound as a yellow oil. It is used in the next step without purification.
Reaction SMILES: C(O)(C)C.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([CH3:30])[C:14]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)([OH:19])[C:15]([F:18])([F:17])[F:16]>CCCCCCC>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C@@H:13]([CH3:30])[C@:14]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)([OH:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccc2ncccc2c1)C(F)(F)F
Solvent: CCCCCCC
Solvent: CC(C)O
Product: C[C@H](c1ccc(Cl)cc1Cl)[C@@](O)(c1ccc2ncccc2c1)C(F)(F)F

Procedure:
These materials were obtained by preparative HPLC (Column: Chiralpack AD; solvent: 1% isopropanol in heptane) from racemic 3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-2-quinolin-6-yl-butan-2-ol (example 52).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1.[C:15](OC1C(Cl)=CC(Cl)=CC=1Cl)(=[O:29])[CH2:16][C:17](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:18].ClC1C=CC=CC=1>CCCCCC>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:15]([OH:29])=[CH:16][C:17](=[O:18])[N:6]2[N:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1nnc(SCc2ccccc2)s1
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: Clc1ccccc1
Solvent: CCCCCC
Product: O=c1cc(O)nc2sc(SCc3ccccc3)nn12
Reaction time: 0.33 h
Yield: 97.9 %

Procedure:
A mixture of 44.7 g of 2-amino-5-benzylthio-1,3,4-thiadiazole, 98.1 g of bis(2,4,6-trichlorophenyl) malonate and 140 ml of chlorobenzene was heated to 130°-140° C. and stirred for 20 minutes. After cooling, hexane was added to the mixture, and the formed precipitate was separated by filtration. The solid was washed with hexane and thus 57.1 g of 2-benzylthio-7-hydroxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[CH2:24][OH:25])=[CH:17][CH:16]=2)=[N:6][CH:7]=1.[H-].[Na+].[F:28][CH2:29][CH2:30]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[CH2:24][O:25][CH2:30][CH2:29][F:28])=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: FCCI
Reactant: Cn1cnc(-c2ccc([C@H]3C[C@@H]3CO)cc2)c1Sc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccc([C@H]3C[C@@H]3COCCF)cc2)c1Sc1ccc(Cl)cn1
Temperature: 25 °C

Procedure:
[(1S,2S)-2-(4-{5-[(5-Chloropyridin-2-yl)thio]-1-methyl-1H-imidazol-4-yl}phenyl)cyclopropyl]methano 1 (product of Example 23, 20 mg, 0.054 mmol) was dissolved in DMF (1 mL), to which was added NaH (0.25 mmol) and 1-fluoro-2-iodoethane (0.25 mmol) at 0° C. The reaction was warmed to rt and then heated at 55° C. for 2 hours. After it was cooled t rt, the reaction was quenched with 1 mL of aqueous NH4Cl and diluted with 5 mL of EtOAc. The mixture was washed with water (two times) and brine. The organic layer was dried and concentrated to give the crude product that was purified by column (40-100% EtOAc in hexanes) to afford the title compound. 1H NMR (500 MHz, (CDCl3): 9.83 (s, 1H), 8.38 (s, 1H), 7.88 (d, 2H), 7.63 (d, 1H), 7.19 (d, 1H), 7.18 (d, 2H), 4.63 (m, 1H), 4.58 (m, 1H), 4.02 (s, 3H), 3.76 (m, 1H), 4.71 (m, 1H), 3.57 (d, 2H), 1.85 (m, 1H), 1.46 (m, 1H), 1.03 (m, 2H). LCMS: m/z 418 (M+H)+. Human FAAH lysate assay: IC50=69.3 nM.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[N:27]=[CH:26][N:25](C4CCCCO4)[N:24]=3)=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][N:4]2[N:3]=1.Cl[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:44])[F:43])=[N:40][CH:41]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O.O>[CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[N:27]=[CH:26][NH:25][N:24]=3)=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([O:10][CH2:35][C:36]3[CH:41]=[N:40][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:38][CH:37]=3)[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: Cc1nn2ccc(O)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn2ccc(OCc3ccc(C(F)(F)F)nc3)cc2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
A mixture of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridin-5-ol (100 mg, 0.22 mmol) obtained in Example 31-B(i), 5-(chloromethyl)-2-(trifluoromethyl)pyridine (64 mg, 0.33 mmol), potassium carbonate (60 mg, 0.44 mmol) and DMF (4 mL) was stirred at 60° C. for 2 h. Water (100 mL) and EtOAc (100 mL) were added to the reaction mixture, and the mixture was stirred for 30 min. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL) and THF (30 mL), 6 N hydrochloric acid (3 mL) was added, and the mixture was stirred at 70° C. for 3 h. The reaction mixture was allowed to cool to rt, and the mixture was concentrated under reduced pressure. To the residue were added EtOAc (50 mL), THF (50 mL), 8 N aqueous sodium hydroxide solution (3 mL) and water (30 mL), and the mixture was stirred for 30 min. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was crystallized from EtOAc to give the title compound (107 mg, 92%) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[N:4].Br[C:14]1[N:19]=[CH:18][C:17]([N:20]2[C:29]3[N:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]4=[N:32][C:28]=3[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:37])=[CH:16][CH:15]=1>N1C=CC=CC=1>[O:37]=[C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[N:32]=[C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][N:30]3[C:29]=2[N:20]1[C:17]1[CH:16]=[CH:15][C:14]([CH:5]([C:3]#[N:4])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[N:19][CH:18]=1
Reactant: O=c1c2ccccc2c2nc3ccccn3c2n1-c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C(C#N)c1ccc(-n2c(=O)c3ccccc3c3nc4ccccn4c32)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.1 %

