Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:41](=[O:43])[CH3:42])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCS(=O)(=O)N(C(C)=O)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F

Procedure:
The title compound was prepared according to the procedure as described in Example 3 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.2 g, 0.41 mmol), triethylamine (1 mL) and acetyl chloride (116 μL, 1.64 mmol) in 1,4-dioxane (10 mL). The title compound was obtained as a white solid (69 mg, 31.8%). The title compound was characterized by LCMS and 1H NMR as shown below:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C:6]([CH2:16][CH3:17])([CH2:14][CH3:15])[N:5]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:4]=2[N:3]=1.C[CH:24]1[CH2:28][C:27]2=[C:29]([C:34]([OH:36])=[O:35])[CH:30]=[CH:31][C:32]([NH2:33])=[C:26]2[O:25]1.Cl>C(O)C.O>[CH:18]1([N:5]2[C:4]3[N:3]=[C:2]([NH:33][C:32]4[CH:31]=[CH:30][C:29]([C:34]([OH:36])=[O:35])=[C:27]5[C:26]=4[O:25][CH2:24][CH2:28]5)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C:6]2([CH2:16][CH3:17])[CH2:14][CH3:15])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC1Cc2c(C(=O)O)ccc(N)c2O1
Reactant: CCC1(CC)C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCC1(CC)C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Yield: 38.4 %

Procedure:
2-Chloro-8-cyclopentyl-7,7-diethyl-5-methyl-pteridin-6-one 42a (100 mg, 0.31 mmol) and methyl 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid 1g (50 mg, 0.28 mmol) were dissolved in 17 mL of the mixture solvent of ethanol and water (V/V=5:12) followed by the addition of 0.2 mL of concentrated hydrochloric acid. The reaction mixture was heated to reflux for 16 hours with stirring. The resulting solution was concentrated under reduced pressure, added dropwise with 1 M lithium hydroxide solution to adjust pH to 12 and extracted with ethyl acetate (50 mL×2), the combined aqueous phase was added dropwise with 1 M hydrochloric acid to adjust pH to 1 and extracted with dichloromethane (50 mL×3). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain 7-[(8-cyclopentyl-7,7-diethyl-5-methyl-6-oxo-pteridin-2-yl)amino]-2,3-dihydrobenzofuran-4-carboxylic acid 42b (50 mg, yield: 38.0%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[C:8](=[O:18])[C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[C:8](=[O:18])[C:5]2=[N+:6]([O-:27])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1c2ccc(Cl)cc2CCc2cc(Br)cnc21
Solvent: ClCCl
Product: O=C1c2ccc(Cl)cc2CCc2cc(Br)c[n+]([O-])c21
Reaction time: 42 h
Yield: 66 %

Procedure:
To a solution of 3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (2 g) (6.2 mmoles) in anhydrous dichloromethane (14 ml) at 0° C. and under an argon atmosphere, was added a solution of 3-chloroperbenzoic acid (1.76 g) (10.4 mmoles) in anhydrous dichloromethane (35 ml) dropwise over a period of 30 minutes. The mixture was allowed to warm to room temperature and after 18 h additional 3-chloroperbenzoic acid (0.88 g) (5.2 mmoles) in anhydrous dichloromethane (25 ml) was added and the mixture was stirred for a total of 42 h. The mixture was diluted with dichloromethane and washed with 1N NaOH (200 ml). The aqueous layer was extracted with additional dichloromethane (2X200 ml) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The product was chromatographed on silica gel using 0.25%-0.5%-1% (10% conc. NH4OH in methanol)dichloromethane as the eluant to give the title compound (Yield:1.386 g, 66%): ESIMS; m/z 338.1 (MH+); δc (CDCl3) CH2: 30.5, 34.0; CH: 126.9, 127.6, 130.3, 132.5, 140.4; C: 121.0, 135.1, 138.3, 139.7, 141.6, 145.3, 188.0 ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[CH:18]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:23]([S:20]([CH:18]=[CH:19][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17])(=[O:22])=[O:21])[CH3:24]
Reactant: C=CS(=O)(=O)CC
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCS(=O)(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Yield: 65.3 %

