Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C@@H:5]2[O:6][C:7](=[O:9])[CH2:8][C@@H:4]2[C@H:3]1[CH2:11][CH2:12][C@@H:13]([OH:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.[C:29](=[O:32])(O)[O-].[Na+]>C1COCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:16]1([CH2:15][CH2:14][C@H:13]([O:22][CH:4]2[CH2:3][CH2:2][CH2:10][CH2:29][O:32]2)[CH2:12][CH2:11][C@@H:3]2[C@@H:4]3[C@@H:5]([O:6][C:7](=[O:9])[CH2:8]3)[CH2:10][C@H:2]2[O:1][CH:28]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1C[C@@H]2[C@@H](CC[C@@H](O)CCc3ccccc3)[C@H](O)C[C@@H]2O1
Reactant: C1=COCCC1
Reactant: O=C([O-])O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Reaction time: 2.5 h
Yield: 95 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.46 g, 2.4 mmol) was added to a solution of (3aR,4R,5R,6aS)-hexahydro-5-hydroxy-4-((R)-3-hydroxy-5-phenylpentyl)cyclopenta[b]furan-2-one (15.0 g, 49.3 mmol) and 3,4-dihydro-2H-pyran (12.4 g, 147.4 mmol) in THF (200 mL) at room temperature and the mixture was stirred for 2.5 hr (TLC monitoring). Saturated aqueous solution of sodium bicarbonate (200 mL) was poured into reaction mixture and the reaction was stirred for 5 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were dried over magnesium sulfate, the solid was filtered off and the filtrate was concentrated under reduced pressure to give 26.0 g of crude product. The crude product was purified by column chromatography and then concentrated under reduced pressure to provide 22.1 g of the title compound (95.0% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH3:25].CCN(CC)CC>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH3:25])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CNCCOC
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (3.07 g, 10 mmol), N-(2-methoxyethyl)methylamine (2.43 mL, 23 mmol) and Et3N (4.2 mL, 30 mmol) in DMSO (20 mL) at 23° C. according to the general procedure C. Obtained as a brown oil (3.57 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[C:3]=1[Cl:13].[Cu][C:15]#[N:16].O>CN(C)C=O>[Cl:13][C:3]1[C:4]([F:12])=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][C:2]=1[C:15]#[N:16]
Reactant: CC(=O)Nc1ccc(Br)c(Cl)c1F
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(C#N)c(Cl)c1F
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-bromo-3-chloro-2-fluorophenyl)acetamide (17.0 g) and copper(I) cyanide (5.88 g) in N,N-dimethylformamide was stirred at 150° C. overnight. After warming to room temperature, water was added, and the mixture was extracted with methyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give N-(3-chloro-4-cyano-2-fluorophenyl)acetamide. Ethanol (250 mL)-concentrated hydrogen chloride (26.6 mL) was added to N-(3-chloro-4-cyano-2-fluorophenyl)acetamide, and the mixture was refluxed overnight. The mixture was ice-cooled, and neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column, and the obtained solid was washed with hexane to give the title compound as a pale-yellow solid (yield: 7.0 g, 64%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]([CH3:27])[C:12]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[C:13]([CH:15]([CH3:18])[C:16]#[N:17])[N:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>O1CCCC1>[Cl:26][C:22]1[CH:21]=[C:20]([S:19][C:12]2[N:11]([CH3:27])[C:10]([CH2:9][OH:8])=[N:14][C:13]=2[CH:15]([CH3:18])[C:16]#[N:17])[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C#N)c1nc(CO[Si](C)(C)C(C)(C)C)n(C)c1Sc1cccc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C#N)c1nc(CO)n(C)c1Sc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
In dry tetrahydrofuran (2 ml)was dissolved 70 mg of 2-(2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1-methyl-1H-imidazol-4-yl)propiononitrile (50'), followed by addition of 0.33 ml of 1 M tetrabutylammoniumfluoride-tetrahydrofuran solution, and the reaction mixture was stirred at room temperature for 10 minutes. To the reaction mixture, water was added, extracted with methylene chloride, the organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate)to obtain 50 mg of 2-[5-(3-chlorophenylthio)-2-hydroxymethyl-1-methyl-1H-imidazol-4-yl]propiononitrile (50) as oil (yield 98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][CH:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([OH:22])=[CH:7][CH:8]=2)[O:3]1.[H-].[Na+].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Cl>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1([CH3:23])[CH2:11][CH:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:22][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])=[CH:7][CH:8]=2)[O:3]1
Reactant: CC1(C)CC(c2cccc3ccccc23)c2ccc(O)cc2O1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2c1cccc2ccccc12
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a stirred solution of 2,2-dimethyl-4-(1-naphthyl)-7-chromanol (7.48 g) in dry toluene (50 ml) was added sodium hydride (1.5 g, ~1.5 eq., 60% dispersion in oil) and the mixture was brought to reflux. To the resulting solution was added dropwise over 10 minutes a solution of 2-dimethylaminoethyl chloride (2.70 g, ~1.1 eq.) in dry toluene (10 ml) and the mixture was stirred under reflux for 2 hours, cooled, diluted with water and left to stand overnight. Next day the toluene layer was separated and evaporated in vacuo. The aqueous layer was extracted with ether and the extract used to dissolve the residue from the toluene evaporation. The organic layer was extracted with 5N hydrochloric acid (45, 35 and 20 ml respectively), the combined acid extract was basified and extracted into ether. After being dried the ether was removed in vacuo to give a yellow oil (6.2 g) which was chromatographed on alumina in 8% ether -- 92% petroleum ether (b.p. 60-80) to give the title compound (4.71 g, 51%) as a colourless oil. The hydrochloric salt had m.p. 178.5°-181.5° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][N:6]=[C:7]([NH2:19])[C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=2[F:18])[CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1.C(OCC)(=O)C>C1C=CC=CC=1>[CH:1]1([CH2:4][O:5][N:6]=[C:7]([NH:19][C:29](=[O:30])[CH2:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:8]2[C:13]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=2[F:18])[CH2:3][CH2:2]1
Reactant: NC(=NOCC1CC1)c1c(F)cccc1C(F)(F)F
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)NC(=NOCC2CC2)c2c(F)cccc2C(F)(F)F)cc1

