Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Mg]Br)C.Cl.Cl[CH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[O:20][CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:16][C:17]2[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=2)[O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: CC[Mg]Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1cc(Cc2c[nH]c3ccccc23)cc(OCc2ccc3ccccc3n2)c1
Temperature: 65 °C

Procedure:
Indole (230 mg, 2.0 mmol) is dissolved in tetrahydrofuran (3 mL) and ethylmagnesium bromide (1 M, 2.0 mL, 2.0 mmol) is added and the reaction is heated for 2 h at 65° C. The free base of 2-(3-chloromethyl-phenoxymethyl)-quinoline hydrochloride (400 mg, 1.2 mmol, example 49) is prepard by partioning the material between ethyl ether and sodium bicarbonate and drying the organic phase with magnesium sulfate. This free base is dissolved in tetrahydrofuran (2 mL) and is added to the cooled indole/Grignard solution, along with catalytic tetrabutylammonium iodide. This mixture is heated 6 h at 65° C. The reaction is then cooled and partitioned between ethyl ether and ammonium chloride. The organic phase is washed with brine, dried over magnesium sulfate, concentrated and purified by column chromatography (silica, dichloromethane) to yield the title compound. MS (ESI) 365 (M+H)+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)=[CH:32][CH:31]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.5 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.103 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.046 g, 11%). MS (ISP) 426.0 [(M+H)+]; mp 275° C.
Reaction SMILES: [NH2:1][C:2]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([OH:30])[CH:27]=4)[NH:22][C:21]3=[O:31])[CH2:16][CH2:15]2)=[O:13])[C:8](O)=[O:9])=[CH:4][C:3]=1[Cl:38].[O:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[NH2:1][C:2]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([OH:30])[CH:27]=4)[NH:22][C:21]3=[O:31])[CH2:16][CH2:15]2)=[O:13])[C:8]([N:48]2[CH2:47][CH2:46][N:45]([CH:42]3[CH2:43][CH2:44][O:39][CH2:40][CH2:41]3)[CH2:50][CH2:49]2)=[O:9])=[CH:4][C:3]=1[Cl:38]
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3Cc4cc(O)ccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Product: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3Cc4cc(O)ccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 81 from 80.0 mg (0.14 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(6-hydroxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-4-oxo-butanoic acid and 24.5 mg (0.14 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36]([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([O:39][CH3:36])[CH3:44])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)OC)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f28) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][CH:2]1[CH2:7][S:6][C:5]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:4]=2[C:3]1=[O:15].[BH4-].[Na+].Cl>CO.O>[Br:1][CH:2]1[CH2:7][S:6][C:5]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:4]=2[CH:3]1[OH:15]
Reactant: NS(=O)(=O)c1cc2c(s1)SCC(Br)C2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NS(=O)(=O)c1cc2c(s1)SCC(Br)C2O
Temperature: -10 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A suspension of 5,6-dihydro-5-bromo-4H-thieno[2,3-b]thiopyran-4-one-2-sulfonamide (2.58 g, 0.0079 m) in methanol (100 ml) was cooled to -10° C. and vigorously stirred while a solution of sodium borohydride (0.45 g, 0.012 m) in water (10 ml) was added over 25 minutes while maintaining the temperature at -10° to -5° C. The mixture was stirred at ambient temperature for 2 hours, then acidified with 6N hydrochloric acid and concentrated in vacuo below 40° C. The residue was distributed between ethyl acetate (100 ml) and water (100 ml), the aqueous layer was separated and again extracted with ethyl acetate (2×75 ml). The combined extracts were washed with water, dried over sodium sulfate and concentrated in vacuo to give 2.42 g (93%) of crude product. Partial purification was effected by chromatography on silica gel, eluting with 5% methanol-chloroform, to yield 1.71 g of product which was used in the subsequent step without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[O:21])[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2].[BH4-].[Na+].[Cl-].[NH4+]>COCCOC.O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][OH:21])[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: CCOCCOc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Reaction time: 3 h
Yield: 121.8 %

