Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.CCCCC.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C@:23]12[CH2:32][O:31][C@@H:30]([CH2:33]O)[CH2:29][C@H:28]1[C@@H:27]([CH3:35])[S:26][C:25]([NH:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[N:24]2>ClCCl>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C@:23]12[CH2:32][O:31][C@@H:30]([CH2:33][F:7])[CH2:29][C@H:28]1[C@@H:27]([CH3:35])[S:26][C:25]([NH:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[N:24]2
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@@H]12
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CCCCC
Product: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@@H]12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(Diethylamino)sulfur trifluoride (126 μL, 0.954 mmol) was added to a 0° C. solution of pentane (8 mL) and dichloromethane (5 mL). To this mixture was added N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P2) (275 mg, 0.636 mmol) drop-wise over 10 minutes. The ice bath was removed, and the reaction mixture was allowed to warm to room temperature. After 6 hours, it was diluted with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with dichloromethane (3×35 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a white solid. Yield: 154 mg, 0.354 mmol, 56%. 1H NMR (400 MHz, CD3OD) δ 8.08-8.16 (m, 2H), 7.51-7.58 (m, 1H), 7.40-7.50 (m, 3H), 7.01-7.11 (m, 2H), 4.34-4.55 (m, 2H), 4.17 (br d, J=12 Hz, 1H), 3.92 (d, J=11.9 Hz, 1H), 3.9-4.02 (m, 1H), 3.18-3.28 (br m, 1H), 2.98-3.08 (br m, 1H), 1.73-1.81 (m, 1H), 1.55-1.67 (m, 1H), 1.26 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH3:17])[NH:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:12]2[C@H:13]([CH3:17])[CH2:14][CH2:15][CH2:16][C@@H:11]2[CH3:10])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCC[C@H](C)N1Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
A mixture of 1-bromo-4-bromomethylbenzene (500 mg, 2.0 mmol), cis-2,6-dimethylpiperidine (0.30 mL, 2.2 mmol) and potassium carbonate (332 mg, 2.4 mmol) in acetonitrile (20 mL) was heated under reflux for 2 h. The reaction mixture was allowed to cool to ambient temperature, the solid removed by filtration and the filtrate evaporated in vacuo. The resultant residue was partitioned between ethyl acetate (100 mL) and water (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give the title compound as a pale brown oil (464 mg, 82%). 1H NMR (CDCl3, 300 MHz): 7.40 (d, J=8.3 Hz, 2H), 7.27 (d, J=7.0 Hz, 2H), 3.71 (s, 2H), 2.56-2.36 (m, 2H), 1.68-1.61 (m, 1H), 1.61-1.47 (m, 2H), 1.33-1.24 (m, 3H), 1.01 (d, J=6.2 Hz, 6H). LCMS (Method B): RT=0.8 min, M+H+=282/284.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([NH:29][C:2]3[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc2[nH]ccc2c1
Product: COCCN1C(=O)C(Nc2ccc3[nH]ccc3c2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1H-indol-5-amine in a similar manner as described for e.g. Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 7.78 (bs, 1H), 7.18 (t, 1H), 7.14-7.10 (m, 2H), 7.09-7.05 (m, 2H), 7.03-6.98 (m, 3H), 6.69 (dd, 1H), 6.23-6.20 (m, 1H), 3.92 (t, 2H), 3.74 (t, 2H), 3.39 (s, 3H); Mass Spectrum: M+H+ 398.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[CH2:5][NH:4]1)[CH3:2]
Reactant: CCC1Cc2ccc([N+](=O)[O-])cc2C=N1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC1Cc2ccc([N+](=O)[O-])cc2CN1
Yield: 99 %

Procedure:
