Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][C:12]([CH3:33])([CH3:32])[CH2:13][C:14]1[N:15]([CH2:28][CH2:29][O:30][CH3:31])[N:16]=[C:17]2[C:26]=1[C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:19]=[C:18]2[NH2:27]>C(OCC)(=O)C>[NH2:27][C:18]1[C:17]2=[N:16][N:15]([CH2:28][CH2:29][O:30][CH3:31])[C:14]([CH2:13][C:12]([NH:11][C:2](=[O:9])[C:3]3[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=3)([CH3:33])[CH3:32])=[C:26]2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)c1cccnc1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
Using the method of Example 68, nicotinoyl chloride hydrochloride (668 mg, 4.75 mmol) was reacted with 1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (470 mg, 1.5 mmol, prepared as described in Example 590). The crude product was purified by IFC (silica gel eluting with a gradient of 10 to 40% CMA in chloroform) to provide a pale yellow resin. The resin was refluxed with 35% ethyl acetate in hexanes (50 mL) and ethyl acetate (75 mL) and cooled to ambient temperature with stirring. The resulting solid was isolated by filtration, rinsed with 35% ethyl acetate in hexanes, and dried to provide 278 mg of N-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}nicotinamide as a light beige solid, mp 212-214° C. MS (APCI) m/z 419 (M+H)+; Anal. Calcd for C23H26N6O2: C, 66.01; H, 6.26; N, 20.08. Found: C, 65.74; H, 6.50; N, 20.09.
Reaction SMILES: O.[NH2:2][NH2:3].C([O:6][C:7](=O)[CH:8]=[CH:9][C@@H:10]1[CH2:14][C@H:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][N:11]1[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])C>C(O)C>[CH2:38]([O:37][C:35]([N:11]1[CH2:12][C@@H:13]([S:15][C:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:14][C@H:10]1[CH:9]1[NH:3][NH:2][C:7](=[O:6])[CH2:8]1)=[O:36])[CH:39]=[CH2:40]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1C=CC(=O)OCC
Reactant: NN
Solvent: CCO
Solvent: O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1C1CC(=O)NN1
Reaction time: 1.5 h
Yield: 55.7 %

Procedure:
Hydrazine monohydrate (0.61 ml, 12.6 mmol) was dropwise added to a solution of 3-[(2S,4S)-N-allyloxycarbonyl-4-tritylthiopyrrolidin-2-yl]acrylic acid ethyl ester (1.53 g, 2.9 mmol) in ethanol (7.5 ml) under cooling with ice, and the mixture was stirred at the same temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, 2% methanol-chloroform) to obtain (2S,4S)-N-allyloxycarbonyl-2-(3-pyrazolidinon-5-yl)-4-tritylthiopyrrolidine (830 mg, yield: 51.1%). This compound was immediately dissolved in methylene chloride (10 ml). Then, triethylamine (0.24 ml, 1.7 mmol) and allyl chloroformate (0.18 ml 1.7 mmol) were dropwise added thereto under cooling with ice, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (50 ml). The organic layer was washed with water and a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, 1% methanol-chloroform) to obtain (2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-3-pyrazolidinon-5-yl)-4-tritylthiopyrrolidine (592 mg, yield: 62%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH2:10][CH2:9]3.Cl[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)=[O:32]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]([CH2:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)=[O:32])[CH:17]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: O=C(CCl)c1cccc(F)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21
Product: O=C(Cn1cc(C(=O)N2CCC3(CC2)OC(=O)c2cc(Br)ccc23)c2ccc(Cl)cc21)c1cccc(F)c1

Procedure:
Following the general procedure III as described above, the alkylation of 5-bromo-1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with commercially available 2-chloro-1-(3-fluoro-phenyl)-ethanone gave the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:19])=[O:18]
Reactant: OCC1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC1CCOCC1

