Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10](O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.C([O-])(=O)C.CC(OC(C)=O)=O.N#N>C1(C)C=CC=CC=1.C(Cl)Cl.N1C=CC=CC=1>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:6]([CH2:12][CH2:13][C:14]4[C@@H:20]3[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=4)[C@@H:7]1[CH2:8][CH:9]=[CH:10]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@@H]3[C@H]1CC2
Yield: 28 %

Procedure:
This synthesis is depicted in FIG. 11. 19-Nor-testosterone (XIX) is commercially available, e.g., from Chemical Dynamics Corp. It provides the starting material for 19-Nor-16-androstene derivatives. 19-Nor-testosterone (XIX) was converted into the acetate (Hartman, J. A. et al., J. Am. Chem. Soc. (1956) 78:5662) with acetanhydride and pyridine. (a) A solution of this acetate (4.8 g, 15.17 mmol) in toluene (10 ml) was pyrolyzed (b) at 540° (200 Torr, slow N2 -stream) in a glass tube packed with quartz pieces. Chromatography of the crude pyrolysate (3.1 g) on silica gel (150 g) with CH2Cl2 gave 1.1 g (28%) of the homogenous oily ketone 9; +57.9° (C 1) ((27): m.p. 71°-73°).--IR. (CHCl3): 1660s, 1615m, 1585w,--1H-NMR. (90 MHz): 0.84 (s, 3H); 5.82 (m, 2H); 5.87 (br. s, 1H).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][CH2:6][C:7]([NH2:9])=[O:8].C(O)(=O)C.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:29][CH3:30])=[C:19]([C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=1>CO>[NH2:9][C:7](=[O:8])[CH2:6][NH:5]/[C:21](/[C:19]1[CH:20]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[O:29][CH3:30])=[CH:22]\[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Reactant: NCC(N)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(\NCC(N)=O)c1cc(Cl)ccc1OC
Temperature: 65 °C
Yield: 105.4 %

Procedure:
A 5-L reaction vessel was charged with methanol (3.3 L), sodium methoxide (102.4 g, 1.8 moles), and glycinamide hydrochloride (202 g, 1.8 moles). The mixture was heated at 65° C. for 1 hour before cooling to 50° C. and adding acetic acid (514.25 mmoles, 30.88 g, 29.47 mL) and ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (300 g, 1.03 mole). After heating to reflux for 16 hours, the reaction mixture was stirred as it was cooled to 10° C. After 30 min the resulting solid was collected by vacuum filtration, pulling dry to form a cake that was dried in a vacuum oven (20 mm Hg, 65° C.) for 14 hours to afford the title compound (339.4 g).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:12]([OH:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[C:3]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cccc(F)c1C(O)c1ccccc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc(F)c1C(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
205 mg (0.75 mmol) N-[3-fluoro-2-(hydroxyl-o-tolyl-methyl)-phenyl]-acetamide are dissolved in 9 ml chloroform, combined with 652 mg (7.5 mmol) manganese(IV)-oxide and stirred for 3 d at ambient temperature. Then excess manganese(IV)-oxide is filtered off through Celite and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (80:20).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].S(Cl)(Cl)=O.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: c1ccccc1
Reactant: COc1cc(C(=O)O)ccc1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc(C(=O)c2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 4-bromo-3-methoxybenzoic acid (1.00 g, 4.33 mmol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed oh the pump. Benzene (20 mL, 0.2 mol) and aluminum trichloride (0.676 g, 5.07 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[CH3:11][C:12]1[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2[C:28]([F:31])([F:30])[F:29])=[N:14][NH:15][C:16]=1[CH3:17].Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:15]1[C:16]([CH3:17])=[C:12]([CH3:11])[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2[C:28]([F:29])([F:30])[F:31])=[N:14]1)=[O:10]
Reactant: Cc1[nH]nc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)c1C
Reactant: CN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CNC(=O)n1nc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)c(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
Potassium carbonate (0.50 g, 3.6 mmol) and methyl isocyanate (0.17 g, 3.0 mmol) were added to a solution of 4,5-dimethyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole (1.08 g, 3.6 mmol) in ethyl acetate (20 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a white solid of N-methyl-4,5-dimethyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.88 g, yield: 81.9%). mp: 113-115° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.88 (s, 3H), 2.57 (s, 3H), 2.94 (d, J=5.0 Hz, 3H), 6.70-6.95 (m, 1H), 7.44 (d, J=9.2 Hz, 1H), 8.39 (dd, J=2.7 and 9.2 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:8][C:7]=1[CH3:16])=[O:5])C.[OH-].[Na+].Cl>CO>[CH3:15][S:12]([NH:11][C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:16])[N:8]=1)(=[O:13])=[O:14]
Reactant: CCOC(=O)c1sc(NS(C)(=O)=O)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(NS(C)(=O)=O)sc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of Ethyl-2-[(methylsulfonyl)amino]-4-methyl-thiazole-5-carboxylate (300 mg, 1.14 mmol) in methanol (9 mL) was treated with a 1N NaOH solution (28.4 mL, 28.4 mmol). The mixture was stirred at rt overnight. The solution was cooled to 0° C. and acidified with 6N aq. HCl solution to pH 1. The solution was extracted with dichloromethane-chloroform mixture. The organic extract was dried (MgSO4), filtered and concentrated in vacuo to obtain the title acid (148 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:17][N:18]([CH3:28])[C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([N:18]([CH3:28])[CH3:17])=[CH:20][CH:21]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: CN(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(N(C)C)cc2)cc1-c1c(Br)cnn1C
Reaction time: 48 h

