Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=O)=[CH:27][CH:26]=3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[NH2:41][C:42]1[NH:43][CH2:44][CH2:45][N:46]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35](=[O:37])[NH:41][C:42]4[NH:46][CH2:45][CH2:44][N:43]=4)=[CH:29][CH:30]=3)[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[O:14])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)OC(C)(C)C)cc1
Reactant: NC1=NCCN1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCN2)cc1)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Reaction time: 8 h
Yield: 40 %

Procedure:
436 mg (0.8 mmol) of tert-butyl (2S)-2-(1-adamantylmethyloxycarbonylamino)-3-(4-(3-ethoxycarbonylpropyloxy)phenyl)propionate were added to a solution of 388 mg (3.2 mmol) of 2-amino-4,5-dihydroimidazole hydrochloride and 359 mg (3.2 mmol) of potassium tert-butoxide in 10 ml of DMF. The mixture was stirred overnight. After the reaction had ended, it was worked up analogously to Example 4c and chromatographed on silica gel using the same eluent mixture. 188 mg (0.32 mmol) of (5.1) were obtained.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[NH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:17]=1[C:18]#[N:19].[OH-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:16]2[C:17]=1[C:18]([NH2:19])=[C:2]1[C:1]([CH2:6][CH2:5][CH2:4][CH2:3]1)=[N:15]2
Reactant: N#Cc1c(N)cccc1F
Reactant: O=C1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1c2c(nc3cccc(F)c13)CCCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 10.1 %

Procedure:
To a stirred solution of cyclohexanone (1.0 g, 10.0 mmole) in methylene chloride (10 ml) at -20° C., a 1M solution of titanium (IV) chloride in methylene chloride (20 ml) was added. The reaction mixture became yellow in color and to it a mixture of triethylamine (2.0 g, 20 mmole) and 2-amino-6-fluorobenzonitrile (1.36 g, 10.0 mmole) in methylene chloride (30 ml) were added. The reaction mixture immediately became dark in color and was allowed to warm to room temperature (about 25° C.) and stirred further for 15 hours. At the end of this period, the reaction mixture was treated with 12% aqueous NaOH (100 ml), and methylene chloride (100 ml). The reaction mixture was then filtered through a 2 inch diatomaceous earth pad (Celite (trademark)) which was washed with methylene chloride (50 ml) and water (100 ml). The organic layer was separated, washed with water (1×30 ml) and dried (anhydrous MgSO 4). The methylene chloride was removed under vacuum to afford an oil which was triturated with ether to give the title compound as a white solid (218 mg, 10%, m.p. 175° C.). 1H-NMR (CDCl3, 300 MHz,δ): 4H, m, 2.0 ppm; 2H, t, 2.59 ppm (J=7.0 Hz); 2H, t, 3.06 ppm (J=7.0 Hz); 2H, bs, 5.37 ppm; 1H, dd, 7.0 ppm (J=7.5, 14 Hz); 1H, dd, 7.46 ppm (J=8, 16 Hz); 1H d, 7.72 ppm (J=8.5 Hz). HRMS: Calculated--216.1053; Found--216.1039.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][C:22]=2[F:29])=[CH:18][C:17]=1[C:32]([F:35])([F:34])[F:33]>CN(C=O)C>[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:2]3[CH:3]=[C:4]4[N:11]([CH3:12])[CH2:10][CH2:9][N:5]4[C:6](=[O:8])[N:7]=3)=[CH:23][C:22]=2[F:29])=[CH:18][C:17]=1[C:32]([F:35])([F:33])[F:34]
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (80 mg, 0.431 mmol), sodium hydride (35 mg, 0.875 mmol) and (4-(4-chloro-3-(trifluoromethyl)phenoxy)-3-fluorophenyl)methanol (138 mg, 0.431 mmol) in DMF (2 mL).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[CH2:5].[F-].[Cs+].[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](=[O:39])[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][C:33]2[O:36][CH2:37][O:38][C:32]=2[CH:31]=1>CS(C)=O>[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](=[O:39])[CH2:28][CH:29]([C:30]1[CH:35]=[CH:34][C:33]2[O:36][CH2:37][O:38][C:32]=2[CH:31]=1)[CH2:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5]
Reactant: C=C(O[Si](C)(C)C)c1ccc2ccccc2c1
Reactant: O=C(C=Cc1ccc2c(c1)OCO2)c1ccccc1O
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1ccccc1O)c1ccc2c(c1)OCO2)c1ccc2ccccc2c1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(naphthalen-2-yl)ethylene (7.0 mmol; prepared according to J. Chem. Soc., Perkin Trans. I 1989, 1585) and CsF (0.27 g, 1.76 mmol) were added to a suspension 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-2-propen-1-one on Wang resin (2.0 g, 1.76 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and. alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-5-(naphthalen-2-yl)-1,5-pentanedione on Wang resin.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([CH3:30])=[C:11]([CH2:28]O)[C:12]2[O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:13]=2[C:26]=1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.CCCCCC>C(Cl)(Cl)Cl>[C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([CH3:30])=[C:11]([CH3:28])[C:12]2[O:16][CH2:15][C@H:14]([C:17]3[CH:18]=[CH:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[C:13]=2[C:26]=1[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(CO)c2c(c(C)c1NC(=O)NC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)NC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Yield: 57 %

