Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=O)[C:11](=[O:14])[O:12][CH3:13])[CH3:9])=[CH:4][CH:3]=1.[CH3:26][C:27]([S@@:30]([NH2:32])=[O:31])([CH3:29])[CH3:28]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:15][CH2:16]/[C:17](=[N:32]/[S@:30]([C:27]([CH3:29])([CH3:28])[CH3:26])=[O:31])/[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:11](=[O:14])[O:12][CH3:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: COC(=O)N(CCC(=O)c1ccc(F)cc1)[C@@H](C)c1ccc(Br)cc1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(CC/C(=N/[S@@](=O)C(C)(C)C)c1ccc(F)cc1)[C@@H](C)c1ccc(Br)cc1
Temperature: 70 °C
Yield: 77.6 %

Procedure:
To a solution of (S)-methyl 1-(4-bromophenyl)ethyl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (982 mg, 2 mmol) and (S)-2-methylpropane-2-sulfinamide (265 mg, 2 mmol) in anhydrous THF (20 mL) at rt was added Ti(OEt)4 (1 g, 4 mmol). The reaction mixture was heated at 70° C. for 24 h. After cooling to rt, the reaction mixture was poured into brine with vigorous stirring. The resulting suspension was filtered through a pad of celite and the solid was washed with brine. The combined organic phases were dried, filtered and concentrated to give methyl (1S)-1-(4-bromophenyl)ethyl((Z)-3-((S)-tert-butylsulfinylimino)-3-(4-fluorophenyl)propyl)carbamate (794 mg, 65%). 1H NMR (CD3OD): 1.24 (m, 9H), 1.58 (d, 4H), 1.61 (m, 1H), 2.95 (m, 1H), 3.48 (m, 2H), 3.66 (m, 1H), 3.80 (m, 3H), 4.58 (m, 1H), 3.78 (m, 3H), 5.36 (m, 1H), 7.18 (m, 3H), 7.30 (m, 2H), 7.50 (m, 2H), 7.96 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10](O)[C:9]2=[O:18])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: O=C1C(O)c2ccccc2N1Cc1ccc(Cl)s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Cc2ccccc2N1Cc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.8 %

