Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:19])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]3[N:16]=[C:15]([CH3:17])[O:14][N:13]=3)[C:6]=2[CH:18]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2>C(O)(=O)C>[F:19][C:3]1[C:2]([N:1]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[CH:18][C:6]2[N:7]([CH2:11][C:12]3[N:16]=[C:15]([CH3:17])[O:14][N:13]=3)[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: Cc1nc(Cn2c(=O)sc3cc(F)c(N)cc32)no1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: Cc1nc(Cn2c(=O)sc3cc(F)c(N4C(=O)C5=C(CCCC5)C4=O)cc32)no1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A mixture of 5-amino-6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (2.8 g) and acetic acid (20 ml) was admixed with 3,4,5,6-tetrahydrophthalic anhydride (1.6 g), stirred at a temperature of 20° to 30° C. for 30 minutes, and then heated under refluxing for 2 hours. The reaction mixture was distilled under a reduced pressure to remove the acetic acid therefrom, and the residue was worked up by chromatography, wherein a silica gel column was used together with an eluant comprising a tetrahydrofuran/toluene mixture (a 1:3 mixture), so that the aimed compound, i.e. 6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-5-(4,5,6,7-tetrahydro-2H-isoindole-1,3-dion-2-yl)-2(3H)-benzothiazolone (2.9 g) was obtained. m.p. 198°-199° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].OS(O)(=O)=O.[CH3:21]O>C(OCC)(=O)C>[CH3:21][O:14][C:13](=[O:15])[CH2:12][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: CO
Reactant: O=C(O)Cc1cc2cccnc2cc1F
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc2cccnc2cc1F
Yield: 98 %

Procedure:
To a solution of (7-fluoro-quinolin-6-yl)-acetic acid (13.4 g, 65.36 mmol) in methanol (140 mL) was added conc.H2SO4 (3.5 mL, 68.63 mmol). The reaction mixture was concentrated to give a brown residue, which was diluted with 100 ml of ethyl acetate, washed with sat. aq. NaHCO3 and brine, then the organic layer was dried over anhydrous Na2SO4, and concentrated to give (7-fluoro-quinolin-6-yl)-acetic acid methyl ester as yellow solid (14.0 g, yield: 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][CH:4]=1.CCN(CC)CC.Cl.[NH2:21][OH:22]>CO>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[N:21]\[OH:22])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)/C(=N/O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To the solution of 6-methoxy-2,3-dihydro-1H-inden-1-one (6.5 g, 40 mmol) in 100 mL of MeOH was added Et3N (11.1 mL, 80 mmol) and hydroxylamine hydrochloride (3.9 g, 56 mmol). The mixture was stirred at rt for 2 h. The mixture was evaporated and redissolved in EtOAc, the organic phase was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give (E)-6-methoxy-2,3-dihydro-1H-inden-1-one oxime (intermediate 16) (6.6 g, 93%).
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].CS[C:8](=[NH:10])[NH2:9].[OH:11][CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][NH:14][CH2:13]1.CS>O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[C:8]([N:14]1[CH2:13][CH:12]([OH:11])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1)(=[NH:9])[NH2:10]
Reactant: CSC(=N)N
Reactant: OC1CNCc2ccccc21
Agent: CS
Agent: O=S(=O)(O)O
Solvent: O
Product: N=C(N)N1Cc2ccccc2C(O)C1
Reaction time: 36 h

Procedure:
A solution of 1.3 g. of S-methyl-isothiourea sulfate in 5 ml. of water at about 20° C. was added to 1.2 g. of 4-hydroxy-1,2,3,4-tetrahydroisoquinoline. The resulting mixture was maintained at about 25°-30° C. with occasional shaking. After a short time, methyl-mercaptan began to escape and, upon standing for 1-2 days, crystals formed. The crystals were removed by filtration and rinsed with ice-cold water and with ether. Recrystallization from water yielded 2-amidino-4-hydroxy-1,2,3,4-tetrahydroisoquinoline sulfate, having a melting point of 264°-266° C. (uncorrected).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O-:26])=[O:25])=[C:18]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:17]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26][C:3]([CH3:4])([CH3:14])[CH3:1])=[O:25])=[C:18]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:17]=3)=[O:13])=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)COc1cc(N)ccc1OCC(=O)[O-]
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1OCC(=O)OC(C)(C)C
Yield: 169.2 %