Procedure:
Using (+)-N-(tert-butyl)-N′-((3R)-7-(hydroxymethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea obtained in Example 49, the title compound was synthesized in the same manner as in Example 45. Yield: 57%. Melting point: 209-210° C. (ethyl acetate-hexane). [α]D20=+53.2° (c=0.47, chloroform).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[CH:10][CH:11]1[O:20][CH:14]2[O:15]C(C)(C)[O:17][CH:13]2[CH2:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl.CC(C)=O.C([O-])(O)=O.[Na+]>CC#N>[CH2:1]([O:3][P:4]([CH:9]=[CH:10][CH:11]1[CH2:12][CH:13]([OH:17])[CH:14]([OH:15])[O:20]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(C=CC1CC2OC(C)(C)OC2O1)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)=O
Product: CCOP(=O)(C=CC1CC(O)C(O)O1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.8 %

Procedure:
Compound 9.6 (3.6 g, 11.76 mmol) in MeCN (40 mL) was treated with 1 N HCl (10 mL) and stirred at 50° C. for 5 h with slow distillation of residual acetone. The solution was cooled to ambient temperature and treated with NaHCO3 (1.0 g) then concentrated in vacuo. The residue was lyophilized overnight and MeOH (20 mL) was added and the solution was filtered. The solution was then co-evaporated with MeCN to afford crude compound 9.7 (3.5 g, >100% yield).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][CH2:14][CH3:15])=[C:4]([CH3:16])[CH:3]=1.ClCC1C2C(=CC=CC=2)C=CC=1C.C(Br)CC.CCOCC>C1(C)C=CC=CC=1>[CH2:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH:3][C:4]=1[CH3:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1c(C)cc(Br)c2ccccc12
Agent: Cc1ccc2ccccc2c1CCl
Solvent: CCCBr
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCc1c(C)ccc2ccccc12

Procedure:
1-Bromo-4-butyl-3-methylnaphthalene-- A solution of 1-chloromethyl-2-methylnaphthalene (32.3 g) in dry toluene (150 ml) was dropwise added to a Grignard reagent, from n-propylbromide (27.1 g), Mg(5.3 g), and dry ether (150 ml). The ether was evaporated, and the resulting solution was refluxed for 2 hrs. The reaction mixture was cooled and poured into an ice-cooled aqueous ammonium chloride. The organic layer was taken, and aqueous layer was extracted with ether. Combined organic solution was washed with 10% HCl, 10% NaOH, and water and dried. The solvent was evaporated, and the residue was distilled to give an oil (8.8 g) of 1-butyl-2-methylnaphthalene, bp2 82°-86° C. The oil (8.8 g) was brominated by a similar manner given in Example 9 to afford an oil (8.0 g, 65.1%) of bp2 124°-128° C.
Reaction SMILES: C[NH:2][S:3]([CH2:6]Cl)(=[O:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.C(N(CC)CC)C>CCOCC>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:6][S:3](=[O:5])(=[O:4])[NH:2][C:16]2=[O:17])=[CH:11][CH:10]=1
Reactant: CNS(=O)(=O)CCl
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1NS(=O)(=O)CN1c1ccc(Cl)cc1
Yield: 31.3 %

