Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([OH:33])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:38](Br)[CH2:39][CH2:40][CH2:41][CH3:42]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH:21]4[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:16]4)[C:10]=3[N:9]=2)=[CH:34][CH:35]=1
Reactant: CCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C

Procedure:
A solution of (RS) 2-(4-chlorophenoxymethyl)-4-hydroxy-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole (75 mg, 0.15 mmol, 1.0 eq) in dry N,N-dimethylformamide (1.0 ml) was treated with sodium hydride (60% in oil, 7.5 mg, 0.18 mmol, 1.20 eq). The resulting mixture was stirred at room temperature for thirty minutes, after which time 5-[1-(t-butoxycarbonyl)piperidin-4-yl)]pentyl bromide (0.18 mmol, 1.2 eq) was added. The resulting mixture was stirred for three hours at 70° C. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with diethyl ether (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to give a crude product. The title product was further purified by flash chromatography to provide a crystalline product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4].C(N(C(C)C)CC)(C)C.[CH3:40][O:41][CH2:42]Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH2:40][O:41][CH3:42])[CH2:25][CH2:26]3)[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4]
Reactant: COC(=O)c1nc2n(CCN3CCNCC3)c3ccccc3n2c(=O)c1OC(C)=O
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCN1CCN(CCn2c3ccccc3n3c(=O)c(OC(C)=O)c(C(=O)OC)nc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.9 %

Procedure:
3-Acetoxy-4-oxo-10-(2-piperazin-1-yl-ethyl)-4,10-dihydro-benzo[4,5]imidazo[1,2-a]pyrimidine-2-carboxylic acid methyl ester (Example 15.3) (97 mg, 0.235 mmol) was dissolved in Dichloromethane (1 mL) and to it was added diisopropylethylamine (95 μL, 0.52 mmol), followed by methoxymethyl chloride (20 L, 0.258 mmol). The reaction was stirred at room temperature for 24 h before the solvents were evaporated and the residue purified by column chromatography (98:1.5:0.5 dichloromethane:methanol:aqueous ammonia) to afford the desired product (30 mg, 28%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:7]3[CH:8]=[C:3]([CH:4]=[CH:5][CH:6]=3)[C:1]#[N:2])=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2ccc(Cn3ccnc3)cn2)c1

Procedure:
Synthesized using 3-cyanophenylboronic acid (185 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 135 mg, 0.52 mmol, 82%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.21 (s, 2H), 6.94 (s, 1H), 7.13 (s, 1H), 7.54 (dd, J=8.2, 2.4 Hz, 1H), 7.55-7.60 (m, 2H), 7.70 (d, J=7.9 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 8.21 (d, J=7.9 Hz, 1H), 8.31 (s, 1H), 8.61 (d, J=1.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 113.1, 118.6, 119.0, 120.6, 129.7, 130.4, 130.6, 131.0, 131.3, 132.5, 136.0, 137.3, 139.6, 148.77, 148.81, 155.1; MS (ESI): m/z=261.41 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:8]=3[C:7]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[N:6][N:5]2[C:26]=1[CH3:27]>C(O)(=O)C.[Fe]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:7]2[C:8]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:9]=3[CH2:10][C:4]3=[N:3][C:2]([CH3:1])=[C:26]([CH3:27])[N:5]3[N:6]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc2c(c1)C(c1ccc([N+](=O)[O-])cc1)=Nn1c(nc(C)c1C)C2
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(c1ccc(N)cc1)=Nn1c(nc(C)c1C)C2

