Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2N=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[C:22]([O:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23].[C:39]1([S:45]([NH:48][NH2:49])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.Cl>CN(C)C=O>[C:39]1([S:45]([NH:48][NH:49][C:34]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:38][CH:37]=2)=[O:36])(=[O:46])=[O:47])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Reactant: NNS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)NNS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.1 mmol (1.65 g) of 1-hydroxy-7-azabenzotriazole and 18 mmol (3.45 g) of EDCI are added in succession to a solution of 12 mmol (2.85 g) of 4-[(tert-butoxycarbonyl)amino]benzoic acid in 20 ml of dimethylformamide. The reaction mixture is stirred at room temperature for one hour, and 18 mmol (3.1 g) of benzenesulphonohydrazide are added. After stirring for eight hours at room temperature, the reaction mixture is poured into 100 ml of a 10% hydrochloric acid solution and extracted four times with 50 ml of ethyl acetate. The organic phase is washed twice with 50 ml of water and then three times with an aqueous saturated sodium hydrogen carbonate solution and once with 50 ml of an aqueous saturated sodium chloride solution. After drying over magnesium sulphate, filtration and concentration, the expected product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][S:34](Cl)(=[O:36])=[O:35])([O-:26])=[O:25].C(N(CC)C(C)C)(C)C>C1COCC1.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([S:34]([CH2:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N+:24]([O-:26])=[O:25])(=[O:35])=[O:36])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)Cc3ccccc3[N+](=O)[O-])CC2)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
A light brown solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 560 mg, 1.78 mmol) and (2-nitrophenyl)methanesulfonyl chloride (837 mg, 3.55 mmol) in THF (30 mL) was cooled to 0° C. under nitrogen and then N,N-diisopropylethylamine (930 μL, 5.34 mmol) was added. The resulting light brown solution was stirred for 2 hours at 0° C. temperature and then allowed to warm to room temperature and stirred for 36 hours. The reaction mixture was diluted with water and brine and the organic compound was extracted into ethyl acetate (2×100 mL). The combined organic layers were washed with brine and dried over MgSO4, filtered, and concentrated. The crude product was purified using flash chromatography (120 g ISCO column eluting with 0-60% ethyl acetate/hexanes) to give {6-fluoro-3-methyl-4-[1-(2-nitro-phenylmethanesulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (645 mg, 71%) as a light yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 8.07-8.1 (m, 1H), 7.85 (br. s, 1H), 7.55 (dd, J=8.8, 6.3 Hz, 1H), 7.67-7.72 (m, 2H), 7.56-7.64 (m, 2H), 7.16-7.24 (m, 1H), 4.83 (s, 2H), 3.89 (d, J=10.0 Hz, 2H), 3.82 (br. s, 2H), 3.72 (s, 3H), 3.43-3.63 (m, 1H), 2.90 (t, J=11.5 Hz, 2H), 2.32-2.71 (m, 5H), 1.77 (d, J=13.8 Hz, 2H). MS cald. for C26H27FN2O6S [(M+H)+] 514, obsd. 515.2.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH2:18])[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.Br[CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: BrCCCCBr
Reactant: Cc1c(O[C@@H]2CCC[C@H](N)C2)ccc2c1cnn2C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(O[C@H]2CCC[C@@H](N3CCCC3)C2)ccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
