Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:12]2[CH2:18][CH:17]([CH:19]([CH3:21])[CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:22])=[CH:6][CH:5]=1.O[Li].O.O[NH:38][C:39](=[NH:41])[CH3:40].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([N:11]([CH:12]2[CH2:18][CH:17]([CH:19]([CH3:20])[CH3:21])[CH2:16][CH2:15][NH:14][C:13]2=[O:22])[CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]3[O:33][N:41]=[C:39]([CH3:40])[N:38]=3)=[CH:5][CH:6]=2)(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(CN(C2CC(C(C)C)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CC(=N)NO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(-c2ccc(CN(C3CC(C(C)C)CCNC3=O)S(=O)(=O)c3ccc(Cl)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{[(4-Chloro-benzenesulfonyl)-(5-isopropyl-2-oxo-azepan-3-yl)-amino]-methyl}-benzoic acid methyl ester (0.30 g, 0.60 mmol) was saponified to the acid using LiOH.H2O (0.04 g, 0.90 mmol). The acid (0.10 g, 0.21 mmol) was dissolved in THF (3 ml) and added dropwise to a solution of 1,1-carbonyl diimidazole (CDI, 0.04 g, 0.23 mmol) in THF (0.5 ml). After 30 min, N-hydroxy-acetamidine (0.04 g, 0.23 mmol) was added. A further two equivalents each of CDI and N-hydroxy-acetamidine were added during a further 48 h stirring at r.t. The reaction mixture was concentrated and crude, coupled amidine was purified over silica gel (gradient ethyl acetate to ethyl acetate/methanol 15%): white solid 0.09 g (73%); MS: m/e=535.5 (MH+). Purified amidine (0.08 g, 0.15 mmol) cyclised in the presence of tetrabutylammonium fluoride (1 M, THF 5 ml) over 36 h at r.t. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organice extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The concentrated, crude product was purified using preparative RP(C18) chromatography: lyophilisate 15 mg; MS: m/e=517.4 (MH+).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C@H:10]1[CH2:25][CH3:26])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:23][C:17]1[C:16]([CH3:24])=[C:15]([N:11]2[C:12](=[O:14])[CH2:13][C@H:9]([OH:8])[C@@H:10]2[CH2:25][CH3:26])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: CC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
To a solution of 4-[(2S,3S)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-chloro-3-methylbenzonitrile (134.5 mg) in tetrahydrofuran (10 mL)-methanol (5 mL) was added 6 mol/L hydrochloric acid (5 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1→1/4) to give the title compound as a colorless solid (yield: 66.2 mg, 69%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1cnccc1OCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1cnccc1OCc1ccccc1)S(C)(=O)=O
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a suspension of N-(4-(benzyloxy)pyridin-3-yl)methanesulfonamide (30 g, 0.11 mol) and K2CO3 (14.9 g, 0.11 mol) in DMF (300 mL) was added dropwise CH3I (15.3 g, 0.11 mol) at 0° C. under N2, and then the mixture was stirred for 1 hour at this temperature. H2O was added to the mixture and extracted with dichloromethane. The combined organic layer was washed with H2O, brine, dried over Na2SO4, filtrated and concentrated in vacuo to give N-(4-(benzyloxy)pyridin-3-yl)-N-methylmethanesulfonamide (15 g, yield: 50%), which was used for the next step without further purification. 1H-NMR (CDCl3, 400 MHz) δ 8.46 (s, 1H), 8.41 (d, J=6.0 Hz, 1H), 7.37˜7.39 (m, 5H), 6.94 (d, J=6.0 Hz, 1H), 5.15 (s, 2H), 3.22 (s, 3H), 2.79 (s, 3H). MS (M+H)+: 293.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[C:9](=[O:13])[NH:10]2)=[CH:5][C:4]=1[C:20]([O:22][CH3:23])=[O:21].N1C=CC=CC=1.[O:30](S(C(F)(F)F)(=O)=O)[S:31]([C:34]([F:37])([F:36])[F:35])(=O)=[O:32]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[C:9]([O:13][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:30])=[N:10]2)=[CH:5][C:4]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(=O)[nH]c2cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(OS(=O)(=O)C(F)(F)F)nc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl 7-methoxy-3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1.0 g, 3.15 mmol) in dichloromethane (80 ml) was added pyridine (990 mg, 12.52 mmol) and Tf2O (1.69 g, 5.99 mmol), and the reaction was stirred overnight under an atmosphere of nitrogen at room temperature. The reaction mixture was then quenched with water (200 ml), extracted with dichloromethane (3×30 mL), the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford (S)-methyl 7-methoxy-3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (1.20 g, crude), which was used in the next step directly.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9].[Br:16][C:17]1[N:22]=[C:21]([CH2:23]O)[CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:16][C:17]1[N:22]=[C:21]([CH2:23][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH:20]=[CH:19][CH:18]=1
Reactant: OCc1cccc(Br)n1
Reactant: CC(C)CNS(=O)(=O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CN(Cc1cccc(Br)n1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 45, step 1, 2-chloro-N-isobutyl-benzenesulfonamide (example 42, step 1) was reacted with 6-bromo-2-pyridinemethanol (CAS [33674-96-3]), triphenylphosphine and diethyl azodicarboxylate in tetrahydrofuran to give N-(6-bromo-pyridin-2-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][C:13]3[CH:15]=[N:16][C:17](Cl)=[CH:18][C:12]=3[N:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]2=[O:24])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:25][NH2:26]>[Cu]I>[NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][C:13]3[CH:15]=[N:16][C:17]([NH:26][CH3:25])=[CH:18][C:12]=3[N:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]2=[O:24])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)N1C(=O)N(c2ccc(F)c(N)c2)Cc2cnc(Cl)cc21
Reactant: CN
Agent: [Cu]I
Product: CNc1cc2c(cn1)CN(c1ccc(F)c(N)c1)C(=O)N2C(C)(C)C
Temperature: 180 °C
Yield: 46 %

