Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:26][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:25]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2nc3ccccc3nc2-c2ccc(F)cc2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
For example, in synthetic route `A2` of FIG. 2, 4,4'-difluorobenzil, 1,2-phenylenediamine and chloroform are charged together in a reaction vessel and stirred. A catalytic amount of trifluoroacetic acid is added slowly and the reaction mixture heated to about 50° C. with continued stirring. After about 16 h, the mixture is cooled to provide 2,3-bis(4-fluorophenyl)quinoxaline after removal of the chloroform. Recrystallization results 2,3-bis(4-fluorophenyl)quinoxaline having a melting point of 127-1290° C.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.P(Br)(Br)[Br:11].Br.S(=O)(=O)(O)O>C(OCC)C>[Br:11][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: OCCC1CCCCC1
Reactant: BrP(Br)Br
Agent: Br
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: BrCCC1CCCCC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 115.6 %

Procedure:
To a solution of 10 g of (2-hydroxyethyl)cyclohexane in 50 ml of dry diethyl ether was added dropwise a solution of 9.85 g of phosphorous tribromide in 20 ml of dry diethyl ether at -40° C., and the mixture was stirred at -40° to -10° C. for 30 minutes and at 2° to 4° C. for 2.5 hours. The reaction mixture was then poured into ice-water and extracted with diethyl ether. The extract was washed with water, an aqueous solution of sodium bicarbonate and water, dried over magnesium sulphate and concentrated under reduced pressure. To the residue thus obtained were added 50 ml of 47% w/v hydrobromic acid at -30° C. 20 ml of sulphuric acid were then added dropwise at the same temperature. The reaction mixture was refluxed at 100° to 110° C. for 3 hours and extracted with diethyl ether. The extract was washed with water, an aqueous solution of sodium bicarbonate and water, dried over magnesium sulphate and concentrated under reduced prssure. The residue was purified by distillation under reduced pressure to give 8.04 g of the title compound having the following physical characteristics:
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:39]2[C@H:40]([CH3:63])[C@H:41]3[C@@H:58]([C@H:59]([OH:61])[CH3:60])[C:57](=[O:62])[N:42]3[C:43]=2[C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=2)=[O:45])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[C:15]([C:13]1[N:14]=[C:10]([N:7]2[CH2:8][CH2:9][C@@H:5]([S:4][C:39]3[C@H:40]([CH3:63])[C@@H:41]4[C@@H:58]([C@H:59]([OH:61])[CH3:60])[C:57](=[O:62])[N:42]4[C:43]=3[C:44]([O:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([N+:54]([O-:56])=[O:55])=[CH:52][CH:53]=3)=[O:45])[CH2:6]2)[S:11][CH:12]=1)(=[O:17])[NH2:16]
Reactant: CC(=O)S[C@@H]1CCN(c2nc(C(N)=O)cs2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@@H]3CCN(c4nc(C(N)=O)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of (3R)-3-acetylthio-1-(4-carbamoyl-1,3-thiazol-2-yl)pyrrolidine (500 mg, 1.84 mmol) (obtained as described in Reference Example 20) in dimethylformamide (25 ml) was added hydrazine acetate (204 mg, 2.21 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.09 g, 1.84 mmol) in acetonitrile (55 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (1.28 ml, 7.36 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride—9% methanol and methylene chloride as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[(3R)-1-(4-carbamoyl-1,3-thiazol-2-yl)pyrrolidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate as a pale yellow solid (917 mg, yield 87%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH2:22][C:23](O)=[O:24]>>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:23](=[O:24])[CH2:22][C:21]([CH3:20])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[N:11]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O
Product: CC(C)(CC(=O)Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O)c1ccccc1

Procedure:
The product from Example 29B and 3-methyl-3-phenylbutanoic acid were processed using a method similar to that described in Example 10C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.46 (s, 1H), 8.63 (dd, J=5.0, 0.7 Hz, 1H), 8.40-8.43 (m, 1H), 7.93-8.04 (m, 2H), 7.77-7.79 (m, 1H), 7.74 (dd, J=1.4, 0.7 Hz, 1H), 7.66 (dd, J=5.0, 1.5 Hz, 1H), 7.43-7.46 (m, 2H), 7.29-7.33 (m, 2H), 7.16-7.21 (m, 1H), 2.63 (s, 2H), 1.47 (s, 6H); MS (APCI+) M/Z 433 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:7]([NH:9][NH2:10])=O)[CH3:2].[CH3:17][N:18]=[C:19]=[S:20].C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[N:18]([CH3:17])[C:19]([SH:20])=[N:10][N:9]=2)[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH3:2]
Reactant: CN=C=S
Reactant: CCOc1cc(C(=O)NN)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1cc(-c2nnc(S)n2C)ccc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 22 h
Yield: 72.3 %

