Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[Cl:16][CH2:17][C:18](O)=[O:19].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:18](=[O:19])[CH2:17][Cl:16])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=C(O)CCl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCl)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)aniline (3.74 g, 16.3 mmol) in DCM (60 mL) was added chloroacetic acid (2.31 g, 24.4 mmol), EDC (5.0 g, 32.6 mmol) and DMAP (cat.). The reaction mixture was stirred at RT overnight. The contents were transferred to a separatory funnel and DCM layer was washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4. The crude product was purified by flash column chromatography using 3:1 Pet. Ether:DCM in. Purified product was isolated as a white solid weighing 3.67 g (yield: 74%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:27]=[CH:26]C3N[C:23](=O)[NH:24][C:20]=3[CH:19]=2)=[N:15][N:14]=1.IC.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:40][N:41]([CH:43]=[O:44])[CH3:42]>C(OCC)(=O)C>[CH3:40][N:41]1[C:42]2[CH:26]=[CH:27][C:18]([C:16]3[O:17][C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])=[N:14][N:15]=3)=[CH:19][C:20]=2[N:24]([CH3:23])[C:43]1=[O:44]
Reactant: CN(C)C=O
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3[nH]c(=O)[nH]c3c2)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3c(c2)n(C)c(=O)n3C)o1
Reaction time: 18 h
Yield: 13 %

Procedure:
5-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dihydro-benzoimidazol-2-one (200 mg, 0.56 mmol) was heated in DMF (2 mL) until the suspension turned into solution. After the solution was cooled to ambient temperature iodomethane (38 μL, 0.61 mmol) was added and stirred for 18 h at this temperature. The resulting suspension was diluted with DMF (2 mL) and warmed until the reaction mixture became homogeneous. A solution of potassium bis(trimethylsilyl)amide (0.91 M in THF, 673 μL, 0.61 mmol) was added and stirred for 1 h at ambient temperature. Additional iodomethane (38 μL, 0.61 mmol) was added and stirring was continued for another 18 h. Additional potassium bis(trimethylsilyl)amide (0.91 M in THF, 673 μL, 0.61 mmol) was added, stirred for 15 min at ambient temperature, treated with iodomethane (0.38 μL, 0.61 mmol) and stirred for 5 h at this temperature. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with aqueous sodium carbonate (saturated, 20 mL), water (20 mL) and brine (20 mL). The combined aqueous layers were extracted with ethyl acetate (20 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=40:40:20 to 10:70:20) afforded the title compound (29 mg, 13%) as a white solid. MS: m/e=388.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:25]=[C:24]2[C:20]([C:21]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:27]([CH3:39])([CH3:38])[C:22]=3[N:23]2[CH3:26])=[CH:19][CH:18]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]4[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:27]([CH3:39])([CH3:38])[C:22]=4[N:23]3[CH3:26])=[CH:19][CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2(C)C
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2(C)C
Temperature: 135 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
A suspension of 4-(benzyloxy)pyridin-2(1H)-one (107 mg, 0.532 mmol), tert-butyl 7-bromo-1,1,9-trimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (251 mg, 0.639 mmol), CuI (122 mg, 0.639 mmol), 8-hydroxyquinoline (93 mg, 0.639 mmol) and Cs2CO3 (190 mg, 0.585 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and heated at 135° C. with stirring overnight. The suspension was cooled, 40:9:1 CH2Cl2/MeOH/NH4OH was added and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The solution was dried over Na2SO4 and concentrated under reduced pressure to afford an amorphous solid. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH) 100:0 to 1:1) yielded the title compound (74 mg, 27%) as a white powder: 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=8.1 Hz, 1H), 7.46-7.35 (m, 4H), 7.33-7.25 (m, 3H), 7.12 (dd, J=8.1, 2.1 Hz, 1H), 6.09 (d, J=2.6 Hz, 1H), 6.04 (dd, J=7.5, 2.6 Hz, 1H), 5.06 (s, 2H), 3.80 (s, 3H), 3.77 (t, J=4.8 Hz, 2H), 2.77 (t, J=4.8 Hz, 2H), 1.89 (s, 6H), 1.54 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([B:9]([O-:17])[O:10]C(C(C)(C)C)C)=[CH:5][CH:4]=1)=[O:2]>CO>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([B:9]([OH:17])[OH:10])=[CH:7][CH:8]=1
Reactant: CC(OB([O-])c1ccc(C=O)cc1)C(C)(C)C
Solvent: CO
Product: OCc1ccc(B(O)O)cc1
Yield: 96.2 %

