Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][CH:4]([CH3:16])[CH2:5][C:6](=O)[CH2:7][C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[Na]>C(O)(=O)C>[CH3:3][CH:4]([CH3:16])[CH2:5][C:6]1[NH:2][N:1]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1
Reactant: CCOC(=O)C(=O)CC(=O)CC(C)C
Reactant: NN
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC(C)C)[nH]n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous hydrazine (3.58 g, 112 mmol) was added dropwise over a period of 30 minutes to a solution of ethyl 6-methyl-2,4-dioxoheptanoate, sodium salt (24.8 g, 112 mmol) in acetic acid (160 mL). The reaction was stirred overnight at ambient temperature, and then the solvent was removed under reduced pressure. The residue was dissolved in a mixture of diethyl ether and water, and solid sodium bicarbonate and sodium carbonate were added to adjust the mixture to pH 8. The aqueous layer was extracted twice with diethyl ether; the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on a HORIZON HPFC system (FLASH 65I cartridge, eluting with 50:50 ethyl acetate/hexanes) to provide 21.0 g of ethyl 5-(2-methylpropyl)-1H-pyrazole-3-carboxylate as a solid.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH:11]2[CH2:16][CH2:15][CH:14]([CH:17]3[CH2:22][CH2:21][C:20](=[O:23])[CH:19]=[CH:18]3)[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[Cl-].[NH4+]>C1COCC1>[CH2:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH:11]2[CH2:16][CH2:15][CH:14]([CH:17]3[CH2:22][CH2:21][C:20]([CH2:3][CH2:2][CH2:1][CH2:5][CH3:6])([OH:23])[CH:19]=[CH:18]3)[CH2:13][CH2:12]2)[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC[C@H](C2CCC(C3C=CC(=O)CC3)CC2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC1(O)C=CC(C2CCC([C@H]3CC[C@H](CCCC)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 3.0 g of 4-(4-(trans-4-butylcyclohexyl)cyclohexyl)-2-cyclohexenone (r-3) was dissolved into 50 mL of THF, 11.4 mL of pentylmagnesium bromide THF solution (1 M/L) was added dropwise thereto, and the resultant mixture was stirred at 50° C. for 30 minutes, and then stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added dropwise under ice-cooling, the resultant mixture was subjected to extraction with ethyl acetate, and then organic layers were combined, the resultant organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. A solvent was evaporated under reduced pressure, and the resultant residue was purified by fractionation on silica gel column chromatography (eluate:heptane:ethyl acetate=7:3 (in a volume ratio)), and thus 2.68 g of 4-(4-(trans-4-butylcyclohexyl)cyclohexyl)-1-pentyl-2-cyclohexene-1-ol (compound (r-4)) was obtained.
Reaction SMILES: C[O-].[Na+].[NH:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[C:9]1([S:15]([C:18]2[C:19]([S:29][CH3:30])=[N:20][N:21]3[C:26](Cl)=[CH:25][C:24]([CH3:28])=[N:23][C:22]=23)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[C:9]1([S:15]([C:18]2[C:19]([S:29][CH3:30])=[N:20][N:21]3[C:26]([N:4]4[CH:8]=[CH:7][N:6]=[CH:5]4)=[CH:25][C:24]([CH3:28])=[N:23][C:22]=23)(=[O:17])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nn2c(-n3ccnc3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.9 %

Procedure:
0.08 g (1.5 mmol) of sodium methanolate was added to a suspension of 0.122 g (1.8 mmol) of imidazole in 30 ml of DMF and stirred at 60° for 15 min. Subsequently, a solution of 0.53 g (1.5 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]-pyrimidine in 10 ml of DMF was added to this suspension and stirred at 60° for 1 hr. