Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]=O)=[CH:5][CH:4]=1.[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14]>C(O)(=O)C.N1CCCCC1>[C:13](/[C:15](=[CH:11]\[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)/[C:16]([O:18][CH3:19])=[O:17])#[N:14]
Reactant: COc1ccc(CCC=O)cc1
Reactant: COC(=O)CC#N
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COC(=O)/C(C#N)=C/CCc1ccc(OC)cc1
Yield: 72.3 %

Procedure:
A solution of 13d (0.616 g, 3.75 mmol) in 0.51 mL glacial acetic acid was treated with NCCH2CO2CH3 (0.338 g, 3.75 mmol, 0.3 mL, 1.0 equiv), then a premixed solution of piperidine (0.0011 g, 0.128 mmol, 13 mL, 3.4 mol %) and 125 mL of acetic acid at room temperature (24 h). The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (15 mL, pH>7) and extracted with EtOAc (3×15 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. SGC chromatotron (SiO2, 1 mm, 0-10% EtOAc/hexanes) afforded 15d (0.665 g, 0.920 g theoretical, 72%). For 15d: 1H NMR (CDCl3, 400 MHz) d 7.63 (t, 1H, J=7.5 Hz, CH=C), 7.09 (d, 2H, J=8.5 Hz, Ar C2-H and C6-H), 6.83 (d, 2H, J=8.5 Hz, Ar C3-H and C5-H), 3.83 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 2.70-2.90 (m, 4H, ArCH2CH2); IR (neat) nmax 2955, 1837, 2359, 2341, 1732, 1612, 1513, 1436, 1270, 1248, 1178, 1116, 1061, 1039, 823, 761, 668 cm-1. See FIG. 19c.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][S:5][C:6]1[C:7](=[O:14])[O:8][C:9]([CH3:13])=[CH:10][C:11]=1[OH:12].C(OO)(=[O:22])C>C(O)(=O)C.O>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][S:5]([C:6]1[C:7](=[O:14])[O:8][C:9]([CH3:13])=[CH:10][C:11]=1[OH:12])=[O:22]
Reactant: Cc1cc(O)c(SCc2ccc(Cl)cc2Cl)c(=O)o1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(O)c(S(=O)Cc2ccc(Cl)cc2Cl)c(=O)o1

Procedure:
3-(2,4-Dichlorobenzylthio)-4 -hydroxy-6-methyl-2-pyrone (13.0 g., 0.041 mole) and 40% peroxyacetic acid (7.8 g., 0.041 mole) were dissolved in glacial acetic acid (200 ml.). The solution was allowed to stand at room temperature for two weeks, then was diluted with water and extracted with methylene chloride. The extract was dried (MgSO4) and evaporated to dryness, leaving 12.6 g. (93 percent) of an off-white solid. Recrystallization from benzene gave the pure product as white needles, m.p. 144°-146°C.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[NH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=[CH:27][CH:28]=1>>[N+:19]([C:10]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=2[CH:17]=[CH:18][C:9]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:36])[CH:24]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2c1CCCC2
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2ccc3c(c2[N+](=O)[O-])CCCC3)c1

Procedure:
1-Nitro-5,6,7,8-tetrahydronaphthalen-2-yl triflate and tert-butyl 3-aminophenylcarbamate were used in a process similar to Example 1(1) to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)CCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CN1CCNCC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(Br)cc2C#N)CC1
Temperature: 140 °C
Yield: 92.8 %

Procedure:
A mixture of 5-bromo-2-fluorobenzonitrile (0.20 g, 1.0 mmol), 1-methylpiperizine (0.15 g, 1.5 mmol) and triethylamine (0.20 g, 2.0 mmol) in 1-butanol (3.0 mL) was heated at 140° C. for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate, washed with water, brine, dried over Na2SO4, filtered and concentrated to provide the desired product (0.26 g, 92%). LCMS calculated for C12H15BrN3(M+H)+: m/z=280.0. Found 280.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)=[CH2:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:32]1[CH:33]=[CH:34][C:29](/[CH:27]=[CH:28]/[C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C@@:15]5([C:21]6[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:9][CH2:10]3)=[CH:4][CH:3]=2)=[CH:30][CH:31]=1
Reactant: C=Cc1ccncc1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4)CC3)C2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(/C=C/c5ccncc5)cc4)CC3)C2)c2ccccc21

