Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:20])[NH2:19])=[CH:14][CH:13]=3)[C:6]=2[O:5][CH2:4][CH2:3]1.C([O-])=O.[NH4+]>[Pd].CO>[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([NH2:19])=[O:20])[CH2:14][CH2:13]3)[C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: NC(=O)c1cc[n+](-c2cccc3c2OCCO3)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Cl-]
Solvent: CO
Product: NC(=O)C1CCN(c2cccc3c2OCCO3)CC1
Yield: 70.9 %

Procedure:
1-(1,4-Benzodioxan-5-yl)-4-carbamoylpyridinium chloride (2.0 g) was added to 10% palladium-on-carbon catalyst (1.8 g) under nitrogen. Ammonium formate (3.5 g) was added and the resulting mixture was stirred while methanol (35 ml) was added dropwise. The resulting mixture was heated under reflux for 3.5 hours. Ammonium formate which crystallised in the condenser was washed back in with methanol (35 ml). The mixture was cooled and filtered (Celite) under nitrogen. The filtrate was basified by the addition of solid sodium hydrogen carbonate and the solvent removed in vacuo. The residue was diluted with water (100 ml) and the product extracted into dichloromethane (3×100 ml). The combined extracts were washed with water (100 ml), dried over magnesium sulphate, filtered and the solvent removed in vacuo to give 1-(1,4-benzodioxan-5-yl) piperidine-4-carboxamide as a white solid (1.27 g), m.p. ~194° C.
Reaction SMILES: [CH2:1]([O:4][CH:5]([O:15][CH2:16][CH2:17][CH3:18])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH2:2][CH3:3].[CH:19]1([N:22]=[C:23]=[O:24])[CH2:21][CH2:20]1.[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH:19]1([NH:22][C:23](=[O:24])[O:14][C:11]2[CH:10]=[CH:9][C:8]([S:7][CH2:6][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[O:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:12]=2)[CH2:21][CH2:20]1
Reactant: O=C=NC1CC1
Reactant: CCCOC(CSc1ccc(O)cc1)OCCC
Agent: [N-]=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCOC(CSc1ccc(OC(=O)NC2CC2)cc1)OCCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(2,2-Dipropoxyethylthio)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. Cyclopropylisocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[4-(2,2-dipropoxyethylthio)phenyl] N-cyclopropylcarbamate as the residue.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[C:13](=[O:17])[NH:14][C:15](=[O:16])[CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(=O)[C@@H]2CNC[C@@H]2C(=O)N1.[H-].[H-].[H-].[H-].[Al+3].[Li+].[OH-].[Na+]>O1CCCC1.O>[CH2:1]([N:8]1[CH2:12][CH:11]2[CH:13]([OH:17])[NH:14][C:15](=[O:16])[CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C2CN(Cc3ccccc3)CC12
Agent: O=C1NC(=O)[C@@H]2CNC[C@H]12
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(O)C2CN(Cc3ccccc3)CC12
Temperature: 3 °C
Reaction time: 0.42 h
Yield: 55 %

