Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]([CH:21]=[O:22])[C:7]([CH3:23])=[C:6]([Cl:24])[CH:5]=1)(=[O:3])[CH3:2].[OH-:25].[Na+].Cl>CO.O.OO.NC(N)=O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][NH:13][C:14]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:20])=[C:8]([C:7]([CH3:23])=[C:6]([Cl:24])[CH:5]=1)[C:21]([OH:25])=[O:22])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(C)c(C=O)c1OCCNC(=O)OC(C)(C)C
Reactant: [OH-]
Agent: Cl
Agent: NC(N)=O
Agent: OO
Solvent: O
Solvent: CO
Product: CC(=O)c1cc(Cl)c(C)c(C(=O)O)c1OCCNC(=O)OC(C)(C)C
Yield: 84 %

Procedure:
tert-Butyl [2-(6-acetyl-4-chloro-2-formyl-3-methylphenoxy)ethyl]carbamate (85 mg, 0.24 mmol) was stirred in methanol (7 mL) and 1.0 M sodium hydroxide in water (2.7 mL) and urea hydrogen peroxide addition compound (200 mg, 2 mmol) was added. Additional urea hydrogen peroxide addition compound (20 mg) and 1.0 M sodium hydroxide in water (0.5 mL) were added and the mixture was stirred for 3 more hours. 1 N HCl was added to pH 5 and the methanol was evaporated. The mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and evaporated to give the desired compound (75 mg, 84%). LCMS calculated for C17H22ClNO6Na (M+Na)+: m/z=394.1; found: 393.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[F:11].Br[C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:20][C:18]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([F:11])[CH:4]=2)[CH:19]=1
Reactant: Nc1ccc(F)cc1Br
Reactant: Cc1ccc(B(O)O)cc1F
Product: Cc1ccc(-c2cc(F)ccc2N)cc1F

Procedure:
Starting from 4-methyl-3-fluorophenylboronic acid and 2-bromo-4-fluoroaniline and proceeding analogously to Example (III-1), the compound 5,3′-difluoro-4′-methylbiphenyl-2-ylamine with a logP (pH 2.3) of 2.94 is obtained.
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([CH2:10][CH2:11][CH3:12])=[N:7][C:6]=1[CH2:13][CH3:14])([O:3][CH3:4])=[O:2].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[C:18]([F:24])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:9]2[C:5]([C:1]([O:3][CH3:4])=[O:2])=[C:6]([CH2:13][CH3:14])[N:7]=[C:8]2[CH2:10][CH2:11][CH3:12])=[C:18]([F:24])[CH:17]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CCCc1nc(CC)c(C(=O)OC)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(C(=O)OC)n1Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Carbomethoxy-4-ethyl-2-n-propylimidazole (U.S. Pat. No. 5,137,902) (10.62 g, 54 mmol, 1 eq), 1-bromo-4-bromomethyl-3-fluorobenzene (19.58 g, 54 mmol, 1 eq), potassium carbonate (7.48 g, 54 mmol, 1 eq), and DMF (200 mL) were mixed and stirred overnight at room temperature. Ethyl acetate was added (500 mL) and the mixture was washed with water (3×300 mL). The ethyl acetate layer was dried (MgSO4), and the solvent removed in vacuo to yield 25.42 g of an oil. Flash chromatography in 75:25 to 65:35 hexanes/ethyl acetate yielded 13.65 g of product as an amber oil. NMR (CDCl3) δ 7.35-7.22 (m, 1H); 7.22-7.10 (m, 1H); 6.45 (t, 1H, J=7Hz); 5.49 (s, 2H); 3.78 (s, 3H); 2.90 (q, 2H, J=7Hz); 2.59 (t, 2H, J=7Hz); 1.70 (t of q, 2H, J=7,7Hz); 1.35-1.15 (m, 3H); 0.95 (t, 3H, J=7Hz). ##STR48##
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:22][CH3:23])=[C:8]([S:10]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([NH2:20])=[C:15]([NH2:21])[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[C:24]([O-])(O)=O.[Na+]>C(O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:22][CH3:23])=[C:8]([S:10]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]3[NH:20][CH:24]=[N:21][C:15]=3[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: O=C([O-])O
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(N)c(N)c(Cl)c2)c(SC)s1
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)c1cc(S(=O)(=O)c2cc(Cl)c3[nH]cnc3c2)c(SC)s1
Temperature: 25 °C
Yield: 87 %

