Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[C:22]1[O:23][CH2:24][C:25]([CH3:28])([CH3:27])[N:26]=1.[Cl:29]C(Cl)(Cl)C(C(Cl)(Cl)Cl)=O>C1COCC1.O>[Cl:29][C:19]1[C:14]([F:13])=[C:15]([C:22]2[O:23][CH2:24][C:25]([CH3:28])([CH3:27])[N:26]=2)[CH:16]=[C:17]([F:21])[C:18]=1[F:20]
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Reactant: CC1(C)COC(c2cc(F)c(F)cc2F)=N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CC1(C)COC(c2cc(F)c(F)c(Cl)c2F)=N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
A solution of 7.6 ml (54.2 mmol) of diisopropylamine in 100 ml of dry THF was cooled to -78° C. under argon, treated with 20.5 ml (47.2 mmol) of 2.3M n-butyllithium, and stirred for 15 minutes. To this solution was added a solution of 10.3 g (45.0 mmol) of 2-(2,4,5-trifluorophenyl)-4,4-dimethyl-2-oxazoline in 100 ml of dry THF. The reaction mixture was stirred at -78° C. for 45 minutes. To this mixture was added 26.5 g (100 mmol) of hexachloroacetone, and the solution was warmed to room temperature. Water was added; the organic phase was washed with water, 1N hydrochloric acid, and 5% sodium bicarbonate, and was dried over magnesium sulfate. Concentration gave a dark oil which was chromatographed on silica gel to give 7.05 g of the title compound as a yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:31])[C:23]=4[O:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:41][CH:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[O:28])=[C:24]([F:31])[C:23]=4[O:32][CH3:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: COc1c(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc(C(=O)O)c1F
Product: COc1c(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc(C(=O)NC2CCN(C)CC2)c1F

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-3-methoxybenzoic acid and 1-methylpiperidin-4-amine as described in the General procedure for amide bond synthesis. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37-1.66 (m, 7H) 1.75 (m, 4H) 1.82-2.04 (m, 4H) 2.15 (m, 3H) 2.66-2.81 (m, 2H) 3.16 (s, 1H) 3.70 (m, 1H) 3.90 (s, 3H) 4.05 (t, J=13.8 Hz, 2H) 4.77 (m, 1H) 7.24 (t, J=8.1 Hz, 1H) 7.96-8.13 (m, 2H) 8.26 (s, 1H) 8.35 (s, 1H). [M+H] calc'd for C27H34F3N7O3, 562. found 562.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][C:13]([O:15]CC)=[O:14])[CH2:7][CH2:6]2.[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]2
Reactant: CCOC(=O)CC1CCc2cc(OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CCC2CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of the crude ester (416 g, 1.77 mol) prepared in Example 2 in EtOH (1 L), was added a solution of NaOH (142 g, 3.54 mol) in water (1.5 L). The reaction mixture was heated to reflux, during which time the color changed to dark red, and the reaction became homogeneous. After 1 h, the reaction was cooled to rt, and the EtOH was removed under reduced pressure. The remaining basic aqueous layer was washed with Et2O (3×500 mL), then acidified with HCl (conc. aqueous solution) to pH˜4 at which point an oily residue formed. The mixture was then extracted with Et2O (4×500 mL), the combined extracts washed with water (2×300 mL) and brine, and then dried over Na2SO4. Filtration and evaporation of the solvents under reduced pressure gave the title compound (305 g, 83%) as a yellow solid after drying for 12 h under vacuum. 1H NMR (CDCl3) δ 7.34 (d, 1H), 6.71 (s, 1H), 6.65 (dd, 1H), 3.71 (s, 3H), 3.47 (m, 1H), 2.80 (m, 3H), 2.35 (m, 2H), 1.71 (m, 1H). MS (Cl) m/z 207 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:18][CH:19]1[CH2:22][CH2:21][CH2:20]1)[CH:13]([OH:17])[C:14](O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:24]1C(=O)CC[C:25]1=O.C(Cl)CCl.CN>C(Cl)Cl.C1COCC1>[CH:19]1([CH2:18][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]([OH:17])[C:14]([NH:24][CH3:25])=[O:15])[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(NC(CC1CCC1)C(O)C(=O)O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)C(O)C(CC1CCC1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of 3-(benzyloxycarbonylamino)-4-cyclobutyl-2-hydroxybutanoic acid (250 mg, 0.81 mmol) in DCM (20 mL) was added HOSu (140 mg, 1.22 mmol), EDC (234 mg, 1.22 mmol). After stirring for 1 hour, methylamine in THF (2 N, 0.81 mL) was added to the above mixture. The reaction mixture was stirred for 18 hours and then concentrated in vacuo. The residue was purified by Gilson Prep to afford the title compound (135 mg). 1H-NMR (CDCl3): δ 7.54-7.28 (m, 5H), 6.67 (NH, 1H), 5.03 (dd, 2H), 3.68 (m, 1H), 2.73 (m, 3H), 2.26 (m, 1H), 1.97-1.31 (m, 9H). (M+1) 321.
Reaction SMILES: O=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[NH:9][C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2.P(Br)(Br)([Br:21])=O.[C:24]1([CH3:30])C=CC=CC=1>>[Br:21][C:2]1[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[CH:13][C:12]([C:16]([O:18][CH2:24][CH3:30])=[O:17])=[CH:11]2
Reactant: O=P(Br)(Br)Br
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccc2c(=O)c3c([nH]c2c1)CCCC3
Product: CCOC(=O)c1ccc2c(Br)c3c(nc2c1)CCCC3
Temperature: 25 °C