Procedure:
To a solution of 345-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chloro-2-thienyl)methyl]-3-hydroxy-1,3-dihydro-2H-indol-2-one (4.90 g, 10.3 mmol) in dichloromethane (100.0 mL) were added trifluoroacetic acid (12.9 g, 113.2 mmol) and triethylsilane (13.2 g, 113.2 mmol). The reaction mixture was stirred at ambient temperature for 4 h, then concentrated in vacuo to dryness. The gummy residue was diluted with ethyl acetate (100.0 mL), washed with water (3×100.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with diethyl ether, filtered and dried to afford 345-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiophen-2-yl)methyl]-1,3-dihydro-2H-indol-2-one (2.90 g, 61%) as a colourless solid: mp 173-175° C.; 1H NMR (300 MHz, CDCl3) δ9.11 (s, 1H), 7.3-7.27 (m, 5H), 7.18 (dd, J=7.5, 7.5 Hz, 1H), 7.09 (d, J=3.8 Hz, 1H), 7.06 (dd, J=7.9 Hz, 1H), 6.97-6.86 (m, 3H), 6.79-6.68 (m, 3H), 5.04 (ABq, 2H), 4.91 (s, 2H), 4.84 (s, 1H); 13C NMR (75 MHz, CDCl3) δ175.9, 151.5, 149.7, 142.8, 138.8, 137.8, 130.2, 128.8, 128.2, 128.1, 128.1, 128.0, 127.4, 126.8, 125.2, 124.2, 122.7, 117.6, 117.6, 116.3, 114.9, 109.1, 70.2, 48.1, 38.6; MS (ES+) m/z 464.3 (M+1), 462.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([OH:22])[CH2:11][P:12]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)(=[O:14])[OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[C:23]1([O:14][P:12]([CH2:11][C@H:10]([OH:22])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[O:13])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
To a solution of ((R)-3-tert-butoxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid (0.67 g, 2.0 mmol) in 10 mL THF at 0° C. was added 1-chloro-N, N-2-trimethyl-1-propenylamine (319 mg, 2.4 mmol). After stirring for 10 min at 0° C., a solution of phenol (188 mg, 2.0 mmol) and triethylamine (243 mg, 2.4 mmol) in THF (3 mL) was added dropwise. After addition the reaction mixture was stirred at 0° C. for 2 h and then room temperature for 16 h. The reaction was diluted with ethyl acetate and washed with water and brine. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo to give the crude product. Purification by gradient flash chromatography (methanol/methylene chloride) on a 35 g RediSep disposable column gave ((R)-3-tert-butoxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid phenyl ester (500 mg, 1.22 mmol). 1H-NMR (CDCl3, 300 MHz): δ 7.35 (m, 2H), 7.18 (m, 3H), 4.18 (br s, H), −33.21-3.09 (m, 2H), 2.01-1.58 (m, 10H), 1.43-0.95 (m, 15H). 31P NMR (CD3OD, 300 MHz): 57.90, 58.65.
Reaction SMILES: [CH2:1]=O.[CH:3]1[C:15]2[CH:14]([CH2:16][O:17][C:18]([NH:20][C@@H:21]([CH2:25][S:26][S:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([OH:24])=[O:23])=[O:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1>C1(C)C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[C:28]([S:27][S:26][CH2:25][C@H:21]1[C:22](=[O:24])[O:23][CH2:1][N:20]1[C:18]([O:17][CH2:16][CH:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:19])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)SSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: C=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CC(C)(C)SSC[C@H]1C(=O)OCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
Paraformaldehyde (843 mg, 9.26 mmol) and 10-camphorsulfonic acid (75 mg, 0.324 mmol) were added to a solution of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(tert-butyldisulfanyl)propanoic acid (Compound 2α-B) (2.00 g, 4.63 mmol) in toluene (10 ml), and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was returned to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→70/30) to afford (R)-(9H-fluoren-9-yl)methyl 4-((tert-butyldisulfanyl)methyl)-5-oxooxazolidine-3-carboxylate (Compound 2b-B) (1.936 g, 94%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+](C)([O-])=O.[CH3:9][O:10][C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH:21]=[N:20][C:19]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:18]2)=[C:13]2[NH:29][CH:30]=[CH:31][C:12]=12.Cl[C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35]>C(Cl)Cl>[CH3:9][O:10][C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH:21]=[N:20][C:19]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:18]2)=[C:13]2[NH:29][CH:30]=[C:31]([C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35])[C:12]=12
Reactant: COc1cnc(-n2cnc(NC(=O)C(C)(C)C)n2)c2[nH]ccc12
Reactant: COC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: COC(=O)C(=O)c1c[nH]c2c(-n3cnc(NC(=O)C(C)(C)C)n3)ncc(OC)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
To an oven-dried flask in ice bath was added AlCl3 (382 mg, 2.86 mmol), then CH2Cl2 (4 mL) was introduced at 0° C. Nitromethane (10.84 μL, 0.201 mmol) was added at that temperature. Ice bath was removed and the mixture was stirred at room temperature for 30 min. N-(1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)pivalamide (90 mg, 0.286 mmol) and methyl 2-chloro-2-oxoacetate (0.079 mL, 0.859 mmol) were added at 0° C. The reaction mixture was stirred for three hours at room temperature. The reaction mixture was quenched with ammonium acetate (8 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford methyl 2-(4-methoxy-7-(3-pivalamido-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (40 mg, 45%) as white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][C:21]=1[F:29]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][C:21]=1[F:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: COCc1ccc(Br)c(F)c1
Product: COCc1ccc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c(F)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-bromo-2-fluoro-4-(methoxymethyl)benzene (obtained in Step 1), the title compound was obtained as a dark orange sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[C:18]([NH:28][CH2:29][CH2:30][C:31](O)=[O:32])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:18]([NH:28][CH2:29][CH2:30][C:31]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)=[O:32])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)CCNC(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.1 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (3.00 g, 13.0 mmol) was dissolved in dimethylformamide (200 ml). To this solution, N-carbobenzyloxy-β-alanine (4.40 g, 19.5 mmol), WSC-HCl (3.50 g, 19.5 mmol), and HOBT (1.00 g, 7.2 mmol) were added, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was condensed under reduced pressure, and the residue was subjected to extraction using a solvent mixture (chloroform--methanol =4:1) combined with 1N-HCl. The organic phase was washed with saturated aqueous NaCl solution, followed by drying and condensing under reduced pressure. The resultant residue was recrystallized from chloroform--methanol--ether. As a result, 2.61 g of the title compound was obtained as colorless powdery crystals (46.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[S:11][C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:15]=2[N:16]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([S:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:15]=3[N:16]=2)=[C:2]([Cl:1])[CH:7]=1
Reactant: N#Cc1ccc2sc(Sc3ccc([N+](=O)[O-])cc3Cl)nc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc2sc(Sc3ccc(N)cc3Cl)nc2c1
Yield: 92.7 %

