Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9]Cl>CN(C)C=O>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: ClCl
Solvent: CN(C)C=O
Product: Oc1ccc(Cl)nc1Cl
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
100 g (0.77 mole) of 2-chloro-3-pyridinol is dissolved in 350 ml of dimethylformamide. In the course of 1.5 hours, 70 ml of chlorine (measured at -80°; 0.93 mole) is introduced at 0° into the stirred solution. The reaction mixture is subsequently stirred for 1.5 hours at 20° C and afterwards concentrated in a rotary evaporator (bath: 50°; 10 torr). To the residue are added 400 ml of water and 100 ml of ether. The two phases are separated, and the aqueous phase is extracted 5 times with 100 ml of ether each time. The combined ether phases are washed with water and dried. The solvent is removed in vacuo; the semisolid residue is stirred with 1.6 liters of water, and the resulting suspension is adjusted to pH 3. The suspension is heated to boiling, and after a few minutes the solution is decanted from an oily residue. The solution is purified with active charcoal, and the yellow product, obtained on cooling, is recrystallised from water; m.p. 136°-138° C; yield: 42 g;
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].C(N)=O.[O-]C1C=CC=CC=1.[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31]Cl)(=[O:26])[CH3:25]>CN(C)C=O>[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[CH:12][CH:11]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OCCCCCl
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: NC=O
Solvent: CN(C)C=O
Product: CC(=O)OCCCCOc1ccc(C(C)(C)C)cc1

Procedure:
To a stirred slurry of 1.6 g sodium hydride (as 50% dispersion in oil) in 50 ml dry dimethyl formamide was added, dropwise, a solution of 5.0 g p-tert-butylphenol (33.3 mmoles) in 50 ml dry diemthyl formamide and the solution stirred under nitrogen until the phenoxide had totally formed. To the phenoxide was added a solution of 5.0 g 4-chlorobutyl acetate (33.3 mmoles) in 50 ml dry dimethyl formamide and the solution was stirred for fourteen hours. The reaction mixture was partitioned between water/ toluene. The organic layer was removed, washed with water, then 1 N sodium bicarbonate. The organic layer was removed, dried and evaporated to an orange oil, 5.6g. The oil was chromatographed on 500 g, 90 to 200 mesh silica gel (CH2Cl2 eluent) yielding pure 4-(p-tert-butylphenoxy)-butyl acetate.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](=O)[CH3:21])=[CH:15][CH:14]=1)[CH3:12]>>[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:21])=[CH:15][CH:14]=1)[CH3:12]
Reactant: CCc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccccc1
Product: CCc1ccc(CC(C)NCC(O)c2ccccc2)cc1

Procedure:
The title compound was prepared in the manner described in Example 3 using 2-hydroxy-2-phenylethanamine and 4-ethylphenyl acetone. Recrystallization of the chromatographed material from hexane gave the title compound m.p. 76-82 as a 19:81 mixture of diastereoisomers (analysed as the hemi-hydrate). τ(CDCl3), 8.9 (3H, d, J=6 Hz), 8.8 (3H, t, J=6 Hz), 7.5 (2H, disappears with D2O), 7.0-7.5 (7H, m), 5.35 (1H, dd), 2.9 (4H, s), 2.7 (5H, s).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN(C=O)C>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:20][CH2:21][O:22][CH3:23])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COCCBr
Reactant: COc1cc(C=O)c(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(F)c(C=O)cc1OC
Reaction time: 86 h

