Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]([C:22]2[C:40]([CH:41]3[CH2:43][CH2:42]3)=[CH:39][C:25]3[C:26]([C:36]([OH:38])=[O:37])=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[O:28][C:24]=3[CH:23]=2)[S:18]([CH3:21])(=[O:20])=[O:19])[CH:5]=[CH:6][C:7]=1[B:8]1[O:12]C(C)(C)C(C)(C)[O:9]1.I([O-])(=O)(=O)=O.[Na+].Cl.O>C1COCC1.CCOC(C)=O>[B:8]([C:7]1[CH:6]=[CH:5][C:4]([N:17]([C:22]2[C:40]([CH:41]3[CH2:42][CH2:43]3)=[CH:39][C:25]3[C:26]([C:36]([OH:38])=[O:37])=[C:27]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)[O:28][C:24]=3[CH:23]=2)[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:3][C:2]=1[Cl:1])([OH:9])[OH:12]
Reactant: CC1(C)OB(c2ccc(N(c3cc4oc(-c5ccc(Cl)cc5)c(C(=O)O)c4cc3C3CC3)S(C)(=O)=O)cc2Cl)OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N(c1ccc(B(O)O)c(Cl)c1)c1cc2oc(-c3ccc(Cl)cc3)c(C(=O)O)c2cc1C1CC1
Yield: 24 %

Procedure:
A solution of 6-(N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylic acid (110 mg, 0.171 mmol) and sodium periodate (183 mg, 0.856 mmol) in THF (14 mL) and aqueous 1N HCl (7 mL) was stirred at RT for 4 h then water and EtOAc were added. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by Reverse Phase HPLC (water/ACN+0.1% formic acid) to give 6-(N-(4-borono-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylic acid (24 mg, 0.041 mmol, 24% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.31 (br. s., 1H), 8.33 (s, 2H), 8.16 (s, 1H), 8.03 (d, 2H), 7.52-7.70 (m, 3H), 7.37-7.48 (m, 2H), 7.34 (dd, 1H), 3.40 (s, 3H), 2.09-2.22 (m, 1H), 0.64-1.11 (m, 3H), 0.47 (br. s., 1H). LCMS (m/z, ES+)=558.1 (M−H).
Reaction SMILES: [OH:1]O.[C:3]1([CH3:12])[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[OH:11]>>[CH3:12][C:3]1[CH2:8][C:7]([CH3:9])([OH:1])[CH:6]=[C:5]([CH3:10])[C:4]=1[OH:11]
Reactant: OO
Reactant: Cc1cc(C)c(O)c(C)c1
Product: CC1=CC(C)(O)CC(C)=C1O

Procedure:
If this procedure is not adopted, but instead a solvent rendered alkaline is admixed with a mixture of hydrogen peroxide and mesitol, then the yields of product 2,4,6-trimethylquinol obtained are not as high as can be seen in example 31.
Reaction SMILES: C([NH:4][C:5]1([CH2:12][NH:13]C(=O)C)[CH2:10][CH:9]2[CH2:11][CH:6]1[CH2:7][CH2:8]2)(=O)C.[ClH:17]>O>[ClH:17].[ClH:17].[NH2:4][C:5]1([CH2:12][NH2:13])[CH2:10][CH:9]2[CH2:11][CH:6]1[CH2:7][CH2:8]2
Reactant: CC(=O)NCC1(NC(C)=O)CC2CCC1C2
Agent: Cl
Solvent: O
Product: NCC1(N)CC2CCC1C2