Procedure:
3-Ethoxy-4-nitrobenzohydrazide (Preparation 118, 1287 mg 5.72 mmole) was stirred in THF (26 mL) and a solution of methyl isothiocyanate (422 mg 5.78 mmole) in THF (5 mL) was added. Triethylamine (102 uL, 0.71 mmole) was added and the reaction was stirred at 20° C. for 22 hours. The solvent was evaporated and replaced with 1M sodium hydroxide solution (85 mL) and the reaction was stirred at 45° C. for 2.5 hours. The reaction was filtered through Celite and the filtrate extracted with ether (2×45 mL). The aqueous was acidified using conc. hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate extracts were washed with water and with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound (1.16 g, 72%).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1[Cl:24].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:28]2[CH2:27][CH2:26][N:25]([C:20]3[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=3)[CH2:30][CH2:29]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)nn1C(C)(C)C

Procedure:
103 mg (97%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(3,4-dichlorophenyl)piperazine (52 mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[C:5]1(=[O:12])[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1>C(O)C>[OH:4][CH2:3][CH2:2][S:1][C:10]1[C:5](=[O:12])[CH:6]=[CH:7][C:8](=[O:11])[CH:9]=1
Reactant: OCCS
Reactant: O=C1C=CC(=O)C=C1
Solvent: CCO
Product: O=C1C=CC(=O)C(SCCO)=C1
Reaction time: 0.01 h

Procedure:
2-Mercaptoethanol (25.9 ml, 0.368 mole) is added in a single amount to a suspension of p-benzoquinone (80 g, 0.736 mole) in absolute ethanol (500 ml), with stirring and while bubbling nitrogen through the suspension. The temperature rises from 22° C. to 45° C. within 30 seconds and the mixture becomes a homogeneous red-brown. At the end of 15 minutes, a precipitate appears. The mixture is left to stand with stirring for 2 hours and filtered through a no. 4 frit. The orange-red precipitate is washed with 3×50 ml of cold ethanol and dried. Orange crystals are obtained
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([NH2:20])=[O:19]>CC(C)=O>[C:1]([NH:9][C:10](=[S:11])[NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([NH2:20])=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cccn1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: NC(=O)c1cccn1NC(=S)NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A solution of benzoylisothiocyanate (1.2 mL, 8.8 mmol) in acetone (10 mL) was treated with 1-aminopyrrole-2-carboxamide (1.0 g, 8.0 mmol) at ambient temperature. The resulting suspension was stirred for one hour and then cooled to 0° C. The solid material was collected by vacuum filtration and washed with diethyl ether before drying under high vacuum to afford 1A (2.2 g, 96%). HPLC tR=2.55 min (YMC S5 Combiscreen ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 254 nm). [M+H]+=289.29. 1H NMR (400 MHz, DMSO-d6) δ 12.9 (s, 1H), 11.9 (s, 1H), 8.0 (dd, 2H, J=1.2, 7.2 Hz), 7.68 (t, 1H, J=7.6 Hz), 7.55 (m, 3H), 7.03 (s, 1H), 6.92 (br s, 1H), 6.82 (dd, 1H, J=1.6, 4.0 Hz), 6.11 (dd, 1H, J=3.2, 4.0 Hz).
Reaction SMILES: [C:1]1([S:11](Cl)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH2:16]([N:19]([CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]2[O:33][CH2:32][CH2:31][NH:30][C:29]=2[CH:34]=1)[CH2:20][CH2:21][CH3:22])[CH2:17][CH3:18].C(N(CC)CC)C.[C:42]([OH:49])(=[O:48])[CH2:43][CH2:44][C:45]([OH:47])=[O:46]>C(#N)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.O>[C:42]([OH:49])(=[O:48])[CH2:43][CH2:44][C:45]([OH:47])=[O:46].[CH2:16]([N:19]([CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]2[O:33][CH2:32][CH2:31][N:30]([S:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)(=[O:13])=[O:12])[C:29]=2[CH:34]=1)[CH2:20][CH2:21][CH3:22])[CH2:17][CH3:18]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CCCN(CCC)CCc1ccc2c(c1)NCCO2
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(O)CCC(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCN(CCC)CCc1ccc2c(c1)N(S(=O)(=O)c1cccc3ccccc13)CCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-naphthalenesulfonyl chloride (388 mg, 1.72 mmol) in acetonitrile (5 ml) was added to a solution of 3,4-dihydro-6-[2-(N,N-propylamino)ethyl]-2H-1,4-benzoxazine hydrochloride (300 mg, 1.14 mmol) obtained in Example 134, 4-dimethylaminopyridine (140 mg, 1.14 mmol) and triethylamine (0.48 ml, 3.43 mmol) in acetonitrile (15 ml) under cooling with ice-bath, and the mixture was stirred at room temperature for 4 hours. Water (50 ml) was added to the reaction solution which was then extracted with ethyl acetate. The extract was washed with 10% aqueous potassium carbonate and a saturated saline solution, dried over anhydrous sodium sulfate and concentrated. The residues were purified by silica gel column chromatography (developing solvent; ethyl acetate), and succinic acid (1 equivalent) was added thereto, and the product was recrystallized from ethyl acetate-diisopropyl ether, whereby the title compound (220 mg) was obtained as crystals with a mp of 144 to 145° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([S:11][C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14](O)=O)=[CH:7][CH:8]=2)[NH:3]1.C[N:22]([C:24]([O:28]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C1COCC1>CN(C=O)C>[CH3:14][C:13]1[C:12]([S:11][C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[C:24]([NH2:22])=[O:28]
Reactant: O=C1Cc2ccc(Sc3ccccc3C(=O)O)cc2N1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(Sc2ccc3c(c2)NC(=O)C3)cccc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
(2-Oxo-2,3-dihydro-1H-indol-6-ylsulfanyl)-benzoic acid (as prepared in Preparation 2; 0.228 g, 0.77 mmol) was dissolved in DMF (3 mL). The resulting solution was treated with HATU (0.434 g, 1.16 mmol) and 2M MeNH2 in THF (2.68 mL, 5.36 mmol) then allowed to stir for 3 hours at room temperature. The reaction mixture was then concentrated in vacuo and the crude was re-dissolved in EtOAc (15 mL) and washed with brine (3×15 mL). The combined organics were then dried over Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified via flash silica gel chromatography (5% MeOH in CHCl3) affording the title compound as a white solid in 31% yield (71 mg, 0.239 mmol).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>CCO>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:20][CH2:17][CH2:18][CH3:19])[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CCCN
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CCCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Temperature: 140 °C
Yield: 120.4 %