Procedure:
2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (0.500 g, 2.94 mmol) was dissolved in DMF (2.6 mL) containing Cs2CO3 (2.88 g, 8.82 mmol). 1-Bromo-2-methoxy-ethane (1.23 g, 828 μL, 8.82 mmol) was added and the reaction mixture was allowed to stir for 86 h. The reaction mixture was filtered and the filtrate was evaporated to dryness to give 2-fluoro-5-methoxy-4-(2-methoxyethoxy)benzaldehyde. ESI-MS m/z calc. 228.1, found 229.0 (M+1)+. Retention time: 1.14 minutes (3 min run).
Reaction SMILES: [OH-].[Na+].O.[C:4]1([CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[OH:5].[Cl:12][C:13]1[CH:14]=[C:15]([F:20])[C:16](F)=[N:17][CH:18]=1>CS(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]([F:20])[C:16]([O:5][C:4]2[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=2)=[N:17][CH:18]=1
Reactant: Oc1ccc(O)cc1
Reactant: Fc1cc(Cl)cnc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Reaction time: 0.33 h
Yield: 26.1 %

Procedure:
A solution of NaOH (1.76 g, 0.044 mol) in a few ml of water was added to hydroquinone (4.86 g, 0.044 mol) in 250 ml DMSO. The mixture was stirred under nitrogen for 20 minutes. 5-Chloro-2,3-difluoropyridine (6.0 g, 0.040 mol) was added. The reaction mixture was heated at 60°-70° C. for 3 hours, then poured over ice. Aqueous NaOH was added to pH 12 and the solid diether side-product was filtered off. The filtrate was acidified, extracted with ether, treated with Norite adsorbent, and the solvent was removed by rotary evaporation to give a yellow oil which solidified on standing and was purified by high pressure liquid chromatography (HPLC) (80% hexane/20% ethyl acetate) to give a white solid (2.5 g, 26% yield, m.p. 90°-92° C.).
Reaction SMILES: NC1CCCNC1.C1(=O)OC(=O)C2=CC=CC=C12.C(C1C=CC=CC=1C([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([N:32]2[C:36](=[O:37])[C:35]3=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]3[C:33]2=[O:42])[CH2:27]1)=O)(O)=O.Cl>>[C:33]1(=[O:42])[N:32]([CH:28]2[CH2:29][CH2:30][CH2:31][NH:26][CH2:27]2)[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]12
Reactant: O=C(O)c1ccccc1C(=O)N1CCCC(N2C(=O)c3ccccc3C2=O)C1
Agent: Cl
Agent: NC1CCCNC1
Agent: O=C1OC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1C1CCCNC1

Procedure:
A mixture of 10 g. of 3-aminopiperidine and 29.6 g. of phthalic anhydride is heated at 150° C. for 30 minutes. This mixture which contains 1-(2-carboxybenzoyl)-3-phthalimidopiperidine is heated at reflux with 500 ml. of 6N hydrochloric acid for two hours. The aqueous phase is extracted with ether and then concentrated in vacuo. The residue is extracted with dilute aqueous sodium hydroxide solution and methylene chloride. The organic phase is dried and concentrated in vacuo to give 3-phthalimidopiperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.C([O-])(=O)C.[Na+].[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C(O)(=O)C>[OH:13][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:12])[NH:10]2
Reactant: Nc1ccc(O)c2c1NC(=O)CC2
Reactant: CS(=O)(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc(O)c2c1NC(=O)CC2
Yield: 54.1 %