Procedure:
A suspension of 9-oxo-5,6,7,8,9,10-hexahydro-acridine-3-carboxylic acid (1 g, 0.42 mmols) in toluene (10 mL) was heated with phosphorous oxybromide (3.54 g, 1.2 mmols) to 100° C. for 4 h. Reaction completion was monitored by TLC. Alter completion, the reaction mixture was cooled to 25° C., quenched with methanol (10 mL), concentrated the reaction mixture under vacuum and purified the crude product with silica gel column (60:120). Product eluted with 2% methanol in chloroform. Fractions were collected and concentrated to get the pure product as off white solid. This compound was taken as such to next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C@H:8]([O:22][CH2:23][CH2:24][OH:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:7]=1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C@H:8]([O:22][CH2:23][CH2:24][O:25][S:35]([CH3:34])(=[O:37])=[O:36])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:10]2)[CH:7]=1
Reactant: Cc1ccc(Cl)cc1[C@H](OCCO)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)cc1[C@H](OCCOS(C)(=O)=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (7 g, 18.3 mmol) in dry CH2Cl2 (100 mL) was added Et3N (54 g, 10 mL, 0.73 mmol) at −5-0° C. Then a solution of MsCl (4.2 g, 36.5 mmol) in dry CH2Cl2 (50 mL) was added dropwise at the same temperature. After addition, it was allowed to warm to rt gradually. The reaction mixture was washed with 10% citric acid solution (30 mL), NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated to give (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (8.4 g), which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2Br)[CH:7]=[C:6]([NH2:16])[CH:5]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1B(O)O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([NH2:16])[CH:7]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:27]2[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:26]=2[O:25][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:9]=1
Reactant: COC(=O)c1cc(N)cc(C2=C(Br)CCC2)c1
Reactant: OB(O)c1cc(Br)ccc1OCc1ccccc1
Product: COC(=O)c1cc(N)cc(C2=C(c3cc(Br)ccc3OCc3ccccc3)CCC2)c1

Procedure:
Prepared by general procedure 3 but using 3-amino-5-(2-bromocyclopent-1-enyl)benzoic acid methyl ester instead of 3-(2-bromocyclopent-1-enyl)benzoic acid ethyl ester and 2-(benzyloxy)-5-bromophenylboronic acid instead of 5-chloro-2-methoxyphenylboronic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN([Si](C)(C)C)C(=O)C(F)(F)F.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][S:30]([NH:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(N2CCOCC2)ccc1C(=O)O
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(N2CCOCC2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-amino-4-morpholin-4-yl-benzoic acid (230 mg; 1.04 mmol) in CH2Cl2 (3 mL) was added N-methyl-N-(trimethylsilyl)trifluoroacetamide (0.4 mL; 2.1 mmol) via syringe at room temperature under a nitrogen atmosphere. The resulting mixture was heated to reflux for 10 minutes, then allowed to cool to room temperature. Methanesulfonyl chloride (1.2 eq.) and triethylamine (1.2 eq.) were added, and the resulting mixture allowed to stir for 2 hours. The reaction was diluted with CH2Cl2 (30 mL) and washed with water (2×10 mL) and brine, then dried (MgSO4), filtered, and concentrated in vacuo to provide the sulfonamide as a white solid (280 mg; 90%).
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-:23])=[O:22])[C:11]([Cl:24])=[CH:10][C:9]=2[F:25])[C:6](=[O:26])[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[N:3]=1.[C:31]1(=[N:36][OH:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>O>[Cl:24][C:11]1[C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])=[CH:13][C:8]([N:7]2[C:6](=[O:26])[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[N:3]=[C:2]2[O:37][N:36]=[C:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:9]([F:25])[CH:10]=1
Reactant: ON=C1CCCC1
Reactant: O=c1cc(C(F)(F)F)nc(Cl)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1cc(C(F)(F)F)nc(ON=C2CCCC2)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Yield: 84.7 %

