Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[S:9][CH2:10][C:11](=[O:14])[CH2:12][Cl:13].[CH3:15][N:16]1[CH:20]([CH3:21])[CH:19]([CH3:22])[N:18]([CH3:23])[C:17]1=[S:24]>C(O)C>[Cl-:13].[Cl-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[S:9][CH2:10][C:11](=[O:14])[CH2:12][S:24][CH:17]1[N:18]([CH3:23])[C:19]([CH3:22])=[C:20]([CH3:21])[NH+:16]1[CH3:15]
Reactant: CN1C=C[NH+](C)C1SCC(=O)CCl
Reactant: CC1C(C)N(C)C(=S)N1C
Agent: [Cl-]
Solvent: CCO
Product: CC1=C(C)[NH+](C)C(SCC(=O)CSC2N(C)C=C[NH+]2C)N1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 0.255 g (0.001 mole) of 1,3-dimethyl-2-[(3-chloro-2-oxopropyl)thio]-1H-imidazolium chloride was added a solution of 0.156 g (0.001 mol) of 1,3,4,5-tetramethylimidazoline-2-thione in 5 mL of ethanol and the reaction mixture was stirred for 3 hours at ambient temperature. At the end of this period, the solvent was evaporated and the residue was crystallized from isopropyl alcohol-acetonehexane to obtain the desired 2-{(3-[(1,3-dimethyl-1H-imidazolium-2-yl)thio]-2-oxopropyl)thio}- 1,3,4,5-tetramethyl-1H-imidazolium dichloride compound as a hygroscopic solid.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH:13]=2)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[BH4-].[Na+].C(O)(=O)C(O)=O>COCCOCCOC>[C:1]([N:6]1[CH2:7][CH2:8][N:9]([CH:12]2[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH2:13]2)[CH2:10][CH2:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)N1CCN(C2=Cc3cc(C)ccc3Sc3ccc(Cl)cc32)CC1
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCOC(=O)N1CCN(C2Cc3cc(C)ccc3Sc3ccc(Cl)cc32)CC1

Procedure:
41.5 G. of 1-carbethoxy-4-(8-chloro-2-methyl-dibenzo[b,f]thiepin-10-yl)piperazine are reacted together with 1 l. of absolute diglyme (diethyleneglycoldimethylether) with 26.5 g. of sodium borohydride and stirred at 25° for 30 minutes. The reaction mixture is then mixed dropwise at 20°-30° over a 45-minute period with a solution of 138.6 g. of oxalic acid in 800 ml. of diglyme. The reaction mixture is maintained at 100° for 15 hours. The resulting mixture is evaporated under reduced pressure. The residue is suspended in 1 l. of 2N aqueous sodium hydroxide and extracted with benzene. The benzene extract is washed with water, dried and evaporated, whereby there is obtained 1-carbethoxy-4-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)piperazine as a red-brown oil, whose nmr and ir spectra are consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N+:9]([O-:32])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1cncnc1-2
Solvent: ClCCl
Product: [O-][N+]1=C(c2ccccc2Cl)c2cc(Cl)ccc2-c2ncncc2C1