To a solution of 3-ethyl-7-nitro-3,4-dihydroisoquinoline (15.8 g, Example 2 (d)) in methanol (100 ml) at 0° C. was added sodium borohydride (4g). After foaming had stopped, the reaction was poured into water (750 ml) and then the aqueous phase was extracted with ethyl acetate (3×300 ml). Evaporation gave 3-ethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline as a tan oil (15.8 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([C:20](OC)=[O:21])=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][C:19]=2[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cnccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccncc2CO)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A solution of methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)nicotinate (2.6 g, 8.1 mmol, 1.0 eq.) in THF (50 mL) was added dropwise to a solution of lithium aluminium hydride (617 mg, 16.3 mmol, 2.0 eq.) in THF (100 mL) at 0° C. under nitrogen. The resulting solution was stirred for 0.5 hours while the temperature was maintained at 0° C. in an ice/salt bath. The reaction was then quenched with water (0.6 mL) and 15% NaOH (1.8 mL). The mixture was stirred for 10 minutes. The solids were filtered and washed with EtOAc (30 mL). The filtrate was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/MeOH (10:1) to yield the title compound (1.6 g) as a white solid. ES m/z: [M+H]+293.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[C:25]([NH:30]S(C5C=CC(F)=CC=5)(=O)=O)[C:26]([Cl:29])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+]>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:22][C:23]3[CH:24]=[C:25]([NH2:30])[C:26]([Cl:29])=[N:27][CH:28]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)n2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cccnc2Nc2cnc(Cl)c(N)c2)n1
Yield: 63.4 %

Procedure:
A solution of N-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (0.087 g, 0.120 mmol) in trifluoroacetic acid (Aldrich) (0.622 mL, 8.37 mmol) and trifluoromethane sulfonic acid (TCI) (0.265 mL, 2.99 mmol).was heated at 80° C. in a sealed tube for 20 min. The reaction mixture was first neutralized with sat. NaHCO3 and then extracted with CHCl3 (3×15 mL). The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 20% to 30% acetone in hexanes) to give the product as a white solid (0.025 g). m/z (ESI, +ve ion) 329.0 (M+H)+. 1H NMR (300 MHz, d6-DMSO) δ 12.01 (s, 1H); 8.79 (d, J=7.16 Hz, 1H); 8.37 (d, J=4.39 Hz, 1H); 7.96 (s, 2H); 7.61-7.88 (m, 2H); 6.96 (dd, J=7.89, 4.82 Hz, 1H); 5.48 (s, 2H); 2.45 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[C:17](=[O:22])[NH:18][CH:19]=[CH:20][CH:21]=3)[C:13]([CH2:23][OH:24])=[N:12][C:11]=2[CH:25]([CH3:27])[CH3:26])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:30]([N:32]=C=O)=[O:31].C(N(CC)CC)C.O>O1CCCC1.CO>[C:30]([O:24][CH2:23][C:13]1[N:14]([CH2:15][C:16]2[C:17](=[O:22])[NH:18][CH:19]=[CH:20][CH:21]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:25]([CH3:27])[CH3:26])[N:12]=1)(=[O:31])[NH2:32]
Reactant: CC(C)c1nc(CO)n(Cc2ccc[nH]c2=O)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1nc(COC(N)=O)n(Cc2ccc[nH]c2=O)c1Sc1cc(Cl)cc(Cl)c1
Temperature: -40 °C
Yield: 80 %

Procedure:
In 20 ml of tetrahydrofuran was dissolved 200 mg of 5-(3,5-dichlorophenylthio)-2-hydroxymethyl-1-(2-oxo-1,2-dihydro-pyridin-3-yl)methyl-4-isopropyl-1H-imidazole (116b), and the mixture was cooled to -40° C. Under stirring, 84 μl of trichloroacetylisocyanate was added, the mixture was allowed to stand to reach room temperature, and stirred for 30 minutes. There were added 500 μl of triethylamine, 5 ml of water and 5 ml of methanol, and the mixture was stirred at 70° C. for 1 hour. After completion of the reaction, the solution was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The crystals were washed with diethyl ether, filtered, and 177 mg of Compound I-132 was obtained (yield 80%). mp 214° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[O:18])[N:14]([O:16][CH3:17])[CH3:15])[N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:17][O:16][N:14]([CH3:15])[C:13]([C:11]1[N:12]=[C:8]([NH2:7])[S:9][CH:10]=1)=[O:18]
Reactant: CON(C)C(=O)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON(C)C(=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