Procedure:
5.0 g of 8-amino-5-hydroxy-3,4-dihydrocarbostyril was suspended in 30 ml of acetic acid, and 4.0 g of sodium acetate was added to the suspension while stirring. 3.5 g of methanesulfonyl chloride was then added to the mixture followed by heating for 7 hours while refluxing. After completion of the reaction, 100 ml of water was added to the reaction mixture which was then concentrated to dryness under reduced pressure. The resulting residue was added to 200 ml of water, and the mixture was stirred. The crystals formed were recovered by filtration, washed with water and recrystallized from methanol to obtain 3.89 g of 5-hydroxy-8-methanesulfonylamino-3,4-dihydrocarbostyril as colorless amorphous crystals having a melting point of 269.4°-269.8° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].[CH:23]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:23]([N:36]1[CH2:41][CH2:40][N:39]([C:20](=[O:21])[CH2:19][N:3]2[CH2:4][CH2:5][C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:2]2=[O:1])[CH2:38][C:37]1=[O:42])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CNCCN1C(c1ccccc1)c1ccccc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.18 g, 0.6 mmol) and the product from Example 28A (0.18 g, 0.6 mmol) in methylene chloride (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.23 g, 0.6 mmol) and diisopropylethylamine (0.5 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with methylene chloride, and then washed with 1 N HCl, water, 1 N NaOH, and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.28 (m, 20H), 6.91 (s, 1H), 4.26 (d, J=21.70 Hz, 2H), 4.18 (d, J=12.88 Hz, 2H), 3.69 (m, 2H), 3.35 (m, 2H), 3.13 (m, 1H), 3.07 (m, 1H), 2.71 (m, 2H), 2.69 (s, 1H); MS (ESI+) m/z 544 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH2:9])[CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][N:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:37]([C:36]2[CH:40]=[CH:41][C:33]([N:30]3[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:28][CH2:29]3)=[N:34][CH:35]=2)=[O:38])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Reactant: NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[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: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methanamine 84-2 (53 mg, 0.195 mmol), 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid 46-1 (16 mg, 0.195 mmol), and HATU (81.5 mg, 0.214 mmol) were added N,N-diisopropylethylamine (DIEA, 52 μL, 0.298 mmol) and DMF (1.0 mL). The solution was stirred overnight at room temperature and was subjected to silica gel column chromatography with 1:1 ethyl acetate/hexanes as eluent to give tert-butyl 4-(5-(((3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate 46-2.
Reaction SMILES: Cl.Cl.Cl[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19](=[O:26])[NH:18][C:17]3[CH:27]=[CH:28][CH:29]=[N:30][C:16]2=3)=[O:14])[CH2:8][CH2:7]1.[NH4+:31].[OH-]>>[NH2:31][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19](=[O:26])[NH:18][C:17]3[CH:27]=[CH:28][CH:29]=[N:30][C:16]2=3)=[O:14])[CH2:8][CH2:7]1
Reactant: O=C1Nc2cccnc2N(C(=O)CN2CCN(CCCl)CC2)c2ccccc21
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: NCCN1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Reaction time: 8 h
Yield: 97 %

Procedure:
Compound 26 (8.6 mg,0.017 mmol) was dissolved in concentrated NH4OH (0.4 mL) and stirred overnight. The crude product was extracted into CHCl3, and the organic layer was evaporated to dryness. The remaining residue was recrystallized from chloroform/petroleum ether to yield 7.2 mg of 27 (97%); mp 188°-190 ° C.: 1H NMR (CDCl3) δ 2.00-2.70 (m, 12 H), 3.20 (d, J=14 Hz, 1 H), 3.60 (br d, J=14 Hz, 1 H), 7.26 (dd, J= 7.8, 4.7 Hz, 1 H), 7.40 (m, 1 H), 7.55 (dd, J= 7.9, 1.4 Hz, 1 H), 7.58-7.62 (br s, 1 H), 7.92 (d, J= 7.7 Hz, 1 H), 8.26 (br s, 1 H), 9.35 (br s, 1 H); MS (CI/NH3) m/e 381 (MH+base) , 338, 252, 212.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.7 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (93.5 mg, 72%).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>CCOC(C)=O>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: BrCc1ccccc1I
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccccc1I)OCC
Temperature: 160 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
A mixture of 2-iodobenzyl bromide 10 (5 g, 16.84 mmol) and triethyl phosphite (3.3 g, 20 mmol) was stirred at 160° C. After 4 h, the mixture was cooled to room temperature. The residue was subjected to flash chromatography (EtOAc: Hex, 1:4), and gave 2.3 g of 11 (39%). 1H NMR (200 MHz, CDCl3): δ1.24 (t, J=7.04 Hz, 6H), 3.40 (d, J=22.00 Hz, 2H), 4.03 (m, 4H), 6.91 (m, 1H), 7.32 (m, 1H), 7.44 (m, 1H), 7.82 (m, 1H); 13C NMR (50 MHz, CDCl3): δ 16.27 (J=6.00 Hz), 38.31 (J=137.50 Hz), 62.16 (J=6.70 Hz), 101.16 (J=9.45 Hz), 128.23 (J=3.35 Hz), 128.45 (J=3.55 Hz), 130.60 (J=5.10 Hz), 135.36 (J=8.80 Hz), 139.60 (J=2.85 Hz).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:7])(=O)[CH3:2].[OH-].[Na+]>OS(O)(=O)=O>[CH3:2][C:1]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=1
Reactant: CC(=O)NC(C(=O)c1ccncc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(-c2ccccc2)c(-c2ccncc2)o1
Temperature: 100 °C