Procedure:
A solution of 6.8 g (20 mmole) of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine, 6 g (30 mmole) of 85% m-chloroperbenzoic acid in 200 ml of methylene chloride was stirred at room temperature for 4 hrs. The mixture was washed with an excess of ice cold dilute sodium hydroxide, dried over ahydrous sodium sulfate and filtered over hyflo. The filtrate was concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of methylene chloride and ether to give a crude product, mp 228°-229° C. Recrystallization from a mixture of methylene chloride and ether gave the product, mp 216°-217° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C([O-])([O-])=O.[K+].[K+].[Cl:16][C:17]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:18]=1[CH2:19][O:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([OH:33])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[S:27][C:23]=2[CH:22]=1.CN(C=O)C>O>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:33][C:25]1[C:24]2[CH:34]=[CH:35][C:21]([O:20][CH2:19][C:18]3[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:17]=3[Cl:16])=[CH:22][C:23]=2[S:27][C:26]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of t-butyl bromoacetate (0.736 mL), K2CO3 (0.626 g), ethyl 6-((2,4-dichlorobenzyl)oxy)-3-hydroxy-1-benzothiophene-2-carboxylate (1.8 g) and DMF (20 mL) was stirred at room temperature for 20 h. Water was added to the mixture and the mixture was extracted with EtOAc. The EtOAc extract was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.330 g). The obtained crystals were recrystallized from acetone-hexane.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:5]=1[C:6]1[C:7]([O:18][CH3:19])=[CH:8][CH:9]=[C:10]([CH3:17])[C:11]=1[NH:12]2)(=[O:3])[NH2:2].[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:22]([N:12]1[C:11]2[C:10]([CH3:17])=[CH:9][CH:8]=[C:7]([O:18][CH3:19])[C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[CH:16][C:4]=2[C:1](=[O:3])[NH2:2])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C)c2[nH]c3cccc(C(N)=O)c3c12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(C)c2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.148 g of 5-carbamoyl-4-methoxy-1-methylcarbazole in 1.1 ml of dimethylformamide was added to 0.026 g of sodium hydride (60% in mineral oil) in 0.4 ml of dimethylformamide and stirred for 60 minutes at room temperature. Benzyl bromide (0.076 ml) was then added and the reaction was stirred overnight. The reaction mixture was poured into 20 ml of saturated ammonium chloride solution and then extracted twice with ethyl acetate. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was rinsed with hexane and dissolved in dichloromethane, filtered and concentrated to afford 0.21 g of the subtitle compound. FDMS m/e 344 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:18])=O)=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl.N>C1COCC1.CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[CH3:18])=[N:9][N:8]=2)[CH:7]=1
Reactant: C[C@H]1CCCCN1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1CCCCN1c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of Intermediate 81b (657 mg, 2.60 mmol), Ph3P (1.37 g, 5.21 mmol) and Et3N (1.45 mL, 10.4 mmol) in THF (20 mL) at 0° C. was added hexachloroethane (1.23 g, 5.21 mmol) and the resulting yellow suspension was stirred at RT for 2 h, and at reflux for 19 h. The cooled solution was filtered and concentrated in vacuo. The brown oil was redissolved in MeOH (3 mL) and applied to an SCX-2 cartridge (20 g), washing with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo gave a brown oil. FCC, using 1-5% [2M NH3 in MeOH] in DCM, gave the title compound as a brown oil (542 mg, 89%). LCMS (Method 3): Rt 3.00 min, m/z 235 [MH+].
Reaction SMILES: [CH:1]([CH:4]1[C:8](=O)[O:7][C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:5]1)([CH3:3])[CH3:2].[CH3:20][CH2:21][O:22][C:23]([C:25]([CH3:45])=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:24]>C1(C)C=CC=CC=1>[CH2:21]([O:22][C:23](=[O:24])[CH:25]([C:8]1[O:7][C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:5][C:4]=1[CH:1]([CH3:3])[CH3:2])[CH3:45])[CH3:20]
Reactant: CC(C)C1N=C(c2ccc(C(F)(F)F)cc2)OC1=O
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C

Procedure:
4-Isopropyl-2-(4-trifluoromethyl-phenyl)-4H-oxazol-5-one (1.0 g, 3.69 mmol) and (carbethoxyethylidine)triphenyl-phosphorane (2.67 g, 7.37 mmol) are stirred in toluene (20 mL) at reflux 3 hr. The mixture is concentrated in vacuo and the residue is purified over silica eluting with 9:1 hexanes:ethyl acetate affording 2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propionic acid ethyl ester as a pale orange oil, 1.11 g, 85%. MS (M++1) 356.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH2:10]O)=[C:8]([CH2:12][O:13][CH3:14])[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:5]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:27])=O>ClCCl>[Cl:27][CH2:10][C:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=2)=[N:7][C:8]=1[CH2:12][O:13][CH3:14]
Reactant: O=S(Cl)Cl
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1CO
Solvent: ClCCl
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A solution of 1.29 g (3.8 mmol) [4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol in 12 ml dichloromethane was treated with 0.29 ml (3.99 mmol) thionylchloride. After 2 h stirring at RT, the mixture was partitioned between ether and water. The ether-phase was concentrated under reduced pressure giving 1.35 g pure crystalline 5-chloromethyl-4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=O)=[CH:23][CH:22]=1)([O-:20])=[O:19]>ClCCl>[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([CH2:25][N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: c1cc2c(s1)CCCCN2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCCCc3sccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 10.71 g of 5,6,7,8-tetra-hydro-4H-thieno[3,2-b]azepine and 19.4 ml of triethylamine in 150 ml of dichloromethane under argon is added in small portions 4-nitrobenzoyl chloride (exothermic). The mixture is stirred for 3 hours at 25° C. and then washed with water, sodium bicarbonate solution, brine and dried (Na2SO4). The solvent is removed, the residue dried under vacuum and recrystallized by dissolving in hot ethyl acetate and diluting with hexane. Chilling overnight and filtering gives 16 g of light brown crystals, m.p. 141°-142° C.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].N1CC[C@@H]1C(O)=O.[C:15]([C@@H:18]([C@H:20]([C:22]([O-:24])=[O:23])[OH:21])[OH:19])([O-:17])=[O:16]>>[NH:1]1[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:15]([C@H:18]([C@@H:20]([C:22]([O-:24])=[O:23])[OH:21])[OH:19])([O-:17])=[O:16]
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: O=C(O)[C@@H]1CCN1
Agent: O=C(O)[C@H]1CCN1
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Temperature: 95 °C
Reaction time: 3 h