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 15:1) and crystallization from EtOH yielded 0.30 g (51%) of 3-benzenesulphonyl-7-imidazol-1-yl-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as colorless crystal, m.p. >230°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13].Cl>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OCc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)c(Cc2ccc(OCc3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.9 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(4-pyridylmethyloxy)benzoate (0.600 g, 1.28 mmol) was dissolved in a mixed solution of an aqueous 1N NaOH solution (3 ml) and 1,4-dioxane (3 ml) and the resulting solution was stirred at room temperature for 6 hours. The reaction solution was diluted with water, rendered acidic with concentrated hydrochloric acid and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.500 g, 1.10 mmol, 86%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[CH2:25])([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:22]=[C:23](/[CH:24]=[CH:25]/[C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:26]=[CH:27][CH:28]=1)([O-:20])=[O:19]
Reactant: C=Cc1cccc([N+](=O)[O-])c1
Reactant: Fc1ccc(-c2n[nH]c3ccc(Br)cc23)cc1
Product: O=[N+]([O-])c1cccc(/C=C/c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)c1
Yield: 37.3 %

Procedure:
The title compound (0.134 g, 52% yield) was prepared as described in Example 132 D, using 5-bromo-3-(4-fluorophenyl)-1H-indazole (0.291 g, 1.0 mmol) and 3-nitrostyrene (0.298 g, 2.0 mmol). 1H NMR (CDCl3) δ 10.12 (br s, 1H), 8.41 (t, 1H), 8.11 (ddd, 1H), 8.07 (s, 1H), 7.97 (m, 2H), 7.82 (d, 1H), 7.73 (dd, 1H), 7.54 (m, 2H), 7.40 (d, 1H), 7.26 (m, 2H), 7.16 (d, 1H); ES-MS (m/z) 360 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[NH:18])[C:5]1[CH:6]=[C:7]([CH:13]=[C:14](OC)[N:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].Cl[C:20]1[CH:21]=C(C=C(CC)N=1)C(OCC)=O>>[CH2:1]([O:3][C:4](=[NH:18])[C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([CH2:20][CH3:21])[N:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)nc(CC)c1
Reactant: CCOC(=N)c1cc(C(=O)OCC)cc(OC)n1
Product: CCOC(=N)c1cc(C(=O)OCC)cc(CC)n1

Procedure:
The title compound was prepared by a method analogous to Intermediate 17 but using ethyl 2-chloro-6-ethylisonicotinate as the starting material. GCMS analysis of the reaction mixture showed the presence of the desired product. MS (EI+) (M+) 250; GCMS retention time 3.611 minutes (Method O).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].II>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:6][C@H:5]2[C@@H:7]3[O:8][C:9]([CH3:11])([CH3:7])[O:10][C@:9]3([CH2:11][OH:12])[O:4][C@H:3]2[CH2:2][O:1]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: II
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H]2O[C@@]3(CO)OC(C)(C)O[C@H]3[C@@H]2O1
Temperature: 60 °C
Reaction time: 6 h
Yield: 154.3 %

Procedure:
To 200 ml of acetone were added 10.0 g of L-sorbose and 127 mg of iodine and the mixture was refluxed with stirring in a water bath at 60° C. for 6 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. The reaction mixture was then subjected to an after-treatment similar to that described in Example 11 to give 11.15 g (77.2%) of 2,3:4,6-di-O-isopropylidene-L-sorbofuranose (purity ≥98.5%).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[CH3:28][S:29]([O:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:12]2[N:13]=[C:9](/[CH:8]=[CH:7]/[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][CH:11]=2)=[CH:21][CH:20]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: CS(=O)(=O)OCCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Yield: 96 %

Procedure:
In substantially the same manner as in Reference Example 12, 5-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]pentanol was allowed to react with methanesulfonyl chloride to give 5-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]pentyl methanesulfonate. The yield was 96%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 105-106° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:14]N1C(=O)CCC1=O>CC#N>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][C:11]=2[Cl:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)N1CCc2cc(Br)ccc21
