Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C1C=CC=CC=1)C.C[Si](C)(C)Cl.C1(CC([NH:24][CH:25]2[C:46](=[O:47])[N:27]3[C:28]([C:43]([OH:45])=[O:44])=[C:29]([O:32][S:33]([C:36]4[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=4)(=[O:35])=[O:34])[CH2:30][S:31][C@H:26]23)=O)C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl.O.CO.C(N(CC)CC)C>[NH2:24][CH:25]1[C:46](=[O:47])[N:27]2[C:28]([C:43]([OH:45])=[O:44])=[C:29]([O:32][S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=3)(=[O:34])=[O:35])[CH2:30][S:31][C@H:26]12
Reactant: Cc1ccc(S(=O)(=O)OC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3SC2)cc1
Agent: C[Si](C)(C)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Cc1ccc(S(=O)(=O)OC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)cc1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
Triethylamine (3.41 g.), N,N-dimethylphenylamine (10.3 g.) and trimethylchlorosilan (5.64 g.) were added to a stirred solution of 7-phenylacetamido-3-tosyloxy-3-cephem-4-carboxylic acid (15 g.) in methylene chloride (150 ml.) at room temperature in turn, and the solution was stirred at room temperature for an hour. Phosphorus pentachloride (7.03 g.) was added to the solution at -35° C., and stirred at -25° to -20° C. for 1.5 hours. Methanol (61 ml.) was added to the solution and stirred at the same temperature for 40 minutes. To the resultant solution was added water (50 ml.) at -20° to -10° C. The organic layer was separated and washed with water twice. The aqueous layer and the washings were combined, and washed with methylene chloride twice and diethyl ether in turn. After the solution was adjusted to pH 4.7 with 10% aqueous sodium hydroxide under cooling, the precipitates were collected by filtration, washed with water, acetone and diethyl ether in turn, and then dried over phosphorus pentoxide to give 7-amino-3-tosyloxy-3-cephem-4-carboxylic acid (5.01 g.), mp 172° C. (dec.).
Reaction SMILES: [C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12]([NH2:13])=[N:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1.CO[CH:18](OC)[N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH:20]([N:19]([CH:18]=[C:2]1[CH2:3][C@@H:4]([CH2:5][OH:6])[O:7][C@H:1]1[N:8]1[CH:15]=[CH:14][C:12]([NH2:13])=[N:11][C:9]1=[O:10])[CH:23]([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: COC(OC)N(C(C)C)C(C)C
Reactant: Nc1ccn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Solvent: CN(C)C=O
Product: CC(C)N(C=C1C[C@@H](CO)O[C@H]1n1ccc(N)nc1=O)C(C)C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
In a typical example of such procedure, previously dried 2', 3'-dideoxycytidine (153 mg, 0.724 mmoles) which was previously prepared by the literature procedures described above is treated with diisopropylformamide dimethylacetal (1.27 g, 7.24 mmoles) in anhydrous DMF (2 mL) under an argon atmosphere. The product is stirred overnight and thereafter solvent and excess reagent are removed by rotary evaporation. The syrupy residue remaining is crystallized from ethanolether to give pale lemon-colored crystals (185 mg, 79%) of diisopropylaminomethylene 2', 3'-dideoxycytidine.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[C:14]1[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=O)C.[CH3:28][NH2:29]>C(O)CCC>[CH3:28][NH:29][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[C:14]1[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:3]
Reactant: CN
Reactant: CCOC(=O)CCCCCCCn1c(-n2ccnc2)c(C)c2ccccc21
Solvent: CCCCO
Product: CNC(=O)CCCCCCCn1c(-n2ccnc2)c(C)c2ccccc21

Procedure:
A solution of 4 g of 1-(7-ethoxycarbonylheptyl)-3-methyl-2-(1-imidazolyl)indole in 40 ml of n-butanol is saturated with methylamine and heated on a steam bath in a pressure bottle for 3 days. The reaction mixture is evaporated to dryness to yield 1-[7-(N-methylcarbamoyl)heptyl]-3-methyl-2-(1-imidazolyl)indole.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:25])[CH2:6]1)[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[CH3:26]OC(OC)(C)C.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.N1C=CC=CC=1>C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:25])[CH2:6]1)[C@:19]1([CH3:20])[C:14]([CH:15]=[C:16]([O:24][CH3:26])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC(=O)[C@@]2(C)CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@H]12
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC1=CC2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reaction time: 5 h