Procedure:
A mixture of 2-chloro-3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-4(3H)-pyrimidinone(1.28 g, 0.0027 mol), cyclopentanone oxime(027 g, 0.0027 mol), potassium carbonate(0.38 g, 0.027 mol) and tetrahydrofuran(11 ml) was heated under reflux for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and washed with brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel(20% ethyl acetate/hexane) to give compound II-3 (1.23 g, yield 84.7%) as a white amorphous solid, m.p.76-78° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[H-].[Na+].Cl[CH2:12][C:13]1[N:18]=[C:17]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:16]2=[CH:15][C:14]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>C1COCC1.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][CH2:12][C:13]2[N:18]=[C:17]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:16]3=[CH:15][C:14]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:2]=1
Reactant: OCc1cccnc1
Reactant: CCOC(=O)c1cc2c(nc1CCl)CCCCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(nc1COCc1cccnc1)CCCCC2
Reaction time: 1 h
Yield: 21.2 %

Procedure:
In an atmosphere of argon, 3-pyridinemethanol (0.41 ml, 4.20 mmol) was dissolved in anhydrous THF (4.0 ml), and the solution was mixed with sodium hydride (173.6 mg, 4.34 mmol) at 0° C. and stirred at the same temperature for 1 hour. To this was added dropwise THF solution (4.0 ml) of ethyl 2-chloromethyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (1.07 g, 3.98 mmol) at 0° C., and the mixture was stirred at from 0° C. to room temperature for 20 hours. The reaction solution was diluted with ethyl acetate, mixed with water and then extracted with ethyl acetate. Thethus obtainedorganiclayer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ethyl acetate:hexane=1:3—chloroform:methanol=40:1) to obtain the title compound (287.8 mg, 20.1%) as yellow oil.
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.O.CS(O)(=O)=O.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CS(C)=O>[F:1][C:2]1[C:21]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: C1CNCCN1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CS(C)=O
Product: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNCC4)cc3nc21
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A suspension of 2 g of 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid in 2.8 g of piperazine and 40 cm3 of dimethyl sulphoxide is stirred for 15 minutes at a temperature close to 40° C. After cooling to about 20° C., the reaction mixture is poured into 150 cm3 of water and 27.75 cm3 of 2N methanesulphonic acid are added. A very small amount of insoluble matter is removed by filtration through diatomaceous silica. 15 cm3 of 2N aqueous potassium hydroxide solution are added to the solution obtained. The precipitate formed is drained, washed with 3 times 15 cm3 of water and taken up in 100 cm3 of dimethylformamide and the mixture is heated, with stirring, for 10 minutes at a temperature close to 150° C. The suspension is cooled to about 100° C.; the insoluble matter is drained and taken up in 100 cm3 of ethanol and the mixture is heated at a temperature close to 75° C. for 1 hour. The insoluble matter is drained at about 50° C. and washed with 40 cm3 of the same solvent at the same temperature as above. 1.8 g of 7-fluoro-1-methoxy-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a brown solid melting at 298°-300° C., solvated by 2.4% of water.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1.[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH:27]([CH3:31])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].CN(C)C=O>O.C1C=CC=CC=1>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]3[CH:10]=[C:9]([CH3:11])[S:8][C:6]=3[N:7]=2)[CH:27]([CH3:31])[CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cc2c(-c3ccccc3)nc(Cl)nc2s1
Reactant: CC1CN(Cc2ccccc2)CCN1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc2c(-c3ccccc3)nc(N3CCN(Cc4ccccc4)CC3C)nc2s1
Yield: 90.1 %