Procedure:
The refrigerated solution of 4-(3,4-diamino-5-chloro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((from above step b) 0.224 g, 0.570 mmol) in formic acid (4.5 mL) from above was allowed to slowly warm to room temperature and then heated to reflux (110° C.) 3 h. The mixture was cooled to room temperature and poured over ice. The pH was adjusted to pH 8 by carefully adding solid NaHCO3 portionwise with stirring. The aqueous solution was extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed in vacuo to afford the product 4-(7-chloro-1H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.201 g, 87%) as a brown foamy solid. The crude material was used directly in the next reaction.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:23]3[CH2:24][CH2:25][N:20]([C:15]4[C:14]([C:13]([F:27])([F:12])[F:26])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:21][CH2:22]3)[NH:3][C:4]=2[CH:10]=1
Reactant: Clc1ccc2[nH]c(Cl)nc2c1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: FC(F)(F)c1cccnc1N1CCN(c2nc3ccc(Cl)cc3[nH]2)CC1

Procedure:
The benzoimidazole from step (b) above (0.186 g, 0.995 mmol) and 1-(3-trifluoromethylpyridin-2-yl)piperazine (0.23 g, 0.995 mmol, Maybridge) reacted under the conditions of Example 3c to give the title compound as a white solid. M.p. 228-231° C. MS (ESI, pos. ion) m/z: 382 (M+1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:27]=[C:28]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:29]=[CH:30][C:31]=1[CH3:32].[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:35][CH2:34][N:33]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[C:26]([CH3:25])[CH:27]=3)[CH2:38][CH2:37]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)cc1C