Procedure:
Analogously to Example 12, 12 g (52 mmol) of pinacolyl 4-formylphenylboronate were hydrogenated in 100 ml of methanol, giving 11.7 g (50 mmol) of 4-(hydroxymethyl)phenylboronic acid.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=2)[CH2:12][C@H:11]1[O:22][C:23](=[O:25])[CH3:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.O=[Pt]=O>[C:1]([NH:9][C@@H:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=2)[CH2:12][C@H:11]1[O:22][C:23](=[O:25])[CH3:24])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[C@@H]1Cc2ccc([N+](=O)[O-])cc2[C@H]1NC(=O)c1ccccc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1Cc2ccc(N)cc2[C@H]1NC(=O)c1ccccc1

Procedure:
A solution of trans-1-benzamido-2-acetoxy-6-nitroindane (one part), prepared as described in Preparation 2, in EtOAc is treated with H2 (60 psi) in the presence of PtO2 for several hours. The catalyst is removed and the solvent evaporated to give trans-1-benzamido-2-acetoxy-6-aminoindane. A solution of this aminoindane (1 part) in a mixture of pyridine (16 parts), 4-dimethylaminopyridine (0.15 parts), and CH2Cl2 is treated with a solution of an aroyl (RCOCl) chloride (1.2 parts) and the reaction stirred over night. The reaction is poured into ice-water, the organic layer separated and consecutively washed with saturated aqueous sodium bicarbonate and brine. The organics are dried and the solvent evaporated to give trans-1-benzamido-2-acetoxy-6-carboxamino-indane. A solution of this indane in 1 M NaOH in methanol was stirred over night. The reaction is poured into ice-water and extracted with CH2Cl2. The organic extracts are washed with brine, dried, and the solvent evaporated to give the trans-1-benzamido-2-hydroxy-6-carboxamnido-indane.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:10]=2[O:9][C:8]=1C(O)=O)=[O:5])[CH3:2]>C(OCC)(=O)C>[C:18]1([CH2:17][O:16][C:14]2[CH:13]=[CH:12][C:11]3[C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[CH:8][O:9][C:10]=3[CH:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)Nc1c(C(=O)O)oc2cc(OCc3ccccc3)ccc12
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1coc2cc(OCc3ccccc3)ccc12
Reaction time: 0.08 h
Yield: 73 %

Procedure:
A reactor containing 38.6 g (0.11 mol) of 3-[(ethoxycarbonyl)amino]-6-(phenylmethoxy)benzofuran-2-carboxylic acid under nitrogen is immersed in an oil bath at 185-190° C. for 5 minutes. The residue is then taken up in ethyl acetate and the solution is then washed with an aqueous potassium hydrogencarbonate solution and then with a saturated aqueous sodium chloride solution. The organic phase is then dried over sodium sulphate, the solvent is evaporated and the residue is purified on a silica column with a mixture containing 20% of ethyl acetate in cyclohexane. After trituration in diisopropyl ether, 25 g of product are obtained.
Reaction SMILES: N1C=CC=CC=1.[S:7]1[CH2:11][CH2:10][S:9][CH:8]1[CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:19][OH:20].[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([O:20][CH2:19][C@@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]1[CH2:12][CH:8]1[S:9][CH2:10][CH2:11][S:7]1)(=[O:23])[CH3:22]
Reactant: OC[C@@H]1CCCC[C@@H]1CC1SCCS1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H]1CCCC[C@@H]1CC1SCCS1
Reaction time: 0.25 h