Procedure:
A solution of 5-benzyltetrahydropyrrolo[3,4-c]pyrrole-1,3-dione, (12.7 g; 55 mmol) {preparation described for the preparation of cis-perhydropyrrolo[3,4-c]pyrrole-1,3-dione (b)} is added to a suspension of lithium aluminum tetrahydride (2 g; 55 mmol) in tetrahydrofuran, cooled to 3° C. in an ice bath, in a 500 ml three-necked flask. The reaction mixture is agitated at this temperature for 25 minutes and then water (2 ml), 4 N aqueous sodium hydroxide (2 ml) and water (6 ml) are successively added. The solid thus formed is removed by filtration; the filtrate is dried over magnesium sulfate and then evaporated under reduced pressure, resulting in a white solid which is triturated in diisopropyl ether (50 ml). The solid formed is filtered off, washed with diisopropyl ether (25 ml), and then dried under reduced pressure at constant weight. 5-Benzyl-3-hydroxyhexahydropyrrolo[3,4-c]pyrrol-1-one (7 g; 55%) is isolated, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-benzyloxyestra-1,3,5(10)-trien-17-one BLE99049 (3.46 g, 9.59 mmol) in THF (15 ml) and MeOH (38 ml) was added sodium borohydride (0.36 g, 9.58 mmol) at 0° C. The reaction mixture was stirred for 30 min at room temperature, then quenched with 10 ml of saturated aqueous NH4Cl and 50 ml of H2O added. The precipitate was collected by filtration and washed with H2O to afford 3.50 g of 3-benzyloxyestra-1,3,5(10)-trien-17β-ol BLE99051 (100% crude yield) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH2:17][CH2:18][Cl:19])(=O)=O)=CC=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([Cl:29])[CH:23]=1>CN(C=O)C>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:17][CH2:18][Cl:19])=[C:24]([Cl:29])[CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCOc1ccc(Br)cc1Cl
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (8.29 g, 60 mmol, 3.0 eq.) and 2-chloroethyl p-toluenesulfonate (5.16 g, 22 mmol, 1.1 eq.) were added in sequence to a solution of 4-bromo-2-chlorophenol (4.19 g, 20 mmol, 1.0 eq.) in DMF (25 mL). The resulting mixture was heated up to 60° C. and stirred at that temperature for 4 hours. The mixture was allowed to cool down to r.t. and was partitioned between AcOEt (290 mL) and water (120 mL). The layers were separated. The org. phase was washed with water (4×120 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 4-bromo-2-chloro-1-(2-chloro-ethoxy)-benzene as a colorless oil that solidified upon standing. The product was used without further purification.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10]([O:12]C)[C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH:22]=3)=[C:16]([CH3:33])[N:15]=2)=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].Br>C(O)(=O)C>[C:1]([NH:5][C:6]1[NH:11][C:10](=[O:12])[C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH:22]=3)=[C:16]([CH3:33])[N:15]=2)=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nc(NC(C)(C)C)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc(-c2cnc(NC(C)(C)C)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
A solution of N-(tert-butyl)-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (0.069 g, 0.155 mmol) in acetic acid (1.5 mL) was treated with HBr (48% aq., 0.071 mL, 0.623 mmol) and heated at 90° C. for 4 h. The mixture was removed from heat, treated with ice and EtOAc, neutralized with satd. NaHCO3, extracted with 1:1 EtOAc/THF (3×) and the combined organics were washed with brine, dried over MgSO4 and concentrated to dryness. The resulting material was treated with MeCN, heated to near-reflux and allowed to stand at RT overnight. The solid was removed via filtration and the filtrate was concentrated to dryness and purified twice via silica gel chromatography (MeOH/DCM, then MeOH/EtOAc) to afford 2-(tert-butylamino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (11 mg, 15%). 1H NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1H), 8.67 (s, 1H), 8.37 (d, J=5.6 Hz, 1H), 8.27-8.22 (m, 2H), 7.97 (s, 1H), 7.52 (d, J=8.9 Hz, 1H), 7.23 (d, J=2.6 Hz, 1H), 6.60 (dd, J=6.1, 2.6 Hz, 1H), 6.52 (s, 1H), 3.84 (s, 3H), 2.34 (s, 3H), 1.41 (s, 9H); MS (ESI) m/z: 432.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:29]1[CH2:33]OC[CH2:30]1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:10][C:11]2([C:15]([O:17][CH3:18])=[O:16])[CH2:30][CH2:29][CH2:33][CH:12]2[C:13]1=[O:14]
Reactant: COC(=O)C1CC(=O)N(c2c(C)cccc2C)C1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COC(=O)C12CCCC1C(=O)N(c1c(C)cccc1C)C2
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To methyl 1-(2,6-dimethylphenyl)-5-oxopyrrolidine-3-carboxylate (1.5 g, 6.1 mmol) dissolved in 5 mL anhydrous THF and cooled to −40° C., lithium bis(trimethylsily)amide (1.0 M in THF, 6.1 mL, 6.1 mmol) was added with a syringe. After stirring for 10 min, the bath was replaced with a 0° C. bath and stirring continued for another 10 min. The reaction mixture was then cooled to −40° C. and another 6.1 mL of lithium bis(trimethylsily)amide solution (6.1 mmol) was added. After stirring for 10 min at −40° C., the reaction mixture was allowed to gradually warm to room temperature, quenched with saturated ammonium chloride solution (15 ml) and the crude product was extracted with ether. The combined organic layer was dried over anhydrous Na2SO4, the solvent was evaporated and the residue purified by flash chromatography (SiO2, 10-100% EtOAc/hexanes) to yield 920 mg of methyl 2-(2,6-dimethylphenyl)-1-oxooctahydrocyclopenta[c]pyrrole-3a-carboxylate (32% yield). LC-MS Rt (retention time): 2.12 min, MS: (ES) m/z 288 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=O)[N:3]1[C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:16]([NH:18][CH:19]1[CH2:21][CH2:20]1)=[O:17].[BH4-].[Na+].Cl>CO.C(Cl)Cl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]1[C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:16]([NH:18][CH:19]1[CH2:21][CH2:20]1)=[O:17]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N1C(=O)Cc2ccccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 51.8 %