Procedure:
A 50-ml flask was charged with 5.0 grams (0.035 mol) of N-methyl chloromethane sulfonyl chloride (from Example 1) and 5.3 grams (0.035 mol) of p-chlorophenylisocyanate. Then 3 ml of triethylamine were added. There was an exothermic reaction, and the mixture turned solid. After standing for 3/4 hour at 25° C., ether was added to form a slurry. This slurry was filtered to give a white solid which was reslurried in ether, filtered and dried to give 2.7 grams of 4-p-chlorophenyl-1,2,4-thiadiazolidine-1,1,3-trione having a melting point of 155°-157° C. Analysis for C9H9ClN2O3S: S, 12.3%; Cl, 13.6%. Found, S, 12.4%; Cl, 13.7%. The infrared spectra had strong absorption at 1720, 1485, 1435, 1370, 1340, 1280, 1255, and 1145 cm-1. The NMR spectra in 6D-dimethylsulfoxide had major peaks at 7.7 (4H), 5.6 (2H), and 3.3 (3H) ppm, and minor peaks at 4.0 and 2.8 ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C(=O)CCCCl)cc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: COc1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-methoxyphenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 421.2 (M+H)+.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:9][C:10](=[O:12])[O-:11])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].[C:13]([Cl:23])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOCC>C(O)(C(F)(F)F)=O.CC(C)=O>[ClH:23].[C:13]([C:3]([CH2:9][C:10](=[O:11])[O-:12])([CH2:4][N+:5]([CH3:8])([CH3:6])[CH3:7])[OH:2])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: CC(C)=O
Product: C[N+](C)(C)CC(O)(CC(=O)[O-])C(=O)C=Cc1ccccc1
Reaction time: 4.5 h
Yield: 70 %

Procedure:
4.55 g (0.023 moles) of carnitine hydrochloride are dissolved in 6.9 mls of CF3COOH, and to the solution an excess (16 mls) of cinnamoyl chloride is added. The mixture is kept under stirring at 40°-45° C. for 4-5 hours. At the end of this period of time, the mixture is diluted with 60 mls of acetone and some ether is slowly added till complete precipitation. The mixture is filtered and the precipitate which has the tendency to become hygroscopic is quickly washed with ether and dried under vacuum at a temperature not exceeding 50° C.; 5.3 g of a product are obtained (yield 70%) having the following characteristics:
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:15][CH2:14][CH:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[N:12](CC2C=CC(OC)=CC=2)[C:11]1=[O:31])(C)(C)C.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC#N.O.CCOC(C)=O>[CH:16]1([CH:13]2[NH:12][C:11](=[O:31])[CH:10]([CH2:9][CH2:8][CH2:7][OH:6])[O:15][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COc1ccc(CN2C(=O)C(CCCO[Si](C)(C)C(C)(C)C)OCC2C2CCCCC2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1NC(C2CCCCC2)COC1CCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a solution of 2-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-5-cyclohexyl-4-(4-methoxy-benzyl)-morpholin-3-one (400 mg, 0.84 mmol, 1.0 equiv) in CH3CN (0.3 mL) and water (0.3 mL) was added CAN (922 mg, 1.68 mmol, 2.0 equiv). The mixture was stirred at room temperature for 1 hour then second portion of CAN (900 mg) was added. After stirred at room temperature for 1 hour, the reaction mixture was diluted with EtOAc and the phases were separated. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, EtOAc/heptane 50% to 100% EtOAc to give 5-cyclohexyl-2-(3-hydroxy-propyl)-morpholin-3-one 134 mg.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.CN1CCN(C)C1=O.O>C(O)(=O)C>[N:22]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Solvent: CN1CCN(C)C1=O
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccnc3)cc2c1=O
Temperature: 140 °C
Yield: 35.1 %