Procedure:
Sodium hydride (2.2 equiv., 0.844 mmol, 0.034 g (60%)) was added to a solution of tert-butyl cyanoacetate (1.2 equiv., 0.460 mmol, 0.065 g) in dry pyridine (1 ml) under Ar atmosphere. The catalyst—prepared as described above—was injected, and the mixture was stirred at room temperature for 5 min. Compound 21 (1.0 equiv., 0.383 mmol, 0.150 g) was then added and the reaction mixture was heated at 85° C. for 2 h. After destruction of excess sodium hydride with methanol, the solvent was concentrated under vacuum. The residue was purified by column chromatography (dichloromethane/methanol (7M NH3) 95:5) to give dimethylethyl 5-[5,6-dihydro-5-oxo-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-6-yl]-α-cyano-2-pyridineacetate (I12) (0.078 g, yield=45%).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=2)[CH2:3][CH2:2]1.CI.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([N:4]([CH3:16])[C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(NC2CC2)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1ccc([N+](=O)[O-])cn1)C1CC1
Temperature: 200 °C

Procedure:
The intermediate, cyclopropyl-(5-nitro-pyridin-2-yl)-amine, from the above procedure, was methylated with methyl iodide. To a 2 mL microwave vial was added cyclopropyl-(5-nitro-pyridin-2-yl)-amine (146 mg, 0.812 mmol), DMF (2 mL), potassium carbonate (224 mg, 1.62 mmol), and the MeI (56 μl, 0.893 mmol). The mixture was heated by microwave for two 10 min increments at 200° C. using a Personal Chemistry, Emrys Optimizer. Then followed addition of another portion of MeI (56 μL, 0.893 mmol) microwave at 200° C. for 10 min and then conventional heating at 70° C. for 15 hr. At the end of this period a third addition of MeI (56 μL, 0.893 mmol) took place and the mixture was heated by microwave once more for 10 min at 200° C. The reaction mixture was then concentrated to dryness, suspended in ethyl acetate (100 mL) and washed with water (100 mL) two times and one time with brine. The aqueous layers were combined and extracted once with ethyl acetate (50 mL). The combined organic layer was washed once with brine (100 mL), concentrated, supported onto silica gel, and purified by flash chromatography using the Analogix system with a 12 g Silicycle silica gel column with increasing concentrations of ethyl acetate in hexanes (20 mL/min, equilibrate with 0%, 0 to 5 min: 0%; 5 to 25 min: 0 to 30%; 25-45 min: 30%). The appropriate fractions were collected and dried to afford 90 mg of cyclopropyl-methyl-(5-nitro-pyridin-2-yl)-amine, a yellow solid (yield 57%). LCMS calcd. for C9H11N3O2 (m/e) 193, observed 194 (M+H). This intermediate nitropyridyl compound was then reduced, as described in the preparation of cyclopentyl-pyridine-2,5-diamine above, to afford N2-cyclopropyl-N2-methyl pyridine-2,5-diamine. LCMS calcd. for C9H13N3 (m/e) 163, observed 164 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])[C:3]=1[Br:21].[C:22](Cl)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:17]([OH:20])(=[O:24])[CH3:18].[C:22]([OH:24])(=[O:8])[CH3:23].[Br:1][C:2]1[C:7]([OH:8])=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])[C:3]=1[Br:21]
Reactant: CC(=O)Cl
Agent: CC(C)(c1ccc(O)cc1)c1c(Br)c(Br)c(O)c(Br)c1Br
Solvent: c1ccncc1
Product: CC(=O)O
Reaction time: 8 h