Procedure:
3-(3-Amino-4-fluorophenyl)-1-tert-butyl-7-chloro-3,4-dihydro-1H-pyrido[4,3-d]pyrimidin-2-one (2.0 g, 5.7 mmol), CuI (200 mg, 1.05 mmol) and methylamine (200 mL) were combined in a steel bomb and heated to 180° C. for 48 h. The reaction vessel was cooled to −78° C., unsealed, and warmed to RT. The reaction was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine (2×100 mL), dried (Na2SO4), concentrated and purified by neutral aluminum oxide column chromatography to provide 3-(3-amino-4-fluorophenyl)-1-tert-butyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (900 mg, 46% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.76 (s, 1 H), 6.91 (dd, J=11.1, 8.7 Hz, 1 H), 6.61 (dd, J=8.1, 2.4 Hz, 1 H), 6.35-6.32 (m, 3 H), 5.14 (s, 2 H), 4.29 (s, 2 H), 2.74 (d, J=4.8 Hz, 3 H), 1.55 (s, 9 H); MS (ESI) m/z: 344.0 [M+H]+.
Reaction SMILES: FC1C=C(C(Cl)=O)C=CC=1.[F:11][C:12]1[CH:13]=[C:14]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH:15]=[CH:16][CH:17]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[C:40]([CH3:45])[CH:39]=1.C1(C)C=CC=CC=1>C(O)C>[F:11][C:12]1[CH:13]=[C:14]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH:15]=[CH:16][CH:17]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:21]([NH:20][C:18](=[O:19])[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=2)=[S:22])=[C:40]([CH3:45])[CH:39]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Agent: O=C(Cl)c1cccc(F)c1
Agent: O=C(N=C=S)c1cccc(F)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(F)c4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
3-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Fluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (64 mg, yield 81%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:15]1([N:21]2[CH:25]=[CH:24][N:23]=[C:22]2[SH:26])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[N:5]1([C:3](=[O:4])[CH2:2][S:26][C:22]2[N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:25]=[CH:24][N:23]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: Sc1nccn1-c1ccccc1
Reactant: O=C(CCl)N1CCCc2ccccc21
Product: O=C(CSc1nccn1-c1ccccc1)N1CCCc2ccccc21
Yield: 69 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 1-phenyl-1H-imidazole-2-thiol as the nucleophile to yield 27 as a yellow gum (69%): MS m/z: 350 (M+H)+. Anal. Calcd. For, C20H19N3OS: C, 68.74; H, 5.48; N, 12.02; S, 9.18. Found: C, 68.47; H, 5.71; N, 11.75; S, 8.96.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[N:14]([CH:22]([CH3:24])[CH3:23])[C:13](=[O:25])[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Br:26]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][Br:26])=[CH:18][CH:19]=3)[N:14]([CH:22]([CH3:23])[CH3:24])[C:13](=[O:25])[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(-c2nc(=O)n(C(C)C)c3cc(C)ccc23)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cccc(-c2nc(=O)n(C(C)C)c3cc(CBr)ccc23)c1
Temperature: 25 °C