Procedure:
A mixture of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (0.25 g), ethyl vinyl sulphone (0.14 g), tri-o-tolylphosphine (0,075 g), palladium (II) acetate (0.013 g), triethylamine (0.25 mL) and acetonitrile (3 mL) was heated under reflux for 17 hours in an atmosphere of nitrogen. The mixture was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:8:1) gave the title compound as a foam (0.185 g): TLC (dichloromethane/-ethanol/concentrated aqueous ammonia, 90:10:1): Rf =0.5. Anal. Calcd for C18H24N2O2S. 0.2 CH2Cl2 : C,62.55; H,7.04; N,8.02. Found: C,62.65; H,6.94; N,7.92.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2Br)=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>COCCO.O.[Cu]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:17]3[S:18][CH:19]=[CH:20][C:21]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=NO)c2sccc2Br)CC1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2noc3ccsc23)CC1
Temperature: 65 °C
Reaction time: 6 h
Yield: 49.5 %

Procedure:
Add to a stirring solution of 4-[(3-bromo-thiophen-2-yl)-hydroxyimino-methyl]piperidine-1-carboxylic acid tert-butyl ester (Example 21b)(25 g., 64.2 mmol) in 2-methoxyethanol (200 mL), a solution of potassium hydroxide (7.2 g, 128.4 mmol) in water (20 mL). Heat the reaction to 60° C. and then add copper powder (1.25 g). Stir at 60-70° C. for 6 h and then at ambient temperature overnight. Pour the reaction mixture into water (500 mL) and extract with EtOAc (3 times). Concentrate to a dark residue and purify by column chromatography over silica gel (heptane/EtOAc, 4:1) to provide 9.8 g (50%) of a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH:22]1[CH:21]=[C:20]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[CH:9][C:10]4[CH2:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=4[CH:16]=3)[CH2:28][CH2:27]2)[C:19]([Cl:18])=[C:24]([Cl:25])[CH:23]=1
Reactant: O=C1CCc2ccc(OCCCCBr)cc2N1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1

Procedure:
Conventional anhydrous aripiprazole crystals are prepared by well-known methods, as described in Example 1 of Japanese Unexamined Patent Publication No. 191256/1990. 7-(4-bromobutoxy)-3,4-dihydrocarbostyril, is reacted with 1-(2,3-dichlorophenyl)piperazine and the thus obtained crude aripiprazole crystals are re-crystallized from ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH:23]5[CH2:25][CH2:24]5)=[CH:19][N:18]=4)[CH2:13][CH2:12]3)([CH3:10])[CH2:7][C:6]=2[CH:26]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1([C:20]2[CH:19]=[N:18][C:17]([N:14]3[CH2:15][CH2:16][CH:11]([C:8]4([CH3:10])[CH2:7][C:6]5[CH:26]=[C:2]([C:35]6[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=6)[CH:3]=[CH:4][C:5]=5[O:9]4)[CH2:12][CH2:13]3)=[N:22][CH:21]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC1(C2CCN(c3ncc(C4CC4)cn3)CC2)Cc2cc(Br)ccc2O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)CC(C)(C2CCN(c4ncc(C5CC5)cn4)CC2)O3)CC1
Temperature: 100 °C
Yield: 68.3 %