Under nitrogen, the cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.304 mmol) obtained in Example 724 was dissolved in N,N-dimethylacetamide (3 ml), followed by adding thereto 1,4-dibromobutane (36 μl, 0.304 mmol) and potassium carbonate (105 mg, 0.759 mmol), and the resulting mixture was stirred at 80° C. for 1.5 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extraction with chloroform (twice). The combined chloroform layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: acetonitrile/aqueous ammonia=100/0, 100/2) to obtain 4-methyl-5-[(cis-3-pyrrolidin-1-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole (64 mg, yield 55.0%) as light-yellow tar.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:13]([CH3:18])[C:14]([O:16]C)=O)[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[NH2:21][CH2:20][CH2:19][NH:22][C:14](=[O:16])[CH:13]([C:7]1[CH:8]=[C:9]([CH3:12])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=1)[CH3:18]
Reactant: COC(=O)C(C)c1cc(C)c(O)c(C(C)(C)C)c1
Reactant: NCCN
Product: Cc1cc(C(C)C(=O)NCCN)cc(C(C)(C)C)c1O
Reaction time: 1 h
Yield: 84.9 %

Procedure:
125 g of methyl 3-tert-butyl-4-hydroxy-5-methylphenylpropionate and 300 g of ethylenediamine are heated together at 110° C. for 5 hours, after which a vacuum is applied and the resulting methanol and the excess ethylenediamine are distilled off. 0.3 l of toluene are added to the residue, and the mixture is left to stand at room temperature for one hour. The precipitate is filtered off under suction and dried to give 118 g of the product which, after recrystallization from ethyl acetate, has a melting point of 156°-159° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4C=CC=[CH:24][N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:4][N:3]=1.C[N:29]1[C:33](CO)=[N:32]C=N1>>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:23]([CH3:24])[N:29]=[CH:33][N:32]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:4][N:3]=1
Reactant: Cn1ncnc1CO
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)on1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ncnn4C)nn23)on1

Procedure:
The title-compound was prepared from the product of Example 120 part a and 2-methyl-1,2,4-triazole-3-methanol (prepared using the conditions of Itoh and Okongi, EP-A-42120) following the procedure given for Example 98, 1H NMR (400 MHz, CDCl3) δ 2.43 (3H, s, CH3), 4.16 (3H, s, CH3), 5.82 (2H, s, CH2), 7.07 (1H, s, Ar—H), 7.84 (1H, m, Ar—H), 7.95-8.04 (2H, m, 2 of Ar—H), 8.21 (1H, d, J=8.0 Hz, Ar—H), 8.62 (1H, d, J=8.0 Hz, Ar—H); MS(ES30) m/e 363 [MH]+; Anal. Found. C, 56.12; H, 3.90; N, 30.74. C17H14N8O2 requires C, 56.35; H, 3.89; N, 30.92%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:33]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)OCCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: N
Product: CC(C)OCCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3,4-difluorophenyl)-4-[2-(2-propoxy)ethoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 110 mg, 34%). mp 54-56° C. 1H NMR (300 MHz, DMSO-d6) δ 1.0 (d, 6H), 3.43 (m, 1H), 3.54 (m, 2H), 4.63 (m, 2H), 7.5 (m, 3H), 7.6 (m, 1H), 7.8 (m, 1H), 7.95 (m, 4H), 8.2 (s, 1H). MS (DCI/NH3) m/z 466 (M+H)+, 483 (M+NH4)+. Anal. calc. for C21H21F2N3O5S: C, 54.19; H, 4.55; N, 9.03. Found, C, 54.29; H, 4.67; N, 8.95.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[CH3:19][N:20]1[CH:24]=[C:23]([S:25](Cl)(=[O:27])=[O:26])[N:22]=[CH:21]1>N1C=CC=CC=1>[CH3:19][N:20]1[CH:24]=[C:23]([S:25]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])(=[O:27])=[O:26])[N:22]=[CH:21]1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cn(C)cn1
Reaction time: 96 h
Yield: 79.4 %

Procedure:
Pyridine (25 mL) was added to a mixture of 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol) and 1-methylimidazole-4-sulfonyl chloride (1.82 g, 10 mmol) and the mixture agitated then allowed to stand at room temperature. After 4 days, the mixture was partitioned between ethyl acetate (400 mL) and water (400 mL). The insoluble material was collected by filtration, washed with water, and air dried. The organic extract was washed with water (2×400 mL), 1N HCl (100 mL), and brine (100 mL), then dried over magnesium sulfate, filtered, and stripped of solvent. The residue was combined with the solid obtained above