Procedure:
A mixture of 14 g of 4-(3-acetoxyphenyl)-1-isopropyl-7-methyl-2(1H)-quinazolinone, 20 g of N-bromosuccinimide, and 600 ml of carbon tetrachloride is irradiated with infrared light for 15 minutes in a 1000 ml flat-bottom flask while stirring and refluxing. After cooling to room temperature with an ice bath, the mixture is washed successively with 500 ml and 100 ml of water in a 2 liter separatory funnel. Each water phase is washed with an additional 100 ml of carbon tetrachloride. The combined carbon tetrachloride phase is evaporated to dryness. The resulting residue is dissolved in 200 ml of methanol and evaporated to dryness to obtain crude 4-(3-acetoxyphenyl)-7-bromomethyl-1-isopropyl-2(1H)-quinazolinone. A thin-layer chromatogram on Silica Gel GE with ethyl acetate as the mobile phase shows the presence of the desired monobrominated product and dibrominated by-product.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl.[OH:25][C:26]1[C:35]([N:36]([CH3:38])[CH3:37])=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2>>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][CH:34]=[C:35]([N:36]([CH3:38])[CH3:37])[C:26]=4[OH:25])[CH2:31]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)nc2ccccc12
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(C(F)(F)F)cc3)nc3ccccc13)C2
Yield: 15 %

Procedure:
Reaction of 2-(4-(trifluoromethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 40 (15% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.56 and 2.70 (2s, 6H), 2.85 and 3.10 (2t, 2H), 3.58 and 4.22 (2t, 2H), 4.48 and 5.10 (2s, 2H), 6.33 and 6.83 (2d, 1H), 6.97 and 7.16 (2d, 1H), 7.62-8.55 (m, 7H), 8.74-8.80 (m, 2H); MS (ESI) m/z 493 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]([C:13]([N:15]2[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:16]2[C:21]([O-])=[O:22])=[O:14])=[C:11]([N+:28]([O-:30])=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[BH4-].CCOC(C)=O>C1COCC1>[CH2:1]([O:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]([C:13]([N:15]2[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:16]2[CH2:21][OH:22])=[O:14])=[C:11]([N+:28]([O-:30])=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)N2C[C@H](O)C[C@H]2C(=O)[O-])c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2C[C@H](O)C[C@H]2CO)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A solution of the ester 19 (3.8 g, 8.83 mmol, 1.0 equiv.) in THF (100 mL) was cooled to 0° C. and treated with LiBH4 (0.29 g, 13.25 mmol, 1.5 equiv.) in portions. After stirring for 30 min at 0° C., the reaction mixture was allowed to warm to room temperature and stirred under a nitrogen atmosphere for 4 h at which time TLC (SiO2, EtOAc) revealed complete consumption of ester 19. The mixture was cooled to 0° C. again and water (100 mL) was carefully added followed by 1N HCl (250 mL) which provoked vigorous effervescence. After evaporation of the THF in vacuo, the mixture was neutralised to pH 7 with 1N NaOH. The aqueous solution was then extracted with EtOAc (4×70 mL), the combined organic layers washed with brine (50 mL), dried (MgSO4), filtered and evaporated in vacuo to furnished the pure diol 20 (3.2 g, 7.96 mmol, 90%), which was used in the subsequent reaction without further purification. [α]29D=−96° (c=0.15, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.85-1.99 (m, 1H, 1-H), 2.09-2.28 (m, 1H, 1-H), 3.11-3.20 (m, 1H, 11-H), 3.25-3.39 (m, 1H, 11-H), 3.70-3.82 (m, 1H, 3-H), 3.85-4.04 (m, 5H, 3-H, 7-OMe, OH), 4.30-4.38 (m, 1H, 11a-H), 4.46-4.61 (m, 2H, 2-H), 5.20 (m, 2H, OCH2Ph), 6.86 (s, 1H, 6-H), 7.29-7.50 (m, 5H, Ph), 7.74 (s, 1H, 9-H); 13C NMR (CDCl3, 100 MHz): δ 37.1, 56.8, 56.9, 59.9, 65.0, 69.4, 71.4, 109.1, 109.3, 127.6, 127.7, 128.5, 128.8, 135.2, 137.2, 148.2, 155; IR (neat): 3357, 2938, 1614, 1576, 1520, 1454, 1434, 1333, 1276, 1220, 1069, 1048, 1006, 730, 698, 647 cm−1; MS (ES+) m/z (relative intensity) 426 ([M+Na]+., 5), 403 ([M+H]+., 100), 404 ([M+2H]+., 40).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([C:10](OC)=[O:11])[N:9]=1)(=[O:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:10]([C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)c1nc(NC(C)=O)sc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C=O)c(-c2ccccc2)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 33.8 %