Procedure:
The procedure is as in Example 3, but starting from 2-acetylamino-2-acetylaminomethyl-bicyclo[2.2.1]heptane (7.85 g), in the form of the exo racemate, in a 6N solution (250 cc) of hydrochloric acid in water for 8 hours under reflux; taking up the residue from the evaporation in ethanol (100 cc) and diethyl ether (300 cc), 2-amino-2-aminomethyl-bicyclo[2.2.1]heptane dihydrochloride (6.87 g) is obtained in the form of white crystals which melt at 271° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[CH2:12]([S:18](Cl)(=[O:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O>N1C=CC=CC=1>[CH2:12]([S:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1)(=[O:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: CCCCCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCS(=O)(=O)Nc1ccc2oc(C)nc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 29.6 g of 5-amino-2-methylbenzoxazole in 100 ml pyridine cooled to 0° C. was added 41.3 g hexanesulfonyl chloride. After 1 hour stirring at 0° C., a reddish precipitate formed. The reaction mixture was stirred at room temperature for 2 days and then poured into 1.4 l of water and stirred for 2 hours. A heavy oil deposited and the supernatant was decanted. The oil was dissolved in 1.0 l dichloromethane, which was extracted with 4×200 ml of 1N hydrochloric acid, then dried over magnesium sulfate. The solvent was removed, leaving a reddish brown liquid of 5-hexylsulfonamido-2-methylbenzoxazole (Intermediate A).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[CH:5][C:4]=1[CH3:8].[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:2][C:3]1[O:7][N:6]=[CH:5][C:4]=1[CH3:8])[CH3:10]
Reactant: Cc1cnoc1CCl
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1oncc1C

Procedure:
prepared by reaction of 5-chloromethyl-4-methyl-isoxazole with 2M ethylamine in THF.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[N:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])[N:3]=1)(=[O:30])=[O:29]
Reactant: Nc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
The compound 21-4 (200 mg) prepared in Step 4 was dissolved in dichloromethane (10 ml) and to the solution were added triethylamine (130 μl) and methanesulfonyl chloride (67 g), followed by stirring at room temperature for 24 hours. The resulting mixture was extracted with water and dichloromethane, dried, concentrated under reduced pressure, and then crystallized (dichloromethane/petroleum ether) to yield the compound 21-5 (260 mg, 99%) as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([OH:22])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24]/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([O:22][CH2:24]/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Reactant: COC(=O)/C=C/CBr
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: COC(=O)/C=C/COC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.8 %

Procedure:
A mixture of 96C [1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-ol] (63 mg, 0.213 mmol), methyl 4-bromocrotonate (0.075 mL, 0.64 mmol), 2,6-di-tert-butylpyridine (0.334 mL, 1.49 mmol), and AgOTf (164 mg, 0.64 mmol) in DCM (0.5 mL) was stirred at rt in the dark for 3 days. LC-MS showed the presence of the product, and the reaction was filtered. The filtrate was concentrated in vacuo. The crude product was chromatographed [SiO2; continuous gradient of EtOAc/hexane (0% to 10% over 10 min)] to give the title compound (42 mg, 0.106 mmol, 50% yield) as an oil. 1H NMR (CDCl3) δ: 7.28-7.17 (m, 3H), 7.07-6.98 (m, 3H), 6.94-6.86 (m, 3H), 6.78 (ddd, J=8.1, 2.4, 1.0 Hz, 1H), 6.02 (dt, J=15.6, 2.2 Hz, 1H), 4.07 (dd, J=4.2, 2.1 Hz, 2H), 3.84 (t, J=1.4 Hz, 2H), 3.67 (s, 3H), 2.11-2.03 (m, 4H), 1.97-1.88 (m, 2H), 1.86-1.77 (m, 2H).
Reaction SMILES: [NH2:1][C:2]([NH:4]CC1C=CC=CC=1[N+]([O-])=O)=[S:3].Br.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=O.[NH4+].[Cl-].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.CCN(CC)CC>[Fe].CO>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:1]=[C:2]([NH2:4])[S:3][CH:17]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: NC(=S)NCc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Br
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nc(-c2ccccn2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[(2-Nitrophenyl)methyl](4-(2-pyridyl)(1,3-thiazol-2-yl)amine was prepared according to the method described in Example 16 (Step b) by employing amino{[(2-nitrophenyl)methyl]amino}-methane-1-thione (Example 16, Step a) (1.04 g, 4.9 mmol), 2-(bromoacetyl)pyridine hydrobromide (Aust. J. Chem. 1989, 42, 1735; 1.34 g, 4.9 mmol), and 50% MeOH (10 mL). After 2 h, the reaction was cooled to RT and the solvent was removed in vacuo. The crude material was dissolved in 50% aqueous EtOH and iron dust (Aldrich) (1.419 g, 25.2 mmol) and NH4Cl (190 mg, 3.5 mmol) was added. The reaction was heated to reflux for 1 h, then concentrated in vacuo. The residue was dissolved in THF (20 mL) and to this solution was added 4-nitrophenyl chloroformate (1.17 g, 5.8 mmol) followed by Et3N (1 mL, 7.2 mmol). The reaction was heated at reflux for 2.5 h then cooled to RT. The solvent was removed in vacuo and the crude material was purified by flash chromatography on silica gel with Hexanes:EtOAc (4:1, 1:1, 0:1) as eluant to give a tan solid. Mp: >275° C. MS m/z: 309 (M+1); 307 (M−1). Anal. Calc'd for C16H12N4OS.0.5H2O: C, 60.55; H, 4.13; N, 17.65. Found: C, 60.20; H, 4.17; N, 16.92.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:5]2=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:47][C:48]([O:50][CH3:51])=[O:49]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:33][CH2:34][N:35]([CH2:47][C:48]([O:50][CH3:51])=[O:49])[CH2:36][CH2:37]3)[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OC2CCNCC2)N1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)CN1CCC(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Temperature: 80 °C
Yield: 53 %