Procedure:
A mixture of POPd1 catalyst (CombiPhos Catalysts, Inc) (2 mg), (1R)-1′-{[1-(4-bromophenyl)cyclopropyl]-carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (15 mg, 0.036 mmol), 4-vinylpyridine (19 mg, 0.18 mmol), potassium carbonate (5.5 mg, 0.04 mmol) in N,N-dimethylformamide (0.3 ml) was microwave irradiated at 135° C. for 30 minutes. Then the desired product was obtained from the mixture by prep-HPLC followe by chiral HPLC (13 mg, 82%). LCMS: m/z 437.2 (M+H)+; 459.2 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(C)c2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)c1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 2) 30.0 mg (0.071 mmol) in 3 ml of EtOH and 2 ml of THF was added 28.0 mg (0.70 mmol, 0.7 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCI. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ7.90 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz), 7.46 (2H, s), 7.32-7.13 (4H, m), 7.10 (1H, s), 6.98 (1H, t, J=4.5 Hz), 2.34 (3H, s), 2.31 (2H, d, J=4.5 Hz), 1.30 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[C:5]([CH3:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCCCCC>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[O:22][C:6]1[C:5]([CH3:10])=[CH:4][C:3]([N+:11]([O-:13])=[O:12])=[C:2]([CH3:1])[C:7]=1[Cl:8]
Reactant: Cc1ccc(O)c(C)c1
Reactant: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2c(C)cc([N+](=O)[O-])c(C)c2Cl)c(C)c1
Yield: 69.6 %

Procedure:
Into a round bottom reaction flask equipped with a magnetic stirrer, condenser, thermometer and nitrogen inlet was added 50.0 grams (0.23 mol) of 2,5-dimethyl-3,4-dichloronitrobenzene, 38.5 grams (0.32 mol) of 2,4-dimethylphenol, 50 grams (0.36 mol) of potassium carbonate and 125 milliliters of dimethylformamide. The reaction mixture was heated to a temperature of 90° C.-100° C. and maintained at this temperature for a period of 72 hours. The reaction mixture was then cooled, filtered and concentrated to give a dark oil. The dark oil was partitioned between toluene (300 milliliters) and 4% sodium hydroxide (250 milliliters) and then separated. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to give a dark oil. The dark oil was trituated with hexane and a solid was formed. The solid was washed with cold hexane and vacuum dried to give 47.8 grams (0.16 mol) of 4-(2,4-dimethylphenoxy) 2,5-dimethyl-3-chloronitrobenzene as a tan powder having a melting point of 78° C.-80° C. Elemental analysis of the tan powder indicated the following:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([CH3:20])(C(=O)C)[C:14]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.ClC1C=[C:33](C=CC=1)[C:34]([O:36]O)=[O:35]>C(Cl)Cl.C(OCC)C>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([CH3:20])([O:36][C:34](=[O:35])[CH3:33])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:7][CH:8]=1
Reactant: CC(=O)C1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OC1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 72 h

Procedure:
To 2.0 g (4.7 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-methyl-4-acetyl-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 13a) in 10 ml of methylene chloride was added 2 g (9.8 mmole) of 85% 3-chloroperoxybenzoic acid (MCPBA). After standing for 72 hours at room temperature an additional 0.6 g of MCPBA was added and the reaction was let stand an additional 72 hours. The reaction mixture was diluted with diethyl ether, washed with dilute aqueous sodium bisulfite, dilute aqueous sodium bicarbonate, and brine. The resulting solution was dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and crystallized from diethyl ether and hexanes to yield the title compound, a white solid, mp 92°-96° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH2:15][C:16](OC)=[O:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.[BH4-].[Na+].C(O)(C)(C)C.Cl>CO>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:14][CH2:15][CH2:16][OH:17])(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: COC(=O)CCS(=O)(=O)c1ccc(NC(C)=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CO
Product: Nc1ccc(S(=O)(=O)CCCO)cc1
Yield: 20 %