Procedure:
Methyl 2-(acetylamino)-5-phenyl-1,3-thiazole-4-carboxylate (2.34 g) was suspended in THF (23 ml), and then lithium aluminium hydride (482 mg) was added portionwise to the solution at 0° C. The reaction mixture was stirred at 0° C. for 1.5 hours and quenched with MeOH. AcOEt and 1N HCl were added to the mixture, and the mixture was extracted. The aqueous layer was extracted with AcOEt (twice). The combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residual solid was dissolved in MeOH (5 ml) and CHCl3 (90 ml). Then manganase(IV) oxide (11 g) was added to the solution under N2 atmosphere. The reaction mixture was stirred at r.t. for 13 hours, and filtered through a celite pad. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with CHCl3/MeOH (20:1) as an eluent to give N-(4-formyl-5-phenyl-1,3-thiazol-2-yl)acetamide (705.2 mg) as a brown amorphous substance.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([O:25][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: OC1CCCCC1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OC1CCCCC1

Procedure:
The title compound, white solid, m.p. 117-119° C. and MS: m/e 337.4 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and cyclohexanol.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:50][CH2:51][C:52]1[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=1[CH3:58]>ClCCl>[OH:60][C:53]1[C:52]([CH2:51][NH:50][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([N:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]3=[O:1])[CH3:9])=[CH:18][CH:17]=2)=[C:57]([CH3:58])[CH:56]=[C:55]([CH3:59])[N:54]=1
Reactant: CC(c1ccc(C(=O)O)cc1)n1ccccc1=O
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)n3ccccc3=O)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.8 %

Procedure:
To a solution of 4-(1-(2-oxopyridin-1(2H)-yl)ethyl)benzoic acid (111 mg, 0.46 mmol) in dichloromethane (20 mL) were added o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol) and triethylamine (151 mg, 1.5 mmol). Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The mixture was stirred at room temperature for 12 hours. The resultant mixture was washed with water (20 mL×3) and the organic layer was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(2-oxopyridin-1(2H)-yl)ethyl)benzamide (57 mg, 33%). LRMS (M+H+) m/z: calcd 377.17. found 377. HPLC purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.35-8.33 (m, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.60-7.57 (m, 1H), 7.33-7.30 (m, 3H), 6.39 (d, J=9.3 Hz, 1H), 6.22-6.18 (m, 2H), 5.84 (s, 1H), 4.27 (s, 2H), 2.15 (s, 3H), 2.10 (s, 3H), 1.68 (d, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)#[N:17]>>[C:16]([CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1)#[N:17]
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: N#CCOc1ccc(N)cc1
Product: Cc1cccc(Nc2cc(Nc3ccc(OCC#N)cc3)ncn2)c1
Yield: 24 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 4-chloro-6-(3'-methylanilino)pyrimidine (1.0 g) was reacted with 4-cyanomethoxyaniline (0.6 g). The reaction product was chromatographed on silica to give 4-(4'-cyanomethoxyanilino)-6-(3'-methylanilino)pyrimidine in 24% yield, m.p. 207°-210° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6]>[Pd].C(OCC)(=O)C>[NH2:23][C:20]1[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[C:4]([CH:19]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=1)=[O:6]
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.8 %

Procedure:
2-Methoxy-5-nitro-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide (14.6 g, 41.2 mmol) and 146 ml of ethyl acetate were mixed and, after 10% palladium on activated carbon (2.6 g) was added, the mixture was stirred for 5 hours at room temperature. Catalyst was filtered, washed with ethyl acetate, and the reaction mixture was concentrated. The residue was recrystallized from a mixed solvent of n-hexane with ethyl acetate to obtain 12.4 g (93%) of the title compound as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br:24][CH:25]=[CH:26][CH2:27][CH2:28]Br>CN(C=O)C.CCOCC.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:28][CH:27]=[CH:26][CH2:25][Br:24])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc21
Reactant: BrC=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCc2cc(OCC=CCBr)ccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
514 mg (2.3 mmol) 5-Hydroxy-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 12 ml DMF were treated with 830 mg (6 mmol) powdered K2CO3 and 1070 mg (5 mmol) 1,4-dibromobutene. The suspension was stirred at 50° C. for 3 h, cooled to RT, diluted with ether and water. The aqueous phase was extracted with ether, the organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with hexane/EtOAc 9:1 yielded 270 mg (31%) 5-(4-Bromo-but-2-enyloxy)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as colorless solid, MS: 368 (MH+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH2:4]O.[ClH:14]>>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH2:4][Cl:14]
Reactant: Cl
Reactant: Nc1cccc(C(F)(F)F)c1CO
Product: Nc1cccc(C(F)(F)F)c1CCl
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To 4.06 g (7.8 mmole) of 2-amino-6-trifluoromethylbenzyl alcohol in a pressure bottle was added 60 ml of concentrated hydrochloric acid, the bottled stoppered and immersed in an oil bath maintained at 100°. The mixture was stirred for 1.5 hr., cooled and the precipitate filtered under suction. The colorless solid was washed with water and dried under high vacuum, yielding 3.28 g (75% yield) of a colorless solid; mp 155-161°. The sample was used as such without further purification.