Procedure:
834 mg of 2,3-dimethyl-8-methoxy-6-(4-nitrophenyl)-11H-imidazo[1,2-c][2,3]benzodiazepine in 33 ml of glacial acetic acid together with 2.25 g of iron powder are heated for 20 minutes in an oil bath that is preheated to 90° C. It is suctioned off hot and rewashed with glacial acetic acid. The filtrate is concentrated by evaporation, and the residue is dispersed in ethyl acetate and 1N sodium hydroxide solution. The aqueous phase is shaken out twice with ethyl acetate, and the collected organic phase is washed with water, dried, filtered and concentrated by evaporation. This residue is chromatographed on silica gel with methylene chloride:ethanol=10:1 as an eluant. After the corresponding fractions that are concentrated by evaporation are absorptively precipitated with ethyl acetate/hexane, 331 mg of 6-(4-aminophenyl)-2,3-dimethyl-8-methoxy-11H-imidazo[1,2-c][2,3]benzodiazepine with a melting point of 280° C. is obtained.
Reaction SMILES: Cl.C[O:3][C:4]([C:6]1[N:7]([CH3:12])[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH:19]1[C:31]2[CH:30]([CH2:32][O:33][C:34](Cl)=[O:35])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1>>[CH:19]1[C:31]2[CH:30]([CH2:32][O:33][C:34]([NH:11][C:9]3[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]([CH3:12])[CH:8]=3)=[O:35])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)c1cc(N)cn1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1cc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1C(=O)O
Reaction time: 8 h
Yield: 59.6 %

Procedure:
After dissolving 9 (10.9 g, 57.2 mmol) into distilled water (80 ml), sodium hydroxide (9.2 g) was added to the solution. After stirring overnight, the solution was neutralized with 1N hydrochloric acid, followed by distillation under a reduced pressure. The residue was dissolved into a mixed solution of water and ethyleneglycoldimethylether (100 ml, 1:1, v/v) to be used for next reaction. After dissolving sodium carbonate (5.3 g) into the solution, 9-fluorenylmethylchloroformate (17.8 g, 68.6 mmol) was added thereto. After stirring the mixture overnight, precipitates were collected by filtration to obtain 11 (12.3 g, 34.1 mmol). The filtrate was added to a mixed solution of 1M sodium carbonate solution and diethylether (1:1, v/v). Precipitates were collected by filtration to further obtain 11 (3.4 g). After acidifying the water layer with 10% hydrochloric acid, the water layer was extracted with ethyl acetate. The organic layer was distilled under a reduced pressure and then recrystallized with hexane-dioxane to further obtain 11 (1.6 g). (Total yield: 17.3 g, 84%)
Reaction SMILES: C(C1C=CC=CC=1C=C)=C.[CH2:11]([CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:12].[Cl:21][CH:22]([SiH3:24])[Cl:23]>>[Cl:21][CH:22]([SiH2:24][CH2:12][CH2:11][CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[Cl:23]
Reactant: [SiH3]C(Cl)Cl
Reactant: CCC=Cc1ccccc1
Agent: C=Cc1ccccc1C=C
Product: ClC(Cl)[SiH2]CCC=Cc1ccccc1
Reaction time: 48 h

Procedure:
A 500 ml three-neck, round bottom flask equipped with a magnetic stirrer, a condenser and an addition funnel was charged with 60 ml (0.337 mol) of divinylbenzene (Aldrich Chemical Co., Milwaukee, Wis.); mixture of 80% m- and p- isomers and 20% ethylvinylbenzene) under an argon atmosphere and at room temperature (RT). While stirring, 200 ml of distilled and dried hexanes were added followed by 0.5 ml of the above described platinum catalyst solution (SIP6830.0 from Gelest). Dichloromethylsilane (39.0 ml; 0.371 mol) was placed in the addition funnel, the argon supply was disrupted and a drying tube was attached to the system. The dichloromethylsilane was added dropwise at room temperature and the reaction was monitored by 1H NMR spectroscopy. After 48 hours, it was determined that hydrosilation was complete, the addition funnel and condenser were replaced by a distillation head and the crude product was purified by fractional distillation. The desired product was obtained as a mixture, 77% thereof corresponding to a combination of meta- and para-(2-dichloromethylsilyl-ethyl)-styrene (DSiSt) of the formula
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:15]=[N:14][C:8]2[S:9][CH2:10][C:11](=[O:13])[NH:12][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>O1CCCC1>[O:13]=[C:11]1[CH2:10][S:9][C:8]2[N:14]=[CH:15][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[NH:12]1
Reactant: COC(=O)c1cnc2c(c1)NC(=O)CS2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1CSc2ncc(C(=O)O)cc2N1
Yield: 95.2 %