Procedure:
In 200 ml of benzene was dissolved 20.0 g of N'-cyclopropylmethyloxy-2-fluoro-6-trifluoromethylbenzamidine, and to the solution was added 16. 0 g of 4-methoxyphenylacetylchloride. The solution was heated under refluxing for 10 hours. After cooling, ethyl acetate was added to the solution, followed by washing with water and drying over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to obtain 23.6 g of the objective compound.m.p. 75-76° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1OC.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C[C:29](C)([O-:31])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:29][O:31][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:19][CH2:20][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:17]1
Reactant: COc1ccc(OC(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)[O-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(OC(F)(F)F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 72 h
Yield: 82.1 %

Procedure:
A solution of 2-bromo-1-methoxy4-(trifluoromethoxy)benzene (Description 16, 3 g, 11 mmol), 1,1-dimethylethyl 1-piperazinecarboxylate (2.47 g) and sodium tert-butoxide (1.49 g) in toluene (100 mL) was degassed with bubbling argon. (RS)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (56 mg) and tris(dibenzylideneacetone)dipalladium (0) (13.8 mg) were added and the mixture was degassed and stirred at 80° C. for 72 h. The mixture was cooled, diluted with ether (150 mL) and filtered through celite. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (95:5 increasing to 85:15), to give the title compound (3.4 g, 82%). 1H NMR (250 MHz, CDCl3) δ1.48 (9H, s), 2.98-3.01 (4H, m), 3.58-3.61 (4H, m), 3.87 (3H, s), and 6.74-6.85 (3H, m). m/z (ES+) 377 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C([N:29](CC)CC)C>C(#N)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:29][C:18]3[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:15]=2)[NH:10][CH:9]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccccc12
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CC#N
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Nc3ncccc3[N+](=O)[O-])cc12
Yield: 81 %