Procedure:
A mixture of 2-acetamido-2-phenyl-1-(4-pyridyl)ethanone (0.101 g, 0.397 mmol) in conc. H2SO4 (1 mL) was heated at 100° C. for 18 h. After cooling, the mixture was poured onto ice and neutralized with 2.5N NaOH. The aqueous mixture was extracted with CH2Cl2 and the combined organic extracts were washed with sat'd NaCl and dried over MgSO4. Evaporation of solvent gave an oil which was purified by flash chromatography, eluting with 0-2% MeOH/CHCl3. The title compound was obtained as a gold oil (3.0 mg): MS(DCI/NH3) (m/z): 237 (M++H).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:3]=1[O:4]C1CCCCO1.C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>C1COCC1>[OH:4][C:3]1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:2]=1[B:26]([OH:27])[OH:25]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(OC2CCCCO2)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(O)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
2-(2-Bromo-4-methoxyphenoxy)tetrahydropyran (1.9g, 6.62 mmol) was dissolved in dry THF (25 ml) and the solution cooled to -78° C. under nitrogen. n-Butyl lithium (1.6M in hexanes, 4.6 ml, 7.36 mmol) was added dropwise with stirring over 10 minutes. The reaction was stirred at −78° C. for 1 hour. Triisopropoxy borane (1.6 ml, 6.9 mmol) was added dropwise and the mixture allowed to warm to room temperature overnight. The reaction was quenched with water, acidified to pH 1 with 2N hydrochloric acid and extracted with DCM (2×200 ml). The combined organic extracts were washed with 2N hydrochloric acid (50 ml), dried with magnesium sulphate and concentrated under vacuum. The oily solid produced was triturated with cyclohexane to give the title compound as a pale brown solid (660 mg, 59%); MS 166/167 (M−H)−; HPLC retention time (system 2) 3.53 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:38])(=O)=O>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][Cl:38])=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(CO)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 2.1 g (5.77 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-hydroxymethylphenyl)acrylamide in 100 mL of dichloromethane is combined with 1.7 mL (12.19 mmol) of triethylamine and then combined with 0.46 mL (5.88 mmol) of methanesulfonic acid chloride. The reaction mixture is stirred for 3 hours at ambient temperature, diluted with water, and extracted several times with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered through silica gel, and the filtrate is evaporated down. Yield: 0.4 g (18.1% of theory); C22H17Cl2NO (M=382.29); calc.: molecular ion peak (M+H)+: 381/383/385; found: molecular ion peak (M+H)+: 381/383/385.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][OH:11].Cl>N>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: OCCBr
Agent: Cl
Agent: N
Product: OCCSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
280 ml of 28% aqueous ammonia was added to a mixture of 50 g of 4-hydroxythiophenol and 54.56 g of ethylene bromohydrin and the mixture was stirred vigorously at room temperature for 2 h. 225 ml of concentrated hydrochloric acid was added thereto under cooling with ice to adjust the pH of the aqueous phase to 1. After extraction with ethyl acetate, the ethyl acetate layer was washed with a saturated aqueous common salt solution and then dried over anhydrous magnesium sulfate. The resulting solution was filtered and the filtrate was concentrated and subjected to silica gel column chromatography to obtain 44.77 g (yield: 66%) of the intended compound having the following physical properties:
Reaction SMILES: [Na+].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:16])[CH:11]2[NH2:15])[C:8]=1[C:17]([O-:19])=[O:18])(=[O:4])[CH3:3].[C:20]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]O)=[CH:29][CH:28]=1)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:20]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][O:18][C:17]([C:8]2[N:9]3[CH:12]([S:13][CH2:14][C:7]=2[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH2:15])[C:10]3=[O:16])=[O:19])=[CH:29][CH:28]=1)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)C(=O)Oc1ccc(CO)cc1
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(N)C2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OCc2ccc(OC(=O)C(C)(C)C)cc2)N2C(=O)C(N)C2SC1

