Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN1CCCC1>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([O:8][C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:1])[CH:7]=2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccnc(O)c1
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: O=c1cc(Oc2ccc([N+](=O)[O-])cc2)cc[nH]1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A suspension of 2,4-dihydroxy-pyridine (2.33 g, 21 mmol), 4-fluoro-nitrobenzene (2.22 ml, 21 mmol) and Cs2CO3 (10.2 g, 31.3 mmol) in N-methyl-pyrrolidine (30 ml) is stirred for 3 h at 100° C. under N2-atmosphere. The reaction mixture is poured into water and the precipitate filtered off and washed with water. The solid is dissolved in CH2Cl2/MeOH. Then SiO2 (≈20 g) is added and the mixture Is concentrated in vacuo. The resulting powder is put on top of a SiO2-column and eluted with toluene/AcOEt 3:1→AcOEt→AcOEt/EtOH 9:1, yielding the title compound: m.p.: 227-228° C.; 1H-NMR (DMSO-d6): 11.60 (s, HN), 8.31 (d, 2H), 7.47 (d, 1H), 7.39 (d, 2H), 6.07 (dd, 1H), 5.67 (d, 1H).
Reaction SMILES: [C:1]([NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])(=S)[CH3:2].[NH2:15][C:16]1[C:20]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[C:19]([CH2:26][CH3:27])[NH:18][N:17]=1>O1CCOCC1>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[C:5]1[N:17]2[N:18]=[C:19]([CH2:26][CH3:27])[C:20]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[C:16]2[N:15]=[C:1]([CH3:2])[N:4]=1
Reactant: CCc1[nH]nc(N)c1C(CC)CC
Reactant: CC(=S)NC(=O)c1ccc(Cl)cc1Cl
Solvent: C1COCCO1
Product: CCc1nn2c(-c3ccc(Cl)cc3Cl)nc(C)nc2c1C(CC)CC
Temperature: 25 °C
Yield: 25.3 %

Procedure:
A mixture of N-(thioacetyl)-2,4-dichlorobenzamide (200 mg, 0.81 mmol) and 3-amino-5-ethyl-4-(3-pentyl)pyrazole (146 mg, 0.81 mmol) in dioxan (1 mL) was stirred at reflux temperature for 16 h. After being cooled to room temperature, the reaction mixture was concentrated in vacuo. Preparative TLC using EtOAc:hexanes::1:1 generated the title product (77.3 mg, 24% yield): mp=91-93° C.; NMR (CDCl3,300 MHz): δ 7.64 (d, 1H, J=8), 7.57 (d, 1H, J=2), 7.44 (dd, 1H, J=8,2), 2.77 (q, 2H, J=8), 2.69 (s, 3H), 2.80-2.60 (m, 1H), 2.00-1.80 (m, 4H), 1.25 (t, 3H, J=8), 0.82 (t, 6H, J=7); CI-HRMS m/z Calcd: 377.1294, Found: 377.1303.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)[CH3:2].C1C(=O)N([Br:21])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:21][CH2:12][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cc1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)Cc1cccc(CBr)c1
Temperature: 70 °C
Yield: 433.6 %