Procedure:
To a degassed solution of 2-(4-(5-bromo-2-methyl-2,3-dihydrobenzofuran-2-yl)piperidin-1-yl)-5-cyclopropylpyrimidine (424 mg, 1.02 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (380 mg, 1.23 mmol), and K2CO3 (424 mg, 3.07 mmol) in dioxane (6 mL) and water (2 mL) was added Pd(Ph3P)4 (59.1 mg, 0.051 mmol). Upon completion of addition, the reaction mixture was heated in 100° C. oil bath for 3 hours. After this time, the reaction mixture was cooled to room temperature, diluted with water, and extracted with CH2Cl2 (3×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 50% EtOAc) to afford Compound 11F as a white solid (360 mg, 0.697 mmol, 68% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.11 (s, 2 H), 7.15 (s, 1 H), 7.13 (d, J=8.5 Hz, 1 H), 6.65-6.71 (m, 1 H), 5.88 (br. s., 1 H), 4.75-4.87 (m, 2 H), 4.05 (br. s., 2 H), 3.73 (t, J=6.2 Hz, 1 H), 3.62 (t, J=5.5 Hz, 2 H), 3.16 (d, J=15.7 Hz, 1 H), 2.74-2.87 (m, 2 H), 2.39-2.54 (m, 2 H), 1.86-1.96 (m, 2 H), 1.76-1.84 (m, 1 H), 1.67-1.74 (m, 1 H), 1.61 (m, 1 H), 1.49 (s, 9 H), 1.37-1.41 (m, 3 H), 1.23-1.36 (m, 1 H), 0.84-0.92 (m, 2 H), 0.54-0.60 (m, 2 H). LC/MS (m/z)=517 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Mg]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]([OH:15])([CH3:14])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:16])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C(C)(O)Cc2ccccc2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of (R)-4-acetyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.80 g, CAS 167102-63-8) in THF (40 ml) was cooled under an argon atmosphere to 0° C. and treated dropwise with benzylmagnesium chloride solution (1 M in diethylether, 34.5 ml). The reaction mixture was stirred at r.t. overnight, then quenched with saturated aqueous NH4Cl (50 ml) and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane ->cyclohexane/EtOAc 3:1) to give (R)-4-(1-hydroxy-1-methyl-2-phenyl-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.45 g, 89%) as off-white waxy solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]#[CH:15])[C:8](=[O:16])[CH:7]=1.C1C(=O)N([Br:29])C(=O)C1>>[Br:29][C:7]1[C:8](=[O:16])[N:9]([CH2:13][C:14]#[CH:15])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: C#CCn1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Product: C#CCn1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 56.9 %

Procedure:
Bromination of 4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-prop-2-ynylpyridin-2(1H)-one (500 mg, 1.67 mmol) with NBS (300 mg, 1.67 mmol) was carried out in the manner described above to give 350 mg (57%) of the desired compound. 1H-NMR (DMSOd6/300 MHz) δ 7.67 (app q, J=9.0 hz, 1H), 7.36 (app dt, J=10.5, 2.4 hz, 1H); 7.23-7.16 (m, 1H); 6.60 (s, 1H), 5.29 (s, 2H), 4.90 (d, J=2.4, Hz, 1H), 3.35 (s, 3H), 3.32 (s, 1H), 2.53 (s, 3H); ES-HRMS m/z 368.0107 (M+H calcd for C16H13BrF2NO2=368.0098).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1)[CH2:3][OH:4].CO[C:18](OC)([CH3:20])[CH3:19].[C@@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(C)=O>[CH3:19][C:18]1([CH3:20])[O:1][CH:2]([C:5]2[CH:14]=[CH:13][C:12]3[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=3[N:6]=2)[CH2:3][O:4]1
Reactant: COC(C)(C)OC
Reactant: O=C1CCCc2nc(C(O)CO)ccc21
Agent: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)=O
Product: CC1(C)OCC(c2ccc3c(n2)CCCC3=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A mixture of 2-(1,2-dihydroxyethyl)-7,8-dihydroquinolin-5(6H)-one (Preparation 54D, 0.226 g, 1.09 mmol), 2,2-dimethoxypropane (0.402 mL, 3.27 mmol), and (1R)-(−)-camphorsulfonic acid (0.051 g, 0.22 mmol) in acetone (6 mL) was stirred at room temperature overnight. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate and concentrated under reduced pressure. The aqueous residue was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated and purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (50%) to afford 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-7,8-dihydroquinolin-5(6H)-one (0.182 g, 0.736 mmol, 68% yield) as a clear, colorless oil. The product had an HPLC ret. time=1.75 min. (condition A); LC/MS M+1=247.9.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[CH:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)O.C(OOC(C)(C)C)(C)(C)C>O.C(O)(=O)C>[C:10]([C:5]1[N:4]=[CH:3][C:2]([C:7]([OH:9])=[O:8])=[N:1][CH:6]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1cnccn1
Reactant: O=Cc1ccccc1
Agent: CC(C)(C)OOC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cnc(C(=O)c2ccccc2)cn1
Reaction time: 1 h
Yield: 36 %