Procedure:
27.2 g of tetrabromobisphenol A are dissolved in 176.6 ml of pyridine. 7.8 g of acetyl chloride are added slowly to this solution with cooling, and the reaction mixture thus obtained is kept at room temperature overnight. The mixture is filtered, poured into ice water and acidified using concentrated HCl. The precipitated ester is filtered off under suction, taken up in methylene chloride, washed with sodium bicarbonate solution and water, dried and evaporated. The product is recrystallized from acetonitrile, m.p.: 169° C., NMR: 7.42 ppm, 2.40 ppm, 1.68 ppm.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[CH3:28].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[CH:26][C:27]([CH3:28])=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(C(C)(C)C)n3)CC2)cc1C

Procedure:
126 mg (71%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-(3,4-dimethylphenyl)piperazine (69 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[F:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][CH:2]([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(I)cc1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Product: Cc1c(C)c(N2CCN(c3ccc(F)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 21.8 %

Procedure:
By using 1-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (400 mg, 1.54 mmol) synthesized in Reference example 56 and 1-fluoro-4-iodobenzene (1.54 g, 6.92 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 119 mg (yield 16%).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]2[CH2:13][CH2:14][O:15][CH2:16][CH:10]2[CH2:9]1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH2:12]1[NH:8][CH2:9][CH:10]2[CH2:16][O:15][CH2:14][CH2:13][CH:11]12
Reactant: c1ccc(CN2CC3CCOCC3C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C1CC2CNCC2CO1
Reaction time: 12 h
Yield: 53.2 %

Procedure:
To a solution of 2-benzyloctahydropyrano[3,4-c]pyrrole (0.45 g) in EtOH (30 mL) was added 20% Pd(OH)2 (0.30 g). The suspension was stirred under H2 for 12 h and filtered. The filtrate was concentrated in vacuo to give the title compound (0.14 g). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 128.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:46][S:47]([CH2:50][CH2:51][CH2:52][CH3:53])(=[O:49])=[O:48])[CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:35]2[CH:34]=[C:33]([NH:46][S:47]([CH2:50][CH2:51][CH2:52][CH3:53])(=[O:48])=[O:49])[CH:32]=[C:31]([O:30][CH3:29])[CH:36]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CCCCS(=O)(=O)Nc1cc(OC)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCS(=O)(=O)Nc1cc(OC)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.27 mmol) were added N-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butane-1-sulfonamide (121 mg, 0.33 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (22 mg, 0.03 mmol) and 273 μl of a 2M aqueous solution of cesium carbonate in dioxane (5 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (0 to 80%, hexane-ethyl acetate) to give 130 mg (79% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][CH:25]1[NH:29][C:28](=[O:30])[CH2:27][CH2:26]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:29]3[CH:25]([CH3:24])[CH2:26][CH2:27][C:28]3=[O:30])=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: CC1CCC(=O)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3)CC2)c(C)c1
Yield: 46.9 %

Procedure:
Using (4-bromophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (747 mg) described in Preparation Example 170 and 5-methylpyrrolidin-2-one (198 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (367 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]2)=[CH:28][CH:27]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH:32]4[CH2:36][CH2:35][NH:34][CH2:33]4)=[CH:30][CH:31]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2cnc(Nc3ccc(C4CCNC4)cc3)nc2n2ccnc2n1-c1ccccc1Cl
Temperature: 35 °C
Reaction time: 5 h