Procedure:
A solution of the ester (b) (2.8 g) in tetrahydrofuran (50 ml) was treated with 1M sodium hydroxide (30 ml). After 2 hours the mixture was concentrated to near dryness and acidified with 2M hydrochloric acid. Filtration and washing with water afforded a solid (2.5 g).
Reaction SMILES: O.C([O:5][CH2:6][C:7]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:8]=1[O:9][C:10](=[CH:15][O:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CO>[OH:5][CH2:6][C:7]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:8]=1[O:9][C:10](=[CH:15][O:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC=C(Oc1ccc(Cl)cc1COC(C)=O)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC=C(Oc1ccc(Cl)cc1CO)C(=O)OC
Temperature: 25 °C
Yield: 84.5 %

Procedure:
Water was added to a solution of 1.42 g of methyl 2-(2-acetyloxymethyl-4-chlorophenoxy)-3-methoxyacrylate in methanol, and stirred at room temperature. Sodium carbonate (0.53 g) was added. After a further 0.5 hour water and ethyl acetate were added. The organic phase was dried with anhydrous sodium sulfate, evaporated and the residue purified by silica gel column chromatography to give methyl 2-(2-hydroxymethyl-4-chlorophenoxy)-3-methoxyacrylate (1.04 g).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=3[C@H:5]1[CH2:4][CH2:3]2.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([O:20][C:18]1[CH:17]=[CH:16][C:15]2[C@@H:5]3[C@H:6]([C@H:7]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C@@H:10]([O:11][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:8]4)[CH2:12][CH2:13][C:14]=2[CH:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCc1ccccc1
Reaction time: 0.17 h
Yield: 190 %

Procedure:
Dimethylformamide (11 ml) was added to β-estradiol (1.08 g, 4.0 mmol) under nitrogen atmosphere, followed by cooling on ice. Sodium hydride (480 mg of 60% suspension) was added to the reaction mixture followed by stirring for 10 minutes on ice and then stirred for 1 hour at room temperature. After cooling again on ice, Benzyl bromide (2.05 g, 12 mmol) was added to the reaction mixture followed by stirring for 10 minutes on ice and then stirred for 20 hours at room temperature. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure using an evaporator and the resulting residue was triturated with methanol to precipitate solids. The solids were collected by filtration and vacuum dried to give 3,17β-bis(benzyloxy)estra-1,3,5(10)-triene (1.72 g, Yield 95%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29].[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCN
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCNC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 2 ml of methylene chloride was dissolved 0.31 g of dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. After 2 ml of acetic anhydride was added to the solution under ice cooling, the mixture was stirred for 30 minutes at room temperature. The reaction solution was concentrated under reduced pressure and ether was added to the residue to solidify. The solid was recrystallized from chloroform-n-hexane to give 0.26 g of dimethyl 4-[2-[4-(acetylamino)butoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. This compound has the following physicochemical properties.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1([NH2:26])[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:26][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CON=C1C[C@@H](C(=O)Nc2ccccc2N)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 48 h
Yield: 99.2 %