Procedure:
A mixture of 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (0.50 g, 1.63 mmol), propan-1-amine (2.0 ml, 24.3 mmol), EtOH (3.0 ml) was heated in a micro wave oven at 140° C. for 30 min. The mixture was evaporated to dryness. The residue was chromathographed on a silica column using EtOAc:MeOH (5:1) as eluent, affording the title compound as a light-yellow solid (0.56 g). The product was washed with several portions of ethyl acetate to give a pure white powder as the title compound (0.43 g, 90%). 0.24 g of the title compound was converted into the hydrochloric acid salt and crystallized from EtOH/DEE. M.p. 213° C. MS m/z (rel. intensity, 70 eV) 285 (M+, 1), 123 (10), 77 (15), 72 (bp), 51 (12).
Reaction SMILES: C(O)(=O)C.Br[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=O.[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16]>C(O)C.O>[CH3:16][CH:15]([CH3:17])[CH2:14][N:18]1[CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[CH:7]=[CH:6]1
Reactant: CC(C)(CC=O)CCBr
Reactant: CC(C)CN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CN1C=CC(C)(C)CC1
Yield: 92.7 %

Procedure:
Acetic acid was added to a mixture of ethanol (40 ml) and water (20 ml) until the pH was 4. 5-Bromo-3,3-dimethylpentanal (19.3 g, 0.1 mol) was added to the mixture, which was then cooled to 0°-5° C. and purged with nitrogen. Isobutylamine (7.3 g, 0.1 mol) was added over 5 minutes to the solution stirring under an atmosphere of nitrogen. After 3 hours stirring at 0°-5° C., most of the ethanol was removed under reduced pressure, the residue then diluted with water (20 ml) and the solution taken to pH 10 with solid potassium carbonate. The mixture was extracted with ether (3×50 ml), the organic layer dried over anhydrous MgSO4 and concentrated to yield a pale yellow oil (15.5 g, 93%) which was essentially pure by 1H NMR spectroscopy. A pure colourless liquid (13.0 g, 78%) was obtained after vacuum distillation, b.p. 50°-53° C./2 mm Hg. The 1H NMR spectrum was found to be the same as for material prepared by the procedure hereafter described in Example 25 Part (C).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([C:22](OCC)=[O:23])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([CH2:22][OH:23])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1CO
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of 1-tert-butyl 2-ethyl (2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}piperidine-1,2-dicarboxylate (Intermediate 191, 9.99 g) in THF (100 mL) was added lithium aluminium hydride (1M in THF, 30 mL). After 2 hours, the reaction was quenched with ethyl acetate, washed with 1 N HCl, NaHCO3 and brine solutions, dried (Na2SO4), filtered and concentrated yielding 7.9 g of product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:13])[CH2:11][CH3:12])[CH:5]=[CH:6][C:7]=1[O:8]C.C([O-])([O-])=O.[Na+].[Na+]>Br>[F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:13])[CH2:11][CH3:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCC(=O)c1ccc(OC)c(F)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC(=O)c1ccc(O)c(F)c1
Yield: 66.2 %