Procedure:
(R)-3-(N-Methylpyrrolidin-2-ylmethyl)indole and 2-chloro-3-nitropyridine were used. Triethylamine was used as base, acetonitrile was used as solvent, and the reaction was heated at reflux for 3.5 hours. Chromatography afforded the title compound (81%) as a dark red foam: 1H NMR (CDCl3) δ10.11 (br s, 1H), 8.52 (dd, J=1.7 Hz, J=1.8 and 8.4 Hz, 1H), 8.43 (1.8 and 4.5 Hz; 1H), 8.33 (br s, 1H), 7.77 (d, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.26 (dd, J=2.0 and 8.6 Hz, 1H), 7.03 (d, J=2.1 Hz, 1H), 6.74 (dd, J=4.44 and 8.4 Hz, 1H), 3.21-3.12 (m, 2H), 2.68-2.58 (m, 1H), 2.54-2.46 (m, 1H), 2.47 (s, 3H), 2.28-2.18 (m, 1H), 1.89-1.73 (m, 2H), 1.73-1.54 (m, 2H); 13C NMR (CDCl3) δ155.7, 151.5, 135.5, 134.3, 129.5, 128.2, 128.1, 123.1, 119.4, 114.3, 113.0, 111.4, 66.7, 57.5, 40.8, 31.5, 29.9, 21.9, Anal. calcd. for C19H21N5O2.1/3H2O: C, 63.85; H, 6.11; N, 19.59. Found: C, 63.86; H, 5.86; N, 19.31.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]1[CH2:20][CH2:19][C@@H:18]([CH2:21][N:22]2[C:26]3=[N:27][C:28]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([S:39](=[O:42])(=[O:41])[NH2:40])[CH:33]=4)=[N:29][CH:30]=[C:25]3[CH:24]=[N:23]2)[CH2:17][CH2:16]1)(C)(C)C>C(Cl)Cl>[NH2:14][C@@H:15]1[CH2:16][CH2:17][C@H:18]([CH2:21][N:22]2[C:26]3=[N:27][C:28]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([S:39]([NH2:40])(=[O:42])=[O:41])[CH:33]=4)=[N:29][CH:30]=[C:25]3[CH:24]=[N:23]2)[CH2:19][CH2:20]1
Reactant: Cc1ccc(Nc2ncc3cnn(C[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c3n2)cc1S(N)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Nc2ncc3cnn(C[C@H]4CC[C@@H](N)CC4)c3n2)cc1S(N)(=O)=O
Reaction time: 2 h

Procedure:
TFA (1.0 mL, 13 mmol) was added drop-wise over about 1 min to a 100 mL round-bottomed flask containing a solution of tert-butyl-cis-4-((6-(4-methyl-3-sulfamoylphenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.55 g, 1.1 mmol, Example #B.1.1) in DCM (5 mL) at ambient temperature. The reaction mixture was allowed to stir for about 2 h then concentrated under reduced pressure. The crude product was purified by RP-HPLC (Table 2, Method b) to give 5-(1-((cis-4-aminocyclohexyl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylbenzenesulfonamide (0.435 g. 95%) as a white solid. LC/MS (Table 2, Method a) Rt=1.39 min; MS m/z: 414 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH:7]=[C:8]([NH2:35])[C:9]1(SC2C=CC(Cl)=CC=2)[CH2:16][C:15]2[C:10]1=[CH:11][C:12]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:13]([O:17][CH3:18])[CH:14]=2)([CH3:4])([CH3:3])[CH3:2]>ClC1C=CC=CC=1Cl>[C:1]([O:5][C:6]([C:7]1[C:8]([NH2:35])=[CH:9][C:10]2[C:15](=[CH:14][C:13]([O:17][CH3:18])=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:11]=2)[CH:16]=1)=[O:36])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc2c(cc1OCc1ccccc1)C(Sc1ccc(Cl)cc1)(C(N)=CC(=O)OC(C)(C)C)C2
Solvent: Clc1ccccc1Cl
Product: COc1cc2cc(C(=O)OC(C)(C)C)c(N)cc2cc1OCc1ccccc1
Temperature: 179 °C
Yield: 76.9 %