Procedure:
In the same manner as in Example 1 (2), 5-cyano-2-benzofurancarboxylic acid (200 mg, 1.07 mmol) and t-butyl [(4-amino-o-phenylene)dioxy]diacetate (415 mg, 1.17 mmol) were condensed and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1-1/1) to give 473 mg of di-t-butyl [[4-[(5-cyano-2-benzofuranyl)carbonylamino]-o-phenylene]dioxy]diacetate as a colorless solid (84%).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:26](=[O:44])[NH:27][C@H:28]([C:33](=[O:43])[NH:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][OH:42])=[CH:37][CH:36]=3)[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>C(Cl)Cl>[OH:42][CH2:41][C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:33](=[O:43])[C@@H:28]([NH:27][C:26](=[O:44])[C@@H:18]([NH2:17])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:40][CH:39]=1
Reactant: CCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(CO)cc1
Solvent: CCNCC
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)Nc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
In a round-bottomed flask, the above prepared {(S)-1-[(S)-1-(4-hydroxymethyl-phenylcarbamoyl)-pentylcarbamoyl]-2-phenyl-ethyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (4.738 g, 7.822 mmol, Eq: 1.0) was dissolved in CH2Cl2 (28 ml). At 0°, diethylamine (28 ml, 19.80 g, 271 mmol, Eq: 35) was added and the reaction mixture stirred at ambient temperature overnight. All volatiles were evaporated i. V.; ensuing flash chromatography SiO2/CH2Cl2/10% MeOH, followed by crystallization from AcOEt, yielded 2.116 g of the title compound as light brown crystals. MS (ISP): (M+H) 384.2.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:4]=2[NH:3]1.C1C(=O)N([Br:26])C(=O)C1.O.N>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:26][C:13]1[S:14][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ccsc12
Agent: N
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)c1cc(Br)sc12
Temperature: 70 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
Methyl 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (1.0 eq, 17 mg, 0.066 mmol) was suspended in a mixture of chloroform (0.3 ml) and acetic acid (0.1 ml). NBS was added (9.5 eq, 112 mg, 0.63 mmol) and the mixture stirred at 70° C. for 16 hours. Water and aqueous ammonia was added and the material was extracted with CH2Cl2 (2×). The combined extracts were dried over Na2SO4 and the solvent removed in vacuo to provide methyl 2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (17 mg, 76%). LCMS (ES): >85% pure, m/z 338 [M]+, 340 [M+2]+; 1H NMR (CDCl3/CD3OD, 9:1, 400 MHz) δ 3.99 (s, 3H), 7.30 (m, 1H), 7.69 (d, J=8.4, 1H), 7.45 (m, 1H), 7.88 (br d, J=8, 1H), 8.05 (br s, 1H) ppm.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:17])[CH3:16].C[Si](C)(C)[O:21][C:22]1[CH2:26][CH2:25][CH2:24][CH:23]=1>>[C:15]([N:6]1[CH:7]([CH:23]2[CH2:24][CH2:25][CH2:26][C:22]2=[O:21])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: C[Si](C)(C)OC1=CCCC1
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: CC(=O)N1c2ccccc2-c2ccccc2C1C1CCCC1=O