Procedure:
1-(3-Fluoro-4-methoxyphenyl)propan-1-one (421 mg, 2.31 mmol) in 20 mL 40% HBr was refluxed for 1 h., neutralized with solid Na2CO3 at 0° C., and extracted with EtOAc. The extract was washed with brine, dried, concentrated, and purified by column chromatography (eluent: petroleum ether/EtOAc=5/1) over silica gel to give the product (257 mg, 66% yield) as a yellow solid.
Reaction SMILES: C([Li])CCC.[C:6]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[O:21][CH3:22])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>O1CCCC1>[NH:12]([C:13]([C:14]1[CH:19]=[CH:18][C:17]([B:24]([OH:29])[OH:25])=[CH:16][C:15]=1[O:21][CH3:22])=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1cc(Br)ccc1C(=O)Nc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)ccc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
n-Butyl lithium (1.6 M in hexane solution, 5.1 ml, 8.16 mmol) was added slowly to a solution of N1-phenyl-4-bromo-2-methoxybenzamide (1.0 g, 3.26 mmol) in tetrahydrofuran (25 mL) at −78° C. After 30 minutes, triisopropyl borate (1.13 mL, 4.90 mmol) was added rapidly. The reaction mixture was allowed to warm up to room temperature after 15 minutes and stirred at room temperature for 16 hours. Hydrochloric acid (2.5N, 18 mL) was added and the mixture was stirred for 5 h hours. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was re-crystallized from ethyl acetate/heptane to give 4-(anilinocarbonyl)-3-methoxyphenylboronic acid (0.549 g, 62%). 1H NMR (DMSO-d6) δ 3.91 (s, 3H), 7.08 (m, 1H), 7.33 (m, 2H), 7.47 (d, J=7.57 Hz, 1H), 7.59 (m, 2H), 7.73 (d, J=7.36 Hz, 2H), 8.24 (s, 2H), 10.10 (s, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:35]2([CH3:36])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:37])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:30])[CH2:18]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][C@@H:7]([O:38][C:39](=[O:41])[CH3:40])[CH2:6]1)(=[O:3])[CH3:2].[I-:42].[Na+]>C1(C)C=CC=CC=1.[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.O>[C:1]([O:4][C@@H:5]1[C@@:35]2([CH3:36])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:37])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:30])[CH2:18][I:42])[CH2:8][C@@H:7]([O:38][C:39](=[O:41])[CH3:40])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)COS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reactant: [I-]
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CI)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Yield: 97.5 %

Procedure:
Second process. A solution of 23.4 g of (20S)-1α,3β-diacetoxy-20-methyl-21-p-toluenesulphonyloxy-pregn-5-ene in 260 ml of toluene is treated with 1.04 g of hexadecyl-tri-n-butyl-phosphonium bromide and a solution of 132 g of sodium iodide in 260 ml of water and the mixture is heated under reflux for 5 hours. After cooling, the organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated at 30°/11 Torr. Chromatography of the residue on 270 g of silica gel with hexane/ether (19:1 and 9:1) gives 21.1 g of product of melting point 135°-136°. After recrystallization from concentrated pentane solution, there are obtained 16.0 g of product of melting point 136°; [α]D20 =-11.0° (c=1.0 in CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[C:16]3[S:21][CH2:20][CH2:19][CH2:18][S:17]3)[CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH2:24]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14](=[C:16]3[S:17][CH2:18][CH2:19][CH2:20][S:21]3=[O:24])[CH3:15])=[CH:12][CH:13]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(Oc2ccc(C(C)=C3SCCCS3)cc2)cc1
Reactant: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Oc2ccc(C(C)=C3SCCCS3=O)cc2)cc1
Yield: 16.2 %

Procedure:
2-[1-{4-(4-Methoxyphenoxy)phenyl}ethan-1-ylidene]-1,3-dithiane, 5 g, was dissolved in a solvent mixture of 100 ml of tetrahydrofuran and 50 ml of methanol and, 15 g of an aqueous solution containing 2.45 g of oxon was dropwise added to the solution under ice cooling. After stirring for an hour at the same temperature, water was added to the reaction mixture followed by extraction with chloroform. The organic phase was washed with a sodium thiosulfate aqueous solution and then with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride) to give 0.85 g of white crystals.