Procedure:
50 g of a mother liquor containing enantiomerically-enriched AzeOH containing 16 g (68% e.e.) of D-AzeOH (prepared in accordance with Example 1) was concentrated under vacuum to give a viscous oil, which was further dewatered by azeotropic distillation with isopropanol. Acetic acid (72 mL) was added to the concentrated residue. The mixture was heated to 95° C. and D-tartaric acid (25 g) and caproic aldehyde (2.8 g) were added. The mixture was seeded with L-AzeOH-D-tartrate, kept at 95-100° C. for 3 hours and then gradually cooled to 0° C. The crystalline product was filtered, washed and dried at 60° C. under vacuum to yield 29.3 g of L-AzeOH-D-tartrate with a d.e. of 94.6%. Recrystallisation of 28 g of the diastereomeric salt from ethanol:water (140 mL; 1.25:1.0) yielded 21.4 g of L-AzeOH-D-tartrate with a d.e. of 100%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[CH:13]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].CCN(CC)CC>C1COCC1>[CH2:19]([O:21][C:22](=[O:25])[CH2:23][NH:1][CH2:2][C:3]1([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[CH:13]3)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1)[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: NCC1(Nc2ccc3[nH]ncc3c2)CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNCC1(Nc2ccc3[nH]ncc3c2)CCCCC1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To a stirred solution of (1-aminomethyl-cyclohexyl)-(1H-indazol-5-yl)-amine (0.775 g, 3.18 mmol) in THF (7 mL) at 0° C. under nitrogen was added ethylbromoacetate (0.530 g, 0.351 mL, 3.18 mmol) and Et3N (1.42 mL, 10.2 mmol) then the reaction mixture warmed to room temperature. After 90 minutes the mixture was concentrated in vacuo then redissolved in DCM (100 mL) and washed with saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered and concentrated in vacuo to an oil (1.4 g). Purification by chromatography (silica, 0 to 10% of a 9:1 MeOH:NH4OH solution in DCM) gave {[1-(1H-indazol-5-ylamino)-cyclohexylmethyl]-amino}-acetic acid ethyl ester (0.877 g, 2.66 mmol, 84%) as a solid.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C@@H:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])=[CH:8][CH:7]=1.Br[C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][CH2:25][C:26]2=[O:29])=[C:22]([F:30])[CH:21]=1>O1CCOCC1>[CH:2]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([O:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:20]4[CH:28]=[C:27]5[C:23](=[C:22]([F:30])[CH:21]=4)[CH2:24][CH2:25][C:26]5=[O:29])[C:14]3=[O:18])=[CH:8][CH:7]=2)[CH2:3][CH2:1]1
Reactant: O=C1NCC[C@H]1Oc1ccc(OCC2CC2)nc1
Reactant: O=C1CCc2c(F)cc(Br)cc21
Solvent: C1COCCO1
Product: O=C1CCc2c(F)cc(N3CC[C@@H](Oc4ccc(OCC5CC5)nc4)C3=O)cc21
Temperature: 80 °C