Procedure:
2-(5-Acetyl-5,6-dihydro-phenanthridin-6-yl)-cyclopentanone was prepared from phenanthridine, acetyl chloride, and 1-(trimethylsilyloxy)cyclopentene according to GP 2. Yield, 25%. 1H-NMR (DMSO-d6): δ=1.23-1.38 (m, 2H), 1.43-1.61 (m, 1H), 1.67-1.81 (m, 1H), 1.81-2.27 (m, 6H), 6.15 (s, 1H), 7.21-7.56 (m, 6H), 7.85-7.97 (m, 2H); (+)-ESI-MS: m/z=306 [M+H]+, 222, 180.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.Br[C:43]1[CH:48]=[CH:47][C:46]([C:49]2([OH:53])[CH2:52][O:51][CH2:50]2)=[CH:45][CH:44]=1>CN(C)C=O>[OH:7][C:8]([CH3:40])([CH3:41])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:20]=[CH:21][C:22]([C:43]3[CH:48]=[CH:47][C:46]([C:49]4([OH:53])[CH2:52][O:51][CH2:50]4)=[CH:45][CH:44]=3)=[CH:23][CH:24]=2)[CH3:18])[CH2:12][CH2:11]1
Reactant: OC1(c2ccc(Br)cc2)COC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccc(C3(O)COC3)cc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2 M aqueous Na2CO3 solution (0.21 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one (100 mg) and 3-(4-bromo-phenyl)-oxetan-3-ol (53 mg) in N,N-dimethylformamide (2 mL). The resulting mixture was sparged with argon for 10 min prior to the addition of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (17 mg). The mixture was heated to 100° C. and stirred at this temperature for 4 h. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by HPLC on reversed phase (acetonitrile/water) to afford the title compound as a foam-like solid. Yield: 34 mg (32% of theory); Mass spectrum (ESI+): m/z=502 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 0.82 (s, 3H), 1.19 (s, 3H), 1.47 (d, J=6.9 Hz, 3H), 2.02 (s, 2H), 2.15 (mc, 1H), 2.38-ca. 2.50 (m, 2H) superimposed by D3CSOCHD2 signal, 3.01 (mc, 1H), 4.23 (s, 1H), 4.70 (d, J=6.3 Hz, 2H), 4.79 (d, J=6.3 Hz, 2H), 5.44 (incompletely resolved q, 1H), 6.35 (s, 1H), 6.94 (d, J=7.9 Hz, 2H), 7.26-7.43 (m, 7H), 7.59 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H).
Reaction SMILES: C(N[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)(=O)C.[C:16](#[N:18])C.S(Cl)(Cl)=O.CC(O)C>C(OCC)(=O)C>[C:16]([CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10]1)#[N:18]
Reactant: CCOC(=O)N1CCC(NC(C)=O)CC1
Reactant: CC#N
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CC(C)O
Product: CCOC(=O)N1CCC(C#N)CC1
Temperature: 0 °C

Procedure:
A mixture of 4-acetamido-N-ethoxycarbonylpiperidine (17.0 g) and acetonitrile (200 ml) was cooled to 0° C., and 15.5 g of thionyl chloride was added dropwise, under nitrogen, with stirring. The reaction mixture was allowed to warm to ambient temperature. To the reaction imixture was added 2-propanol (20 ml) and the mixture was heated under reflux for 1 hr. Ethyl acetate was added, the layers were separated, and the organic phase was washed with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on a preparatory liquid chromatograph, eluting with 4:1-heptane-ethyl acetate. The appropriate fractions were collected and evaporated to give 15 g of residue. A 4-g sample of the residue was distilled to give 3.5 g (84.6%) of product, bp 130° C. (4 mm mercury).