Procedure:
A mixture of methyl 3-(4-acetamidophenylsulfonyl)propionate (54.2 g, 190 mmol), sodium borohydride (22.3 g, 590 mmol), and 400 mL of t-butanol was stirred mechanically and heated to reflux. Methanol (11 mL) was added dropwise over 20 minutes, and the resulting solution was stirred at reflux for 2 hours. The reaction mixture was cooled, and 250 mL of 3M aqueous HCl was added slowly with vigorous gas evolution occurring. The resulting mixture was partially concentrated at reduced pressure to remove t-butanol, and the residue was heated at reflux for 2 hours. The mixture was cooled, and solid sodium bicarbonate was added slowly until the pH of the mixture was 6-7. The mixture was allowed to stand several hours at 23° C. and then the precipitated product was filtered. After recrystallization from methanol containing a small amount of ether, 8.2 g (20%) of cream-colored powder was obtained, mp 99°-102° C.
Reaction SMILES: Cl.[F:2][C:3]1[C:12]2[O:11][CH2:10][C@H:9]([N:13]([CH:17]([CH3:19])[CH3:18])[CH2:14][CH2:15][CH3:16])[CH2:8][C:7]=2[C:6]([O:20]C)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(Cl)(Cl)Cl>C(Cl)Cl>[F:2][C:3]1[C:12]2[O:11][CH2:10][C@H:9]([N:13]([CH:17]([CH3:19])[CH3:18])[CH2:14][CH2:15][CH3:16])[CH2:8][C:7]=2[C:6]([OH:20])=[CH:5][CH:4]=1
Reactant: CCCN(C(C)C)[C@H]1COc2c(F)ccc(OC)c2C1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCN(C(C)C)[C@H]1COc2c(F)ccc(O)c2C1
Temperature: -40 °C
Yield: 97 %

Procedure:
(R)-8-Fluoro-3-(N-isopropyl-N-propylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran hydrochloride (1.03 g, 3.24 mmol) was dissolved in anhydrous CH2Cl2 (30 mL) and cooled to -40° C. To the solution was BBr3 (0.77 mL, 8.1 mmol), dissolved in anhydrous CH2Cl2 (5 mL), added dropwise. The cooling-bath was removed and after 3 h at room temperature the reaction was complete. The reaction was poured out onto an ice/2M NH3 solution and the mixture was extracted, twice, with diethyl ether. The combined ether portions were treated with brine, dried (Na2SO4), filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 20% ethyl acetate/hexane) gave 0.84 g (97% yield) of the title compound as a clear oil [α]21D =-94.2° (C=0.1 CHCl3) GC-MS (70 eV) M=267 (26%). The hydrochloride salt was made by dissolving the pure base in diethyl ether and dropping an excess of an ethereal HCl solution. The salt was recrystallized from CHCl3 /diethyl ether/ethyl acetate to give a white solid. Mp: 220°-2° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[N+:10]([O-])([O-:12])=[O:11].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:10]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=1[OH:9])([O-:12])=[O:11]
Reactant: CCc1cccc(O)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 24.8 %