Procedure:
A solution was prepared containing the central building block, e.g. (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid (Intermediate 7) (2.1 g, 8.1 mmol), an ortho-substituted aromatic amine or amine salt, e.g. 1,2-benzenediamine (0.88 g, 8.1 mmol) and DMAP (1.59 g, 13.0 mmol). in dry dichloromethane (30 ml). This solution was cooled to 0° C. and treated with EDC (1.56 g, 8.2 mmol) before warming to room temperature and stirring for 2 days. The solvent was removed in vacuo and the product purified by silica gel chromatography, eluting with a gradient of 30–80% ethyl acetate in hexane to give the desired anilide product, e.g. tert-butyl (2S,4EZ)-2-[(2-aminoanilino)carbonyl]-4-(methoxyimino)-1-pyrrolidinecarboxylate 2.8 g, 97% as a colourless foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])=[C:6]([C:19]([F:22])([F:21])[F:20])[N:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:25]([C:30]2[S:34][CH:33]=[N:32][C:31]=2[CH:35]=O)[C:26]([CH3:29])=[CH:27][CH:28]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:23][C:24]1[N:25]([C:30]2[S:34][CH:33]=[N:32][C:31]=2[C:35]2[N:10]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:9])[C:7]3[C:6]([C:19]([F:22])([F:20])[F:21])=[N:5][CH:4]=[CH:3][C:2]=3[N:1]=2)[C:26]([CH3:29])=[CH:27][CH:28]=1
Reactant: Nc1ccnc(C(F)(F)F)c1C(=O)NCCc1ccccc1
Reactant: Cc1ccc(C)n1-c1scnc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1scnc1-c1nc2ccnc(C(F)(F)F)c2c(=O)n1CCc1ccccc1
Temperature: 110 °C
Yield: 17.2 %

Procedure:
A solution of 4-amino-N-phenethyl-2-(trifluoromethyl)nicotinamide (25.5 mg, 0.082 mmol), 5-(2,5-dimethyl-1H-pyrrol-1-yl)thiazole-4-carbaldehyde (17 mg, 0.082 mmol) and TsOH (1.4 mg, 0.008 mmol) in toluene was heated at reflux overnight. The reaction was then filtered and to the crude mixture was added manganese oxide. The reaction was heated at 110° C. for 4 h. The reaction mixture was filtered, concentrated and purified with silica gel chromatography providing a solid, 2-(5-(2,5-dimethyl-1H-pyrrol-1-yl)thiazol-4-yl)-3-phenethyl-5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one (7 mg). 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.76 (d, 1H), 7.69 (m, 1H), 7.51 (m, 1H), 7.48 (d, 1H), 7.32 (m, 5H), 4.20 (m, 2H), 3.32 (m, 2H), 2.07 (s, 6H). MS m/z 496.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[N:5][O:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10].Cl>C(O)C>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][O:6][CH2:7][C:8]([CH3:13])([CH3:14])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(C)(C)CON=Cc1ccccc1Cl
Agent: Cl
Solvent: CCO
Product: COC(=O)C(C)(C)CONCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.5 %

Procedure:
A mixture of methyl 2-(2-chlorobenzylideneaminooxymethyl)-2-methylpropanoate (10.0 grams, 0.04 mole) and borane-pyridine complex (10.4 mL; 0.12 mole) in absolute ethanol (30 mL) was cooled in an ice bath. A solution of anhydrous 6.5N hydrogen chloride in ethanol (60 mL) was then added slowly. Upon completion of addition, the reaction mixture was stirred at ambient temperature for four hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride (50 mL) was added to the residue. Aqueous sodium carbonate was then added to adjust the pH to 6-7. The layers were separated, and the organic layer was dried (magnesium sulfate) and concentrated under reduced pressure to yield a mixture of a white solid and liquid. The liquid was decanted off and purified by chromatography through silica gel, eluting successively with hexane and 20:1 hexane:ethyl acetate. Appropriate fractions were combined and concentrated at reduced pressure to yield 3.1 grams of methyl 2-(2-chlorobenzylaminooxymethyl)-2-methylpropanoate as a colorless liquid.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH2:3].[H][H]>[B-](F)(F)(F)F.C1C2C=CC1C=C2.C1C2C=CC1C=C2.[Rh].PP.C1(C)C=CC=CC=1.CO.CO>[CH3:3][CH:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:1]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: [Rh]
Agent: C1=CC2C=CC1C2
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CC(C)C(=O)OC
Temperature: 25 °C