Procedure:
At 0° C., 290 μL (3.5 mmol) of pyridine was added to 0.740 g (3.18 mmol) of rac-cis-2-(1,3-dithiolan-2-yl methyl)cyclohexanemethanol in 5 mL of dichloromethane, followed by dropwise addition of 235 μL (3.5 mmol) of acetyl chloride. After 15 min at 0° C. and 30 min at 20° C., the reaction mixture was partitioned between water and dichloromethane and the organic solution washed with 1.0 N HCl and with 5% KHCO3 solutions, dried (MgSO4) and concentrated under vacuum to 865 mg (98%) of racemic cis-2-(1,3-dithiolan-2-yl methyl)cyclohexanemethanol acetate. TLC Rf 0.48 (SiO2, dichloromethane, I2 -brown).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[C:33]([O:39][CH3:40])[CH:32]=1>>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[C:33]([O:39][CH3:40])[CH:32]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: COc1cc(Br)ccc1CBr
Product: COc1cc(Br)ccc1COc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-Bromo-1-bromomethyl-2-methoxy-benzene following the procedure of Example 478: MS (ES) m/z 592.1.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2/[C:5]/1=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:3])[CH3:2].O>C(Cl)Cl.CO>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C@@H:5]1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(/C=C2\C3=C(CCCC3)CCN2C(C)=O)cc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C[C@H]2C3=C(CCCC3)CCN2C(C)=O)cc1
Reaction time: 5 h
Yield: 94.6 %

Procedure:
In a glove box, a 500 ml steel autoclave was charged with (E)-2-acetyl-1-(p-methoxybenzylidene)-1,2,3,4,5,6,7,8-octahydroisoquinoline (2.1 g, 7.06 mmol) (prepared according to example 2) 130 ml of methanol, a solution of (+)-CYBIPHEMP (8.2 mg, 0.0142 mmol) and [Ru(TFA)2 (COD)]2 --(H2O) (6.3 mg, 0.007 mmol) in 30 ml of methylene chloride and 5 ml of a solution of 0.0035 mmol of Ru(TFA)2 (BIPHEMP) in methanol. The hydrogenation was run at 100° and 60 bar for 5 h. Work-up as described in example 3 afforded 2.0 g of (S)-2-acetyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline, [α]D20 =+45.9° (c=1, methanol), optical purity 86%: e.e. 88.3%.
Reaction SMILES: C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1.[C:28]([O:32][C:33]([N:35]1[CH2:42][C@H:41]([OH:43])[CH2:40][C@H:36]1[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:23]1([NH:27][C:37]([C@@H:36]2[CH2:40][C@@H:41]([OH:43])[CH2:42][N:35]2[C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])=[O:38])[CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: NC1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)NC1CCC1
Yield: 49.6 %

Procedure:
1.17 g of HOAT, 1.60 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.615 g of cyclobutylamine are added to a solution of 2.0 g of (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline in 20 ml of DMF. 1.5 ml of a saturated solution of NaHCO3 is added and the reaction mixture is filtered on a Chem Elut® cartridge, eluting with DCM. The solvents are concentrated under vacuum and the residue is purified by filtration on silica gel, eluting with EtOAc. 1.22 g of the expected compound is obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([F:23])[CH:15]=2)=[C:10]([CH3:24])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[CH3:24][C:10]1[CH2:9][NH:8][CH2:13][CH2:12][C:11]=1[C:14]1[C:22]2[O:21][CH:20]=[CH:19][C:18]=2[CH:17]=[C:16]([F:23])[CH:15]=1
Reactant: CC1=C(c2cc(F)cc3ccoc23)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CC1=C(c2cc(F)cc3ccoc23)CCNC1
Yield: 79.2 %