To a solution of [4-(methoxy-methyl-carbamoyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (1.0 g, 3.48 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (5.0 mL, 64.9 mmol) at 0° C. The reaction was warmed to ambient temperature and stirred for 4 hours. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the organic extracts were combined, washed with brine and dried over sodium sulfate. The solvent was removed to give 2-amino-thiazole-4-carboxylic acid methoxy-methyl-amide as a foam (585 mg, 90%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:29])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C:26]([CH3:28])=[CH2:27])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.C[N+]1([O-])CCOCC1.S(=O)(O)[O-].[Na+].[OH2:43].CC(C)=O.[OH2:48]>CC(O)(C)C.[Os](=O)(=O)(=O)=O>[CH:1]1([NH:4][C:5](=[O:29])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C:26]([OH:48])([CH3:28])[CH2:27][OH:43])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: C=C(C)COc1ccc2ncn(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)c2c1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: O=S([O-])O
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCC(C)(O)CO)cc2c1=O
Reaction time: 1 h

Procedure:
To a solution of N-cyclopropyl-4-methyl-3-[6-[(2-methylprop-2-en-1-yl)oxy]-4-oxoquinazolin-3(4H)-yl]benzamide (1.76 g) in acetone/water (4:1, 40 ml) was added N-methylmorpholine-N-oxide (2.1 g) followed by a solution of osmium tetroxide in 2-methyl-2-propanol (2.5% solution, 1.2 ml). After 18 hours sodium bisulfite (0.1 g) was added and the mixture stirred for a further 1 hour. The crude mixture was poured into water (20 ml) and extracted into ethyl acetate (300 ml). The combined organic extracts were washed with brine (100 ml), dried (magnesium sulfate) and concentrated. Purification by preparative HPLC provided N-cyclopropyl-3-[6-(2,3-dihydroxy-2-methylpropoxy)-4-oxoquinazolin-3(4H)-yl]4 methylbenzamide (AZ12197886) (0.5 g); NMR Spectrum: (CDCl3) 0.45 (m, 2H), 0.75 (m, 2H), 1.32 (s, 3H), 1.70 (m, 2H), 2.10 (s, 3H), 2.70 (m, 1H), 3.60 (d, 1H), 3.70 (m, 1H), 3.90 (m, 2H), 6.70 (d, 1H), 7.30 (m, 1H), 7.45 (m, 1H), 7.50 (m, 2H), 7.70 (m, 1H), 7.90 (s, 1H), 7.95 (t, 1H); Mass Spectrum: M+H+ 424. Further elution provided N-cyclopropyl-3-(6-isobutoxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (AZ12198379) as a clear oil (70 mg); NMR Spectrum (CDCl3) 0.50 (m, 2H), 0.90 (m, 2H), 1.10 (s, 3H), 1.15 (s, 3H), 2.15 (m, 1H), 2.20 (s, 3H), 2.90 (m, 1H), 3.90 (d, 2H), 6.60 (s, 1H), 7.40 (m, 2H), 7.60 (d, 1H), 7.70 (m, 2H), 7.80 (m, 1H), 7.90 (s, 1H); Mass Spectrum M+H+ 392.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH:13]=O)[CH2:6]2.[CH3:15][O:16][C:17]1[C:33]([O:34][CH3:35])=[CH:32][C:20]2[CH2:21][C:22](=[O:31])[N:23]([CH2:26][CH2:27][CH2:28][NH:29][CH3:30])[CH:24]=[CH:25][C:19]=2[CH:18]=1>>[CH3:30][N:29]([CH2:13][C@@H:7]1[C:8]2[CH:9]=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:6]1)[CH2:28][CH2:27][CH2:26][N:23]1[C:22](=[O:31])[CH2:21][C:20]2[C:19](=[CH:18][C:17]([O:16][CH3:15])=[C:33]([O:34][CH3:35])[CH:32]=2)[CH2:25][CH2:24]1
Reactant: CNCCCN1C=Cc2cc(OC)c(OC)cc2CC1=O
Reactant: COc1cc2c(cc1OC)[C@@H](C=O)C2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2

Procedure:
By proceeding as in Example 7, starting from (75)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbaldehyde and 7,8-dimethoxy-3-[3-(methylamino)propyl]-1,3-dihydro-2H-3-benzazepin-2-one, a compound is obtained which is hydrogenated by following the procedure described in patent specification EP 0 534 859 (Example 1, Step D) to yield ivabradine base, which is then converted into its hydrochloride by following the procedure described in patent specification EP 0 534 859 (Example 2, Step E).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH2:9])[CH:8]=1.C(N(CC)C(C)C)(C)C.Cl.[N:32]1([CH2:38][CH2:39][O:40][C:41]2[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[Cl-].[NH4+]>O1CCCC1.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH:9][C:45](=[O:46])[C:44]2[CH:43]=[CH:42][C:41]([O:40][CH2:39][CH2:38][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:49][CH:48]=2)[CH:8]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(N)c1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(NC(=O)c2ccc(OCCN3CCCCC3)cc2)c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 46.5 %