Procedure:
In a 50 ml Schlenk vessel, Rh(nbd)2BF4 (4.7 mg, 1 mol %) and the diphosphine ligand (1 mol %) were dissolved in toluene/MeOH (6 ml, 5:1) under argon. After all of the rhodium complex had gone into solution, dimethyl itaconate (200 mg, 1.26 mmol) dissolved in MeOH (4 ml) was added. The Schlenk vessel was subsequently connected via a three-way stopcock with a hydrogen balloon and an oil pump and the inert gas atmosphere was replaced by hydrogen. The reaction mixture was stirred at room temperature for the time indicated and the solvent was then distilled off on a rotary evaporator. The residue was filtered through a short silica gel column (eluent: diethyl ether). Compound (R)-7 was obtained as a colorless oil in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:21][CH:22]3[CH2:24][CH2:23]3)([CH2:16][C:17]3([CH3:20])[CH2:19][O:18]3)[O:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1.OO>O1CCCC1.COC(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([CH2:21][CH:22]3[CH2:24][CH2:23]3)([CH2:16][C:17]([OH:18])([CH3:20])[CH3:19])[O:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CCC(CC2CC2)(CC2(C)CO2)OC1=O
Agent: OO
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@@](CC2CC2)(CC(C)(C)O)OC1=O
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
LiBHEt3 solution (1 mol/L, 34 mL) was added dropwise to a solution of 3-[(S)-1-(4-bromophenyl)ethyl]-6-(cyclopropylmethyl)-6-[(2-methyloxiran-2-yl)methyl]-1,3-oxazinan-2-one (1.40 g) in tetrahydrofuran (200 mL) at 0° C. The resulting solution was stirred at 2-3° C. for 1.5 h and then at room temperature for another 3 h. 30% aqueous H2O2 solution (30 mL) was added dropwise at 0° C. and the mixture was diluted with tert-butyl methyl ether (200 mL). The mixture was washed with 3% aqueous Na2SO2O3 solution and saturated aqueous NaHCO3 solution (4×100 mL) and dried (Na2SO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 1:1→3:1) to afford the title compound; besides, the diastereomer, 3-[(S)-1-(4-bromophenyl)ethyl]-(R)-6-(cyclopropylmethyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one was also isolated (0.40 g, 29% yield). Yield: 0.55 g (40% of theory).
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:15]([N-]C(C)C)(C)C.[Li+]>>[Cl:1][C:2]1[N:12]=[C:11]([Cl:13])[C:10]([F:14])=[C:9]([CH3:15])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCOC(=O)c1c(Cl)nc(Cl)c(F)c1C

Procedure:
Ethyl 2,6-dichloro-5-fluoronicotinate (Chem. Pharm. Bull. 3.5.(6), 2280 (1987)) was treated with lithium diisopropylamide and quenched with methyl iodide to give, upon work-up, ethyl 2,6-dichloro-5-fluoro-4-methylnicotinate. This material was hydrolyzed to give the corresponding acid which was elaborated in the usual manner to give 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid. 7-chloro-1-cyclopropyl-5-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was synthesized in the same manner.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C[O:8][C:9](=O)[CH:10]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.C[O-].[Mg+2].C[O-].CO>>[CH3:33][S:30]([C:27]1[CH:26]=[CH:25][C:24]([CH:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:9]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:8])=[CH:29][CH:28]=1)(=[O:32])=[O:31]
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCCC1OC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2OC2CCCCO2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Yield: 37.7 %

Procedure:
2-Aminothiazole (314.3 mg, 3.14 mmol) and 2-(4-methanesulfonyl-phenyl)-3-[2-(tetrahydropyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (859.2 g, 2.09 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 12 mL, 8.37 mmol). The resulting reaction mixture was heated under reflux for 24 h. The reaction mixture was allowed to cool to 25° C. and then filtered through a pad of celite. The pad of celite was washed well with ethyl acetate until the washings indicated the absence of product by thin layer chromatography. The filtrate was then washed with a 10% aqueous hydrochloric acid solution (3×100 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 1/1 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-phenyl)-3-[2-(tetrahydropyran-2-yloxy)-cyclopentyl]-N-thiazol-2-yl-propionamide (377.4 mg, 38%) as a yellow oil: EI-HRMS m/e calcd for C23H30N2O5S2 (M+) 478.1596, found 478.1604.