Procedure:
Nitrogen gas is bubbled through a solution of 3-amino-3-[4-benzyloxy-7-(4-chloro-phenylsulfanyl)-3-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-acrylic acid tert-butyl ester (0.6 g, 1.1 mmol) in 1,2-dichlorobenzene (100 mL) for 1 hour and the reaction is heated to 179° C. After one hour the reaction is cooled and reduced in vacuo. The residue is washed with ether, dissolved in methylene chloride and purified through a plug of silica eluting with methylene chloride. The filtrate is reduced and dried to afford 0.321 g of 3-amino-6-benzyloxy-7-methoxynaphthalene-2-carboxylic acid tert-butyl ester as a yellow solid, mp 179-180° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].[CH:24](O)=[O:25].C(OC(=O)C)(=O)C>C1COCC1.C1(C)C=CC=CC=1.O=[Pt]=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[NH:19][CH:24]=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=CO
Reactant: O=[N+]([O-])c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 101.1 %

Procedure:
A Parr hydrogenator was charged with PtO2 and 1-(4-benzyloxy-3-nitro-phenyl)-2-bromo-1-(R)-ethanol (4) (3.60 g, 10.22 mmol) dissolved in a mixed solvent of THF (25 mL) and toluene (25 mL); and the mixture shaken under an atmosphere of hydrogen at 55 psi at rt for 14 h. The hydrogen pressure was then released. To the mixture was added directly a mixture of formic acid (0.65 mL, 17.23 mmol) and acetic anhydride (1.10 mL, 11.65 mmol). The newly resulting mixture was stirred at rt for an additional 16 h. The catalyst was removed by filtration through a Celite pad and the filtrate was concentrated by rotary evaporation. The resulting residue was purified by column chromatography (silica gel, a gradient of 30:70 to 50:50 ethyl acetate/hexanes) to give the desired formamide 5 as a white solid (3.62 g, >99% yield): 1H NMR (300 MHz, CDCl3) δ 2.95 (s, 1H), 3.52 (m, 1H), 3.60 (m, 1H), 4.85 (m, 1H), 5.08 (s, 2H), 6.96 (d, 1H), 7.13 (dd, 1H), 7.39 (m, 5H), 7.88 (br s, 1H), 8.37 (dd, 1H).
Reaction SMILES: [CH2:1]([O:6][CH:7]1[NH:11][C:10](=[O:12])[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([N:11]1[CH:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:8][CH2:9][C:10]1=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCCOC1CCC(=O)N1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCOC1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a mixture of 4 g of 5-(n-pentyloxy)-pyrrolidin-2-one, 0.4 g of n-tetrabutylammonium bromide and 1.96 g of potassium hydroxide hydrated to 85% in 60 cm3 of tetrahydrofuran, there is added, without exceeding 30° C. a solution of 3.99 g of benzyl bromide in 20 cm3 of tetrahydrofuran. After agitating for 1 hour at ambient temperature, filtering, evaporating to dryness and chromatographing the residue on silica (eluent: ethyl acetate--n-hexane, 1--1), 4.5 g of the expected product is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:12]=[C:11]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(OCc2ccccc2)nc(Oc2ccccc2)n1
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(COc2nc(Oc3ccccc3)nc(Oc3ccccc3)n2)cc1
Yield: 98.5 %