Procedure:
A solution of 0.45 gm (1.42 mMol) 1-benzyl-3-methyl-4-(5-fluorobenzofur-7-yl)-1,2,5,6-tetrahydropyridine in 15 mL 1,2-dichloroethane was cooled to 0° C. To this solution was then added 0.40 mL (3.7 mMol) 1-chloroethyl chloroformate dropwise. The reaction was heated to reflux for 4 hours and was then concentrated under reduced pressure. The residue was dissolved in methanol and then placed on an SCX column, eluting with methanol followed by 0.5 N ammonia in methanol. Fractions containing the desired free base were combined and concentrated under reduced pressure. This residue was subjected to silica gel chromatography, eluting with a gradient of dichloromethane containing 0-6% methanol, and then with 9:1:0.1 dichloromethane:methanol:ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 0.26 gm (81%) of 3-methyl-4-(5-fluorobenzofur-7-yl)-1,2,5,6-tetrahydropyridine. A solution of 0.21 gm (0.92 mMol) of this free amine in ethanol was heated at reflux and then 0.11 gm (0.92 mMol) fumaric acid were added. The mixture was stirred at reflux for about 5 minutes and was then concentrated under reduced pressure. The residue was treated with 10 mL diethyl ether and the resulting slurry stirred for 30 minutes at room temperature. The mixture was filtered and the solid dried under vacuum for at 60° C. for 15 hours to provide 0.28 gm (88%) of the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.N1C=CN=C1.[CH3:12][C:13]([Si:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>C(Cl)Cl.O>[Si:16]([O:6][CH:4]1[CH2:5][NH:2][CH2:3]1)([C:13]([CH3:15])([CH3:14])[CH3:12])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC1CNC1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of azetidin-3-ol hydrochloride (5.11 g, 46.7 mmol, 1.0 equiv) and 1H-imidazole (9.52 g, 140 mmol, 3.0 equiv) in DCM (100 mL) at 0° C. was added TBDPSCl (19.18 g, 70 mmol, 1.5 equiv) dropwise. The resulting mixture was stirred at rt overnight and then diluted with water, and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was eluted over a silica gel with DCM/MeOH=100/1 to 10/1 to give 12 g of 3-(tert-butyldiphenylsilyloxy) azetidine as a colorless oil.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH:13]2[CH2:15][C:14]2([F:17])[F:16])=[O:12])=[CH:7][CH:6]=1>C(OCC)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH:13]2[CH2:15][C:14]2([F:16])[F:17])([OH:12])[CH3:1])=[CH:9][CH:10]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CC1(F)F
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(O)(c1ccc(Cl)cc1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.7 ml (17.1 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were added to 2.47 g (11.4 mmol) of the compound from Example 124A in 40 ml of diethyl ether at RT, and the mixture was stirred at RT overnight. The reaction mixture was added to a saturated, ice-cold aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 2.09 g (78% of theory) of a mixture of the diastereomers of the title compound.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([CH2:17][S:18]([CH3:20])=[O:19])=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)C.C(O)(=O)C(CC(O)=O)=C.[N+:34]([O-:39])([N+]([O-])=O)=[O:35]>C(Cl)(Cl)Cl.O>[CH3:20][S:18]([CH2:17][C:14]1[CH:15]=[CH:16][C:4]2[O:3][C:2]([N+:34]([O-:39])=[O:35])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=1)=[O:19]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CS(=O)Cc1ccc2oc(Br)c(-c3ccccc3)c2c1
Agent: C=C(CC(=O)O)C(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CS(=O)Cc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reaction time: 2 h

Procedure:
The product of step A is dissolved in 100 ml. of acetic acid, 3.3 g. of itaconic acid is added followed by 2.3 g. of dinitrogen tetraoxide in 10 ml. of acetic acid (the latter being added dropwise). After two hours, the mixture is poured into water and extracted with diethyl ether. The ether extracts are washed with dilute sodium bicarbonate solution, with saturated sodium chloride solution, then dried. Evaporation provides a solid which is dissolved in chloroform and chromatographically fractionated on silica gel, eluting with chloroform-carbon tetrachloride, then chloroform. The desired product elutes slowly with chloroform. It is washed with hot hexane, then recrystallized from a hexane-chloroform mixture to provide 5-methylsulfinylmethyl-2-nitro-3-phenylbenzofuran, m.p. 161°-163° C. This is the product of Example 19.
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([Cl:35])=[C:7]([C:9](=[N:32][O:33][CH3:34])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>>[ClH:35].[NH2:3][C:4]1[S:5][C:6]([Cl:35])=[C:7]([C:9](=[N:32][O:33][CH3:34])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nc(NC=O)sc1Cl
Agent: Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nc(N)sc1Cl
Yield: 116.2 %