Procedure:
A mixture of 3 g of 2-chloro-6-methyl-4-phenyl-thieno[2,3-d]pyrimidine, 2.2 g of 1-benzyl-3-methylpiperazine, 1.1 g of sodum carbonate and 4 ml of dimethylformamide is reacted under reflux for 3 hours. After cooling, 80 ml of benzene and 80 ml of water are added and two layers are separated. The benzene layer is washed twice with 100 ml of water and then with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After distilling off benzene, purification of the product by silica gel chromatography using 180 g of silica gel and n-hexane/ethyl acetate (10:1) as an eluent is carried out. There is obtained 4.3 g of oily 2-(4-benzyl-2-methylpiperazinyl)-6-methyl-4-phenyl-thieno[2,3-d]pyrimidine.
Reaction SMILES: [H-].[Na+].C(O)C.[C:6]([O:14]CC)(=[O:13])[CH2:7][C:8](OCC)=O.[Br:17][C:18]1[CH:25]=[CH:24][C:21](CBr)=[CH:20][CH:19]=1>C1COCC1>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:8][CH2:7][C:6]([OH:14])=[O:13])=[CH:20][CH:19]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.9 %

Procedure:
Sodium hydride (60% dispersion in oil; 4 g) was added portionwise to an ethanol (100 ml) solution of diethyl malonate (16 g) under ice-cooling. The reaction mixture was stirred at room temperature for 10 minutes, to which was added dropwise a THF (50 ml) solution of p-bromobenzylbromide (12 g) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and concentrated. Acetic acid (200 ml) and6N hydrochloric acid (100 ml) were added to the residue. The reaction mixture was stirred under heating at 90° C. for 18 hours, and concentrated. Water was added to the residue, which was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1), which was recrystallized from IPE to obtain the entitled compound (1.2 g).
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[CH:25])[C:22]34[O:26][C:17]3([C:18](=[O:27])[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[C:14]([O:28][CH3:29])[CH:13]=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:31]=[CH:32][C:33]#[C:34][Si:35]([CH3:38])([CH3:37])[CH3:36].C(N)CCC>[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:31]=[CH:32]\[C:33]#[C:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:22]34[O:26][C:17]3([C:18](=[O:27])[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[C:14]([O:28][CH3:29])[CH:13]=[CH:12][C:11]2=3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)C#CC=CCl
Reactant: C#CC1N(C(=O)Oc2ccccc2)c2ccc(OC)cc2C23OC12CCCC3=O
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Product: COc1ccc2c(c1)C13OC1(CCCC3=O)C(C#C/C=C\C#C[Si](C)(C)C)N2C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
A solution of Compound 314 (5.69 g, 14.6 mmol) in dry degassed benzene (120 mL) was added to copper (I) iodide (0.666 g, 3.51 mmol), and to the resulting mixture was added 1-chloro-4-(trimethylsilyl)-but-1-en-3-yne (3.69 g, 23.4 mmol) followed by n-butylamine (2.89 mL, 29.2 mmol) and tetrakis (triphenylphosphine) palladium (0) (1.01 g, 0.877 mmol) in dry degassed benzene (60 mL). The reaction mixture was stirred at 25° C. for 2 hours, diluted with ethyl ether (200 mL), poured into saturated aqueous ammonium chloride (200 mL), and extracted with ethyl ether (2×70 mL). The combined organic layers were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (silica, 25 percent ethyl ether in petroleum ether) to give 5.43 g (73 percent) of Compound 315: white foam; Rf =0.29 (silica, 30 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2958, 2836, 1717, 1609, 1590, 1493, 1380, 1299, 1251 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J=3.0 Hz, 1 H, aromatic), 7.38-7.06 (m, 6 H, aromatic), 6.89 (dd, J=8.9, 3.0 Hz, 1 H, aromatic), 5.92 (d, J=1.6 Hz, 1 H, H6), 5.86 (d, J=11.0 Hz, 1 H, olefinic), 5.65 (br d, J=11.0 Hz, 1 H, olefinic), 3.81 (s, 3 H, OCH3), 2.78-2.62 (m, 2 H, H9), 2.37-2.25 (m, 2 H, H7), 2.05-1.85 (m, 2 H, H8), 0.20 (s, 9 H, Si(CH3)3); 13C NMR (125 MHz, CDCl3) δ 201.2, 157.2, 154.1, 151.0, 129.3, 128.6, 128.5, 125.7, 124.0, 121.4, 120.7, 118.9, 114.8, 114.8, 103.5, 101.5, 90.5, 83.0, 74.6, 57.4, 55.4, 48.4, 38.8, 23.8, 18.2, -0.17; MS (FAB+) m/e (rel intensity) 511 (M+, 100), 390 (8), 362 (9), 176 (11), 120 (10); HRMS for C30H29NO5Si (M+), calcd 511.1815, found 511.1815.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:22][CH2:21][CH2:20][NH:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:23]([O:40][C:41]1[CH:50]=[CH:49][CH:48]=[C:47]2[C:42]=1[CH2:43][CH2:44][CH:45]1[O:51][CH:46]12)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C.O>O1CCCC1>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH:46]3[C:47]4[C:42](=[C:41]([O:40][Si:23]([C:36]([CH3:38])([CH3:37])[CH3:39])([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:50]=[CH:49][CH:48]=4)[CH2:43][CH2:44][CH:45]3[OH:51])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc(C3CCCN3)oc2-c2ccccc2)cc1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC1OC21)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cccc2c1CCC(O)C2N1CCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Reaction time: 120 h
Yield: 30 %