Procedure:
A mixture of 530 mg (1.665 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide, 567 mg (8.325 mmol) of imidazole and 7.7 ml of dry 1,3-dimethyl-2-imidazolidinone is heated to 140° C. (oil bath temperature) for 90 minutes in a closed vial. After cooling, the dark solution is poured on 130 ml of water and the pH adjusted to ˜5 by adding 2 M acetic acid. The precipitate formed is filtered and recrystallized four times from DMSO/water, yielding 214 mg of the title compound as a red powder, m.p. >270° C.
Reaction SMILES: CS[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][C:28]([C@@H:31]4[CH2:33][C@H:32]4[C:34]([OH:36])=[O:35])=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[CH:9]=1)=[O:7].O[O:38][S:39]([O-:41])=O.[K+].[CH2:43]1COCC1.CO.O>O>[CH3:43][S:39]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:19]2[CH:20]=[C:21]([C:25]3[CH:26]=[CH:27][C:28]([CH:31]4[CH2:33][CH:32]4[C:34]([OH:36])=[O:35])=[CH:29][CH:30]=3)[CH:22]=[CH:23][CH:24]=2)[CH:9]=1)=[O:7])(=[O:41])=[O:38]
Reactant: C1CCOC1
Reactant: CSCCNC(=O)c1cn(-c2cccc(-c3ccc([C@@H]4C[C@H]4C(=O)O)cc3)c2)c2ncccc2c1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)CCNC(=O)c1cn(-c2cccc(-c3ccc(C4CC4C(=O)O)cc3)c2)c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of EXAMPLE 22 (1 eq) in THF-MeOH—H2O (2:1:1, 0.1M) was added Oxone (2 eq). The mixture was stirred at rt for 18 h and diluted with water. The residue was isolated by filtration, washed with ether to afford the title compound as a solid.
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[CH:5]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[O:11])[C:6](=C)[CH2:7][S:8][C@H:3]12.C[OH:26]>>[NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[O:11])=[C:6]([OH:26])[CH2:7][S:8][C@H:3]12
Reactant: C=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CO
Product: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12

Procedure:
In a further example, p-nitrobenzyl 7-amino-3-methylenecepham-4-carboxylate 1 hydrochloride is dissolved in methanol and ozone is bubbled through the solution at a temperature of about -78° C. Excess ozone is purged from the mixture with nitrogen and the ozonide is decomposed by bubbling sulfur dioxide through the mixture. The reaction mixture is evaporated to dryness and the residue, p-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate is obtained as the hydrochloride salt.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 3-Bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.6) (281 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (310 mg, 54%). MS (ISP) 565.4 [(M+H)+]; mp 161–162° C.
Reaction SMILES: [C:1]([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+].[O:22]=[C:23]1[C:29]([CH3:31])([CH3:30])[CH2:28]C(=O)[CH:25]=[C:24]1[CH3:32]>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[C:12]([O:11][C:9]([O:8][C:1]1[CH:25]=[C:24]([CH3:32])[C:23](=[O:22])[C:29]([CH3:31])([CH3:30])[CH:28]=1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1=CC(OC(=O)OC(C)(C)C)=CC(C)(C)C1=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 80.9 %