Procedure:
Acetonitrile (30 mL) was degased with nitrogen for 5 minutes, and then ethyl-m-tolylacetate (2 mL, 2 mmol), NBS (1.9 g, 10.7 mmol) and benzoyl peroxide (266 mg, 1.1 mmol) were added. The resulting mixture was heated to 70° C. for 18 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, passed through a hydrophobic frit, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography, eluting with 0-50% DCM in isohexane, to provide ethyl 2-[3-(bromomethyl)phenyl]-acetate (2.23 g, 77%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([S:31][CH3:32])=[N:26][CH:27]=[N:28]2)=[CH:23][CH:22]=1.[O:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]#[C:41][CH2:42]O)[CH2:35][CH2:34]1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH3:32][S:31][C:25]1[C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:42][C:41]#[C:40][CH2:39][N:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[CH:22][CH:23]=2)[N:28]=[CH:27][N:26]=1
Reactant: CSc1ncnc2cc(O)ccc12
Reactant: OCC#CCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ncnc2cc(OCC#CCN3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
Triphenylphosphine (4.09 g, 1.56 mmol) was added dropwise to a solution of 7-hydroxy-4-methylsulphanylquinazoline (1.2 g, 6.25 mmol), (prepared as described for the starting material in Example 8), in methylene chloride (30 ml), followed by 4-morpholinobut-2-yn-1-ol (1.26 g, 8.3 mmol), (J. Am. Chem. Soc. 1957, 79, 6184), in methylene chloride (5 ml) and diethyl azodicarboxylate (2.46 ml, 1.56 mmol) was added dropwise. After stirring for 3 hours at ambient temperature, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/methanol (100/0 followed by 95/5). After removal of the solvent, the residue was triturated with ether, collected by filtration and dried under vacuum to give 4-methylsulphanyl-7-(4-morpholinobut-2-yn-1-yloxy)quinazoline (1.3 g, 63%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]([CH2:14][CH3:15])[NH:12][C:11](=[O:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([O:26][CH3:27])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C@@H:9]1[CH2:10][C:11](=[O:16])[N:12]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([O:26][CH3:27])[CH:19]=2)[C@H:13]1[CH2:14][CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1NC(=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(Br)ccc1C#N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(OC)c1

Procedure:
Using (4R,5S)-4-(tert-butyldimethylsilyloxy)-5-ethylpyrrolidin-2-one (1.00 g), 4-bromo-2-methoxybenzonitrile (1.00 g), cesium carbonate (2.08 g), tris(dibenzylideneacetone)dipalladium(0) (193 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (490 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 1.04 g, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OCc3ccccc3)cn2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(O)cn2)CC1
Reaction time: 3 h
Yield: 75.4 %

Procedure:
To a solution of 4-(5-benzyloxy-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (18.2 g, 47.5 mmol, 1.0 equiv) in methanol (200 mL) was added 10% Pd on activated carbon (2.53 g, 2.38 mmol 0.05 equiv) under an atmosphere of Ar. The reaction vessel was twice evacuated and ventilated with hydrogen gas and the well stirred reaction mixture was subsequently hydrogenated at rt and 1 bar H2 for 3 h. After filtration over dicalite the crude reaction mixture was concentrated by evaporation under reduced pressure and purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 10.50 g (75%) of the title compound as a light yellow solid. MS (ISP): 294.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1CCCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CCCCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)butyl]piperidine-1-carboxylate (0.0483 g, 0.119 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0174 g, 0.119 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate), and the resulting crude product was purified again by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}butyl)piperidine-1-carboxylate (0.0454 g, 72%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)cn1
Temperature: 60 °C
Yield: 72.5 %