Procedure:
To a solution of 3-(1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-cyclopropyl-4-methylbenzamide (385 mg) in methanol (8 ml) and methylene chloride (19 ml) under an atmosphere of argon was added NaBH4 (48 mg) portionwise and the reaction stirred at room temperature for 17 hours. Concentrated hydrochloric acid (0.1 ml) was added and the reaction stirred for a further 30 minutes. The reaction mixture was concentrated and the residue resuspended in ethyl acetate, washed 1N NaOH, water, brine, dried (magnesium sulfate) and concentrated to give a white solid which was purified by column chromatography with a gradient of iso-hexane to 80% ethylacetate/iso-hexane to give 3-(1-Oxoisoquinolin-2(1H)-yl)-N-cyclopropyl-4-methylbenzamide as a white solid (190 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.10 (s, 3H), 2.85 (m, 1H), 6.75 (d, 1H), 7.34 (d, 1H), 7.49 (d, 1H), 7.58 (m, 1H), 7.75-7.82 (m, 3H), 7.88 (d, 1H), 8.26 (d, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 319.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=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>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:2]2[S:6][C:5]3=[N:7][CH:8]=[CH:9][N:4]3[N:3]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: Brc1nn2ccnc2s1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3ccnc3s2)cc1OC
Temperature: 110 °C
Yield: 12.2 %

Procedure:
A solution of 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole (0.5 g, 2.5 mmol, 1 eq), 3,4-dimethoxyphenylboronic acid (0.683 g, 3.7 mmol, 1.5 eq), dioxane (12.5 mL) and Na2CO3 (2M aq. solution, 3.8 mL) was degassed for 20 minutes at room temperature. Pd(Ph3P)2Cl2 was added and the reaction heated at 110° C. for 2 h in an argon atmosphere. The reaction mixture was diluted with EtOAc and washed with water. The combined organic layers were dried (Na2SO4), filtered and concentrated, and the residue was purified by column chromatography (SiO2, cyclohexane/20-100% ethylacetate). The product was further purified by triturating with Et2O, filtered off and dried affording the desired product (0.080 g). 1H NMR (300 MHz, DMSO) δ/ppm 8.18 (d, J=1.4, 1H), 7.47 (m, 2H), 7.33 (d, J=1.4, 1H), 7.15 (d, J=8.3, 1H), 3.86 (s, 3H), 3.75 (s, 3H). The filtrate was concentrated, redissolved in DCM and purified by flash-chromatography (SiO2, DCM/1% MeOH) to afford the desired product (0.65 g, containing some Ph3PO) that was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C1(C)C=CC=CC=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCCCN1CCCC1
Temperature: 145 °C
Reaction time: 20 h
Yield: 285.5 %