Procedure:
The tetrahydropyran-4-methanol (Combi-Blocks, Inc., 0.15 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Li+].CC([N-]C(C)C)C.[CH:17](=[O:19])[CH3:18].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[C:7]=1[CH:17]([OH:19])[CH3:18]
Reactant: Brc1cncc(Br)c1
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1c(Br)cncc1Br
Temperature: -78 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a cooled (−78° C.) solution of 3,5-dibromo-pyridine (2.0 g, 8.4 mmol) in dry THF (80 mL) is added LDA in THF solution (2M; 5.1 mL, 10.1 mmol) and the mixture is stirred at −78° C. for 2 h. Acetaldehyde in THF solution (5M; 3.4 mL, 16.9 mmol) is added and the mixture is stirred at −78° C. for 30 min, then at room temperature for 16 h. Saturated aqueous NH4Cl solution is added and the mixture is extracted with EtOAc. The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 2.9 g (67% purity) of 1-(3,5-dibromo-pyridin-4-yl)-ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccc(-c2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccnc1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 2-(4-bromophenyl)-1H-imidazole (1 equiv) in DMF (0.47 M) was added sodium hydride (3 equiv, 60% in mineral oil) at 0° C. under nitrogen. After the resulting reaction mixture was stirred at 0° C. for 15 min, (2-(chloromethoxy)-ethyl)trimethylsilane (1.1 equiv) was added. Then the mixture was stirred at room temperature for 3 h and quenched with saturated aqueous ammonium chloride solution. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration under vacuum gave the crude product, which was purified by silica gel column chromatography (25% ethyl acetate in petroleum ether) to afford the title compound (80% yield). MS (ESI) m/z 354.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:3]=1C(O)=O.C([N:19](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(O)C>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:3]=1[NH2:19]
Reactant: CCN(CC)CC
Reactant: COCCOc1ccc(F)c(F)c1C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCCOc1ccc(F)c(F)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3,4-difluorophenol (1.43 g) and cesium carbonate (4.89 g) in N,N-dimethylformamide (10 mL) was added 2-methoxyethyl bromide (0.94 mL), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (39 mL). To the solution was added n-butyllithium (2.64 mol/L n-hexane solution, 3.25 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dryice (10 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was acidified by addition of 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 2,3-difluoro-6-(2-methoxyethoxy)benzoic acid (1.48 g). The obtained 2,3-difluoro-6-(2-methoxyethoxy)benzoic acid (0.5 g) was dissolved in 1,4-dioxane (10 mL). To the solution were added triethylamine (0.45 mL) and diphenylphosphoryl azide (0.61 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethanol (0.99 g), and the mixture was heated for reflux for 5 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To a suspension of the residue in ethanol (10 mL) was added 5 mol/L aqueous sodium hydroxide solution (4.3 mL), and the mixture was heated for reflux for 2 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give the title compound (75 mg).
Reaction SMILES: F[C@H]1[C@@H](N(C)C)CCNC1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[N:28]=[C:27]3[C:23]([N:24]=[C:25]([CH2:30][N:31]4[CH2:36][CH2:35][CH:34]([N:37]([CH3:39])[CH3:38])[CH:33]([F:40])[CH2:32]4)[N:26]3[CH3:29])=[C:22]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[N:21]=2)=[CH:12]1>>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[N:28]=[C:27]3[C:23]([N:24]=[C:25]([CH2:30][N:31]4[CH2:36][CH2:35][C@H:34]([N:37]([CH3:39])[CH3:38])[C@H:33]([F:40])[CH2:32]4)[N:26]3[CH3:29])=[C:22]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[N:21]=2)=[CH:12]1
Reactant: CN(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(-c4c[nH]c5ccccc45)nc3n2C)CC1F
Agent: CN(C)[C@H]1CCNC[C@H]1F
Product: CN(C)[C@H]1CCN(Cc2nc3c(N4CCOCC4)nc(-c4c[nH]c5ccccc45)nc3n2C)C[C@H]1F

Procedure:
Following the procedures to prepare 104, racemic cis-3-fluoro-N,N-dimethylpiperidin-4-amine was converted to 1-((2-(1H-indol-3-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-3-fluoro-N,N-dimethylpiperidin-4-amine. The enantiomers of the final product were separated by SFC to give 123. LCMS: M+H+=493.2. 1H-NMR (400 MHz, DMSO-d6): δ 11.5 (s, 1H), 8.61 (m, 1H), 8.13 (m, 1H), 7.42 (m, 1H), 7.14 (m, 2H), 4.27 (s, br, 4H), 3.85 (s, 3H), 3.79 (m, 6H), 3.04 (m, 1H), 2.91 (m, 1H), 2.05-2.29 (m, 5H), 1.59-1.84 (m, 2H), 1.17 (t, 1H)
Reaction SMILES: CSC.B.[NH2:5][C:6]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]>C1COCC1>[NH2:9][CH2:8][C:7]1[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:6]=1[NH2:5]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1N
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: NCc1ccc([N+](=O)[O-])cc1N
Reaction time: 3 h
Yield: 74.8 %