Procedure:
7-[2-(2-Formamido-5-chlorothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 5.6 g.) was treated with conc. hydrochloric acid (2.4 ml.) in a similar manner to that of Example 1-(2) to give 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 3.3 g.).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@@H:8]([CH3:33])[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17](=[O:32])[NH:18][C@@H:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][C:25]([Br:31])=[CH:26][CH:27]=3)[N:22]=2)[CH3:20])[NH:12]1)=[O:10])(C)(C)C.Cl.[OH:36][CH2:37][CH2:38][C:39]([CH3:52])([CH:50]=[CH2:51])[C:40]([NH:42][C@@H:43]([CH:47]([CH3:49])[CH3:48])C(O)=O)=[O:41].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C>ClCCl.C(#N)C>[Br:31][C:25]1[CH:24]=[C:23]2[C:28]([CH:29]=[CH:30][C:21]([C@H:19]([NH:18][C:17]([C@@H:13]3[CH2:14][CH2:15][CH2:16][N:11]([C:9](=[O:10])[C@@H:8]([NH:7][C:6](=[O:5])[C@@H:43]([NH:42][C:40](=[O:41])[C:39]([CH2:38][CH2:37][OH:36])([CH3:52])[CH:50]=[CH2:51])[CH:47]([CH3:49])[CH3:48])[CH3:33])[NH:12]3)=[O:32])[CH3:20])=[N:22]2)=[CH:27][CH:26]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=CC(C)(CCO)C(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: C=CC(C)(CCO)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A cooled (0° C.) solution of ((S)-2-{(S)-3-[(R)-1-(7-bromo-quinolin-2-yl)-ethylcarbamoyl]-tetrahydro-pyridazin-1-yl}-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (432.0 mg, 0.808 mmol) in dichloromethane (30 mL) was treated with a solution of hydrochloric acid (2.4 mL, 9.699 mmol, 4 M in 1,4-dioxane). After stirring for 2 h at room temperature the volatiles were removed in vacuo. Residual water was azeotroped off with toluene to provide a white solid that was combined with (S)-2-[2-(2-hydroxy-ethyl)-2-methyl-but-3-enoylamino]-3-methyl-butyric acid (196.6 mg, 0.808 mmol) and anhydrous acetonitrile (30 mL). This mixture was cooled to 0° C. and subsequently treated with N,N-diisopropylethylamine (0.71 mL, 4.04 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (430.1 mg, 1.131 mmol). The reaction was slowly warmed to room temperature. After stirring at room temperature for 20 h, the volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/acetone 1:0 to 1:1 to afford the title compound (186.4 mg, 35%) as a yellow foam and as a 1:1 mixture of diastereoisomers. LCMS (m/z) 659.2, 661.1 [M+H], Tr=2.21 min.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+](=C)=[N-].Br.[C:16]([O:20][C:21]([N:23]1[CH2:31][CH2:30][CH:26]([C:27](=[S:29])[NH2:28])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CCO>[CH2:4]([C:3]1[S:29][C:27]([CH:26]2[CH2:30][CH2:31][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:24][CH2:25]2)=[N:28][CH:2]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CBr)Cc1ccccc1
Agent: Br
Agent: C=[N+]=[N-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(Cc3ccccc3)s2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 65 mg of 1-bromo-3-phenyl-2-propanone (from reacting the acid chloride with diazomethane followed by hydrogen bromide) in 4 ml EtOH was added 74 mg of 1-boc-isonipecot-thioamide (from Step A). The reaction was stirred for 2 hours at 80° C. The solvent was then evaporated under reduced pressure. The residue was purified by flash chromatography with 10% EtOAc in hexane to give 37 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:15][F:16])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:15][F:16])[NH:13][C:12](=[S:26])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1COCC(CF)(c2cccc(Br)c2)N1
Solvent: C1CCOC1
Product: FCC1(c2cccc(Br)c2)COCC(=S)N1
Temperature: 50 °C

Procedure:
A mixture of 5-(3-bromo-phenyl)-5-fluoromethyl-morpholin-3-one (1.52 g, 5.28 mmol) and Lawesson's reagent (2.14 g, 5.28 mmol) in 21 ml of THF was heated at 50° C. for 1 h and then evaporated. The residue was chromatographed on silica gel (cyclohexane/EtOAc=15:1) to give the title compound in the form of a colourless foam. TLC (hexane/EtOAc=3:1): Rf=0.21; HPLC: RtH2=3.49 min; 1H-NMR (400 MHz, CD3OD): 7.65 (s, 1H), 7.58 (d, 1H), 7.47 (d, 1H), 7.39 (t, 1H), 4.87 (s, 2H), 4.63 (d, 1H), 4.50 (s, 2H), 4.02 (d, 1H); MS: 304, 306 [(M+H)+].