Procedure:
2-fluoro-4-nitrophenol (36.73 g, 0.234 mol) was added to a dried chlorobenzene (5v/w, 250 mL). The mixture was heated to 145° C. Intermediate VII (12.5 g, 0.039 mol) was added to the reaction solution. The reaction was conducted at this temperature for 20 h. After completion of the reaction, the solvent was evaporated off to produce a grey solid. This solid was dissolved in CH2Cl2, and washed with a satureated saturated K2CO3 solution several times. The organic layer was collected. The solvent was dried off to produce a solid, which is recrystallized with ethanol to produce a yellow solid (49.16 g) in a yield of 71.4%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[CH3:11][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[CH:4][C:3]=1[CH3:10]
Reactant: C[Mg]Br
Reactant: Cc1cc(C=O)ccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(C)O)ccc1Br
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of 4-bromo-3-methylbenzaldehyde (4 g, 20 mmol) in tetrahydrofuran (40 mL) was cooled to 0° C. then methylmagnesium bromide (20 mL, 1N in tetrahydrofuran) was dropped and the mixture was stirred at 0° C. to room temperature for 2 hours. Ammonium chloride aqueous (40 mL) was added and the mixture was extracted with dichloromethane (3*20 mL), dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1) to give 1-(4-bromo-3-methylphenyl)ethanol as a colorless oil (4.0 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[C:8]([NH:11][C:12]1[CH:21]=[CH:20][C:15]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][CH:13]=1)(=[O:10])[CH3:9].Cl>N1C=CC=CC=1>[CH3:7][C:4]1[S:3][C:2]([NH:1][S:16]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[N:6][N:5]=1
Reactant: Cc1nnc(N)s1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
2-Amino-5-methyl-1,3,4-thiadiazole (250 mg, 2.19 mmol) was suspended in pyridine (0.5 mL). N-Acetylsulfanilyl chloride (410 mg, 1.75 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred for 1 h. The reaction mixture was then added to aqueous 3N HCl and the mixture extracted with ethyl acetate. The organic extracts were washed with water (3×20 mL), brine (3×20 mL), dried over anhydrous Na2SO4, filtered, and volatiles evaporated. The residue was crystallized from MeOH to give the product (491 mg, 1.6 mmol, 97%) as a solid, mp 239-240° C.; 1H NMR (500 MHz, DMSO) δ 2.07 (3, s), 2.44 (3, s), 7.74 (4, s), 10.82 (1, s), 13.85 (1, s); 13C NMR (125 MHz, DMSO) δ 16.1, 24.1, 118.6, 126.9, 135.7, 142.8, 154.3, 167.7, 168.9; MS (ESI+, m/z) Calculated for C11H13N4O3S2 313.0. found 313.0 (M+H)+; HRMS (FAB+, m/z) Calculated for C11H13N4O3S2 313.0429. found 313.0428 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([CH:29]2[CH2:32][C:31]([F:34])([F:33])[CH2:30]2)(O)[CH2:23][Si](C)(C)C)[N:16]=3)=[C:9]([F:35])[CH:8]=1.[H-].[K+]>C1COCC1>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([CH:29]2[CH2:32][C:31]([F:34])([F:33])[CH2:30]2)=[CH2:23])[N:16]=3)=[C:9]([F:35])[CH:8]=1
Reactant: C[Si](C)(C)CC(O)(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CC(F)(F)C1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CC(F)(F)C1
Temperature: 65 °C

Procedure:
1-(2-(4-(1,3-Dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridin-5-yl)-1-(3,3-difluorocyclobutyl)-2-(trimethylsilyl)ethanol (600.0 mg, 1.148 mmol) in THF (16.0 mL) was carefully added dropwise to potassium hydride (35 wt % in mineral oil; 395 mg, 3.44 mmol) at 0° C. The resulting brown solution was heated at 65° C. for 3 h. Excess potassium hydride was then quenched by the sequential addition of water (4 mL) and sat. aq. NH4Cl (4 mL). THF was removed in vacuo, and the resulting mixture was then diluted with EtOAc (150 mL) and sequentially washed with sat. aq. NH4Cl and brine. The combined aqueous layers were extracted with EtOAc), and all organic layers were then combined, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-70% EtOAc/hexanes) furnished 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(3,3-difluorocyclobutyl)vinyl)-thiazolo[5,4-b]pyridine as a light yellow solid. MS (ESI) m/z: Calculated: 432.1; Observed: 433.0 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].[C:12](Cl)(=[O:18])[CH2:13][CH2:14][C:15](Cl)=[O:16]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([O:11][C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)=[O:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(Cl)CCC(=O)Cl
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(OC(=O)CCC(=O)Oc2ccc(C(=O)OC)cc2)cc1

Procedure:
A similar procedure to Example 1 is carried out by using 15.2 g of methyl p-hydroxybenzoate and 7.8 g of succinic dichloride to yield di(p-methyloxycarbonylphenyl)succinate, m.p. 189.5°-190° C., as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH2:4][OH:5].Br[C:12]([CH3:17])([CH3:16])[C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:5][CH2:4][C:3]1[CH:6]=[C:7]([I:10])[CH:8]=[CH:9][C:2]=1[O:1][C:12]([CH3:17])([CH3:16])[C:13](=[O:15])[CH3:14]
Reactant: OCc1cc(I)ccc1O
Reactant: CC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)C(C)(C)Oc1ccc(I)cc1CO
Yield: 104.5 %