Procedure:
4′-(2-Ethoxyethoxy)-2′,6′-dimethyl-3-biphenylcarbaldehyde (2.39 g, 9.70 mmol) was dissolved in a mixed solvent of 1,2-dimethoxyethane (20 mL) and tetrahydrofuran (20 mL), and sodium borohydride (0.227 g, 6.00 mmol) was added under ice-cooling, and the mixture was stirred at the same temperature for 3 hr. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-50% ethyl acetate/hexane) to give the title compound (3.55 g, yield 98%) as colorless crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.ClCCl.[OH-].[Na+]>CCOCC>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: OCCCCc1ccc2ccccc2n1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: BrCCCCCCOCCCCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-quinolinebutanol (2.56 g), 1,6-dibromohexane (5 ml), dichloromethane (2 ml), TAB (150 mg) and 50% aqueous sodium hydroxide (5 ml) was stirred at room temperature for 18 h. Ether (40 ml) was added and the organic phase separated, washed with water (20 ml), brine (20 ml), dried and evaporated in vacuo to an oil. The oil was purified by chromatography over a column of silica (Merck 60, Art. 7734). Elution with hexane and hexane-ether (9:1) followed by hexane-ether (1:1) afforded the title compound (2.12 g) as a colourless oil, t.l.c. (diethyl ether), Rf 0.50.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:16])[C:6](I)=[CH:7][O:8]2.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]=1[C:7]1[O:8][C:9]2[C:4]([C:5](=[O:16])[CH:6]=1)=[C:3]([O:2][CH3:1])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=2
Reactant: COc1cc(OC)c2c(=O)c(I)coc2c1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3nc4ccccc4[nH]3)oc2c1
Temperature: 0 °C
Yield: 67 %