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(4-piperidinyloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.36 g, 0.54 mmol) prepared in example 5a in ethanol (2 mL) was added triethylamine (0.15 mL, 1.08 mmol) and methyl bromoacetate (0.124 g, 0.81 mmol) (Aldrich). The reaction mixture was heated at 80° C. for 2 h, then cooled to room temperature. The mixture was partitioned between dichloromethane and water. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (MeOH:EtOAc=7:93) to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(1-methoxycarbonylmethyl-4-piperidinyloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a light yellow solid (Yield 0.21 g, 53%)
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH3:17])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:18]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH3:17])[CH:10]=3)[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CCCN2CCN(c3ccccc3)CC2)n(-c2ccccc2)n1

Procedure:
41 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-ethyl-1H-pyrazol-5-yl)propanal (31 mg, 0.138 mmol), 1-phenylpiperazine (0.021 mL, 0.138 mmol), DIPEA (0.036 mL, 0.206 mmol) and NaBH(OAc)3 (88 mg, 0.414 mmol).
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].[NH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16]>CO>[Cl:11][C:7]1[CH:6]=[C:5]([C@@:3]2([OH:4])[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[NH:13][C@@H:2]2[CH3:12])[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(N)CO
Reactant: CC(Br)C(=O)c1cccc(Cl)c1
Solvent: CO
Product: C[C@H]1NC(C)(C)CO[C@]1(O)c1cccc(Cl)c1
Reaction time: 18 h
Yield: 73.3 %

Procedure:
To a solution of 2-bromo-3′-chloropropiophenone (19.3 g, 0.08 mol) in MeOH (100 mL) was added dropwise a solution of 2-amino-2-methyl-1-propanol (27.8 g, 0.31 mol) in methanol (200 mL) at ambient temperature. The mixture was stirred for 18 h and concentrated in vacuo. The residue was partitioned between water and diethyl ether. The combined organic phase was extracted with 10% aqueous hydrogen chloride. The combined aqueous acid extracts were chilled in an ice bath and made basic with 40% aqueous sodium hydroxide. The mixture was extracted with diethyl ether, the combined diethyl ether extracts were washed with water and saturated sodium chloride solution, dried (K2CO3) and concentrated in vacuo to give 15.0 g (75%) of (+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol as an off-white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:19][CH2:20][CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:23][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(CCCCCCO)c1ccc(CC(C)C)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CCCCCCBr)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 7-(4-isobutylphenyl)-1-decanol and carbon tetrabromide in tetrahydrofuran was added portionwise triphenylphosphine. The mixture was stirred at room temperature for 2 hours and insoluble materials were filtered off. The filtrate was concentrated and n-hexane was added thereto, then the mixture was filtered again and the filtrate was concentrated. The residue was chromatographed on a silica gel column (n-hexane as eluent) to give the object compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]#[C:15][CH2:16][CH3:17])[CH2:6][O:7][NH2:8].C(N(C(C)C)C(C)C)C.[Cl:27][C:28]1[CH:38]=[CH:37][C:31]([CH:32]([OH:36])[C:33](O)=[O:34])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH:32]([OH:36])[C:33]([NH:8][O:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]#[C:15][CH2:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:34])=[CH:37][CH:38]=1
Reactant: CCC#CCOc1ccc(CON)cc1OC
Reactant: O=C(O)C(O)c1ccc(Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC#CCOc1ccc(CONC(=O)C(O)c2ccc(Cl)cc2)cc1OC
Reaction time: 16 h