to afford the product (3.07 g); m.p. 250-252° C., after trituration in hexanes/ethyl acetate (1:1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.ClC(Cl)Cl.Cl[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])=[O:13]>O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:12](=[O:13])[CH2:11][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(Cn1ccnc1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a refluxing and stirred solution of 457.6 parts of 1H-imidazole in 2400 parts of trichloromethane was added dropwise a solution of 320 parts of 2-chloro-1-(2,4-difluorophenyl)ethanone in 1440 parts of trichloromethane. After stirring for 1/2 hour at reflux temperature, the reaction mixture was poured into water. The organic layer was washed with water (2x), dried, filtered and evaporated. The residue was crystallized from 2-propanol, yielding 244 parts (69%) of 1-(2,4-difluorophenyl)-2-(1H-imidazol-1-yl)ethanone; mp. 125° C. (interm. 1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:20](Cl)(=[O:31])[O:21][CH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=1>C(Cl)Cl>[C:10]([O:9][C:8]([NH:7][CH:4]1[CH2:3][CH2:2][N:1]([C:20]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=2)=[O:31])[CH2:6][CH2:5]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C

Procedure:
A solution of tert-butyl piperidin-4-ylcarbamate (2.0 g, 9.99 mmol) in DCM (40 ml) was treated with sodium bicarbonate solution (50 ml, 9.99 mmol) followed by a solution of 3,5-dichlorobenzyl carbonochloridate (2.392 g, 9.99 mmol) in DCM (10 ml). The reaction mixture was stirred vigorously at RT until gas evolution ceased. The organic layer was separated, dried over MgSO4 (anh), filtered and evaporated under reduced pressure, yielding the title compound as colourless oil that solidified on standing;
Reaction SMILES: F[C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[N:16][N:17]([C:2]2[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH:18]=1
Reactant: Clc1cn[nH]c1
Reactant: COC(=O)c1cnc(F)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(-n2cc(Cl)cn2)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of methyl 6-fluoro-5-methylnicotinate (800 mg, 4.73 mmol, Step-1 of Amine-36), 4-chloro-1H-pyrazole (509 mg, 4.97 mmol), and cesium carbonate (3.08 g, 9.46 mmol) in DMF (16 mL) stirred at 60° C. for 1 hour. After cooling to rt, the mixture is diluted with EtOAc (150 mL) and washed with water (100 mL×3). The organic phase is filtered through silica gel, and the filtrate is concentrated to give 1.19 g (>99% yield) of the title compound as white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[C:9]([NH2:12])[CH:10]=2)[NH:5][C:4](=[O:14])[CH:3]=1.C>C(O)C>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[C:9]([NH2:12])[CH:10]=2)[NH:5][C:4](=[O:14])[CH2:3]1
Reactant: Cc1cc(=O)[nH]c2c(C)cc(N)cc12
Solvent: CCO
Product: Cc1cc(N)cc2c1NC(=O)CC2C

Procedure:
A suspension of 4-methyl-6-amino-8-methyl-2-(1H)-quinolone (0.38 g) in absolute ethanol (50 cm3) was hydrogenated at 100° and 2000 p.s.i. (13.7×106Pa) pressure over 10% palladised charcoal (0.05 g) for 72 hours. The cooled solution was then filtered through "Solkafloc" (Trade mark for a cellulose-base filtering aid) and evaporated in vacuo to give a solid which was chromtographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:chloroform, 1:50 by volume. Combination and evaporation of appropriate fractions gave a residue which on trituration with ethyl acetate afforded the title compound, m.p. 207°-10°, (0.22 g).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.C([N:32](CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[Cl-].[NH4+]>C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH2:32])=[O:26])=[CH:23][CH:22]=4)=[N:19][C:6]2=3)[CH2:2][CH2:3][CH2:4]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CCN(CC)CC
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(N)=O)cc3)ncc21