Procedure:
A mixture of 5,7-dimethoxy-3-iodochromone (166 mg) prepared in Example 16, benzimidazole (236 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) was reacted at 80° C. for 2 hours with stirring. The reaction mixture was added to ice water and extracted from chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography, and recrystallized from benzene/hexane to give the titled compound (107.9 mg; yield =67.0%) as orange plate crystals. Melting point: 245°-246° C. Mass spectrum (M+): 332. 1H-NMR(CDCl3, δ ppm): 6.71 (s, 1H, H3), 6.62 (s, H6), 8.26 (s, H8), 6.43 (s, H3'), 7.80 (d, H4'), 7.58 (t, H5'), 7.34 (t, H6'), 8.11 (d, H7'), 3.96 (s, 3H, 5MeO), 3.97 (s, 3H, 7MeO).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:33]([OH:35])=O)=[N:11][C:12]([CH2:16][C:17]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:36]([O:43][CH2:44][CH2:45][NH:46][CH:47]([CH3:49])[CH3:48])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Si:36]([O:43][CH2:44][CH2:45][N:46]([CH:47]([CH3:49])[CH3:48])[C:33]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:18][CH2:19][C:20]3([O:21][CH2:22][CH2:23][O:24]3)[CH2:25][CH2:26]2)[N:11]=1)=[O:35])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCC3(CC2)OCCO3)nc(O)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccccc3)CCC3(CC2)OCCO3)nc(O)c1OCc1ccccc1
Yield: 72.8 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-ylmethyl)-pyrimidine-4-carboxylic acid (270) (600 mg, 1.26 mmol) in dimethylformamide (12 mL) were added [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) (411 mg, 1.89 mmol), N,N-diisopropylethylamine (0.63 mL, 3.78 mmol) and HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (574 mg, 1.51 mmol) and stirred at room temperature for 17 h (TLC, ethyl acetate:hexane=1:1/UV/SiO2, Rf=0.6). The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (3×50 mL), dried and concentrated in vacuum to get a crude mass which was purified by normal silica gel (100-200 mesh) column chromatography using gradient polarity eluent (1-2% methanol in dichloromethane) to get pure 5-benzyloxy-6-hydroxy-2-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-ylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (271) (620 mg, 72.85%) as a brown sticky solid.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=O.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[CH:26]([OH:29])[CH2:27][NH2:28].O>C1C=CC=CC=1>[OH:3][CH2:1][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:28][CH2:27][CH:26]([C:18]2[O:17][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH:19]=2)[OH:29])[CH3:15])=[CH:9][CH:8]=1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1cc2ccccc2o1
Solvent: c1ccccc1
Solvent: O
Product: CC(Cc1ccc(OCCO)cc1)NCC(O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-carbomethoxymethoxyphenyl)-propan-2-one (1 g) and 2-(2-benzofuranyl)-2-hydroxyethanamine (0.8 g) in benzene (80 ml) was boiled under reflux for one hour, with azeotropic removal of water, using a Dean and Stark head. The solution was evaporated, the residue dissolved in methanol (80 ml), cooled in ice, and excess sodium borohydride added. The solution was stirred at ambient temperature for 1 hour, heated under reflux for one hour, the methanol evaporated and the residue partitioned between water and ethyl acetate. The dried organic extract was evaporated to give an oil which was chromatographed on silica gel in 4% methanol/dichloromethane. The resulting oil was treated with ethereal hydrogen chloride to give the title compound as the hydrochloride salt hemi-hydrate, isolated as a 50:50 mixture of diastereoisomers. (mpt 56°-65°) (Ethyl Acetate-Ether).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[C:13][CH2:14][O:15][CH3:16])[C:5]([O:7]C)=[O:6].CO.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[C:13][CH2:14][O:15][CH3:16])[C:5]([OH:7])=[O:6]
Reactant: COCC#Cc1ccc(C(=O)OC)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCC#Cc1ccc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To methyl 3-fluoro-4-(3-methoxyprop-1-ynyl)benzoate (1.40 g, 6.30 mmol) in 15 ml of 2:1 THF:MeOH at room temperature was added NaOH (1.89 mL of 4 M, 7.56 mmol). The mixture was stirred at room temperature for 1 h before the volatile solvents were removed. The remainder was extracted with ether. The aqueous layer was acidified with 1M HCl and was extracted with ether (3×). The combined ether extracts were dried and concentrated to give 3-fluoro-4-(3-methoxyprop-1-ynyl)benzoic acid as a white solid. ESI-MS m/z calc. 208.2, found 209.2 (M+1)+; Retention time: 1.22 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J=8.0, 1.4 Hz, 1H), 7.80 (dd, J=9.5, 1.3 Hz, 1H), 7.59-7.49 (m, 1H), 4.39 (s, 2H), 3.48 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[C:7]2=[O:12].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>CCOC(C)=O.CO.CN(C=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([CH:13]([CH2:14][OH:15])[CH2:16][OH:17])[C:7]3=[O:12])=[O:27])=[CH:21][C:20]=1[C:29]([F:30])([F:31])[F:32]
Reactant: Nc1cccc2c(=O)n(C(CO)CO)ccc12
Reactant: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(Cl)c(C(F)(F)F)c1)Nc1cccc2c(=O)n(C(CO)CO)ccc12
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 5-amino-2-(1,3-dihydroxypropan-2-yl)isoquinolin-1(2H)-one (100.0 mg, 0.0004055 mol) in N,N-dimethylformamide (8 mL, 0.1 mol) was added 2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid (378.0 mg, 0.001584 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (448.0 mg, 0.001178 mol) and N,N-diisopropylethylamine (600.0 μL, 0.003445 mol). The reaction mixture was stirred for 16 hours at 50° C. After most of the DMF was rotovaped, MeOH (20 mL) and 2N NaOH (5 mL) were added to the residue. The solution was stirred for 1 hour at room temperature. MeOH was rotovaped and EtOAc (100 mL) was added, and the resultant solution was then washed with water (2×100 mL), Sat. NaHCO3, H2O, and brine. The EtOAc layer was dried by MgSO4 and was rotovaped. The resultant solution was washed with DCM and then purified with silica-gel. The final product was obtained as a solid. MS m/z=455.1 (M+1). 1H NMR (400 MHz; DMSO-d6) δ 10.09(s, 1 H), 8.09(d, J=8.0 Hz, 1 H), 7.89(s, 1 H), 7.80(d, J=7.6 Hz, 1 H), 7.75-7.65(m, 2 H), 7.55-7.40(m, 2 H), 6.63(d, J=7.6 Hz, 1 H), 4.98-4.85(m, 3 H), 3.92(s, 2 H), 3.85-3.65 (m, 4 H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1cccc(Cl)c1CCl
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3c(F)cccc3Cl)c2c1