Procedure:
O-(3-methoxy-4-pent-2-ynyloxy-benzyl)-hydroxylamine (5.0 g, 21 mmol) and N-ethyldiisopropylamine (Hünig's base, 5.5 g, 42 mmol) are dissolved in 60 ml of N,N-dimethylformamide. 4-chloro-DL-mandelic acid (4.1 g, 22 mmol) and (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP, Castro's reagent, 10 g, 23 mmol) are added successively and the mixture is stirred for 16 h. After pouring the mixture on ice/water, it is extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The remaining oil is purified by chromatography on silica gel (ethyl acetate/hexane (4:6)) to obtain 2-(4-chloro-phenyl)-2-hydroxy-N-(3-methoxy-4-pent-2-ynyloxy-benzyloxy)-acetamide as yellow resin.
Reaction SMILES: [Br:1]Br.[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)(=[O:5])[CH3:4]>C(O)(=O)C.O>[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:8]=1[Br:1])(=[O:5])[CH3:4]
Reactant: BrBr
Reactant: CC(=O)Nc1ccc(CC(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(CC(=O)O)cc1Br
Temperature: 60 °C
Reaction time: 12 h
Yield: 55.1 %

Procedure:
102.2 g (0.64 mole) of bromine are added dropwise at room temperature, with stirring, to a suspension of 100 g (0.52 mole) of 4-acetamidophenylacetic acid in 1 liter of glacial acetic acid; during this dropwise addition, a solution forms intermittently. Subsequently, heating to 60° C. is effected for 12 hours, followed by cooling to room temperature, diluting with 2 liters of water and extracting three times with diethyl ether. The organic phase is washed with sodium hydrogen sulfite solution and water, dried and concentrated to dryness. The residue is recrystallized from acetonitrile to yield 78 g (55.3% of theory) of 4-acetamido-3-bromophenylacetic acid (m.p. 157° to 159° C.).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:29]2([CH3:30])[CH:9]([CH:10]=[CH:11][C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:32][C:33](=[O:35])[CH3:34])[CH2:6]1)(=[O:3])[CH3:2].C([O-])(=[O:38])C.[Na+]>C(O)(C)(C)C>[C:1]([O:4][C@@H:5]1[C@@:29]2([CH3:30])[C:9](=[CH:10][C:11](=[O:38])[C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:32][C:33](=[O:35])[CH3:34])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2C=C[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(=O)O[C@@H]1CC2=CC(=O)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Yield: 114.7 %

Procedure:
A solution of 0.3 g of 1α,3β-diacetoxycholest-6-ene in 30 ml tert-butanol was treated with 0.3 g mercuric bromide and 0.03 g sodium acetate. The stirred mixture was irradiated with light of 254 nm wavelength at room temperature during 5 hours. After filtration and extraction with 300 ml hexane, there was obtained a quantity of 0.21 g of 1α,3β-diacetoxycholest-5-en-7-one. M.P. = 121°-122°C.
Reaction SMILES: [NH2:1][C:2](=[S:15])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[S:6][C:7]=1[CH3:8].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O>>[CH3:8][C:7]1[S:6][C:5]([C:9]([O:11][CH:12]([CH3:13])[CH3:14])=[O:10])=[CH:4][C:3]=1[C:2]1[S:15][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:1]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1sc(C(=O)OC(C)C)cc1C(N)=S
Product: Cc1sc(C(=O)OC(C)C)cc1-c1nc(-c2ccccc2)cs1