Reaction SMILES: C[O-].[Na+].[O:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[CH2:5]1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16]1>CN(C=O)C>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=[C:5]2[C:6](=[O:14])[NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[O:4]2)=[CH:16]1
Reactant: O=C1COc2ccccc2N1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2OC1=Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (0.65 g, 0.012 mol) was added in one portion to a mixture of 2H-1,4-benzoxazin-3(4H)-one (1.49 g, 0.01 mol) and indole-3-carboxaldehyde (2.32 g, 0.016 mol) in dry DMF (10 ml). The reaction mixture was refluxed for 24 h, then cooled at room temperature and poured into crushed ice and left overnight in the refrigerator. The precipitated solid was collected by filtration, washed with water and dried. The crude product was chromatographed on silica gel using (9:1) toluene:ethyl acetate.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH3:13][C:14]([NH2:18])([CH3:17])[CH2:15][CH3:16]>C1COCC1>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[NH:18][C:14]([CH3:17])([CH3:13])[CH2:15][CH3:16])[CH3:10]
Reactant: CCC(C)(C)N
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: C1CCOC1
Product: CCOc1c(NC(C)(C)CC)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a room temperature solution of 4.9 g (29 mmol) of 3,4-diethoxy-3-cyclobutene-1,2-dione and 50 mL of THF was added 2.5 g (34 mmol) of 1,1-dimethyl-propylamine. After stirring at room temperature overnight, the reaction mixture was evaporated to a yellow oil. Trituration with Et2O and filtration gave 6.2 g (20 mmol, a 100% yield) of the title compound as a white solid: mp: 78-80° C.; 1H NMR: (300 MHz, DMSO-d6): δ 0.91 and 1.47 (t, J=7.5 Hz, 3H, rotamers), 1.36-1.97 (m, 6H), 4.70-4.92 (m, 2H), 5.41 and 5.99 (brs, 1H, rotamers); IR (KBr, cm-1H): 3252w, 3181w, 3067w, 2968m, 2887m, 1788m, 1695s, 1603s, 1578s, 1500-1434brs, 1343s; MS (CI) m/z (relative intensity): 212 (M+ +H, 100); Anal. Calcd. for C1OH15 NO3 : C 62.54; H 8.11; N 6.63. Found: C, 62.54; H, 8.12; N, 6.52.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1N1CCCCC1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Piperidine (320 μl, 3.23 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 1,4-difluoro-2-nitrobenzene (225 mg, 1.41 mmol, commercially available product). The resulting mixture was stirred for two hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=12/1). Thus, 1-(4-fluoro-2-nitrophenyl)piperidine (298 mg, 94.2%) was yielded as an orange-colored oily material.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O.[CH2:26]=[C:27]([CH3:29])[CH3:28].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[Br:17][C:18]1[CH:19]=[C:20]([CH:21]2[CH2:26][C:27]([CH3:29])([CH3:28])[C:12]3[C:13](=[CH:14][CH:15]=[C:10]([S:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)(=[O:9])=[O:8])[CH:11]=3)[NH:16]2)[CH:23]=[CH:24][CH:25]=1
Reactant: C=C(C)C
Reactant: O=Cc1cccc(Br)c1
Reactant: Nc1ccc(S(=O)(=O)N2CCOCC2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(S(=O)(=O)N3CCOCC3)cc21
Temperature: 80 °C
Reaction time: 18 h
Yield: 47.4 %