Procedure:
10.0 g of 15α-acetoxy-4-androstene-3,17-dione is stirred under reflux with 60 ml of dimethoxypropane and 1.0 g of pyridinium-4-toluenesulfonate. After 5 hours, 1 ml of pyridine is added, the mixture is diluted with ethyl acetate, washed neutral with water, and dried. The crude product is recrystallized from hexane/acetone. Yield: 9.6 g of 15α-acetoxy-3-methoxyandrosta-3,5-dien-17-one, mp 209° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)Nc2nc3ccccc3nc2OC)CC1
Yield: 72.4 %

Procedure:
Phenyl N-(2-Methoxyquinoxalin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25](O)=[O:26])=[C:22]([CH3:28])[C:21]=3[CH:29]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].C(Cl)CCl.Cl.[CH3:39][NH:40][CH3:41]>CN(C1C=CN=CC=1)C>[CH3:39][N:40]([CH3:41])[C:25]([C:23]1[O:24][C:20]2[CH:19]=[CH:18][C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:31])[C:2]([CH3:33])([CH3:32])[CH3:1])=[C:7]([CH3:30])[CH:8]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:29][C:21]=2[C:22]=1[CH3:28])=[O:26]
Reactant: CNC
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)O)c(C)c2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)N(C)C)c(C)c2c1
Yield: 37.2 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-benzofuran-2-carboxylic acid (520 mg, 1.154 mmol), DMAP (422 mg, 3.46 mmol), EDC (332 mg, 1.73 mmol), and dimethyl amine hydrochloride (141 mg, 1.73 mmol) are reacted analogous to Example 1, step I to give the title product (205 mg, 37%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]3[C:29]([O:31]C)=[O:30])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]3[C:29]([OH:31])=[O:30])=[CH:18][CH:19]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(OCCC2CCCCC2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(OCCC2CCCCC2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-4-chloro-5-hydroxymethyl-1-[4-[(1-methoxycarbonyl-2-cyclohexyl)ethoxy]benzyl]imidazole and 1N sodium hydroxide solution in ethanol.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:11][CH2:12][CH2:13]O.S(=O)(=O)(O)O>>[CH2:1]([O:10][CH2:13][CH2:12][Cl:11])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: OCCCl
Agent: O=S(=O)(O)O
Product: Oc1ccccc1COCCCl

Procedure:
A solution of 13.8 g (0.1 mole) of salicylic acid in 48.3 g (0.6 mole) of 2-chloro-ethanol in the presence of 4 ml of sulfuric acid is heated to 110° for 2 hours. After removing the excess of 2-chloro-ethanol, the ether solution of the product is extracted with an aqueous solution of 5% CO3HNa. The ether is removed and the product is distilled. B.p.: 128°-129°/11 Torr.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:14]=[C:15]([C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][C:18]=1[F:19]>C1COCC1>[F:12][C:13]1[CH:14]=[C:15]([C:20]2([CH3:8])[CH2:21][O:22]2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(F)c(F)c2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(3,4-difluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]([N:13]([CH:22]([CH3:24])[CH3:23])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:12].[C:25](Cl)(=[O:30])[CH2:26][C:27](Cl)=[O:28]>O1CCCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][C:11]([N:13]([CH:22]([CH3:24])[CH3:23])[C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[O:12])[C:25](=[O:30])[CH2:26][C:27](=[O:28])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: COc1ccc(N(C(=O)CNc2ccc(F)cc2N)C(C)C)cc1
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)Nc3cc(F)ccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
A solution of 1.724 g of 2-(2-amino-4-fluoro-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (5.20 mmol) in 15 mL of tetrahydrofuran was transferred to an addition funnel. A solution of 0.506 mL of malonyl dichloride (5.20 mmol, 1.0 equiv) in 15 mL tetrahydrofuran was transferred to a separate addition funnel. Each solution of each reagent was simultaneously added dropwise over 30 min. to 100 mL of tetrahydrofuran at ambient temperature under nitrogen with vigorous agitation. After stirring for 20 min. at ambient temperature, an additional 0.506 mL of malonyl dichloride (5.20 mmol, 0.1 equiv) was added in a single portion. The reaction was allowed to stir an additional 2.5 hrs. and then evaporated in vacuo to a residue. The residue was purified on flash grade silica gel with 1:3 ethyl acetate/hexane followed by 3:1 ethyl acetate/hexane. The appropriate fractions were combined, evaporated in vacuo to a residue and triturated with hexane. The hexane was removed in vacuo and the residual solid was dried under high vacuum to provide 1.061 g of the title compound as a tan solid. 1H NMR (300 MHz, CDCl3) d 8.14 (b, 1H), 7.45 (dd, 1H, J=5.5. 9.2), 7.29 (m, 1H), 7.05 (m, 1H), 6.94 (m, 3H), 6.78 (m, 1H), 4.99 (m, 1H), 4.37 (d, 1H, J=16.4), 3.82 (s, 3H), 3.69 (d, 1H, J=16.0), 3.40 (m, 2H), 1.09 (d, 6H, J=6.8); low resolution MS (FAB)m/e 400 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH3:15][C:16]1([CH3:24])[O:20][C@@H:19]([CH2:21][O:22][NH2:23])[CH2:18][O:17]1.C(N(CC)CC)C>O1CCOCC1>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:23][O:22][CH2:21][C@H:19]2[CH2:18][O:17][C:16]([CH3:24])([CH3:15])[O:20]2)[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: CC1(C)OC[C@H](CON)O1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@H](CONc2nc(NC=O)nc(Cl)c2NC=O)O1
Temperature: 100 °C
Reaction time: 4 h
Yield: 20.2 %