Procedure:
A solution of 375 mg (1.54 mmol) of isopropyl 4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate was reacted with 307 mg (1.54 mmol) of 2-bromoacetophenone (Aldrich, Milwaukee, Wis., USA) in a manner similar to Example 8, step (a) to give, after crystallization from methanol, isopropyl 5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (347 mg, 66%) as light brown needles. 1H-NMR (DMSO-d6; 300 MHz) δ8.23 (s, 1H), 8.09 (s, 1H), 8.05 (m, 2H), 7.49 (m, 2H), 7.38 (m, 1H), 5.13 (septet, 1H, J=6.2 Hz), 2.86 (s, 3H), 1.33 (d, 6H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C18H17NO2S2 344.1 (M+H), found 344.1.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.C1C=CC=CC=1.Cl[C:17]([C:19]1[N:23]([CH3:24])[C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=1)=[O:18].Cl>CCOCC.[Cl-].[Cd+2].[Cl-]>[CH3:24][N:23]1[C:19]([C:17]([C:4]2[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=2)=[O:18])=[CH:20][CH:21]=[C:22]1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)Cc1ccc(C(=O)Cl)n1C
Reactant: Cc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Cd+2]
Agent: [Cl-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.0516 mole of p-tolyl magnesium bromide in ether (40 ml.) is added 5.0 g. (0.0274 mole) of cadmium chloride. The mixture is refluxed for 20 minutes, 50 ml. of dry benzene is added and the ether is distilled off. To this solution of di-(p-tolyl) cadmium is added dropwise 5.9 g. (0.0258 mole) of ethyl 5-chlorocarbonyl-1-methylpyrrole-2-acetate in 25 ml. of benzene. The mixture is stirred at room temperature for 1 hour and poured into dilute HCl. The mixture is extracted with ether. The ether extract is washed successively with dimethylaminopropylamine solution, dilute HCl. and brine and then dried (anhydrous MgSO4). The solvent is evaporated in vacuo. The residue is crystallized from methyl cyclohexane and recrystallized from ethanol to give white crystalline ethyl 1-methyl-5-p-toluoylpyrrole-2-acetate, m.p. 70°-71°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12](OCC)=[O:13])[N:11]=2)[CH:2]=1.CC(C[AlH]CC(C)C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:2]=1
Reactant: CCOC(=O)c1csc(-c2cccnc2)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=Cc1csc(-c2cccnc2)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A solution containing the product from Example 19A (20 g, 85.5 mmol) in dichloromethane (340 mL) was treated dropwise with DIBAL (86 mL, 1 M in dichloromethane) at −78° C., stirred at −78° C. for 2 hours, treated with DIBAL (43 mL, 1 M in dichloromethane), stirred at −78° C. for 1 hour, treated with methanol (20 mL) at −78° C., warmed to 25° C., treated with dichloromethane (250 mL), saturated aqueous sodium potassium tartrate (350 mL), and pH 7 buffer (300 mL), stirred vigorously with a mechanical stirrer for 16 hours, and filtered through celite®. The aqueous phase was washed with chloroform, and the combined organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting 0-4% methanol/chloroform to give the title compound (11.61 g, 71% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C([N:13]([CH:17]([CH3:19])[CH3:18])C(C)C)C.C1(N)CC1>S(Cl)(Cl)=O.O1CCOCC1.C(OCC)(=O)C>[CH:17]1([NH:13][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[CH2:19][CH2:18]1
Reactant: O=C(O)c1cccc(I)c1
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(NC1CC1)c1cccc(I)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
3-Iodobenzoic acid (4.79 g, 19.3 mmol) was suspended in thionyl chloride (19.3 mL) and stirred for 1 h at 70° C. before it was conc. and azeotropically dried with toluene. The reaction mixture was dissolved in dioxane (19.3 mL) before N-ethyl-N-isopropylpropan-2-amine (13.5 mL, 77.3 mmol) and cyclopropylamine (6.77 mL, 96.6 mmol) were added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with 75 mL of ethyl acetate, added to a separation funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2× with 50 mL of 3 N HCl (aqueous), separated, dried over sodium sulfate, and concentrated in vacuo to give the title compound. MS (ES+): 288 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[OH:8][C:4]1[CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(I)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Oc1cccc(-c2ccccc2)c1
Temperature: 100 °C
Yield: 84.2 %

Procedure:
A stirred mixture of 660 mg(3 mmol) of 3-iodophenol, 439 mg (3.6 mmol) phenylboronic acid, and 173 mg (0.15 mmol) tetrakistriphenylphosphine in 10 mL of toluene, 5 mL ethanol, and 6 mL 2M sodium carbonate (aqueous) was heated at 100° C. in an inert atmosphere of nitrogen for 15 minutes. The cooled mixture was partitioned between EtOAc, ice, and brine and the organic phase was separated, washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by plate layer chromatography (PLC) using CH2Cl2 as the eluant to give 430 mg of the titled product.