Procedure:
To methyl 5-hydroxypyridine-2-carboxylate (0.6 g, 3.92 mmol) in DMF (3.6 mL) was added potassium carbonate (2.2 g, 15.7 mmol) followed by 2-bromopropane (736 μL, 7.8 mmol) The reaction mixture was heated at 60° C. for 1.5 hours. The reaction mixture was cooled and filtered using EtOAc and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water (3×10 mL) and brine solution (10 mL). The organics were separated and dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using 0-50% EtOAc: hexanes as eluent to give methyl 5-isopropoxypyridine-2-carboxylate (555 mg, 73%) as a colorless oil. ESI-MS m/z calc. 195.1. Found 196.3 (M+1)+; Retention time: 1.09 minutes (3 min run). Lithium hydroxide (5.7 mL of 2 M, 11.37 mmol) was added to a solution of methyl 5-isopropoxypyridine-2-carboxylate (555 mg, 2.84 mmol) in dioxane (4 mL) and stirred at 55° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and layers were separated. The aqueous layer was acidified with 1N HCl solution and extracted with ethyl acetate. The organics were separated and dried over sodium sulfate, filtered and concentrated in vacuo to give 5-isopropoxypyridine-2-carboxylic acid (150 mg, 29%). ESI-MS m/z calc. 182.1. Found 182.3 (M+1)+; Retention time: 0.33 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([OH:14])=O)=[C:5]2[OH:15].CN(C)C=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([Cl:33])=[CH:35][CH:36]=1)=[O:14])=[C:5]2[OH:15]
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cnc2ccc(Cl)cc2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(Cl)cc2c1O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a mixture of 0.365 g of 6-chloro-4-hydroxy-3-quinolinecarboxylic acid (J. Amer. Chem. Soc., 68, 1264 (1946)) and 5 mL of dimethylformamide is added 0.29 g of carbonyldiimidazole. The mixture is stirred 18 h at 60° C. and then it is cooled to 25° C. To the resulting solution is added 0.22 mL of 4-chlorobenzylamine. After stirring for 18 hours the mixture is diluted with 10 mL of distilled water. After 30 minutes the precipitate is collected by filtration and it is washed with two successive mL portions of water. It is then washed with 5 mL of diethyl ether. It is dried for 48 h at 85° C. and 20 torr. This procedure yields the title compound as 251 mg of an off-white solid.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[OH:33])=[C:20]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:19]=3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C1COCC1.CN(C=O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[OH:33])=[C:20]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:19]=1
Reactant: O=C(Nc1ccc(NC(=O)c2ccc(F)cc2O)c(OCc2ccccc2)c1)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Nc1ccc(NC(=O)c2ccc(F)cc2O)c(OCc2ccccc2)c1
Yield: 51 %

Procedure:
[3-Benzyloxy-4-(4-fluoro-2-hydroxy-benzoylamino)-phenyl]-carbamic acid 9H-fluoren-9-yl-methyl ester (75) (0.192 g, 0.334 mmol) was dissolved in a mixture of THF (3 mL) and DMF (1 mL). Piperidine (0.57 g, 6.68 mmol) was added. The mixture was shaken at room temperature in a Teflon septum capped vial for 20 minutes. TLC indicated complete de-protection at this point. The mixture was concentrated to give an oil. Purification by flash chromatography using a gradient of hexane and EtOAc (5–100% EtOAc in hexane for 25 minutes followed by 100% EtOAc for 5 minutes) gave the desired product (76) upon concentration (0.060 g, 0.170 mmol, 51% yield). LC-MS (ESI): (exact mass: 352.12) m/e=353.3 [M+1]+ (100%), 705.3 [2M+1]+ (5%).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:13]([O:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc(O)n1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(OCc2ccccc2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
A mixture of methyl 6-hydroxypicolinate (3.06 g, 20.0 mmol), (bromomethyl)benzene (6.84 g, 40.0 mmol), and silver carbonate (11 g, 40 mmol) in toluene (150 mL) was stirred at 80° C. overnight. After cooling and filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (20:1) to give methyl 6-(benzyloxy)picolinate (2.6 g, 53%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:19])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:21].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:19])=[CH:8][CH:9]=2)[N:4]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:3]1=[O:21]
Reactant: CC1(C)C(=O)Nc2cc(NC(=O)c3ccncc3F)ccc21
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(=O)N(CC(F)(F)F)c2cc(NC(=O)c3ccncc3F)ccc21

Procedure:
To a solution of N-(3,3-dimethyl-2-oxoindolin-6-yl)-3-fluoroisonicotinamide (example 72, 78 mg, 261 μmol) in DMF (700 μl) under an argon atmosphere was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (66.5 mg, 39.6 μl, 287 μmol) and cesium carbonate (93.4 mg, 287 μmol). After 3 hours at room temperature the reaction mixture was poured into water and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (with 10% ammonia) as eluent followed by trituration with diethyl ether/heptane. The title compound was obtained as white foam (36 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][CH:21]=[N:22]2)=[C:18]([Cl:25])[N:17]=1>>[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][N:22]2[C@@H:12]([C@@:9]2([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH2:11][O:10]2)[CH3:13])=[C:18]([Cl:25])[N:17]=1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Product: C[C@@H](n1cnc2c(Cl)nc(Cl)nc21)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 17.5 %