Procedure:
A mixture of (R)-3-[6-(2-cyclopropyl-methoxy)-pyridin-3-yloxy]-pyrrolidin-2-one (100 mg), 6-bromo-4-fluoro-2,3-dihydro-1H-inden-1-one (92 mg) and 1,4-dioxane (2 mL) was purged with argon. N,N′-Dimethyl-ethylene-diamine (355 mg), cesium carbonate (263 mg) and copper(I) iodide (8 mg) were added. The mixture was heated to 80° C. for 4 hours. After cooling to r.t. the mixture was filtered and the filtrate purified by preparative HPLC to provide Example 1-11. 1H-NMR (400 MHz, DMSO) δ 7.99 (1H, dd, J=11.2, 1.8 Hz), 7.95 (1H, d, J=3.1 Hz), 7.77 (1H, d, J=1.8 Hz), 7.53 (1H, dd, J=9.0, 3.1 Hz), 6.79 (1H, d, J=9.0 Hz), 5.22 (1H, dd, J=8.3, 8.3 Hz), 4.03 (2H, d, J=7.1 Hz), 3.96 (1H, m), 3.86 (1H, m), 3.10 (2H, m), 2.72 (2H, m), 2.68 (1H, m), 2.13 (1H, m), 1.22 (1H, m), 0.54 (2H, m), 0.30 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15](OC)=[O:16])[S:5][C:6]=1[Cl:7].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][CH2:15][OH:16])[S:5][C:6]=1[Cl:7]
Reactant: COC(=O)CCc1cnoc1-c1cc(Cl)c(Cl)s1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1cc(Cl)c(Cl)s1
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of methyl 3-[5-(4,5-dichloro-2-thienyl)-4-isoxazolyl]propionate (1.30 g) in tetrahydrofuran (40 ml) was gently added diisobutylaluminum hydride (0.95 M hexane solution, 11.2 ml) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(4,5-dichloro-2-thienyl)-4-isoxazolyl]propan-1-ol (1.05 g, yield 89%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl3) δ: 1.35–1.5 (1H, m), 1.8–2.0 (2H, m), 2.65–2.8 (2H, m), 3.65–4.0 (2H, m), 7.29 (1H, s), 8.19 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C1N2CCN(CC2)C1.C(Cl)([Cl:20])=O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:7]([Cl:20])=[O:9])=[CH:5][N:6]=1
Reactant: Cc1ncc(C(=O)O)s1
Reactant: O=C(Cl)Cl
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1C
Product: Cc1ncc(C(=O)Cl)s1
Reaction time: 2 h

Procedure:
In a similar apparatus to Example 1, 10.0 g (0.07 mole) of 2-methylthiazole-5-carboxylic acid were suspended in 100 ml of xylene, followed by the addition of 0.03 g of triethylenediamine. Under heating and reflux, phosgene was blown at a rate of 930 ml/hr for 6 hours (0.25 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 10.5 g of 2-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 96.0% and 92.8%, respectively.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([O:35][C:36]([O:38][CH3:39])=[O:37])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=O)C.C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[CH3:24][C:20]1([CH3:23])[CH2:19][O:18][CH:17]([CH:15]([C@@H:14]2[C@:25]3([CH3:34])[C@H:11]([C@H:10]4[C@H:28]([CH2:27][CH2:26]3)[C@:29]3([CH3:33])[C:7]([CH2:6][C@@H:5]([OH:4])[C@@H:31]5[O:32][C@@H:30]53)=[CH:8][C@H:9]4[O:35][C:36]([O:38][CH3:39])=[O:37])[CH2:12][CH2:13]2)[CH3:16])[O:22][CH2:21]1
Reactant: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Agent: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Product: COC(=O)O[C@@H]1C=C2C[C@@H](O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Yield: 57.5 %

Procedure:
The procedure of Example 23 was repeated except that 5.5 mg (0.01 mmole) of 20-(5,5-dimethyl-1,3-dioxan- 2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate was used in lieu of 5 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate to give 2.9 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-ol (yield: 58%).
Reaction SMILES: [C:1]([C:4]1[C:9]2[O:10][C:11]3([C:14](=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:13][CH2:12]3)(=[O:3])C.Cl[O-].[Na+].S([O-])(O)=[O:20].[Na+].Cl>O>[C:1]([C:4]1[C:9]2[O:10][C:11]3([C:14](=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:13][CH2:12]3)([OH:3])=[O:20]
Reactant: CC(=O)c1cccc2c1OC1(CC1)C2=O
Reactant: O=S([O-])O
Agent: *CCO*
Agent: CCCCCCCCOc1ccccc1
Agent: Cl
Solvent: O
Product: O=C(O)c1cccc2c1OC1(CC1)C2=O