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (3.5 g, 15 mmol), (R)-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)amine (2.65 g, 18 mmol) and triethylamine (20 ml, 150 mmol) in dioxan (80 ml) was stirred at 100° C. for 4 hours. The reaction was cooled, filtered and evaporated under reduced pressure. The residue was chromatographed on silica, eluting with chloroform-methanol (10:1), affording slightly impure (R)-4-chloro-2,5-diformamido-6-(2,2-dimethyl-1, 3-dioxolan-4-ylmethoxyamino)pyrimidine (1.05 g, 20%) as pale orange solid. IR: υmax (nujol) 3400, 3300, 3180, 1690, 1650 cm-1 ;
Reaction SMILES: ClC1C=C2C(C(=O)C(C(O)=O)=CN2CC)=CC=1.[Cl:18][C:19]1[N:28]=[C:27]2[C:22]([C:23](=[O:34])[C:24]([C:31]([OH:33])=[O:32])=[CH:25][N:26]2[CH2:29][CH3:30])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[N:28]=[C:27]2[C:22]([C:23](=[O:34])[C:24]([C:31]([OH:33])=[O:32])=[CH:25][N:26]2[CH:29]=[CH2:30])=[CH:21][CH:20]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(Cl)nc21
Agent: CCn1cc(C(=O)O)c(=O)c2ccc(Cl)cc21
Product: C=Cn1cc(C(=O)O)c(=O)c2ccc(Cl)nc21

Procedure:
Two of the compounds of the formula (a) are known compounds; i.e., 7-chloro-1,4-dihydro-1-ethyl-4-oxo-quinoline-3-carboxylic acid and 7-chloro-1,4-dihydro-1-ethyl-4-oxo-1,8-naphthyridine-3-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C(O)(=O)C.[N:17]([O-])=[O:18].[Na+]>O>[N:17]([C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:12])=[O:18]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Nc1c(O)ccc2cc(Br)ccc12
Reaction time: 23 h

Procedure:
76.2 g (0.342 mol) of 6-bromo-β-naphthol were suspended in 385 ml of 90%-strength acetic acid and nitrosated for two hours at 4° C. with 28.5 g (0.413 mol) of sodium nitrite in 230 ml of water, and stirring was then continued for 23 h at room temperature. The suspension was then made up to twice its volume by filling up with water and the product formed was filtered off by suction. After drying, 83.8 g (97.3%) of crude 1-nitroso-6-bromo-β-naphthol whose purity is adequate for the further reaction was obtained.
Reaction SMILES: O[C:2]1([CH2:19][O:20][C:21](=[O:35])[N:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3]1.C(N(S(F)(F)[F:42])CC)C>C(Cl)Cl>[F:42][C:2]1([CH2:19][O:20][C:21](=[O:35])[N:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3]1
Reactant: CCOC(=O)COc1cccc2c1CCC(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COc1cccc2c1CCC(F)(COC(=O)N(c1ccccc1)c1ccccc1)C2
Reaction time: 0.5 h