Procedure:
To a solution of 5-methoxy-2-(6-methoxynaphthalen-2-yl)phenylamine (275 mg) in tetrahydrofuran (8 ml) were sequentially added triethylamine (1.3 ml), N,N-diisopropylethylamine (1 ml) and 4-(2-piperidine-1-ylethoxy)benzoyl chloride hydrochloride (1.1 g), and the solution was stirred for 2 days at 60° C. A saturated aqueous solution of ammonium chloride was added thereto, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide N-[5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl]-4-(2-piperidin-1-ylethoxy)benz amide (234 mg). To a suspension of lithium aluminum hydride (50 mg) in tetrahydrofuran (4 ml) was added aluminum chloride (176 mg) on an ice bath under a nitrogen atmosphere, the solution was stirred for 20 minutes at room temperature, N-[5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl]-4-(2-piperidin-1-ylethoxy)benzamide (226 mg) was added thereto followed by stirring overnight at room temperature. Obtained by sequentially adding tetrahydrofuran and aqueous ammonia, the suspension was filtered through celite pad, and the filtrate was concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (213 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(OC([CH2:36][NH:37][C:38]([CH3:50])([CH3:49])[CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][CH:41]=1)=O)(C)(C)C.C(OC(CNC(C)(C)CC1C=CC(C(CCNC2C=C(OC)C=CC=2C2CCC3C=C(OC(=O)C(C)(C)C)C=CC=3C2)=O)=CC=1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:44][C:43]1[CH:47]=[CH:48][C:40]([CH2:39][C:38]([CH3:50])([NH:37][CH3:36])[CH3:49])=[CH:41][CH:42]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(Cc1ccc(C(=O)O)cc1)NCC(=O)OC(C)(C)C
Agent: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCC(=O)c2ccc(CC(C)(C)NCC(=O)OC(C)(C)C)cc2)c1
Product: CCN(Cc1ccc(CC(C)(C)NC)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 38.7 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (100 mg) and 4-[2-(tert-butoxycarbonylmethylamino)-2-methylpropyl]benzoic acid (120 mg) according to an analogous synthetic method to Preparation Example 86, pivalic acid 6-{2-{{4-[2-(tert-butoxycarbonylmethylamino)-2-methylpropyl]benzoyl}ethylamino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (97 mg) was used according to analogous synthetic method to the above-mentioned Example 215 and Example 337 to provide the title compound (48 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([OH:12])[C:10]#[N:11].[CH3:13][OH:14].Cl>C(OCC)C.O1CCOCC1>[ClH:8].[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH:9]([OH:12])[C:10](=[NH:11])[O:14][CH3:13])[CH:4]=1
Reactant: CO
Reactant: N#CC(O)c1cc(Cl)ccc1F
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=N)C(O)c1cc(Cl)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 121A (640 mg, 3.48 mmol) in anhydrous diethyl ether (115 mL) at 0° C. was added MeOH (1.4 mL) and 4.0 N HCl in dioxane (3.5 mL). The mixture was stirred at 0° C. for 30 min and then at rt for 4 h. The solvent was removed to give methyl 2-(5-chloro-2-fluorophenyl)-2-hydroxyacetimidate HCl salt. To this salt in CH2Cl2 (10 mL) was added H2O (10 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 121B (610 mg, 80% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.55 (d, J=4.83 Hz, 1H) 3.80 (s, 3H) 5.38 (d, J=4.83 Hz, 1H) 7.03 (t, J=9.23 Hz, 1H) 7.27-7.31 (m, 1H) 7.39 (dd, J=6.15, 2.64 Hz, 1H).