Procedure:
To 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (34.9 mg, 0.124 mmol) in CH2Cl2 (3 mL) was added 4-(dimethylamino)phenyl isocyanate (21 mg, 0.129 mmol) and stirred for two days. The resulting material was purified by HPLC. The product was dried in vacuo to afford Compound 116 as a waxy solid (13.5 mg, 25%). LCMS m/z (%)=444 (M+H79Br, 100), 446 (M+H81Br, 95), 1H NMR (400 MHz, DMSO-d6) δ: 8.51 (bs, 1H), 8.26 (bs, 1H), 7.61 (s, 1H), 7.53 (dd, J=8.97, 2.71 Hz, 1H), 7.34 (d, J=2.70 Hz, 1H), 7.24 (d, J=9.03 Hz, 2H), 7.12 (d, J=9.05 Hz, 1H), 6.68 (d, J=9.07 Hz, 2H), 3.75 (s, 3H), 3.63 (s, 3H), 2.82 (s, 6H).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[C:6]([O:14][CH3:15])[C:5]=1[NH:16]C(=O)CC(=O)C>[OH-].[Na+]>[NH2:16][C:5]1[C:6]([O:14][CH3:15])=[CH:7][CH:8]=[C:9]([C:10]([F:11])([F:12])[F:13])[C:4]=1[C:3]([OH:23])=[O:2]
Reactant: COC(=O)c1c(C(F)(F)F)ccc(OC)c1NC(=O)CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(F)(F)F)c(C(=O)O)c1N
Yield: 85 %