Procedure:
A mixture of Example 1E (0.048 g, 0.133 mmol) and tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (0.056 g, 0.213 mmol) was heated in a capped vial at 90° C. for 1 hour. The reaction mixture was treated with ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was dissolved in CH2Cl2 (2 mL) and treated with trifluoroacetic acid (0.103 ml, 1.334 mmol). The mixture was stirred at 35° C. for 5 hrs, concentrated, and purified by HPLC (see protocol in Example 1F) to provide the title compound as a trifluoroacetic acid salt. 1H NMR (500 MHz, CD3OD) δ 2.24-2.05 (m, 1H), 2.49 (dtd, J=10.2, 7.1, 3.1 Hz, 1H), 3.21 (dd, J=24.8, 13.8 Hz, 1H), 3.46-3.37 (m, 1H), 3.61-3.52 (m, 2H), 3.73 (dd, J=11.4, 7.9 Hz, 1H), 7.07 (d, J=1.8 Hz, 1H), 7.40-7.39 (m, 2H), 7.62-7.51 (m, 3H), 7.73-7.66 (m, 1H), 7.86-7.81 (m, 3H), 9.15 (s, 1H). MS (ESI+) m/z 458.2 (M+H)+.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C@H:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[Br:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1>C(Cl)Cl>[Br:23][C:24]1[S:28][C:27]([S:29]([N:14]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:9][CH:6]3[CH2:5][CH2:4][O:3][CH2:8][CH2:7]3)[CH2:15]2)(=[O:31])=[O:30])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: C1CN[C@@H](CC2CCOCC2)CN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)s1)N1CCN[C@@H](CC2CCOCC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
The (S)-2-((tetrahydro-2H-pyran-4-yl)methyl)piperazine dihydrochloride (390 mg, 1.516 mmol, Intermediate C) was dissolved in CH2Cl2 and the solution was chilled to 0° C. To this solution was added triethylamine (634 μL, 4.55 mmol) followed by 5-bromothiophene-2-sulfonyl chloride (497 mg, 1.90 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was allowed to slowly warm to room temperature and stirring was continued for 2 h. The mixture was concentrated and the crude material was purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give (3S)-1-((5-bromo-2-thiophenyl)sulfonyl)-3-(tetrahydro-2H-pyran-4-ylmethyl)piperazine (520 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=2[C:11]([NH:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=[O:20])=[O:12])=[CH:3][CH:2]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:19]([C:18]2[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=2)[CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=2[NH:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:20])[CH2:32][CH2:31]1
Reactant: O=C(O)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2cccc(CONC(=O)c3ccccc3NCc3ccncc3)c2)CC1

Procedure:
Prepared by a similar procedure as described for preparation of example 405. Starting materials: 3-{2-[(Pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid (see example 403) and 1-methylpiperazine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].Br.[NH2:12][C:13]1[S:14][C:15](Br)=[CH:16][N:17]=1.[OH-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([S:10][C:15]2[S:14][C:13]([NH2:12])=[N:17][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: Nc1ncc(Br)s1
Reactant: CCOc1cccc(S)c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cccc(Sc2cnc(N)s2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
Part A: A mixture of 3-ethoxythiophenol (10.0 g, 0.065 mol), 2-amino-5-bromothiazole monohydrobromide (17.7 g, 0.068 mol), 1 M aqueous NaOH (200 mL), and THF (200 mL) was stirred at RT for 15 min. The reaction mixture was warmed to 55° C. over 1 h, cooled to RT and concentrated under reduced pressure to remove THF. The residue was partitioned between EtOAc (ca. 500 mL) and water (ca 100 mL), and the layers were separated. The organic phase was washed with saturated aqueous NaCl (1×200 mL), dried (Na2SO4), and concentrated under reduced pressure to give a solid. The solid was triturated with CH2Cl2:hexanes (ca. 10:1) to provide 5-(3-ethoxy-phenylsulfanyl)-thiazol-2-ylamine (13.2 g, 80%) as a light brown solid. LCMS (m/z): 253 (M+H)+