Procedure:
To a suspension of 6.6 mM of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt in 35 ml of dimethyl formamide (DMF) is added 2equivalents of p-pivalyloxybenzyl alcohol followed by cooling to 0° C. after which 7.2 mM of dicyclohexylcarbodiimide in 7.5 ml of DMF is added dropwise with stirring. The mixture is stirred at 0° C. for one hour and an additional four hours at room temperature. The formed dicyclohexylurea is removed by filtration. The filtrate is diluted with chloroform, washed with water, dried over magnesium sulfate, filtered, andevaporated in vacuo to give 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid p-pivalyloxybenzyl ester.
Reaction SMILES: CO.C1C[O:6][CH2:5]C1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:18])[C:16]=1Br>O>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:18])[C:16]=1[O:6][CH3:5]
Reactant: Brc1cncc(Br)c1Br
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(Br)cncc1Br
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of MeOH (0.115 mL, 2.85 mmol) and THF (0.5 mL) at 0° C. was added sodium hydride (60% dispersion, 114 mg, 2.85 mmol). After stirring for 15 min, Intermediate 31B (600 mg, 1.900 mmol) was added, and the resulting mixture was stirred at room temperature for 19 hours, diluted with water (3 mL) and extracted with EtOAc (2×10 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield Intermediate 31 (0.480 g, 1.798 mmol, 95% yield) as a beige color solid. MS (ES): m/z=267.9 [M+H]+. 1H NMR (400 MHz, MeOD) δ ppm 8.68 (2 H, s), 3.99 (3 H, s). Intermediate 31 was used in the synthesis of Example 185.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[S:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=1)(=[O:26])(=[O:25])[NH2:24]>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:24][S:23]([C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:31][CH:32]=2)(=[O:25])=[O:26])=[O:21])=[CH:19][CH:18]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)c1ccc(NC(C)=O)cc1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with N-(4-sulfamoyl-phenyl)-acetamide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, DMSO) δ: 2.07 (s, 3), 3.60 (s, 3), 4.71 (s, 2), 6.26 (s, 1), 6.94 (m, 2), 7.21 (m, 2), 7.72 (m, 2), 7.86 (m, 2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[C:19]([CH3:26])([CH3:25])[C:20](OCC)=[O:21].O>CS(C)=O>[CH3:25][C:19]1([CH3:26])[C:20](=[O:21])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)Oc2cc([N+](=O)[O-])ccc2NC1=O
Temperature: 30 °C
Yield: 120.9 %

Procedure:
To a solution of 2-amino-5-nitrophenol (200 g) in dimethylsulfoxide (1000 mL) was added anhydrous potassium carbonate (269 g) under stirring at 30° C. or lower, then to the mixture was added ethyl 2-bromo-2-methylpropionate (278.4 g) at 30° C. or lower, and the mixture was stirred at 26° C. for 24 hours. To the reaction mixture was added water (2000 mL) at 40° C. or lower, and then stirred at room temperature for 3 hours. The reaction product was collected by filtration, and successively washed with dimethylsulfoxide/water (2:1, 800 mL) and water (3200 mL) to obtain the title compound (348.6 g) as a yellow solid (wet material) (yield: 121%, purity: 96%).