Procedure:
Next, a synthesis method of the hydroxy group-protecting agent 2 will be explained. To a 30 mL eggplant flask, 470.6 mg (1.50 m mol) of 6-benzyloxy-2-chloro-4-phenoxy-1,3,5-triazine, 3.00 mL of dichloromethane, 178.8 mg (1.90 m mol) of phenol and 0.390 mL (1.90 m mol) of N,N-diisopropylethylamine were added, and reacted at 0 degree under a nitrogen atmosphere for 4 hours. After the reaction, 50 mL of dichloromethane was added, which was washed with 20 mL of 1 N hydrochloric acid, 20 mL of 1 N hydrochloric acid, 20 mL of water and 20 mL of saturated salt water. A resulting organic phase was dried by magnesium sulfate, from which dichloromethane was distilled away to obtain 548.5 mg of 6-benzyloxy-2,4-diphenoxy-1,3,5-triazine (yield: 99%).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1B(O)O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1I
Reactant: OB(O)c1cc2ccccc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=O)c1cc([N+](=O)[O-])ccc1-c1cc2ccccc2s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
2-Iodo-5-nitrobenzamide (Example 3A; 6.56 g) is introduced into dioxane (130 ml) and sat. sodium carbonate solution (65 ml) and, after addition of benzothiophene-2-boronic acid (6.00 g) and dichlorobis(triphenylphosphine)palladium (1.58 g), stirred at 80° C. overnight. The reaction mixture is filtered through kieselguhr and washed with ethyl acetate (250 ml) and water (100 ml). The organic phase is extracted with water (three times 100 ml) and sat. sodium chloride solution (100 ml) and then dried over sodium sulfate and concentrated in a rotary evaporator. The residue is chromatographed on silica gel (cyclohexane:ethyl acetate 10:1--->pure ethyl acetate). After the product fractions have been concentrated in a rotary evaporator, the target compound is suspended in diethyl ether, filtered off with suction and dried. 4.75 g of product (64% of theory) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[Cl:33])[N:7]=[C:8]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:9][C:10]=1[CH2:11][N:12]1[CH:17]2[CH2:18][NH:19][CH2:20][CH:13]1[CH2:14][O:15][CH2:16]2)=[O:4].C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[Cl:33])[N:7]=[C:8]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:9][C:10]=1[CH2:11][N:12]1[CH:13]2[CH2:20][N:19]([C:41](=[O:43])[CH3:42])[CH2:18][CH:17]1[CH2:16][O:15][CH2:14]2)=[O:4]
Reactant: COC(=O)C1=C(CN2C3CNCC2COC3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1=C(CN2C3COCC2CN(C(C)=O)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a solution of (R)-4-(2-chloro-4-fluoro-phenyl)-6-(3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound AC) (50 mg, 0.1 mmol) and triethylamine (0.042 mL, 0.3 mmol) in CH2Cl2 (5 mL) was added acetyl chloride (16 mg, 0.2 mmol) dropwise at ice-bath. The mixture was stirred at 0° C. for 2 hours. The mixture was concentrated in vacuo. The residue was extracted with ethyl acetate (20 mL×2) and then washed with saturated aqueous sodium bicarbonate solution (20 mL×2). The organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by prep-HPLC to afford (R)-6-(7-acetyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Example 15) as a light yellow solid (45 mg).
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[CH:5]1)(=O)C.[CH3:15]I.O>C(#N)C>[CH3:15][N:6]1[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][N:4]=[CH:5]1
Reactant: CC(=O)n1cnc(-c2ccccc2)c1
Reactant: CI
Solvent: O
Solvent: CC#N
Product: Cn1cncc1-c1ccccc1

Procedure:
To 2.88 g of 1-acetyl-4-phenylimidazole in 50 ml of acetonitrile was added 5.8 ml of methyl iodide and the reaction mixture sealed in a flask over a weekend. The reaction mixture was poured into water and then decanted from insoluble oil. The pH of the decanted solution was adjusted to 9 with sodium carbonate and the solution extracted with chloroform. The extracts were combined, dried over magnesium sulfate and concentrated to give 1.02 g of crude product which was chromatographed on 50 g of silica gel using 30% ethyl acetate in chloroform as the eluent, 640 mg.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][C:5]=2[S:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc2scc(C)c2c(=O)[nH]1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc2scc(CBr)c2c(=O)[nH]1
Yield: 50 %

Procedure:
A mixture of ethyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained according to the method described in U.S. Pat. No. 4,054,656 (1.00 g, 4.20 mmol), N-bromosuccinimide (784 mg, 4.41 mmol), 2,2′-azo-bis-isobutyronitrile (68.9 mg, 0.420 mmol) and carbon tetrachloride (30 mL) was heated under reflux for 3 hr. The solvent was evaporated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The organic layer was washed with water (×3) and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained crude crystals were recrystallized from ethyl acetate to give ethyl 5-(bromomethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate (662 mg, 50%) as a pale-yellow powder.