Procedure:
The titled compound (40 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2-chloro-6-fluorobenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:20][C:21](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:22]>>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:21](=[O:22])[CH3:20])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Product: COC(=O)c1cc(Br)cc(N(C(C)=O)C2CCOCC2)c1C
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (520 mg, 1.58 mmol) was heated at 70° C. in Acetic 3 ml of anhydride for 6 h. The reaction mixture was cooled to room temperature and quenched with sat. NaHCO3 and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated and purified by silica gel (100-200) column chromatography to get the target compound (400 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[NH:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][NH:26][C:25](=[O:29])[CH2:24]2)[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH2:11][N:19]3[CH2:20][CH:21]([N:23]4[CH2:28][CH2:27][NH:26][C:25](=[O:29])[CH2:24]4)[CH2:22]3)[S:8][C:6]=2[N:7]=1
Reactant: O=C1CN(C2CNC2)CCN1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1CN(C2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)C2)CCN1
Reaction time: 16 h
Yield: 75.7 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carbaldehyde (285 mg, 1.00 mmol), 4-azetidin-3-ylpiperazin-2-one (190 mg, 1.22 mmol) and 4 Å powdered molecular sieves (1.0 g) in DCE (10 mL) was allowed to stir at r.t. for 5 h before the addition of sodium triacetoxyborohydride (420 mg, 1.98 mmol). The resulting mixture was allowed to stir for 16 h then filtered through Celite® which was washed with DCM. The filtrate was concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, MeOH:DCM, 2-10%) affording the title compound (321 mg, 75%)._LCMS (method A): RT 1.96 and 0.33 min [M+H]+ 424.3
Reaction SMILES: [CH3:1][C:2]1[CH2:3][N:4]([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[C:5](=[O:8])[NH:6][N:7]=1.C[S-].[Na+]>CN(C=O)C>[CH3:1][C:2]1[CH2:3][N:4]([NH:9][C:10]([C:12]2[CH:17]=[N:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[N:14][CH:13]=2)=[O:11])[C:5](=[O:8])[NH:6][N:7]=1
Reactant: COc1ccc(-c2ncc(C(=O)NN3CC(C)=NNC3=O)cn2)cc1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=NNC(=O)N(NC(=O)c2cnc(-c3ccc(O)cc3)nc2)C1
Temperature: 110 °C
Reaction time: 6 h
Yield: 33.8 %

Procedure:
A mixture of 2-(4-methoxy-phenyl)-pyrimidine-5-carboxylic acid (6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide (100 mg, 0.29 mmol), sodium methanethiolate (206 mg, 2.9 mmol) and DMF (2 mL) is stirred at 110° C. for 6 h., and then cooled to rt. The reaction mixture is concentrated in vacuo, and the residue is purified on a reverse phase HPLC chromatography to afford 2-(4-hydroxy-phenyl)-pyrimidine-5-carboxylic acid (6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide (32 mg). MS: 327 (M+H); 1H NMR (DMSO-d6): δ 1.87 (s, 3H), 4.17 (s, 2H), 6.74 (m, 2H), 8.21 (d, J=6.9 Hz, 2H), 9.08 (s, 2H), 9.53 (s, 1H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20].O>CO>[OH:9][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([NH:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: NCC(O)CO
Solvent: CO
Solvent: O
Product: OCC(O)CNC(c1ccccc1)C(O)c1ccccc1
Temperature: 125 °C
Yield: 22.1 %

Procedure:
A mixture of trans-stilbene oxide (3.93 g, 0.20 mol) and 1-amino-2,3-propanediol (5.46 g, 0.060 mol) was heated at 125° C. for 18 hours in an oil bath. After cooling, the reaction mixture was dissolved in 20 mL of methanol and the solution poured into 150 mL of water. The product separated from the solution as a viscous cream-colored oil that slowly solidified. The solid was collected by filtration and vacuum dried at 40° C. for 18 hours to give 3.81 g (66% yield) of material. The product was recrystallized from methanol-isopropyl ether to give 1.75 g; mp 161°-163° C.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5](CO)[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[CH3:20].CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)=[CH:15][C:14]=1[CH3:20]
Reactant: CN(C)c1cccc(CO)c1
Reactant: Cc1cc(O)ccc1Br
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Cc1cc(OC2CCCCC2)ccc1Br

Procedure:
The title compound was prepared by substituting cyclohexanol for (3-(dimethylamino)phenyl)methanol and 4-bromo-3-methylphenol for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.