Procedure:
To a stirred, cooled (0° C.) solution of 2-pyrazine carboxylic acid (3.0 g, 24.2 mmol) and benzaldehyde (7.4 mL; 73 mmol) in a 50% aqueous solution of sulfuric acid (40 mL) and 25 mL of acetic acid was added FeSO4 7 H2O (20.3 g, 73 mmol dissolved in 50 mL of water) and t-butyl peroxide (9.2 mL; 73 mmol) simultaneously. After stirring for 1 hour, the reaction was treated with 200 mL of water. A precipitate formed which was filtered and washed with methylene chloride (3×100 mL) to yield a tan solid (36% yield).
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH2:42][C:43]34[C:49]([F:51])([F:50])[CH:48]3[CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([OH:38])=O)[CH2:30][CH2:29]1.CS(N)(=O)=O.[N:57]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1>>[N:57]1([S:61]([NH:64][C:36](=[O:38])[C:35]2[CH:39]=[C:31]([CH:28]3[CH2:29][CH2:30]3)[C:32]([O:41][CH2:42][C:43]34[C:49]([F:51])([F:50])[CH:48]3[CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:33][C:34]=2[F:40])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-(((1RS,6SR)-7,7-difluorobicyclo-[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a white gum (0.040 g, 30%): 1H NMR (300 MHz, DMSO-d6) δ 11.61 (br s, 1H), 7.14 (d, J=8.25 Hz, 1H), 6.92 (d, J=12.76 Hz, 1H), 4.17-3.92 (m, 6H), 2.21-2.05 (m, 2H), 2.04-1.54 (m, 6H), 1.36-1.14 (m, 4H), 0.92-0.80 (m, 2H), 0.72-0.63 (m, 2H); MS (ES+) m/z 459.1 (M+1).
Reaction SMILES: N([O-])=O.[Na+].[C:5]([C:9]1[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=1)N)([CH3:8])([CH3:7])[CH3:6].[I-:18].[K+]>O>[C:5]([C:9]1[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([I:18])[CH:15]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: [I-]
Reactant: COc1ccc(C(C)(C)C)cc1N
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(C)(C)C)cc1I
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
A solution of 8 g (0.11 mol) of sodium nitrite in 25 ml of water was added dropwise to a solution of 20 g (0.11 mol) of 5-tert-butyl-2-methoxyaniline in 120 ml of water/conc. HCL (1:1) cooled to 5° C. After stirring at 5° C. for 15 min, a solution of 19.1 g (0.11 mol) of potassium iodide in 25 ml of water was added dropwise and the solution obtained was stirred at RT for 4 h. It was extracted several times with DCM, and the separated organic phase was washed with 10% strength NaHSO3 solution and water, dried over Na2SO4, and concentrated. Chromatographic purification of the residue which remained on SiO2 using EA/heptane (1:40) yielded 27 g of the title compound in the form of a pale red oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:28])C.[Cl-].[Na+]>C(Cl)(Cl)Cl.O>[Cl:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[CH:2]=[O:28]
Reactant: CC(=O)O
Reactant: Clc1cccc(-c2ccccc2)c1CBr
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1c(Cl)cccc1-c1ccccc1