Procedure:
Using (1S)-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (578 mg) and 2,6-dichloropurine (490 mg), (2S)-2-[(1R)-1-[2,6-dichloro-9(9H)-purinyl]ethyl]-2-(2,4-difluorophenyl)oxirane (168 mg) was obtained by the same way as in Reference Example 2.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][C:17]([C:20]2[S:21][CH:22]=[C:23]([C:25]3[C:26]([O:40][CH:41]4[CH2:44][CH2:43][CH2:42]4)=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]([C:35]([O:37][CH3:38])=[O:36])[C@@H:30]([CH3:39])[CH2:29][CH2:28]4)[N:24]=2)([F:19])[CH2:16]1)=O)(C)(C)C>ClCCl>[CH:41]1([O:40][C:26]2[C:25]([C:23]3[N:24]=[C:20]([C:17]4([F:19])[CH2:18][NH:15][CH2:16]4)[S:21][CH:22]=3)=[CH:34][CH:33]=[C:32]3[C:27]=2[CH2:28][CH2:29][C@H:30]([CH3:39])[N:31]3[C:35]([O:37][CH3:38])=[O:36])[CH2:42][CH2:43][CH2:44]1
Reactant: COC(=O)N1c2ccc(-c3csc(C4(F)CN(C(=O)OC(C)(C)C)C4)n3)c(OC3CCC3)c2CC[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N1c2ccc(-c3csc(C4(F)CNC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-3-fluoro azetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.059 g, 0.11 mmol) in dichloromethane (3 mL), and the resulting solution stirred for 2 h at room temperature and was then concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions (Waters I): Column, XBridge C18, 19×150 mm, 5 um; Mobile phase: water (0.05% ammonium bicarbonate) and acetonitrile (5% to 95% acetonitrile in 8 min; flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded (S)-methyl 5-cyclobutoxy-6-(2-(3-fluoro azetidin-3-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.025 g, 53%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.20 (d, J=6.40 Hz, 3H), 1.31-1.40 (m, 1H), 1.45-1.55 (m, 1H), 1.55-1.66 (m, 1H), 2.02-2.18 (m, 4H), 2.22-2.31 (m, 1H), 2.49-2.55 (m, 1H), 2.95-3.06 (m, 1H), 3.80 (s, 3H), 4.08-4.20 (m, 3H), 4.28-4.36 (m, 2H), 4.56-4.64 (m, 1H), 7.24-7.27 (m, 1H), 7.67-7.73 (m, 2H). MS (ESI, pos. ion) m/z 432 [M+H]+.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[OH:17])[CH2:6][CH2:5]1)(=O)C.[ClH:18]>>[ClH:18].[ClH:18].[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)=[C:11]([OH:17])[CH:12]=1
Reactant: CC(=O)N1CCN(c2ccc(F)cc2O)CC1
Agent: Cl
Product: Oc1cc(F)ccc1N1CCNCC1

Procedure:
1-Acetyl-4-(4-fluoro-2-hydroxyphenyl)piperazine (0.64 g) was dissolved in a 1.2N aqueous hydrochloric acid solution (16 ml) and refluxed under heating for 7 days. The reaction mixture was concentrated under reduced pressure to give a pale-brown solid. This solid was recrystallized from methanol-ethyl acetate to give the title compound (0.65 g) as pale-brown crystals.
Reaction SMILES: [CH2:1]([C@:3]1([OH:21])[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[C@H:4]1[CH:18]([CH3:20])[CH3:19])[CH3:2]>[Pd].O>[CH2:1]([C@:3]1([OH:21])[CH2:7][CH2:6][NH:5][C@H:4]1[CH:18]([CH3:20])[CH3:19])[CH3:2]
Reactant: CC[C@]1(O)CCN(C(=O)OCc2ccccc2)[C@H]1C(C)C
Agent: [Pd]
Solvent: O
Product: CC[C@]1(O)CCN[C@H]1C(C)C