Procedure:
A solution of 23.2 g (106.3 mmol) of di-tert.-butyl dicarbonate in 25 ml of tetrahydrofuran was added dropwise to a suspension, stirred at 24° C., of 20.0 g (144.7 mmol) of K2CO3, 20 ml of tetrahydrofuran, 1.1 g (4.2 mmol) of 18-crown-6 and 15.2 g (100 mmol) of ketoisophorone. The suspension was stirred at 60° C. for 5 hours, then the brown reaction mixture was filtered and finally the solvent was evaporated. The brown residue (26.6 g) was dissolved in 200 ml of dichloromethane and the solution was extracted with saturated NaHCO3 solution and with water. The organic phase was dried over Na2SO4, filtered and evaporated. The brown residue (22.6 g) was chromatographed over 150 g of silica gel (n-hexane/ether 2/1). There were obtained 20.4 g (81%) of 4-tert.-butyloxycarbonyloxy-2,6,6-trimethylcyclohexa-2,4-dienone as a yellow oil; anal. calc. for C14H20O4 (252.31): C 66.65, H 7.99; found: C 66.46, H 8.08.1H-NMR (250 MHz, CDCl3): 1.25 (s, 2 CH3 --C(6)); 1.54 (s, (CH3)3C--O); 1.91 (s, CH3 --C(2); 5.88-5.89 (d, H--C(5)); 6.71-6.74 (m, H--C(5)
Reaction SMILES: C([Mg]Cl)CCC.Cl[CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[Mg].C([O:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19](=O)[CH:18]=1)C>C1COCC1>[OH:12][CH2:11][CH2:10][CH2:9][CH2:8][C:19]1[CH2:20][CH2:21][CH2:22][C:17](=[O:16])[CH:18]=1
Reactant: CCOC1=CC(=O)CCC1
Reactant: OCCCCCl
Agent: CCCC[Mg]Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C1C=C(CCCCO)CCC1
Reaction time: 2 h

Procedure:
Butylmagnesium chloride (2.0M, 20.0 ml) is added dropwise over 20 min to a solution of 4-chloro-1-butanol (4.05 g) and THF (40.0 ml). The resultant solution is stirred for 20 min and then is added dropwise over 20 min to a mixture of magnesium (1.46 g) and THF (5.0 ml). The resulting warm mixture is heated at reflux for 3 hr, and then cooled in an ice bath. A solution of 3-ethoxy-2-cyclohexene-1-one (5.39 ml) and THF (20.0 ml) is then added dropwise over 20 min. The resultant solution is allowed to warm to 20°-25° and stir for 2 hr. Acidic workup using ether and hydrochoric acid (1%) and purification by flash chromatography eluting with ethyl acetate/hexane (4/1) provides 3-(4-hydroxybutyl)-cyclohex-2-en-1-one as an oil, IR (neat) 3413, 2942, 1664, 1600, 1257, 1185 cm-1 ; MS (EI) m/e (relative %) 168 (25), 123 (25), 97 (40), 82 (36), 55 (44), 42 (100).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35](C(OC(C)(C)C)=O)[CH:36]=2)O1>>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:23]=[C:2]([C:32]5[CH:33]=[N:34][NH:35][CH:36]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][CH:17]=[N:18]1)([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3cn[nH]c3)ccc1OCC2

Procedure:
Following Example 182, 10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 187 was coupled with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate to give 160. MS: 362.3. 1H NMR (400 MHz, DMSO) δ 8.57 (t, J=4.0, 1H), 7.99-7.94 (m, 4H), 7.56 (dt, J=11.2, 5.6, 1H), 7.06 (t, J=8.6, 1H), 5.81 (p, J=6.6, 1H), 4.53 (d, J=9.5, 4H), 1.53 (d, J=6.6, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48]([OH:50])=O.Cl.[NH2:52][CH2:53][C:54]([C:56]1[CH:60]=[CH:59][S:58][CH:57]=1)=[O:55].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:10]([CH2:11][O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48]([NH:52][CH2:53][C:54](=[O:55])[C:56]1[CH:60]=[CH:59][S:58][CH:57]=1)=[O:50]
Reactant: O=C(O)Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Reactant: NCC(=O)c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)NCC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.3 %

Procedure:
To a mixture of the carboxylic acid 55 (1.04 g, 1.5 mmol), 2-amino-1-(thiophen-3yl)ethanone hydrochloride (533 mg, 3.0 mmol), EDCI (575 mg, 3.0 mmol), and HOBt (507 mg, 3.75 mmol) in DMF (10 mL) was added NMM (0.83 mL, 7.5 mmol). The resulting mixture was stirred at room temperature for 15 h. The reaction mixture was poured into a HCl solution (1.0 M, 50 mL), and extracted with EtOAc. The organic phase was dried over anhydrous MgSO4, filtered and evaporated under vacuum. The residue was further purified by silica column chromatography to provide the titled amide compound (529 mg, 0.65 mmol, 43%).