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3,4-Dimethylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.03 (d, 1H), 6.94 (br s, 1H), 6.84 (br s, 1H), 5.38 (s, 2H), 3.68 (m, 4H), 3.25 (m, 2H), 3.15 (m, 2H), 2.18 (s, 6H), 2.14 (s, 3H) ppm; MS (ES) M+H expected=415.1, found=415.1.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+]>[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH:8][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=1)[CH3:3]
Reactant: CCOC(=O)CCN
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: CCOC(=O)CCNCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A suspension of β-alanine ethyl ester hydrochloride salt (2.0 g, 13.0 mmol), 4-fluorobenzaldehyde (1.61 g, 13.0 mmol), sodium acetate (2.13 g, 26.0 mmol), and 4 Å molecular sieves (0.5 g/mmol) in methanol (50 mL) was treated with sodium cyanoborohydride (1.63 g, 26.0 mmol). The reaction was stirred at 25° C. for 4 h, diluted with a saturated aqueous sodium bicarbonate solution (150 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by flash column chromatography (ISCO RediSep column, 20 to 70% ethyl acetate in hexanes) to give 3-(4-fluoro-benzylamino)-propionic acid ethyl ester (2.08 g, 71%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.26 (t, 3H, J=7.0 Hz), 2.52 (t, 2H, J=6.5 Hz), 2.88 (t, 2H, J=6.2 Hz), 3.76 (s, 2H), 4.14 (q, 2H, J=6.8 Hz), 6.96-7.01 (m, 2H), 7.26-7.28 (m, 2H). LC-MS (ESI) calculated for C12H11FNO2: 225.3, found 226.2 [M+H+].
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:5]1.C(N(CC)CC)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>ClCCl>[Si:22]([O:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:5]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1cc(C)n(CCO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)n(CCO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Ethyl 1-(2-hydroxyethyl)-5-methylpyrazole-3-carboxylate (9.39 g, 47.4 mM) in dichloromethane (150 ml) was cooled to below 0° C. and treated with triethylamine (7.19 ml, 52 mM) followed by t-butyldimethylsilyl chloride (7.85 g, 52 mM). The mixture was stirred at room temperature for 3 days. The reaction mixture was washed with brine, dried (MgSO4) and evaporated. Purification on silica geleluting with 50% ethyl acetate in hexane gave the title compound as a pale yellow solid in quantitative yield; νmax (film) 1719, 1472 and 1388 cm-1 ; δH (CDCl3) -0.08 (6H, s), 0.81 (9H, s), 1.38 (3H, t, J7 Hz), 2.33 (3H, s), 3.98 (2H, t, J5 Hz), 4.21 (2H, t, J5 Hz), 4.39 (2H, q, J7 Hz), and 6.53 (1H, s); NH3DCI m/e 313 (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1>C1COCC1>[N:14]1([CH2:12][C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Nc1cc(C(=O)N2CCOCC2)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: Nc1cc(CN2CCOCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
Dissolve (3-amino-5-trifluoromethyl-phenyl)-morpholin-4-yl-methanone (1.2 g, 4.3 mmol) in THF and dropwise and add BH3-Me2S solution (6.5 mL, 13.1 mmol, 2M in THF). Stir at room temperature for 3 hours. Add another portion of BH3-Me2S solution (2.2 mL, 4.3 mmol, 2M in THF) and heat at 65° C. for 1.5 hours under nitrogen. Cool to room temperature and quench carefully with dropwise addition of 1 N HCl:water 1:1 (8 mL), stir for 30-60 minutes. Extract by EtOAc and wash with saturated aqueous NaHCO3 and aqueous saturated sodium chloride. Purification by silica gel column chromatography with gradient from 100% DCM to 6% MeOH in DCM to 5% (2N NH3 in MeOH)/in DCM, yielding the title compound (600 mg, 54% yield). LCMS (ES), m/z 261 (M+1).
Reaction SMILES: B.CC(C(C)C)=C.[CH3:8][N:9]1[C:13]2=[N:14][CH:15]=[C:16]([CH:18]=[CH2:19])[CH:17]=[C:12]2[O:11][C:10]1=[O:20].C(B)(C(C)C)(C)C.[OH-:28].[Na+]>O1CCCC1.O>[OH:28][CH2:19][CH2:18][C:16]1[CH:17]=[C:12]2[O:11][C:10](=[O:20])[N:9]([CH3:8])[C:13]2=[N:14][CH:15]=1
Reactant: [OH-]
Reactant: C=Cc1cnc2c(c1)oc(=O)n2C
Agent: B
Agent: BC(C)(C)C(C)C
Agent: C=C(C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)oc2cc(CCO)cnc21
Temperature: 0 °C
Yield: 78 %

Procedure:
A solution of boron hydride (1M in tetrahydrofuran) (5 ml, 5 mmol) is cooled using a salt/ice bath, and then 2,3-dimethyl-1-butene (0.6 ml, 5 mmol) are slowly added. The temperature of the solution is increased to 0° C. and stirring is maintained for a further 2 hours at that temperature. 3-methyl-6-vinyloxazolo[4,5-b]pyridin-2(3H)-one (1.14 mg, 5 mmol) dissolved in tetrahydrofuran (20 ml) is added to the previously prepared solution of thexylborane. The whole is stirred at 0° C. for 2 hours, then a 10% aqueous sodium hydroxide solution (2.40 ml) and also oxygenated water (2.00 ml) are added in succession. After 1 hour's stirring at room temperature and evaporation of the solvent under reduced pressure, the residue is taken up in water. Extraction is carried out with dichloromethane; the organic phase is dried over magnesium sulfate and filtered, and then the solvent is evaporated off under reduced pressure. Purification by flash chromatography on silica gel (eluant: dichloromethane/methanol: 95/5) yields 6-(2-hydroxyethyl)-3-methyloxazolo[4,5-b]pyridin-2(3H)-one in a yield of 78%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26](=[O:30])[N:25]([CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:24]=1[CH3:42].C(N(CC)CC)C>C(OCC)(=O)C>[C:14]([O:13][C:12]([NH:11][CH2:10][CH2:9][O:8][CH2:7][C:6]1[CH:5]=[C:4]([CH:21]=[CH:20][CH:19]=1)[CH2:3][CH2:2][NH:1][C:27]1[C:26](=[O:30])[N:25]([CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:24]([CH3:42])=[C:23]([Cl:22])[N:28]=1)=[O:18])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCOCc1cccc(CCN)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)nc(NCCc2cccc(COCCNC(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 45.1 %