Procedure:
By an operation in the same manner as in Reference Example 4 and using benzyl (2S,3S)-3-ethyl-3-hydroxy-2-isopropylpyrrolidine-1-carboxylate (2.2 g) and 50% water containing-10% Pd/C (0.11 g), the title compound was obtained as a colorless solid (yield: 1.33 g, yield: 83%).
Reaction SMILES: [CH3:1][C:2]([CH3:34])([O:4][C:5]([C@H:7]([NH:25][C@H:26]([C:31](O)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])=[O:6])[CH3:3].OC1C2N=NNC=2C=CC=1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][NH2:52])[CH:46]=1.C1(N=C=NC2CCCCC2)CCCCC1>O.CN(C=O)C>[CH3:1][C:2]([O:4][C:5](=[O:6])[C@H:7]([NH:25][C@H:26]([C:31]([NH:52][CH2:51][C:47]1[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=1)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])([CH3:34])[CH3:3]
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)O
Reactant: NCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1cccnc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
100 mg of N-[(R)-1-[(1,1-dimethylethoxy)carbonyl]-3-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)propyl]-L-leucine, prepared as in Example L, was added to 2.5 mL of DMF. 39.2 mg of hydroxybenzotriazol.H2O was added to the mixture followed by 0.026 mL of (pyridin-3-ylmethyl)amine. The mixture was cooled to 0° C. and 52.8 mg dicyclohexylcarbodiimide was added. The mixture was warmed to 23° C. and stirred for 24 h. The solvents were removed by evaporation and the resultant residue was diluted with ethyl acetate. The mixture was extracted with a saturated solution of sodium bicarbonate and the organic layer was separated, dried (MgSO4), and filtered. The solvent was removed by evaporation to afford the title compound; 139 mg.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:8]=[CH:7][N:6]=1)=[O:4].[C:20](C1C=C(C(O[Si](C(C)(C)C)(C)C)C)C=CN=1)(=O)C>>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[CH3:20])[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C(=O)CBr)c1
Reactant: CC(=O)c1cc(C(C)O[Si](C)(C)C(C)(C)C)ccn1
Product: CC(O[Si](C)(C)C(C)(C)C)c1ccnc(C(=O)CBr)c1

Procedure:
The title compound was prepared according to the procedure for preparing 2-bromoacetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine described in Example 95 from 2-acetyl-4-[1-(tert-butyldimethylsilyloxy)ethyl]pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:32]([C:27]1[NH:28][C:29]2[C:25]([CH:26]=1)=[CH:24][C:23]([O:22][CH3:21])=[CH:31][CH:30]=2)=[O:33]
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: COc1ccc2[nH]c(C(=O)Nc3ccc(N4CCC(CN5CCCC5C)C4)cc3C)cc2c1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 5-methoxy-1H-indole-2-carboxylic acid. MS: 447.5 (M+H).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=O)[CH:22]([F:24])[F:23])[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>>[F:23][CH:22]([F:24])[C:21](=[S:38])[NH:20][CH2:19][C@@H:17]1[O:16][C:15](=[O:26])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([N:5]3[CH2:6][CH2:7][S:2](=[O:28])(=[O:1])[CH2:3][CH2:4]3)=[C:9]([F:27])[CH:10]=2)[CH2:18]1
Reactant: O=C(NC[C@H]1CN(c2ccc(N3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: O=C1O[C@@H](CNC(=S)C(F)F)CN1c1ccc(N2CCS(=O)(=O)CC2)c(F)c1

Procedure:
Following the procedure described in Example 1 for the preparation of 1 the reaction of 15 with Lawesson's Reagent provides the title compound (13), which is purified by silica gel chromatography with 2.5% MeOH—CH2Cl2 and crystallization from EtOAc-hexane.