Procedure:
To a solution of 2-(4,5-diphenyloxazol-2-yl)pyrrolidine (0.66 g) and 5-tert-butyldiphenylsilyloxy-1,2-epoxy-1,2,3,4-tetrahydronaphthalene (0.6 g) in tetrahydrofuran (10 ml) was added Ti[O—CH(CH3)2]4 (0.66 ml) at room temperature. After being stirred for 5 days at the same temperature, the mixture was poured into the mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-[2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-2-hydroxy-5-tert-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (0.31 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:8][C@@H:9]([OH:20])[C@H:10]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:11]=[CH2:12])[O:7][CH2:6][CH2:5][O:4]1.N1C=CN=C1.[CH3:26][C:27]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(=O)(O)[O-].[Na+]>ClCCl>[Si:30]([O:1][CH2:2][C:3]1([CH2:8][C@@H:9]([OH:20])[C@H:10]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:11]=[CH2:12])[O:4][CH2:5][CH2:6][O:7]1)([C:27]([CH3:29])([CH3:28])[CH3:26])([CH3:32])[CH3:31]
Reactant: C=C[C@@H](OCOCCOC)[C@H](O)CC1(CO)OCCO1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=C[C@@H](OCOCCOC)[C@H](O)CC1(CO[Si](C)(C)C(C)(C)C)OCCO1
Yield: 97.5 %

Procedure:
A solution of Compound 10 (6.55 g, 22.4 mmol) in dichloromethane (40 mL) at zero degrees C was treated with imidazole (3.21 g, 47.2 mmol), and then TBSCl (3.47 g, 23.1 mmol) in dichloromethane (20 mL) and stirred for two hours. The mixture was poured into saturated aqueous sodium bicarbonate solution (100 mL), extracted with dichloromethane (3×50 mL), concentrated, and the residue purified by flash chromatography (ether) to give Compound 10-1 (8.88 g, 98 percent) as a colorless oil; Rf =0.51 (Et2O); [a]D25 =-33.3° (c 5.3, CH2Cl2); IR (thin film) νmax 3490 cm-1 ; 1H NMR (500 MHz, CDCl3) δ 5.77 (m, 1 H, CH=CH2), 5.30-5.26 (m, 2 H, CH=CH2), 4.73 (ABq, J =6.5 Hz, Dn =40 Hz, 2 H, OCH2O), 4.03-3.95 (m, 5 H, CH--OH, ethylene ketal), 3.93 (dd, J =5.4, 10.0 Hz, 1 H, CH--OMEM), 3.82 (m, 1 H, OCHH--CH2 --OMe), 3.61 (m, 1 H, OCHH--CH2 --OMe), 3.55 (ABq, J =10.4 Hz, Dn =23 Hz, 2 H, CH2 --OTBS), 3.53 (m, 2 H, OCH2CH2 -13 OMe), 3.48 (bs, 1 H, OH), 3.37 (s, 3 H, OMe), 1.94 (dd, J =1.4, 14.9 Hz, 1 H, CHH), 1.83 (dd, J =10.0, 14.9 Hz, 1 H, CHH), 0.88 (s, 9 H, tBu), 0.04 (s, 6 H, SiMe2); 13C NMR (125 MHz, CDCl3) δ 134.7, 119.3, 110.4, 92.9, 80.2, 71.7, 69.5, 67.0, 66.2, 65.5, 65.1, 65.1, 58.9, 37.2, 25.8, 18.2, -5.5; FAB HRMS (NBA/CsI) m/e 539.1430, M+Cs+ calcd for C19H38O7Si 539.1441.