Procedure:
3-ethylphenol (5.00 g, 41 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (3.83 g, 45 mmol). The addition of sulfuric acid (50 mL/3 M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(1.7 g, 25%). 1H NMR (CD3COCD3): δ 8.02 (d,1H), 6.99 (s,1H), 6.85 (d, 1H), 2.69 (q, 2H), 1.30 (t, 3H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:59][O:60][CH3:61])[C:27]([NH:29][CH:30]2[C:57](=[O:58])[N:32]3[C:33]([C:41]([O:43][CH:44]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:42])=[C:34](/[CH:37]=[CH:38]\[CH2:39]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:64]>O.[N+]([O-])([O-])=O.[Ag+]>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:59][O:60][CH3:61])[C:27]([NH:29][CH:30]2[C:57](=[O:58])[N:32]3[C:33]([C:41]([O:43][CH:44]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:42])=[C:34](/[CH:37]=[CH:38]/[CH2:39][OH:64])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CS(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/CO)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
To a mixture of diphenylmethyl 7-[2-(2-tritylaminothia-zol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-3-chloropropen-1-yl]-3-cephem-4-carboxylate (IIa) (715 mg, 0.825 mmol) in DMSO (9 ml) and water (2.5 ml) was added silver nitrate (700 mg) under cooling and the mixture was stirred for 6 hours at room temperature. The mixture was poured into water (50 ml) and extracted with CHCl3 (300 ml). The organic phase was washed with water and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel (Merck kieselgel 60, 20 g) by successively eluting with 0.5% MeOH/CHCl3, 1% MeOH/CHCl3 and 3% MeOH/CHCl3. The eluate was monitored by TLC and the fractions containing the desired product were combined. Evaporation under reduced pressure gave 452 mg (65% yield) of the title product as an amorphous powder.
Reaction SMILES: C(S[C@H:4]1[N:7]([C:8](=[C:22]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([S:38][C:39]3[CH:44]=[C:43]([Cl:45])[C:42]([Cl:46])=[CH:41][C:40]=3[Cl:47])=[O:37])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:48])[C@@H:5]1[C@H:49]([OH:51])[CH3:50])C.[Cl:52]Cl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:52][C@@H:4]1[N:7]([C:8](=[C:22]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([S:38][C:39]3[CH:44]=[C:43]([Cl:45])[C:42]([Cl:46])=[CH:41][C:40]=3[Cl:47])=[O:37])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:25])([CH3:27])[CH3:26])[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[S:10])[C:6](=[O:48])[C@@H:5]1[C@H:49]([OH:51])[CH3:50]
Reactant: ClCl
Reactant: CCS[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(C(=O)Sc2cc(Cl)c(Cl)cc2Cl)cc1)C(=O)C(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N(C(C(=S)OCc2ccc([N+](=O)[O-])cc2)=C(Oc2ccc(C(=O)Sc3cc(Cl)c(Cl)cc3Cl)cc2)C(=O)C(C)(C)C)[C@H]1Cl
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a stirred solution of 1.26 g of 4-nitrobenzyl 2-[4(R)-ethylthio-3(S)-(1(R)-hydroxyethyl)-azetidin-2-on-1-yl]-3-[4-(2,4,5-trichlorophenylthio-(carbonyl))-phenoxy]-3-trimethylacetylthiopropenoate in 30 ml of dry chloroform at -40° C. was added a solution of 1.83 mmol chlorine in 4 ml of carbon tetrachloride, and the solution was stirred for 30 minutes. The reaction mixture was allowed to reach room temperature and evaporated to dryness. Chromatography of the residue (silica gel, hexane/ethyl acetate mixtures as eluant) gave the title compound as a pale yellow foam (0.706 g). νmax (CHCl3) 1784 cm-1.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]2)[C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[N:3]=1.[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]1[CH:28]=O>>[CH3:1][C:2]1[N:6]([C@@H:7]2[CH2:8][CH2:9][C@H:10]([NH:13][CH2:28][CH:20]3[CH2:19][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[CH2:11][CH2:12]2)[C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@@H](N)CC1
Reactant: O=CC1Cc2ccccc2C1