Solvent: CC#N
Product: CC(=O)N1CCc2cc(Br)cc(Cl)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
1-Acetyl-5-bromoindoline (2.47 g, 10.29 mmol) was heated at reflux with N-chlorosuccinimide (1.56 g, 10.40 mmol) in CH3CN for 30 min and an additional amount NCS (1 g, 7.47 mmol) was added while hot and the reaction was stirred at 25° C. for 16 h. The solvent was stripped in vacuo and the residue was chromatographed on silica gel using 20% EtOAc/hexanes as eluent to give 1-acetyl-5-bromo-7-chloroindoline (1.17 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[O:17][CH2:18][C@@:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27](Br)[CH:28]=3)[O:23][C:22]([CH3:32])([CH3:31])[C:21]32[CH2:34][CH2:33]3)[N:20]=1)C(OC(C)(C)C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-:57][Si](C)(C)C)(C)C.[Li+]>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]>[C:1]([O:5][C:6](=[O:7])[NH:8][C:16]1[O:17][CH2:18][C@@:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27]([NH2:57])[CH:28]=3)[O:23][C:22]([CH3:32])([CH3:31])[C:21]32[CH2:34][CH2:33]3)[N:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(CO1)c1cc(Br)ccc1OC(C)(C)C21CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(N)ccc1OC(C)(C)C21CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a mixture of di-tert-butyl[(4′R)-6′-bromo-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]imidodicarbonate (1.98 g, 3.68 mmol), bis(dibenzylideneacetone)palladium(0) (212 mg, 0.369 mmol), and tri-tert-butylphosphonium tetrafluoroborate (108 mg, 0.371 mmol) was added lithium bis(trimethylsilyl)amide (1M solution in toluene, 18 ml, 18 mmol) at room temperature under argon atmosphere. The mixture was stirred at 60° C. for 2 hours and then quenched with saturated aqueous ammonium chloride. The mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100:0-50:50-0:100) to afford tert-butyl[(4′R)-6′-amino-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (1.37 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:26])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:25])([C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:15])[CH2:6][CH2:5]2.C(Cl)Cl.[O:30]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(C#N)(C)=O.O>[OH:30][C:7]([CH3:25])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:26])[C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCc1ccccn1)O2
Agent: CC(=O)C#N
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCc2ccccn2)=C(C)C1=O
Yield: 83.9 %

Procedure:
6-Hydroxy-2,5,7,8-tetramethyl-N-(2-(pyridin-2-yl)ethyl)chroman-2-carboxamide (97.7 mg, 0.276 mmol) was dissolved in 3 mL AcCN and 2 mL CH2Cl2 and cooled to 0° C. prior to treatment with 332.5 mg CAN (0.606 mmol) in 2 mL H2O. The reaction was quenched by the addition of 5 mL EtOAc and 4 mL 1.0 M NaHCO3 followed by extraction of the aqueous layer 3×5 mL EtOAc. The combined organics were back extracted 3×3 mL saturated NaCl, dried over Na2SO4 and concentrated. Flash chromatography yielded 85.8 mg of 2-hydroxy-2-methyl-N-(2-(pyridin-2-yl)ethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:4]1[O:8][C:7]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cccc(-c2ccc(C(C)=O)o2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1ccc(-c2cccc(C(=O)O)c2)o1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A solution of methyl 3-(5-acetylfuran-2-yl)benzoate (1.50 g, 6.1 mmol) in ethanol (15 mL), and sodium hydroxide (6N, 3 mL) was heated at 70° C. for 30 minutes. The reaction mixture was cooled to rt and pH was adjusted (pH=4) with HCl (6N). The resulting precipitate was collected by filtration to give the desired 3-(5-acetylfuran-2-yl)benzoic acid (1.10 g, 4.78 mmol, 77% yield) as a yellow/green solid. LCMS (ES): m/z 231 [M+1]+.