Procedure:
A mixture of 7-acetylspiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (86 mg), 2.4 ml of aqueous solution of sodium hypochlorite and a small amount of surface active agent (polyoxyethylene octyl phenyl ether) was stirred at 60° C. for 2 hours. After cooling, the reaction mixture was diluted with water, and to the mixture was added 40% aqueous solution of sodium hydrogen sulfite. The reaction mixture was made acidic with hydrochloric acid, and resulting crystals were extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give colorless needles of 7-carboxyspiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one. m.p. 259°-262° C. (decomp). Sublime at 183° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].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>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:9]=2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COC(=O)c1ncc2cc(Br)ccc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ncc2cc(-c3ccccc3)ccc2c1O
Temperature: 120 °C
Yield: 75.6 %

Procedure:
A mixture of 7-bromo-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (400 mg, 1.42 mmol), tributylphenyltin (0.6 mL, 1.70 mmol), and PdCl2(PPh3)2 (200 mg, 0.28 mmol) in DMF (14 mL) was heated at 120° C. for 2 h under N2 atmosphere. After cooling the mixture to r.t., brine (10 mL) and EtOAc (30 mL) were added. 1 M HCl was added with stirring until pH was ˜3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent, the crude product was purified by column chromatography (0-40% EtOAc/hexanes) to give 300 mg of the title compound. 1H NMR (CDCl3, 200 MHz): δ ppm=11.7 (s, 1H), 8.87 (s, 1H), 8.46 (d, 1H, J=8.6 Hz), 8.15 (d, 1H, J=1.4 Hz), 8.04 (dd, 1H, J=8.6 Hz, 2.0 Hz), 7.65-7.80 (m, 2H), 7.40-7.60 (m, 3H), 4.12 (s, 3H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]([CH:14]([CH2:17][CH:18]=[CH2:19])[CH2:15][OH:16])([CH3:13])[CH3:12].C(N(CC)CC)C.Cl>ClCCl>[CH:11]([CH:14]([CH2:17][CH:18]=[CH2:19])[CH:15]=[O:16])([CH3:13])[CH3:12]
Reactant: C=CCC(CO)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C=CCC(C=O)C(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Dimethyl sulfoxide (18.70 mL, 263.3 mmol) was added dropwise over 15 minutes to a dichloromethane (290 mL) solution of oxalic acid chloride (17.30 g, 136.3 mmol) cooled to −78° C., and the mixture was then stirred at −78° C. for 15 minutes. Subsequently, a dichloromethane (75 mL) solution of 2-isopropylpent-4-en-1-ol (11.30 g, 88.1 mmol) was added dropwise thereto over 30 minutes, and the mixture was stirred at −78° C. for 1 hour. Triethylamine (62.40 g, 616.7 mmol) was added dropwise thereto over 5 minutes, and the mixture was then stirred at room temperature for 2 hours. The mixture was neutralized with 2 N hydrochloric acid (320 mL). The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain a yellow oil substance as a mixture containing the compound of interest. This compound was used in the next reaction without being further purified.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:4][C:3]1=[O:20].[CH3:21][N:22]([CH3:30])[C:23]1[CH:24]=[C:25](O)[CH:26]=[CH:27][CH:28]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C1COCC1>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([N:22]([CH3:30])[CH3:21])[CH:28]=2)=[O:18])=[CH:4][C:3]1=[O:20]
Reactant: O=C(O)CCCCOC1=CC(=O)C(=O)c2ccccc21
Reactant: CN(C)c1cccc(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CN(C)c1cccc(OC(=O)CCCCOC2=CC(=O)C(=O)c3ccccc32)c1
Reaction time: 2 h
Yield: 35.6 %

Procedure:
A mixture of acid 3 (137 mg, 0.5 mmol), 3-dimethylaminophenol (82 mg, 0.6 mmol), DCC (103 mg, 0.5 mmol), and DMAP (12 mg, 0.01 mmol) in THF (2 mL) was stirred for 2 h. The reaction mixture was concentrated in vacuo, the residue dissolved in benzene, washed with H2O and dried (Na2SO4). Column chromatography (10% EtOAc) in benzene gave 13 as a yellow solid (70 mg, 36%), 1H NMR (CDCl3) 8.13, (d, J=7.3 Hz, 1H), 7.90 (d, J=7.4 Hz, 1H), 7.69 (t, J=6.1 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.22 (dd, J=8.1, 8.1 Hz, 1H), 6.30-6.70 (m, 2H), 5.96 (s, 1H), 4.21 (t, J=5.6 Hz, 2H), 2.69 (t, J=6.5 Hz, 2H), 1.90-2.15 (m, 4H).