Procedure:
To a stirred solution of 4-(morpholine-4-sulfonyl)-phenylamine (3 g, 12.4 mmol) and 3-bromo-benzaldehyde (2.52 g, 13.6 mmol) in acetonitrile (150 mL) were added isobutene (2.7 mL, 37.2 mmoll) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (1.54 g, 2.5 mmol). The resulting mixture was stirred at 80° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-40% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-4,4-dimethyl-6-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydro-quinoline (2.7 g, 47.4%) as a light yellow solid: MS (ESI) M+1=465.0 & 467.0.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:12][C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[C:16](C)=[CH:15][N:14]=1.[OH-].[Na+].[CH2:29](O)C>>[CH3:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1([CH3:29])[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[CH:18]1[CH3:19]
Reactant: CCO
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COCCCOc1c(C)cnc(CCl)c1C
Agent: [Na+]
Agent: [OH-]
Product: COCCCOC1(C)C=CN=C(CSc2nc3ccccc3[nH]2)C1C

Procedure:
A mixture comprising 2.25 g (0.015 mol) of 2-mercaptobenzimidazole, 4.52 g (0.0185 mol) of 2-chloromethyl-4-(3-methoxypropoxy)-3,5-dimethylpyridine, 0.63 g (0.015 mol) of 95% sodium hydroxide and 50 ml of ethanol was stirred at 40° C. for 6 hours. After the completion of the reaction, the reaction mixture was distilled to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to obtain 4.62 g of the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[OH:14][C@@H:15]1[C@@H:34]([N:35]2[CH2:40][CH2:39][O:38][C:37]([CH3:42])([CH3:41])[CH2:36]2)[CH2:33][C@@:32]2([CH3:43])[C@@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:31]2[C:30](=[O:44])[CH2:29][C@@:28]2([CH3:45])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:25](=[O:27])[CH3:26])[CH2:16]1>CO>[OH:14][C@@H:15]1[C@@H:34]([N:35]2[CH2:40][CH2:39][O:38][C:37]([CH3:42])([CH3:41])[CH2:36]2)[CH2:33][C@@:32]2([CH3:43])[C@@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:31]2[C:30](=[O:44])[CH2:29][C@@:28]2([CH3:45])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:25](=[O:27])[CH3:26])[CH2:16]1.[OH:4][C:3]([C:5]([O-:7])=[O:6])([CH2:8][C:9]([O-:11])=[O:10])[CH2:2][C:1]([O-:13])=[O:12]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: CO
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
A solution of citric acid (368 mg) in methanol (4 ml) was added to a solution of (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione of Example 1 (854 mg) in methanol (6 ml). The solvent was removed under reduced pressure to give (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-pregnane-11,20-dione 2-hydroxy-1,2,3-propanetricarboxylate (1:1) salt (1.22 g). [α]D +96.6° (c 1.03).
Reaction SMILES: [CH:1]1([C:6]2[C:15]3[C@@H:14]([OH:16])[CH2:13][C:12]([CH3:18])([CH3:17])[CH2:11][C:10]=3[N:9]=[C:8]([CH:19]([O:21][CH3:22])[CH3:20])[C:7]=2[C:23]2[C:24]([C:31]([F:34])([F:33])[F:32])=[CH:25][CH:26]=[C:27]([CH:29]=[O:30])[CH:28]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.[C:43]([Si:47](OS(C(F)(F)F)(=O)=O)([CH3:49])[CH3:48])([CH3:46])([CH3:45])[CH3:44]>C1(C)C=CC=CC=1>[C:43]([Si:47]([CH3:49])([CH3:48])[O:16][C@H:14]1[CH2:13][C:12]([CH3:17])([CH3:18])[CH2:11][C:10]2[N:9]=[C:8]([CH:19]([O:21][CH3:22])[CH3:20])[C:7]([C:23]3[C:24]([C:31]([F:34])([F:32])[F:33])=[CH:25][CH:26]=[C:27]([CH:29]=[O:30])[CH:28]=3)=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:15]1=2)([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(C)c1nc2c(c(C3CCCC3)c1-c1cc(C=O)ccc1C(F)(F)F)[C@@H](O)CC(C)(C)C2
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: COC(C)c1nc2c(c(C3CCCC3)c1-c1cc(C=O)ccc1C(F)(F)F)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: -18 °C
Reaction time: 0.33 h

Procedure:
840 mg 5-(S)-[4-Cyclopentyl-5-hydroxy-2-(1-methoxy-ethyl)-7,7-dimethyl-5,6,7,8-tetrahydro-quinolin-3-yl]-(4-trifluoromethyl-phenyl)-methanone (Diastereomer 1) are dissolved in 20 ml toluene, 823 μl 2,6-lutidine are added and the solution is cooled to −18° C. 811 μl Trifluoromethanesulfonic acid-tert.-butyldimethylsilylester are added dropwise and the mixture is stirred for further 20 minutes at −18° C. Then it is warmed to 0° C. and stirred for 1 hour whereafter the mixture is partitioned between saturated aqueous ammonium chloride solution and ethylacetate. The aqueous phase is twice extracted with ethylacetate and the combined organic phases are washed with brine. After drying with magnesium sulphate the solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 95:5 to 80:20).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[C:26]([BH3-])#N.[Na+].C(O)=O.C=O.C(=O)(O)[O-].[Na+]>O.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:26])[CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: COc1ccc([N+](=O)[O-])cc1NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: O=CO
Product: COc1ccc([N+](=O)[O-])cc1N(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 27.5 °C
Reaction time: 0.08 h
Yield: 112.6 %

Procedure:
Placed 2-Methoxy-5-nitro-N-(1-Boc piperidin-4-yl)phenylamine (5 grams, 14.24 mmol) obtained at step (I) into a round bottom flask containing methanol (10 mL) and stirred at 25-30° C. for 5 minutes. Added sodium cyanoborohydride (1.06 grams, 17.09 mmol) and formic acid (1.96 grams, 42.7 mmol) and stirred the reaction mass for 10 minutes. White solid mass separated out. Then the reaction mass was cooled to 0-5° C. in an ice bath and added formaldehyde (2.84 mL, 28.4 mmol, 30-50%). A clear solution was obtained. The mass was further stirred for 6 hours at 20-25° C. After completion of reaction (thin layer chromatography), solvent was distilled off to obtain oily mass. Added water (100 mL) and basified to pH: 8 using saturated solution of sodium bicarbonate solution. Extracted the product with ethyl acetate (3×100 mL) and layers separated. The combined organic layer was washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain 5.86 grams of dark yellow colored oil.