Procedure:
A solution of methyl-2-(acetylacetamido)-3-methoxy-6-(trifluoromethyl)benzoate in 2N NaOH was heated to reflux for 4-5 h. The reaction mixture was cooled and pH was adjusted to 2. The product was extracted in ethyl acetate. The ethyl acetate extracts were combined, washed with brine and dried over sodium sulfate. Filtered, evaporated and residue was triturated with hexane. The solid was collected by filtration and dried under vacuum to provide product as light brown solid in 85% yield. ES/MS m/z 236.0 (MH+).
Reaction SMILES: C([O:8][C:9](=[O:33])[C@H:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:11][CH:12]([P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>C(O)C>[CH2:27]([O:26][P:21]([CH:12]([NH:11][C@H:10]([C:9]([OH:33])=[O:8])[CH2:29][CH:30]([CH3:31])[CH3:32])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([O:23][CH2:24][CH3:25])=[O:22])[CH3:28]
Reactant: [H][H]
Reactant: CCOP(=O)(OCC)C(CCc1ccccc1)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Solvent: CCO
Product: CCOP(=O)(OCC)C(CCc1ccccc1)N[C@@H](CC(C)C)C(=O)O
Yield: 98.7 %

Procedure:
To a solution of 445 mg of N-(1-diethoxyphosphoryl-3-phenylpropyl)-leucine benzyl ester in 10 ml of ethanol was added 100 mg of 10% Pd--C, after which the mixture was stirred vigorously under atmospheric pressure of hydrogen at room temperature for 24 hours. The Pd--C was filtered off, and the solvent was distilled off to yield the title compound as a light-yellow oil (356 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Li]CCCC.B(F)(F)F.CCOCC.[O:27]1[CH:33]2[CH:28]1[CH2:29][O:30][CH2:31][CH2:32]2.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:12][S:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH2:1][C@@H:33]2[CH2:32][CH2:31][O:30][CH2:29][C@H:28]2[OH:27])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: CSc1ccc(S(C)(=O)=O)cc1
Reactant: C1CC2OC2CO1
Agent: FB(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(S(=O)(=O)C[C@@H]2CCOC[C@H]2O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
1-Methanesulfonyl-4-methylsulfanyl-benzene (4.33 g) was dissolved in THF (50 mL) and cooled to −78° C. prior to the addition of 1.6 M nBuLi (13.4 mL). After 0.5 h, BF3-Et2O (2.7 mL) was added followed (±)3,4-epoxytetrahydropyran (1.2 g) (Tetrahedron 1974, 4013). After an addition 1 h at −78° C., the solution was warmed to 0° C. After 2 h, the solution was cooled to −78° C. and saturated NH4Cl solution (aq) was added. The solution was warmed to rt and EtOAc was added. The organic layer was washed with brine, dried, filtered, and concentrated. Flash chromatography of the resulting residue gave (±)(3S*,4R*)-4-(4-methylsulfanyl-benzenesulfonylmethyl)-tetrahydro-pyran-3-ol (1.3 g) as the major product. MS found: (M+H)+=303.0.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC1C=C(C)C=C(C)N=1>[CH2:32]([O:31][C:29]([O:12][CH2:11][C@H:9]1[O:10][C@@H:2]([O:1][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])=[O:30])[CH3:33]
Reactant: COc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(OC)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-methoxybenzyl)phenyl β-D-glucopyranoside (0.075 g) in 2,4,6-trimethylpyridine (2 mL) was added ethyl chloroformate (0.04 mL) at room temperature. After the mixture was stirred at room temperature for 16 hours, a saturated aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give amorphous 2-(4-methoxybenzyl)phenyl 6-O-ethoxycarbonyl-β-D-glucopyranoside (0.032 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:5]=[N:4][C:3]=1[C:15]([NH2:17])=[O:16].[CH3:18][C:19](OC(C)=O)=[O:20].S(=O)(=O)(O)O>C(O)C>[C:19]([NH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:5]=[N:4][C:3]=1[C:15]([NH2:17])=[O:16])(=[O:20])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1nnn(Cc2ccccc2Cl)c1N
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC(=O)Nc1c(C(N)=O)nnn1Cc1ccccc1Cl
Reaction time: 0.5 h