Product: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@@H](NCC2Cc3ccccc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-4-(2,5-dimethyl-benzoimidazol-1-yl)-cyclohexylamine and indan-2-carbaldehyde. 1H-NMR is consistent with the assigned structure, LC-MS showed a single peak, C25H31N3 (m/e) calcd 373.2518, obsd 374.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][C@H:25]([CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[N:29]3)[O:24][C:23]2=[O:33])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[N:10][N:11](CC2C=CC(OC)=CC=2)[CH:12]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][C@H:25]([CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[N:29]3)[O:24][C:23]2=[O:33])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[N:10][NH:11][CH:12]=1
Reactant: COc1ccc(Cn2cc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)nn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2c[nH]nn2)c(F)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
(5R)-3-{3-Fluoro-4-[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Intermediate 15, 1.12 g, 2.49 mnol) was dissolved in trifluoroacetic acid (20 ml) and stirred at 65° C. overnight. The solution was concentrated then diluted with water until a precipitate formed. The light green solid was recrystallized using acetone and methanol to give the desired product as a beige solid (0.782 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[C:24]([OH:27])(=[S:26])[CH3:25]>C(#N)C>[S:15]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][S:26][C:24](=[O:27])[CH3:25])=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:17])(=[O:16])[NH2:18]
Reactant: NS(=O)(=O)c1cccc(-c2ccc(CBr)cc2)c1
Reactant: CC(O)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)SCc1ccc(-c2cccc(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4′-(bromomethyl)biphenyl-3-sulfonamide (1.28 g, 3.9 mmol) (WO 01/70753) in acetonitrile (16.4 mL) was treated with sodium bicarbonate (475 mg, 5.7 mmol) and thioacetic acid (0.34 mL, 4.7 mmol). The reaction mixture was stirred at 25° C. for 16 h. Additional sodium bicarbonate and thioacetic acid (0.4 eq. each) were added followed by acetonitrile (5 mL) and the reaction mixture was heated to 50° C. for 30 min. The reaction mixture was washed with water (10 mL) and brine (10 mL), dried with MgSO4, filtered, and concentrated to give a crude residue (quantitative) which was used in the next step without further purification. 1H NMR (500 MHz, CDCl3): δ 8.15 (dd, J=2.0, 2.0 Hz, 1H), 7.92 (ddd, J=7.8, 2.0, 1.0 Hz, 1H), 7.80 (ddd, J=7.8, 2.0, 1.0 Hz, 1H), 7.61 (dd, J=7.8, 7.8 Hz, 1H), 7.58–7.55 (m, 2H), 7.44–7.41 (m, 2H), 4.90 (br s, 2H), 4.19 (s, 2H), 2.40 (s, 3H); LCMS found for C15H15NO3S2Na (M+Na)+: m/z=344.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[F:10][C:11]1[CH:16]=[C:15](Br)[CH:14]=[CH:13][C:12]=1[O:18][CH3:19].C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[F:10][C:11]1[CH:16]=[C:15]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:14]=[CH:13][C:12]=1[O:18][CH3:19]
Reactant: COc1ccc(Br)cc1F
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(-n2ccc3ccccc32)cc1F

Procedure:
Indole (60 g, 0.51 mole), o-fluoro-p-bromoanisole (112.2 g, 0.547 mole), K2CO3 (76 g, 0.55 mole) and Cu2Br2 (14 g) were combined in 600 ml N-methylpyrrolidone and heated at 185°-200° for 48 hours, stirring under N2. The reaction mixture was cooled, poured into ice and water and extracted several times with ethyl acetate. The combined organic layers were washed with H2O, then brine, dried over MgSO4, treated with activated carbon, and concentrated to an oil (148 g). A portion of the oil (25 g) was chromatographed on silica gel (7.5×18 cm) eluting with 1:9 CH2Cl2 : hexane, yielding title product as an oil which crystallized on standing in vacuo overnight, 7.2 g, m.p. 65°-67°.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[N:40]1([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:49]3[CH2:50][CH2:51][CH:46]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[CH2:47][CH2:48]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Product: Cc1ccccc1-c1nc(N2CCC(N3CCOCC3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 87 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 4-(morpholine-4-yl)piperidine (30.7 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-[4-(morpholine-4-yl)piperidine-1-yl]-5-oxopyrimido[4,5-b][1,5]diazocine (86.5 mg, 87%).