Reaction SMILES: CCN(CC)CC.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:16][CH:17]1[C:26](=O)[CH2:25][CH2:24][C:19]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:18]1.CC(OC)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:16][CH:17]1[C:26](=[N:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:25][CH2:24][C:19]2([O:20][CH2:21][CH2:22][O:23]2)[CH2:18]1
Reactant: CC1CC2(CCC1=O)OCCO2
Reactant: NCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CC2(CCC1=NCc1ccccc1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of NEt3 (560 mL, 4.02 mol) and benzylamine (131 mL, 1.20 mol) in CH2Cl2 (500 mL) was added TiCl4 (500 mL of 1.0 M solution in CH2Cl2, 0.500 mol) over 30 min while the internal temperature was kept below −10° C. The resulting dark red suspension was stirred at −20° C. to −30° C. for 15 min, then a solution of 7-methyl-1,4-dioxaspiro[4.5]decan-8-one (170 g, 1.00 mmol) in CH2Cl2 (500 mL) was added at −10° C. The resulting grey-yellow suspension was allowed to warm to room temperature over 2 h, then stirred at room temperature for 16 h. MTBE (1.0 L) was added to the reaction mixture, and the yellow suspension was stirred at room temperature for 30 min and filtered through a pad of Solka Floc. The cake was washed with MTBE (4×500 mL), and the combined filtrates were concentrated to provide N-(7-methyl-1,4-dioxaspiro[4.5]dec-8-ylidene)-1-phenylmethanamine, which was used directly in the next step.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16](=[O:19])[CH2:17][OH:18])[C@H:11]([CH3:20])[CH2:10]2)=[CH:6][CH:5]=1.Cl[C:24]1[C:29]([CH:30]=[O:31])=[CH:28][C:27]([Cl:32])=[CH:26][N:25]=1>C1(C)C=CC=CC=1>[Cl:32][C:27]1[CH:28]=[C:29]([CH:30]=[O:31])[C:24]([O:18][CH2:17][C:16]([N:12]2[CH2:13][C@H:14]([CH3:15])[N:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:22][CH:21]=3)[CH2:10][C@H:11]2[CH3:20])=[O:19])=[N:25][CH:26]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CO
Reactant: O=Cc1cc(Cl)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a 0° C. suspension of sodium hydride (60% dispersion in mineral oil, 0.031 g, 0.78 mmol) in toluene (3 mL) was added 1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-hydroxy-ethanone (0.20 g, 0.71 mmol) in toluene (2 mL). The reaction mixture was stirred at 0° C. for 30 minutes, and then treated with 2,5-dichloro-pyridine-3-carbaldehyde (0.14 g, 0.78 mmol). The resulting mixture was refluxed for 4 hours, cooled to ambient temperature and washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography provided the title compound (0.20 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:16]2[N:12]([C:13](=[O:17])[NH:14][CH2:15]2)[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1.[H-].[Na+].I[CH3:27]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C@H:16]2[N:12]([C:13](=[O:17])[N:14]([CH3:27])[CH2:15]2)[C@H:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1
Reactant: O=C1NCC2C(c3cc(F)ccc3F)=CC(c3ccccc3)N12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C[C@H]2C(c3cc(F)ccc3F)=C[C@@H](c3ccccc3)N2C1=O

Procedure:
A solution of 2-4a (0.02 g, 0.06 mmol), sodium hydride (5 mg), and iodomethane (0.004 mL, 0.03 mmol) in THF (1.0 mL) was stirred at rt for 1 h. The reaction was quenched with water (2.0 mL) and extracted with EtOAc (20 mL). The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated. The remaining oil was dissolved in CH3CN (0.5 mL) and purified on a Gilson automated system affixed with a YMC J'sphere H80 20×50 mm column (eluting with 5-95% CH3CN +0.1% TFA in water +0.1% TFA over 10 min) to afford pure 2A-1a.