Procedure:
10,1 g of 5-amino-1-(o-chlorobenzyl)-1H-triazole-4-carboxamide are added, portionwise with stirring, to a mixture of 30,7 g of acetanhydride and 0,1 ml of sulphuric acid and heated to 60° . Stirring is continued for additional 30 minutes at 60° to 70° , the reaction mixture is poored into 250 ml of ethanol, heated to reflux for 30 minutes and evaporated in vacuo to dryness. The residue is triturated with 250 ml of ethyl acetate, the crystalline precipitate is collected and re-crystallised from ethyl acetate yielding 5-acetylamino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide of m.p. 181°-183°.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[N:14]=[C:13]([N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]3=[O:21])[CH:12]=[CH:11][CH:10]=2)O1.Br[C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([N:32]2[CH2:37][CH2:36][C@:35]([CH2:44][C:45]([OH:48])([CH3:47])[CH3:46])([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[O:34][C:33]2=[O:49])[CH3:31])=[CH:26][CH:25]=1>>[OH:48][C:45]([CH3:46])([CH3:47])[CH2:44][C@@:35]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:34][C:33](=[O:49])[N:32]([C@H:30]([C:27]2[CH:26]=[CH:25][C:24]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([N:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]4=[O:21])[N:14]=3)=[CH:29][CH:28]=2)[CH3:31])[CH2:37][CH2:36]1
Reactant: CC1(C)OB(c2cccc(-n3ccccc3=O)n2)OC1(C)C
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccc(-n3ccccc3=O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 1-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyridin-2(1H)-one (purchased from CombiPhos Catalysts Inc., Princeton, N.J., USA) and (S)-3-[(S)-1-(4-bromophenyl)ethyl]-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 35. LC (method 5): tR=1.53 min; Mass spectrum (ESI+): m/z=466, 524 [M+H]+; 1H NMR (CD3OD) δ 0.94 (s, 3H), 1.26 (s, 3H), 1.57 (d, 3H), 2.16 (s, 2H), 2.25 (m, 1H), 2.47 (m, 2H), 3.04 (m, 1H), 5.59 (q, 1H), 6.54 (t, 1H), 6.64 (d, 1H), 7.08 (d, 2H), 7.25-7.40 (5H), 7.63 (m, 1H), 7.66 (m, 1H), 7.85-8.00 (5H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[S:16]1(=[O:23])[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:19]4([CH2:20][CH2:21][S:16](=[O:23])[CH2:17][CH2:18]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: O=C1CCS(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: O=C1NC2(CCS(=O)CC2)Nc2cc(-c3ccncc3)sc21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 16.6 %