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
A mixture of 0.104 g (0.26 mmole) of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-11), 0.105 g (1.04 mmole) of triethylamine, 0.148 g (0.39 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes, then 0.045 g (0.84 mmole) of ammonium chloride was added. The mixture was stirred for 3 hours, then taken up in 100 mL of ethyl acetate and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (gradient 100:0:0-92:8:0.3) to give 0.060 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzamide (I-12).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>O1CCCC1>[CH3:25][S:26]([O:15][CH2:14][C:12]1[N:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=2)[O:10][CH:11]=1)(=[O:28])=[O:27]
Reactant: OCc1coc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCc1coc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of {2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}methan-1-ol (0.19 g, 0.78 mmol) in tetrahydrofuran (15 ml) was cooled to 0° C., and triethylamine (0.33 ml, 2,34 mmol) was added, followed by methanesulfonyl chloride (0. 12 ml, 1.56 mmol) dropwise. The mixture was stirred for 1 hour at 0° C., then water was added, and product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and solvent removed from the filtrate under reduced pressure, to yield {2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}methyl methylsulfonate, the mesyl derivative of a compound of formula (15),
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3OCCO[C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.ClC1N=C(Cl)C(F)=CN=1.NC1C=CC([CH2:34][OH:35])=CC=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:34][OH:35])=[CH:13][CH:14]=2)[C:5]([F:19])=[CH:4][N:3]=1
Reactant: Nc1ccc(CO)cc1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Agent: Fc1cnc(Cl)nc1Cl
Product: OCc1ccc(Nc2nc(Cl)ncc2F)cc1

Procedure:
In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-aminobenzylalcohol were reacted to yield 2-chloro-5-fluoro-N4-[4-(hydroxymethyl)phenyl]-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.08 (d, 1H, J=2.7 Hz), 7.62 (d, 2H, J=9.0 Hz), 7.40 (d, 2H, J=8.1 Hz), 6.99 (bs, 1H), 4.70 (s, 2H); 19F NMR (CDCl3): −44570 (s, 1F); LCMS: ret. time: 19.57 min.; purity: 99%; MS (m/e): 254 (MH+).
Reaction SMILES: [Cu]C#N.[CH2:4]([Mg]Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:13]([O:15][C:16](=[O:38])[C:17](=[CH:23][C:24]1[CH:25]=[N:26][C:27]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:28][CH:29]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:14].[Cl-].[NH4+]>C1COCC1>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([CH:23]([C:24]1[CH:25]=[N:26][C:27]([NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[CH:28][CH:29]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:16]([O:15][CH2:13][CH3:14])=[O:38])[CH3:22]
Reactant: CCOC(=O)C(=Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Reactant: Br[Mg]Cc1ccccc1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a vigorously stirred suspensin of copper(I)cyanide (0.66 g, 7.32 mmol) in dry THF (5 mL) was added a solution of benzylmagnesium bromide (5 mL 2.93 M in ether, 14.64 mmol) at 0° C. under argon. The mixture was allowed to warm to room temperature, giving a dark brown solution. After 60 minutes a solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethylene)-malonic acid diethyl ester (0.67 g, 1.83 mmol) in dry THF (4 mL) was added at 0° C. The mixture was stirred overnight at room temperature then aqueous ammonium chloride was added. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with brine and dried. Removal of the solvent in vacuo gave a residue which was purified by flash chromatography (CH2Cl2/ethyl acetate, 1:0→100:15) to give 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-phenyl-ethyl]-malonic acid diethyl ester (0.44 g, 53%).