Reaction SMILES: C(OC([O:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:10]=[CH:11][C:12]1[S:13][C:14]2[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[N:21]=1)=O)C.N>CO>[OH:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:10]=[CH:11][C:12]1[S:13][C:14]2[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[N:21]=1
Reactant: CCOC(=O)Oc1cc(C=Cc2nc3c(s2)NCCCC3)ccc1OC
Agent: N
Solvent: CO
Product: COc1ccc(C=Cc2nc3c(s2)NCCCC3)cc1O
Reaction time: 3 h
Yield: 82 %

Procedure:
2-(3-Ethoxycarbonyloxy-4-methoxystyryl)-5,6,7,8-tetrahydro-4H-thiazolo[5,4-b]azepine (13.2 g) was added to a solution of 1N ammonia in methanol (600 ml), and and the whole was stirred for 3 hrs. at room temperature. The solvent was distilled off under reduced pressure and the residue was purified by a column chromatography on silica gel to give 2-(3-hydroxy-4-methoxystyryl)-5,6,7, 8-tetrahydro-4H-thiazolo [5,4-b]azepine (yield 8.74 g, 81.9%). The product (1.50 g) was converted into its hydrochloride which was recrystallized from a mixture of methanol and ethyl ether to give the title compound (0.49 g, 29.0%). m.p. 210°-211°.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[N:40]1[C:49]2[C:44](=[CH:45][C:46]([C:50](Cl)=[O:51])=[CH:47][CH:48]=2)[N:43]=[CH:42][CH:41]=1>>[N:40]1[C:49]2[C:44](=[CH:45][C:46]([C:50]([O:1][CH:2]3[CH2:20][CH:19]4[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]5[C:16]([C:22]([NH:24][S:25]([CH:28]6[CH2:30][CH2:29]6)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]4=[O:21])[CH2:15]5)[CH2:3]3)=[O:51])=[CH:47][CH:48]=2)[N:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)c1ccc2nccnc2c1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc4nccnc4c3)CN2C1=O
Yield: 37.6 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.176 mmol) and 6-quinoxalinecarbonyl chloride (68 mg, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 48 mg (38%) of 18-(6-quinoxalinecarbonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.5% pure (HPLC), MS m/z 723 (M−H)−, HRMS: calcd. 725.2969 and found 725.2947 (M+H)+, mp 158-160° C.
Reaction SMILES: [CH:1]([CH:4]1[NH:8][C:7](=[O:9])[C:6]([CH3:11])([CH3:10])[C:5]1=[O:12])([CH3:3])[CH3:2].Br[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([Cl:22])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)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]>[Cl:22][C:16]1[CH:15]=[C:14]([N:8]2[CH:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:12])[C:6]([CH3:10])([CH3:11])[C:7]2=[O:9])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: CC(C)C1NC(=O)C(C)(C)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)C1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using 5-isopropyl-3,3-dimethylpyrrolidine-2,4-dione (400 mg), 4-bromo-2-chlorobenzonitrile (614 mg), cesium carbonate (1.16 g), tris(dibenzylideneacetone)dipalladium(0) (216 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (410 mg), and in the same manner as in Reference Example 3, the title compound was obtained as colorless crystals (yield: 343 mg, 48%).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C@@H:10]([NH:15]N2CCC[C@@H]2COCC)[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:8][N:7]=[C:6]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH3:4].B.C1COCC1.Cl>C1COCC1>[CH2:1]([N:5]1[C:9]([C@H:10]([NH2:15])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:8][N:7]=[C:6]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H](NN1CCC[C@@H]1COCC)c1cnc(-c2ccccc2)n1CCCC
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCC[C@@H](N)c1cnc(-c2ccccc2)n1CCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 193 (1.43 g, 3.6 mmol) under argon in anhydrous THF (25 mL) at room temperature is slowly added borane-THF complex (1 M in THF, 54 ml, 54 mmol). The mixture is then refluxed under argon for 16 h. After cooling to room temperature, 10% HCl (20 mL) is added very slowly and the mixture is stirred for 2 h at room temperature. The organic solvent is removed under reduced pressure and the residue is extracted with ether. The aqueous phase is saturated with solid potassium carbonate and extracted with sthyl acetate. The residue obtained after removal of the solvent is purified by column chromatography to afford the desired product as a colorless oil. Yield: 0.6 g; LC-MS (MH+): 286.