Procedure:
A stirred solution of 2-bromomethyl-3-chloro-[1,1'-biphenyl] (18.7 g, 0.067 mole) and hexamethylenetetraamine (9.3 g, 0.067 mole) in 200 ml of chloroform was heated at reflux for 221/2 hours. The reaction mixture was cooled and the solvent evaporated under reduced pressure to give a residue. To the residue was added 250 ml of a 1:1 solution of concentrated acetic acid:water. The mixture was heated at reflux for approximately 22 hours, then cooled. The mixture was saturated with sodium chloride and extracted with four 200 ml portions of methylene chloride. The extracts were combined, washed with saturated aqueous sodium chloride solution, followed by saturated aqueous sodium bicarbonate solution, and dried over anhydrous potassium carbonate. The mixture was filtered and the filtrate evaporated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel, elution first with toluene:n-heptane (9:1), followed by toluene:methylene chloride (1:1), and finally methylene chloride to give 3-chloro-[1,1'-biphenyl]-2-carboxaldehyde (3.4 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([OH:24])=[O:23])=[C:15](/[CH:18]=[CH:19]/[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C([O-])([O-])=O.[K+].[K+].[C:36]([O:39][CH:40](Br)[CH3:41])(=[O:38])[CH3:37]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([O:24][CH:40]([O:39][C:36](=[O:38])[CH3:37])[CH3:41])=[O:23])=[C:15](/[CH:18]=[CH:19]/[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC/C=C/C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reactant: CC(=O)OC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC/C=C/C1=C(C(=O)OC(C)OC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(E)-1-butenyl]-3-cephem-4-carboxylic acid (130 mg, 0.3 mmole) and K2CO3 (55 mg, 0.4 mmole) in DMF (2.5 ml) was added at 5° C. 1-bromoethyl acetate (67 mg, 0.4 mmole). The mixture was stirred at 5° C. for 1 hour, diluted with ethyl acetate (25 ml), washed successively with water and an aqueous NaCl solution, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was dissolved in chloroform and chromatographed on a silica gel column with 1% methanol in CHCl3. The desired fractions were combined and concentrated in vacuo to yield 77 mg (49%) of the title compound. Estimated purity 90% (by HPLC). Mp. 110°-115° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:8](OC)=[O:9])=[N:6][CH:7]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH2:39][NH2:40]>C(Cl)(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[C:8](=[O:9])[NH:39][N:40]=[CH:12][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ncc(Br)cc1C
Reactant: NN
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: O=c1[nH]ncc2cc(Br)cnc12
Temperature: 77 °C

Procedure:
To a solution of methyl 5-bromo-3-methylpicolinate (1.785 g, 7.76 mmol) in 30 mL of CCl4 was added N-bromosuccinimide (4.23 g, 23.8 mmol) and benzoyl peroxide (0.199 g, 0.822 mmol). The reaction was heated at 77° C. for 6 h. The reaction mixture was cooled to RT, filtered through a pad of Celite and washed with CCl4. The filtrate was evaporated in vacuo to give a yellow oil. The oil was dissolved in 40 mL MeOH and anhydrous hydrazine (3.00 ml, 95.6 mmol) was added dropwise at 25° C. Upon complete addition the reaction mixture was heated at 78° C. overnight. The reaction mixture was cooled to RT and the solid was filtered, washed with MeOH and CHCl3 and dried by suction. The filtrate was evaporated onto silica gel and purified flash chromatography eluting with 2M NH3 in MeOH:CHCl3 (0:1→3:47) to give the title compound as a light-yellow amorphous solid. MS m/z: 225.9, 227.9 [M+1].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:15])[CH3:14])=[CH:11][N:12]=2)=[C:4]([CH3:16])[CH:3]=1.Cl[C:18]1[CH:26]2[CH:21]([CH:22]3[O:27][CH:25]2[CH2:24][CH2:23]3)[C:20](=[O:28])[CH:19]=1.[H-].[Na+].COCCOCCOCCOC>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([O:15][C:18]3[CH:26]4[CH:21]([CH:22]5[O:27][CH:25]4[CH2:24][CH2:23]5)[C:20](=[O:28])[CH:19]=3)[CH3:14])=[CH:11][N:12]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: O=C1C=C(Cl)C2C3CCC(O3)C12
Reactant: Cc1cc(Br)ccc1-c1ncc(C(C)O)s1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOCCOC
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1-c1ncc(C(C)OC2=CC(=O)C3C4CCC(O4)C23)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.2 %

Procedure:
To a solution of [2-(4-bromo-2-methyl-phenyl)-thiazol-5-yl]-ethanol (450 mg, 1.5 mmol) and 5-chloro-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (277 mg, 1.5 mmol) in tetrahydrofuran (10 ml) is added in one portion the sodium hydride (60% dispersion in mineral oil, 60 mg, 1.5 mmol). The reaction mixture is stirred at room temperature for 24 hours. The crude reaction mixture is vacced down under reduced pressure and 10 ml of triglyme are added. The reaction mixture is therefore heated to reflux for 30 minutes. The crude reaction mixture is vacced down and purified by flash chromatography on silica gel to give a yellow solid. The solid is washed with iso-hexane to give 5-{1-[2-(4-bromo-2-methyl-phenyl)-thiazol-5-yl]-ethoxy}-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (490 mg).