Procedure:
To a stirred solution of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.050 g, 0.23 mmol) in acetic acid (3 mL) were added tetrahydro-4H-thiopyran-4-one 1-oxide (0.061 g, 0.46 mmol) and p-toluenesulfonic acid (0.0040 g, 0.023 mmol). The mixture was heated at 80° C. overnight. Then, the solvent was removed and the obtained residue was taken up in methanol (20 mL). Solid NaHCO3 (1.5 g) was added, and the mixture was stirred for 10 min. The mixture was filtered, and the filtrate was chromatographed (Combiflash, silica gel, dichloromethane to 80:20 dichloromethane/methanol) to give the title compound (0.0127 g, 16%) as a yellow solid:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:26]1([NH:32][OH:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C1C=CC=CC=1.C1COCC1.C1COCC1.O.CCOC(C)=O.CN(C=O)C>[OH:33][N:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:15](=[O:17])[C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc(CCCCc2ccccc2)cc1
Reactant: ONc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(CCCCc2ccccc2)cc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 4-(4-phenylbutyl)benzoic acid (prepared as described in Example 173) (370 mg, 1.45 mmol) in 10 ml of dry benzene under argon, was added oxalyl chloride (0.14 ml, 2.0 eq.). To this solution was added DMF dropwise in 10 minute intervals, until no gas was evolved and the solution turned slightly cloudy (2 drops). The mixture was stirred for 1 hour, then reduced on the rotovap without heating. The crude product was dissolved in 5 ml of THF and added dropwise to a 0° C. solution of N-phenyl hydroxylamine (317 mg, 2.0 eq.) in 20 ml of THF:H2O (1:1) with triethylamine (0.41 ml, 2.0 eq.). The solution was stirred for 1 hour at 0° C., then allowed to warm to room temperature and stir overnight. The reaction mixture was diluted with EtOAc and the organic layer was washed with H2O, 1N HCl (2×), and brine, then dried over anhydrous MgSO4. Concentration in vacuo gave a white solid which was triturated with hexane to remove a yellow impurity and recrystallized from hot hexane/EtOAc, to give title product, 256 mg (51%).
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH2:17]O)([CH3:3])[CH3:2].S(Cl)([Cl:21])=O>C1C=CC=CC=1>[Cl:21][CH2:17][C:5]1[S:6][C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1c(CO)sc2cc(C(F)(F)F)ccc12
Solvent: c1ccccc1
Product: CC(C)c1c(CCl)sc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a solution of 3-isopropyl-6-(trifluoromethyl)-benzothiophene-2-methanol (obtained in Example 12(4), 878 mg, 3.20 mmol) in benzene (27 mL) was added dropwise a solution of thionyl chloride (0.28 mL, 3.8 mmol) in benzene (5 mL) under cooling with ice. The mixture was stirred for 3 hours at room temperature. After the solvent was removed under reduced pressure, the residue was purified by chromatography on silica gel (hexane/ethyl acetate, 10:1) to give the titled compound as a pale yellow oil (655 mg, y. 70%).
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[CH:5][C:6]([Cl:13])=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=1)[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([C:3]2[CH:4]=[CH:5][C:6]([Cl:13])=[C:7]3[C:12]=2[CH2:11][NH:10][CH2:9][CH2:8]3)[CH:20]=1)[CH3:15]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Clc1ccc(Br)c2c1CCNC2
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Cl)c3c2CNCC3)c1
Temperature: 25 °C

Procedure:
To a mixture under N2 of 8-bromo-5-chloro-1,2,3,4-tetrahydro-isoquinoline hydrochloride (566 mg, 2.00 mmol, 1 eq.), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (901 mg, 2.0 mmol, 1.00 eq) and sodium carbonate (1.06 g, 10.0 mmol, 5.00 eq.) in toluene/MeOH/water 20:4:1 (40 mL), tetrakis(triphenylphosphine) palladium (0) (116 mg, 0.1 mmol, 0.05 eq.) was added and the mixture was stirred under reflux for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (75 mL) and water (75 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×50 mL), dried over MgSO4 and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, AcOEt+MeOH 10%) to yield the title product as an orange oil.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN(C)C=O.[CH3:30][N:31]([CH2:33][CH2:34]Cl)[CH3:32]>C1C=CC=CC=1>[C:1]([O:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:34][CH2:33][N:31]([CH3:32])[CH3:30])[C:13]=2[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCl
Reactant: O=C(OC1CCc2[nH]c3ccccc3c2C1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CN(C)CCn1c2c(c3ccccc31)CC(OC(=O)c1ccccc1)CC2

Procedure:
The 3-benzoyloxy-9-[2-(dimethylamino)ethyl]-1,2,3,4-tetrahydrocarbazole was prepared by following an alkylation procedure similar to that described in Example 11 and using 13.1 g. of 3-benzoyloxy-1,2,3,4-tetrahydrocarbazole and 1.93 g. of sodium hydride (50% in mineral oil) in 150 ml. of dimethylformamide, and 4.9 g. of (dimethylamino)ethyl chloride in 10 ml. of benzene. An ethereal solution of the crude product was filtered through alumina and the concentrated ethereal eluate was treated with ethereal hydrogen chloride to give after recrystallization from isopropyl alcohol - ether 5.6 g. of 3-benzoyloxy-9-[2-(dimethylamino)ethyl]-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. 222°-225° C.