Procedure:
A mixture of tert-butyl 2-{[3-(2-aminoethyl)benzyl]oxy}ethylcarbamate (preparation 105) (270 mg, 0.92 mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (300 mg, 0.92 mmol), and triethylamine (140 ml, 1.01 mmol) in ethyl acetate was heated under reflux overnight. The cooled suspension was diluted with ethyl acetate, then washed with hydrochloric acid (2N), NaHCO3 solution, brine, then dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate:pentane (40:60) as eluant, and triturated with ether, to give the title compound as a white solid, (243 mg, 45%). Re-purifiing the ether filtrate by column chromatography on silica gel provided an additional (176 mg, 33%) of the desired product.
Reaction SMILES: [C:1]([N:5]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br-].Cl>CN(C=O)C.O>[CH2:7]([N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)N(C(=O)c1ccccc1)N(Cc1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N'-t-butyl-N,N'-dibenzoylhydrazine (2 g, 0.006M) in DMF (25 ml) at room temperature under nitrogen was added portionwise sodium hydride (60% oil dispersion) (0.3 g, 0.007M). The mixture was stirred at room temperature for 0.5 hours, and thenbenzyl bromide (1.2 g, 0.007M) was added dropwise. The reaction mixture was warmed to 60° C. and allowed to stir for 2 hours. The mixture was then diluted with water (50 ml), neutralized with 1% HCl, and the product extracted into methylene chloride (50 ml). The methylene chloride layer was washed with water (5×20 ml), dried over anhydrous magnesium sulfate, and the methylene chloride removed under vacuum to afford N-benzyl-N'-t-butyl-N,N'-dibenzoylhydrazine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[S:20][C:19]([CH3:21])=[C:18]2[C:14]=1[CH2:15][C@H:16]1[C:22]([CH3:24])([CH3:23])[C@H:17]12)=[O:12].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:25][CH:27]2[CH2:28][O:29]2)[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[S:20][C:19]([CH3:21])=[C:18]2[C:14]=1[CH2:15][C@H:16]1[C:22]([CH3:24])([CH3:23])[C@H:17]12)=[O:12]
Reactant: Cc1sc(C(=O)CCc2ccc(O)cc2Cl)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1sc(C(=O)CCc2ccc(OCC3CO3)cc2Cl)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 18 h
Yield: 48 %

Procedure:
A solution of 3-(2-chloro-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (400 mg, 1.11 mmol, Intermediate 18) in isopropanol (10 mL) and 3 N aq. NaOH (6 mL) is treated with epichlorohydrine (554 mg, 4.43 mmol). The dark red reaction mixture is stirred at rt for 6 h before another portion of epichlorohydrine (554 mg, 4.43 mmol) is added. Stirring is continued for 18 h. The mixture is diluted with diethyl ether (150 mL) and washed with sat. aq. NaHCO3 followed by water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 3-(2-chloro-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (222 mg) as a pale yellow oil; LC-MS: tR=1.16 min, [M+1]+=417.20.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[C:5]([CH3:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH3:14])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11]
Reactant: Cc1cc(S(N)(=O)=O)c(N)cc1Br
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1-c1cc(N)c(S(N)(=O)=O)cc1C
Yield: 90 %