Procedure:
To a solution of 2-hydroxy-2-(N,N-diphenylcarbamoyloxymethyl)-5-ethoxycarbonylmethyloxy-1,2,3,4-tetrahydronaphthalene (100 mg) in CH2Cl2 (10 ml) was added diethylaminosulfur trifluoride (0.5 ml) at -78° C. After being stirred for 30 minutes, the mixture was washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 2-fluoro-2-(N,N-diphenylcarbamoyloxymethyl)-5-ethoxycarbonylmethyloxy-1,2,3,4-tetrahydronaphthalene (40 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][O:22][C:23](=[O:27])[CH2:24][NH:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([N:25]([CH3:26])[CH2:24][C:23]([O:22][CH3:21])=[O:27])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNCC(=O)OC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
N-(tert-Butoxycarbonyl)-phenylalanine (4.85 g, 15 mmol) was condensed with N-methylglycine methyl ester hydrochloride in DMF in the presence of triethylamine, HOBt and WSC.
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:18]=4[O:29][CH3:30])=[N:11][C:10]=3[C:9]([CH3:31])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pt]=O.O1CCCC1>[CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:18]=4[O:29][CH3:30])=[N:11][C:10]=3[C:9]([CH3:31])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)/C=C/c1ccc(-c2nc3c(C)nn(C4CCCCC4)c3c(=O)[nH]2)c(OC)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(-c2nc3c(C)nn(C4CCCCC4)c3c(=O)[nH]2)c(OC)c1
Yield: 81.7 %

Procedure:
To a 2 ml tetrahydrofuran solution of 63 mg (0.15 mmol) of the compound obtained in Example 226, 6 mg of platinum oxide was added, and the mixture was stirred for 3.5 hours in an atmosphere of hydrogen at room temperature and atmospheric pressure. Then, the catalyst was removed by filtration, and the filtrate was distilled under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to obtain 52 mg (82%) of the captioned compound.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.Br[CH2:30][CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CC1ON=C(C2C=CC(CNC(=O)C3C=C(OC)C(C)=C(OC)C=3)=C(NCCOC3C=CC=CC=3)C=2)N=1>>[CH2:33]([O:32][CH2:31][CH2:30][NH:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCCOCc1ccccc1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Agent: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCOc2ccccc2)cc(OC)c1C
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCOCc2ccccc2)cc(OC)c1C
Yield: 51 %