Procedure:
Borane-dimethyl sulfide (40 mL, 80 mmol) was added dropwise to a stirring solution of 2-amino-4-nitro-benzonitrile (2.27 g, 14 mmol) in dry THF (50 mL) at room temperature. The mixture was stirred at same temperature for 3 hours, and then carefully quenched with 1N aqueous HCl. The mixture was made basic (pH>11) with 4N sodium hydroxide and extracted with methylene chloride. The organic phase was dried over sodium sulfate, filtered and concentrated to provide 1.75 g of 2-aminomethyl-5-nitro-phenylamine (75%): 1H NMR (300 MHz, CDCl3) δ7.6 (m, 2H), 7.25 (d, 1H), 5.1 (br, 2H), 4.1 (s, 3H); MS (m/e): 168.1 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N>C(O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CCc1ccc(CCOc2ccc(C=O)cc2)nc1
Agent: N
Solvent: CCO
Product: CCc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)nc1

Procedure:
A mixture of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde (27 g), ethanol (300 ml), 2,4-thiazolidinedione (33 g) and concentrated aqueous ammonia (14 ml) was heated under reflux for 5 hours. The precipitated crystals were separated. Recrystallization from 1,2-dichloroethane gave 21.6 g (57.6% of crystals of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([OH:11])[CH3:10].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([O:11][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:10]
Reactant: CC(O)c1c(F)cccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)c1c(F)cccc1Cl
Yield: 94.6 %

Procedure:
1-(2-Chloro-6-fluorophenyl)ethanol (8.5 g), imidazole (8.1 g) and t-butyldimethylsilylchloride (8.71 g) were stirred in DMF for 24 hours. The mixture was diluted with ether and washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 1-(2-chloro-6-fluorophenyl)ethyl (t-butyldimethylsilyl)ether (13.3 g) as a clear oil, NMR (CDCl3) -0.1(s,3H), 0.05(s,3H), 0.85(s,9H), 1.5(d,3H), 5.4(q,1H), 6.9(m,1H), 7.05(m,2H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:24])=[CH:14][CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CSCc1ccc(F)cc1
Solvent: ClCCl
Product: CCOC(=O)CS(=O)Cc1ccc(F)cc1
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of ethyl 2-(4-fluorobenzylthio)acetate (1.89 g, 8.29 mmol) in DCM (20.0 mL) at −40° C. was added a solution of m-CPBA (77%, 1.86 g, 8.29 mmol) in DCM (20.0 mL) dropwise. The solution was stirred from −40° C. to room temperature overnight. The solution was then quenched with polymer bound diethylene triamine. After filtration and concentration, the residue was purified by flash chromatography on SiO2 to give ethyl 2-(4-fluorobenzylsulfinyl)acetate (2.0 g, 98% yield). MS (ESI+): m/z 267.09 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:35][CH2:36][CH2:37][OH:38])=[C:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:66][C:67]1[CH:72]=[CH:71][C:70](O)=[CH:69][CH:68]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:45])[CH3:46])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:35][CH2:36][CH2:37][O:38][C:70]3[CH:71]=[CH:72][C:67]([I:66])=[CH:68][CH:69]=3)=[C:26]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: Oc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCO
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 2-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-hydroxypropyl)thiazole-4-carboxylate (92 mg, 0.135 mmol), triphenylphosphine (35.4 mg, 0.135 mmol) and 4-iodophenol (29.7 mg, 0.135 mmol) in THF (2 mL) was added DBAD (32 mg, 0.135 mmol). The mixture was stirred at rt for 4 hours. LC/MS showed the expected product as a single peak. The mixture was diluted with EtOAc and washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 3% EtOAc in hexanes to provide 110 mg (92%) of the desired product: 1H NMR (300 MHz, CDCl3) δ ppm 8.30 (1H, m), 7.72 (1H, d), 7.54 (4H, m), 7.34 (3H, m), 6.67 (2H, d), 6.00 (2H, s), 5.14 (2H, s), 3.96 (4H, m), 3.75 (2H, t), 3.22 (2H, t), 3.06 (2H, t), 2.13 (2H, m), 1.59 (9H, s), 0.97 (2H, t), 0.01 (9H, m). MS (ESI(+)): m/z 833 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:16]=3[N:12]2[CH2:11][CH:10]1[CH2:26][C:27]([O:29]C)=[O:28].[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:16]=3[N:12]2[CH2:11][CH:10]1[CH2:26][C:27]([OH:29])=[O:28]
Reactant: CCN(CC)c1cccc2nc3n(c12)CC(CC(=O)OC)N3c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)c1cccc2nc3n(c12)CC(CC(=O)O)N3c1ccc(Cl)cc1Cl
Yield: 65.3 %