Reaction SMILES: [Br-].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[Zn+].[CH:8]([N:11]([CH:33]([CH3:35])[CH3:34])[CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([NH:23][C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22])([CH3:10])[CH3:9]>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][CH:33]([N:11]([CH:8]([CH3:10])[CH3:9])[CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([NH:23][C:24](=[O:32])[C:25]2[CH:26]=[CH:27][C:28]([C:3]3[S:2][CH:6]=[CH:5][CH:4]=3)=[CH:29][CH:30]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH3:34]
Reactant: COc1ccc(NC(=O)c2ccc(I)cc2)cc1OCCN(C(C)C)C(C)C
Reactant: [Zn+]c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2ccc(-c3cccs3)cc2)cc1OCCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-thienylzinc bromide in tetrahydrofuran (0.5M, 5 mL, 2.5 mmol) was added to a solution of N-[3-[2-(diisopropylamino)ethoxy]-4-methoxypheny]-4-iodobenzamide (WO 99/01127) (0.5 g, 1 mmol) in tetrahydrofuran (5 mL) containing tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.06 mmol), and the mixture was stirred at RT for 16 h. The reaction was quenched with saturated ammonium chloride and extracted with ether and dichloromethane. The organic phase was dried (MgSO4), concentrated in vacuo, and chromatographed (silica gel, 5% methanol/dichloromethane) to afford the title compound (0.1 g) MS(ES) m/e 452.8 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:5]([OH:6])[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[CH2:24](Cl)Cl>[Ag]=O>[CH3:1][C:2]1([CH3:23])[CH:5]([O:6][CH3:24])[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:3]1[C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: ClCCl
Reactant: CC1(C)C(c2ccc(S(C)(=O)=O)cc2)=C(c2ccccc2)C1O
Agent: O=[Ag]
Product: COC1C(c2ccccc2)=C(c2ccc(S(C)(=O)=O)cc2)C1(C)C
Temperature: 25 °C

Procedure:
To a solution of Example 62 (70 mg) in CH2Cl2 (1 mL) at r.t., was added silver oxide (100 mg) and Mel (1 mL). The mixture was stirred reflux for 18 hr, cooled to r.t., filtered through celite® and the solvents evaporated. The residue was purified by flash chromatography (silica gel; hexane/EtOAc (85:15)) to give the title product as a white solid, m.p. 130°-132° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH2:14][N:15]2[CH:23]=[N:22][C:21]3[C:20](=[O:24])[NH:19][C:18]([NH2:25])=[N:17][C:16]2=3)[S:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C.O>[Br:1][C:23]1[N:15]([CH2:14][C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)[C:16]2[N:17]=[C:18]([NH2:25])[NH:19][C:20](=[O:24])[C:21]=2[N:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc2c(ncn2Cc2cccs2)c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2c(nc(Br)n2Cc2cccs2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-Bromosuccinimide (2.82 g; 15.7 mmol) was added to a cold (0° C. suspension of 9-(2-thenyl)guanine (3.5 g; 14.1 mmol) in DMF (100 ml) and the mixture was stirred for 30 minutes at 0° C. and then at room temperature for 24 hours. The reaction mixture was then diluted with 75 ml of water and filtered. Recrystallization of the product from DMF gave the analytical sample, yield 3.1 g; mp 294°-295° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:18]=[C:19]([CH2:23][C:24]#[N:25])[CH:20]=[CH:21][CH:22]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1>N.CO.O.[Ni]>[NH2:25][CH2:24][CH2:23][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[N:14]=[CH:15][C:10]3[CH2:9][C:8](=[O:26])[NH:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:11]=3[N:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: N#CCc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: NCCc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1
Temperature: 22 °C
Reaction time: 12 h

Procedure:
To a solution of [3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-phenyl]-acetonitrile (I-78) (0.131 g, 0.349 mmol) in saturated NH3 in MeOH solution (50 mL) was added a catalytic amount of Raney 2800 Ni in H2O and the mixture was placed under H2 (50 psi) and stirred for 12 h at 22° C. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo to give crude product as a yellow oil. Purification by C-18 RP LC-MS chromatography afforded I-86 (0.019 g, 14%): MS (AA) Rt=1.25 min, m/z=380 (M+H).