Procedure:
A mixture containing 2-hydroxy-5-iodobenzyl alcohol (0.63 g, 0.00252 mol), 3-bromo-3-methyl-2-butanone (0.42 g, 0.00254 mol) and potassium carbonate (0.42 g, 0.00377 mol) in methyl ethyl ketone (7 ml) was heated at reflux for three hours. Then a further equivalent of 3-bromo-3-methyl-2-butanone (0.42 g, 0.00254 mol) was added. After heating at reflux for three hours, the cooled mixture was washed successively with water and aqueous sodium hydroxide solution, then extracted with ethyl acetate. The organic layer was evaporated to afford 0.88 g (100%) of crude 3-(2-hydroxymethyl-4-iodophenoxy)-3-methyl-2-butanone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]1[CH2:35][NH:34][CH2:33][CH2:32][NH:31]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:34]4[CH2:33][CH2:32][NH:31][CH:30]([C:26]5[S:25][CH:29]=[CH:28][CH:27]=5)[CH2:35]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: c1csc(C2CNCCN2)c1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(c5cccs5)C4)c(F)cc3cc2c1=O
Yield: 69.4 %

Procedure:
(RS)-3-Ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-[3-(2-thienyl)-1-piperazinyl]1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine (1.68 g) and (RS)-2-(2-thienyl)piperazine (1.01 g). (RS)-3-Ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-[3-(2-thienyl)-1-piperazinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine (1.68 g) is thereby obtained in the form of a yellow solid, m.p. 220° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[CH2:8][O:7][C:6]=2[N:5]=[C:4]([CH2:13][CH3:14])[N:3]=1.[H-].[Na+].[CH3:17]I>CN(C)C=O.O>[Cl:1][C:2]1[C:11]2[N:10]([CH3:17])[C:9](=[O:12])[CH2:8][O:7][C:6]=2[N:5]=[C:4]([CH2:13][CH3:14])[N:3]=1
Reactant: CI
Reactant: CCc1nc(Cl)c2c(n1)OCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(Cl)c2c(n1)OCC(=O)N2C

Procedure:
To a stirred suspension of 5g (0.023 mole) of 4-chloro-6,7-dihydro-2-ethyl-5H-pyrimido[4,5-b][1,4]oxazin-6-one (prepared using the method of Melik-Ogandzhanyan, et al., Khimiya Geterotsiklicheskikh Soedinenii, 1985, 974) in 100 ml of N,N-dimethylformamide was added 0.75g (0.025 mole) of 80% sodium hydride in oil. After ten minutes 3.5g (0.025 mole) of methyl iodide was added. After two hours the solution was diluted with about 400ml of water, and extracted thrice with 250ml portions of chloroform. The extracts were washed with water, dried over magnesium sulfate, treated with decolorizing charcoal, and evaporated in vacuo. The resulting oil was triturated with a mixture of diethyl ether and hexanes to provide light green solid 4-chloro-6,7-dihydro-2-ethyl-5-methylpyrimido[4,5-b][1,4]oxazin-6-one.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][CH2:12][N:7]2[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N[C@@H]1C(=[O:39])N2[C@H](C(OC(C)(C)C)=O)CCCN2CCC1>>[O:39]=[C:6]1[CH2:5][CH2:4][C@H:3]([NH:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:2](=[O:1])[N:8]2[C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][CH2:12][N:7]12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2CCC[C@H](NC(=O)CCc3ccccc3)C(=O)N12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2CCC[C@H](N)C(=O)N12
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)CCc3ccccc3)C(=O)N12

Procedure:
(1S,9S) t-Butyl octahydro-10-oxo-9-(3-phenylpropionylamino)-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate (44b), was prepared from (1S,9S) t-butyl 9-amino-octahydro-10-oxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (Attwood et al., J. Chem. Soc. Perkin 1, pp. 1011-19 (1986)) as for 44a, to afford 810 mg (81%) of a colorless oil: [α]D23 −33.5° (c 0.545, CH2Cl2); IR (film) 3334, 2935, 1737, 1728, 1659, 1642; 1H NMR (CDCl3) δ 7.24 (5H, m), 6.75 (1H, d, J=6.7), 5.27 (1H, m), 4.92 (1H, m), 3.39 (1H, m), 3.03 (4H, m), 2.55 (3H, m), 2.33 (1H, m), 2.17 (1H, m), 1.80 (5H, m), 1.47 (9H, s), 1.39 (1H, m). MS (FAB, m/z): 416 (M++1), 360, 211, 143, 97.