Reaction SMILES: [CH:1]([Si:3]([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])=[CH2:2].[SH:13][CH2:14][CH2:15][CH2:16][Si:17]([O:22][CH3:23])([O:20][CH3:21])[O:18][CH3:19]>>[Si:3]([CH2:1][CH2:2][S:13][CH2:14][CH2:15][CH2:16][Si:17]([O:22][CH3:23])([O:18][CH3:19])[O:20][CH3:21])([O:4][CH2:5][CH3:6])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: CO[Si](CCCS)(OC)OC
Reactant: C=C[Si](OCC)(OCC)OCC
Product: CCO[Si](CCSCCC[Si](OC)(OC)OC)(OCC)OCC
Temperature: 150 °C
Reaction time: 48 h

Procedure:
(CH3CH2O)3SiCH2CH2SCH2CH2CH2Si(OCH3)3 was prepared by reacting 2.28 moles of vinyltriethoxysilane and 2.28 moles of gamma-mercaptopropyltrimethoxysilane. The reaction was heated to 150° C. and maintained at that temperature. After 48 hours the reaction was stopped.
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])C.C(C[CH2:19][N:20]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]1)#N>>[OH:25][C@H:22]1[CH2:23][CH2:24][N:20]([CH2:19][CH2:15][C:14]2[NH:3][C:4](=[O:13])[C:5]3[C:6]([CH:12]=2)=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=3)[CH2:21]1
Reactant: N#CCCN1CC[C@H](O)C1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3CC[C@H](O)C3)cc12
Yield: 7.3 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2,3-dimethylbenzamide (4.07 g) and (S)-1-(2-cyanoethyl)-3-hydroxypyrrolidine (1.6 g), (S)-3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (0.228 g) was obtained.
Reaction SMILES: B(Cl)(Cl)Cl.[NH2:5][C:6]1[N:10]=[C:9]([C@@H:11]2[CH2:17][CH2:16][C@@H:15]3[CH2:18][N:12]2[C:13](=[O:27])[N:14]3[O:19]CC2C=CC=CC=2)[O:8][N:7]=1>C(Cl)Cl>[NH2:5][C:6]1[N:10]=[C:9]([C@@H:11]2[CH2:17][CH2:16][C@@H:15]3[CH2:18][N:12]2[C:13](=[O:27])[N:14]3[OH:19])[O:8][N:7]=1
Reactant: Nc1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Nc1noc([C@@H]2CC[C@@H]3CN2C(=O)N3O)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
BCl3 (1M, 15.87 mL, 15.87 mmol) was added to a solution of (2S,5R)-2-(3-amino-1,2,4-oxadiazol-5-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (1.0 g, 3.17 mmol) in dried DCM (20 mL) at −78° C. The mixture was stirred under N2 atmosphere at 0° C. for 2 hrs, cooled to −78° C. and quenched with MeOH (2 mL). The solvent was removed under vacuum to give ((2S,5R)-2-(3-amino-1,2,4-oxadiazol-5-yl)-6-hydroxy-1,6-diaza-bicyclo[3.2.1]octan-7-one (700 mg), which was used in the next step directly. ESI-MS (EI+, m/z): 226 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:21][N:6]2[C:7]3[C:12]([C:13]([CH2:14][C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[C:5]2[CH2:4][CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C@H:2]2[CH2:21][N:6]3[C:7]4[C:12]([C:13]([CH2:14][C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[C:5]3[CH2:4][CH2:3]2)=[CH:11][CH:10]=[CH:9][CH:8]=4)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](N)CC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NS(=O)(=O)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
To a CH2Cl2 solution (0.2 M) of propyl ([7R]-7-amino-6,7,8,9-tetrahydro-pyrido[1,2-α]indo1-10-yl)acetate from Step 6 was added 4-fluorobenzenesulfonyl chloride (1.1 equiv.) followed by triethylamine (3 equiv.) and DMAP (1 equiv.). The reaction mixture was stirred for 12 h at rt. The mixture was concentrated under reduced pressure, diluted with EtOAc, and washed with aqueous NaHCO3, water and finally with brine. The organic layer was dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using a CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hex (10:90 to 50:50) to give the title compound (97%) as a colorless foam.