Procedure:
Compound 1g was reacted with benzyl 2-bromoethyl ether according to the procedure described in compound 42a, to give compound 51a (79 mg, 51%). ESI-MS m/e 517.4 (M+1).
Reaction SMILES: BrC[C:3]1[S:7][C:6]([C:8]([F:11])([F:10])[F:9])=[N:5][CH:4]=1>C(O)C>[F:9][C:8]([F:11])([F:10])[C:6]1[S:7][CH:3]=[CH:4][N:5]=1
Reactant: FC(F)(F)c1ncc(CBr)s1
Solvent: CCO
Product: FC(F)(F)c1nccs1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A solution of 5-(bromomethyl)-2-(trifluoromethyl)-1,3-thiazole [prepared in accordance with U.S. Pat. No. 5,338,856] (170 mg, 069 mmol) in 5 mL of ethanol was treated sodium methylthiolate (60 mg, 0.86 mmol) at room temperature. The reaction was complete in 10 min and so the solvent was carefully removed under reduced pressure (40 mmHg) without heating. The residue was partitioned between dichloromethane and dilute hydrochloric acid, washed with saturated brine and dried over sodium sulfate. The solvent was again carefully removed under reduced pressure (40 mmHg) without heating to yield 5-[methylthio)methyl]-2-(trifluoromethyl)-1,3-thiazole (140 mg; 96%) as a pale orange liquid: 1H NMR (CDCl3) δ 7.75 (s, 1H), 3.90 (s, 2H), 2.10 (s, 3H); GCMS (FID) m/z 213 (M+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]2[C:10]3[CH:16]=[C:15]([C:17]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=5)[N:19]([CH3:28])[CH:18]=4)[N:14]([CH2:29][OH:30])[C:11]=3[N:12]=[CH:13][C:8]2=[CH:7][N:6]=1.[CH3:31][C:32](OC(C)=O)=[O:33].N1C=CC=CC=1>C1COCC1.C([O-])(O)=O.[Na+]>[OH:30][CH2:29][N:14]1[C:11]2[N:12]=[CH:13][C:8]3[N:9]([C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[CH3:31])=[N:6][CH:7]=3)[C:10]=2[CH:16]=[C:15]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]([CH3:28])[CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(CCCN)n43)n1CO)cn2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(CCCNC(C)=O)n43)n1CO)cn2C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
To a solution of (1-(3-aminopropyl)-7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-6-yl)methanol (0.116 g, 0.287 mmol) in THF (3 mL) at rt was added Ac2O (0.032 mL, 0.344 mmol) and pyridine (1.0 mL, 12.36 mmol). After about 10 min, additional Ac2O (0.027 mL, 0.287 mmol) was added. After about 15 min the mixture was diluted with aqueous NaHCO3 (10 mL) and extracted with EtOAc (20 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give N-(3-(6-(hydroxymethyl)-7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)propyl)acetamide (0.128 g, 100%): LC/MS (Table 2, Method c) Rt=1.26 min; MS m/z 447 (M+H)+.
Reaction SMILES: P(CCCC)(CCCC)CCCC.Br[C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1.C([O-])([O-])=O.[K+].[K+].C(=O)([S:33][CH2:34][CH2:35][C@H:36]1[C@@H:40]([O:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH2:39][C@@H:38]([O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[C@@H:37]1[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])C>C(O)C.O>[CH3:45][S:42]([O:41][C@@H:40]1[C@H:36]([CH2:35][CH2:34][S:33][C:15]2[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[C@@H:37]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C@H:38]([O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[CH2:39]1)(=[O:43])=[O:44]
Reactant: CCCCCCCC[C@@H]1[C@@H](CCSC(C)=O)[C@@H](OS(C)(=O)=O)C[C@H]1OC1CCCCO1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCCCC[C@@H]1[C@@H](CCSc2nc(C(=O)OCC)cs2)[C@@H](OS(C)(=O)=O)C[C@H]1OC1CCCCO1
Temperature: 40 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
PBu3 (20 μL, 0.08 mmol), ethyl 2-bromothiazole-4-carboxylate (6-5, 119 mg, 0.50 mmol) and K2CO3 (107 mg, 0.77 mmol) were added to a solution of 6-3 (183 mg, 0.38 mmol) in 1.6 mL ethanol. The mixture was stirred at 40° C. overnight and then 20 mL H2O was added. The resulting mixture was extracted with ethyl acetate (30 mL) and the ethyl acetate solution was washed with brine (20 mL). The solution was then dried (Na2SO4), filtered, and evaporated. Purification of the residue by flash chromatography on silica gel (Combiflash unit by Isco) gave the title compound (41 mg, 18%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.FC(F)(F)C1C=CC(C(O)=O)=CC=1.N1C=CC=CC=1>O=S(Cl)Cl.C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([C:7]([F:18])([F:17])[F:6])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(O)c1ccc(C(F)(F)F)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
To a cold (0° C.) solution of N,O-dimethylhydroxylamine hydrochloride (2.5 g, 25.6 mmol) and 4-(trifluoromethyl)benzoyl chloride (prepared by refluxing a solution of 4-(trifluoromethyl)benzoic acid in SOCl2, 4.86 g, 23.3 mmol) in DCM (50 mL) was added dropwise pyridine (4.06 g, 51.26 mmol). The reaction mixture was stirred overnight and evaporated. The residue was dissolved in a mixture of DCM/Et2O (1/1) (45 mL) and brine (45 mL) was added. The aqueous layer was separated and extracted twice with DCM/Et2O (1/1) (45 mL). The combined organic layers were washed with brine (45 mL), dried over MgSO4, filtered and concentrated under vacuum to give the title compound as a yellow oil (4.88 g, 90%). 1H NMR (CDCl3, 300 MHz) δ 7.90-7.70 (m, 2H), 7.76-7.60 (m, 2H), 3.65-3.45 (m, 3H), 3.43-3.33 (m, 3H). HPLC (Condition A), Rt: 3.41 min (HPLC purity: 98.0%).