Procedure:
To a solution of methyl [1-(2,4-dichlorophenyl)-5-(diethylamino)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-2-yl]acetate (Example 72; 50.0 mg, 0.112 mmol) in a mixture of tetrahydrofuran (1 mL) and methanol (0.5 mL) was added 1N sodium hydroxide solution (0.224 mL, 0.224 mmol) at room temperature. After the resultant mixture was stirred at room temperature for 1 hr, the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was washed with ethyl acetate to give the title compound as a solid (31.7 mg, 0.0731 mmol, 65%). Analytically pure material was obtained by recrystallization from ethanol/diisopropyl ether.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])=[CH:52][CH:51]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[F:63][C:57]([F:62])([C:58]([F:59])([F:61])[F:60])[CH2:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][CH:39]([NH:38][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)=[O:14])[CH:40]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=2)[OH:41])=[CH:51][CH:52]=1
Reactant: NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of 4-fluoronaphthalene-1-carboxylic acid (153 mg, 0.801 mmol) in N,N-dimethylformamide (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 g, 0.801 mmol) and 1-hydroxybenzotriazole monohydrate (123 mg, 0.801 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(2,2,3,3,3-pentafluoropropyl)phenyl]-1-propanol (0.30 g, 0.763 mmol) was finally added. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The mixture was filtered using a glass filter filled with silica gel, and the filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide (0.284 g, 66%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14].C(N(C(C)C)C(C)C)C>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH2:14][CH2:13][CH2:12][NH2:15])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CCCN
Reactant: Clc1nc(Cl)c2sccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NCCCc1nc(Cl)nc2c1SCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.7 %

Procedure:
10.4 g (50.2 mmol) of 2,4-dichlorothieno[3,2-d]pyrimidine (VII), 8.2 mL (100 mmol) of N-propylamine, and 17.5 mL (100 mmol) of N-ethyldiisopropylamine are placed in 100 mL of tetrahydrofuran and stirred for 20 hours at ambient temperature. The suspension is filtered, the filtrate is concentrated by evaporation. The residue is combined with 100 mL of water and treated in the ultrasound bath. Solid substance is suction filtered, dried, and stirred with 50 mL of petroleum ether. 10.0 g of the product VIII (86%) is obtained as a powder.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21]C(C)C)=[CH:15][CH:14]=2)=[CH:9]1.[CH:26]([N:29]=[C:30]=[O:31])([CH3:28])[CH3:27]>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21][C:30]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:31])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: CC(C)NCC(C)c1ccc(-c2ccsc2)cc1
Reactant: CC(C)N=C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)NCC(C)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl-2-propyl amine trifluoroacetate (prepared in example 1) and i-propyl isocyanate in a manner analogous to the procedure described in Example 7.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15](O)=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][O:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([N:32]3[CH2:33][CH2:34][N:29]([CH2:28][CH2:27][O:26][CH3:25])[CH2:30][CH2:31]3)=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(C(=O)c2ccc3c(OC(C)C)nc(Nc4cc(C)[nH]n4)cc3c2)CC1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and 1-(2-Methoxy-ethyl)-piperazine to give [1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl]-[4-(2-methoxy-ethyl)-piperazin-1-yl]-methanone. LC-MS: m/e 453 (MH+).