Procedure:
3-Bromo-4-methylaniline was transformed by Method B (The isomers were separated by fractional crystallization from MeOH) to give 2-amino-4-bromo-5-methylbenzenesulfonamide. A mixture of 2-amino-4-bromo-5-methylbenzenesulfonamide (100 mg, 0.38 mmol), 2-methoxyphenylboronic acid (76 mg, 0.50 mmol), Pd(PPh3)2Cl2 (13 mg, 5 mol %) in 1,2-dimethoxyethane (20 ml) and Na2CO3 (2M, 1 ml, 2 mmol) were refluxed under N2 for 4 h. The solvents were removed under reduced pressure and the residue was treated with saturated NaHCO3 (10 ml) and extracted with EtOAc (2×25 ml). The organic layer was washed with brine (20 ml), dried (Na2SO4) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on SiO2 using EtOAc:n-hexane (1:1, v/v) as eluent, yielding 100 mg (90%) of 2-amino-4-(2-methoxyphenyl)-5-methylbenzenesulfonamide as colorless powder. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 172-175° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](O)(=O)=O)=[CH:8]C=1>CO>[CH2:10]([C:9]1[S:12][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:8]=1)[CH2:11][CH2:6][CH2:16][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1CCOC1
Solvent: CO
Product: CCCCCCCCc1ccc(CCO)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetrahydrofuran (20 ml) and p-toluenesulfonic acid (0.3 g) were added to a solution (80 ml) of the above-mentioned compound (6.5 g) in methanol and the mixture was stirred at room temperature for 1 hour. The solvent was distilled away and ethyl acetate was added to the resulting mixture. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away and the residue obtained was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to give 4 g of the subject compound as an oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[C:5]([C:14]([NH:16][O:17]C2CCCCO2)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[C:4]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[C:5]([C:14]([NH:16][OH:17])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)NOC2CCCCO2)c1-c1ccc(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c(N2CCOCC2)sc(C(=O)NO)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
4-Cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-yl-N-(tetrahydro-2H-pyran-2-yloxy)thiophene-2-carboxamide (0.050 g, 0.10 mmol) was dissolved in DCM (3 mL) and TFA (0.24 mL, 3.11 mmol) was added. The solution was stirred at room temperature overnight. Solvent was evaporated and the residue was purified by column chromatography (silica gel, elution with DCM to 10% MeOH in DCM over 20 minutes) to give the title compound 24 (0.030 g, 67%). LCMS: (FA) ES+ 398.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:21]3[C:22](=[O:25])[CH:23](Br)[C@H:20]3[S:19](=[O:26])[C:18]2([CH3:28])[CH3:27])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(OC(C2N3C(=O)C(Br)(Br)[C@H]3S(=O)C2(C)C)=O)C2C=CC=CC=2)C=CC=CC=1>>[C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:21]3[C:22](=[O:25])[CH2:23][C@H:20]3[S:19](=[O:26])[C:18]2([CH3:28])[CH3:27])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(Br)[C@H]2S1=O
Agent: CC1(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(Br)(Br)[C@H]2S1=O
Product: CC1(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@H]2S1=O
Yield: 90 %

Procedure:
The same reaction as in Example 2 were conducted except that 6-bromo-2,2-dimethylpenam-3-carboxylic acid 1-oxide diphenylmethyl ester (Compound 3) [compound of the formula (1) wherein X═Br, Y═H, R=diphenylmethyl, n=1] was used in place of Compound 1 to obtain Compound 2 in a yield of 90%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[CH3:18])=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=1.[CH2:19]([O:21][C@@H:22]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]>>[CH2:19]([O:21][C@@H:22]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:17][CH2:16]/[CH:15]=[C:14](/[C:11]2[CH:10]=[CH:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:13][CH:12]=2)\[CH3:18])=[CH:33][CH:34]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2ccccc2C)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccccc3C)cc2)cc1)OCC
Yield: 78.7 %

Procedure:
The title compound (1.80 g, 78%) was prepared as a colourless oil from (E)-3-(2′-methyl-biphenyl-4-yl)-but-2-en-1-ol (1.19 g, 4.99 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (1.31 g, 6.48 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([CH:15]=O)=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.Cl[CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:25]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:15][C:11]2=[CH:10][C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1
Reactant: CC(C)(C)C(=O)CCl
Reactant: O=Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Product: CC(C)(C)C(=O)c1cc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2o1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 0.38 g of the product of Step A dissolved in 3 mL of DW, was added 0.14 mL (1.07 mmol) of 1-chloropinacolone and 0.65 g of Cs2CO3. After stirring for 2 h, another 0.05 mL (0.38 mmol) of 1-chloropinacolone was added and the stirring was continued for another 1 h. Additional 0.325 g (1 mmol) of Cs2CO3 was added and the solution was heated in a 60° C. bath for 3 h. The solution was cooled, diluted with Et2O, washed with water, brine, dried and concentrated. The residue was purified on a prep TLC plate using 20% EtOAc/hexane as eluant to afford the title compound. HPLC/MS: 424 (M+1), 426 (M+3); Rt=4.49 min.