Procedure:
The title compound was prepared using the method of example 270, starting with 2-(2-chloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carbonitrile (263) (1.59 g, 4.58 mmol), tin chloride dihydrate (Aldrich, 5.18 g, 22.9 mmol). Compound 275 (1.35 g, 93%) was obtained as a yellowish solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][CH3:13])=[O:11].[H-].[Na+]>CN(C=O)C>[I:8][C:6]1[CH:7]=[CH:2][C:3]2[NH:9][C:10](=[O:11])[N:12]([CH3:13])[C:4]=2[CH:5]=1
Reactant: CNC(=O)Nc1ccc(I)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2ccc(I)cc21
Reaction time: 0.17 h

Procedure:
A solution of N-(2-fluoro-4-iodophenyl)-N′-methylurea (6-2, 2.9 g, 9.86 mmol) in DMF (12 ml) were treated with Sodium Hydride (308 mg, 12.8 mmol, 1.3 eq). The reaction mixture was irradiated in a microwave at 200 deg C. for 10 min. The starting material was consumed, so it was partitioned between EtOAc (2×75 ml) and water (85 ml), and the combined organic layers were dried over Na2SO4 and concentrated. The residual crude maroon oil was purified via flash column chromatography (SiO2: 100% Hex to 50:50 Hex/EtOAc), which afforded the title compound, 6-iodo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (6-3), as a tan solid. 1H NMR (500 MHz, CDCl3) δ 9.64 (bs, 1H), 7.39 (d, 1H, J=6.6 Hz), 7.30 (s, 1H), 6.87 (d, 1H, J=8.1 Hz), 3.39 (s, 3H). LRMS m/z: Calc'd for C8H7IN2O (M+H) 275.1, found 274.9.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CO.O>[CH:19]1([CH2:18][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: BrCC1CCCCC1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: CC(=O)c1ccc(OCC2CCCCC2)cc1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4′-hydroxyacetophenone (10.6 g, 77.7 mmol) in 600 mL MeOH and 15 mL H2O at room temperature was added Cs2CO3 (25.6 g, 1.01 eq). The reaction mixture immediately turned yellow and was then stirred for 40 min. The MEOH was removed in vacuo, and the remaining H2O was removed azetropically with 5×100 mL toluene. The resulting yellow solid was suspended in DMF (450 mL) and treated with (bromomethyl)cyclohexane (13.0 mL, 1.2 eq). The reaction mixture was heated to 90° C. and stirred overnight. The reaction mixture was then cooled to room temperature, poured into 500 mL of ice water and extracted with Et2O. The Et2O extract was dried over MgSO4 and concentrated in vacuo to a yellow oil, which smelled of the starting bromide. The bromide was distilled off at 50° C. under high vacuum until the bottoms reached a constant weight (13.96 g, 77%). This oil solidified to a white solid upon standing. 1H NMR (300 MHz CDCl3): 7.91 (2H, d, J=8.9 Hz), 6.90 (2H, d, J=8.8 Hz), 3.81 (2H, d, J=6.1 Hz), 2.55 (3H, s), 1.8 (6H, m), 1.2 (3H, m), 1.1 (2H, m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11](=[O:15])OCC)=[N:2]1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.O>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11]([N:26]2[CH2:25][CH2:24][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[F:16])[CH2:28][CH2:27]2)=[O:15])=[N:2]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1n[nH]c2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1n[nH]c2ccccc12)N1CCN(c2ccccc2F)CC1
Temperature: 100 °C
Yield: 54.2 %

Procedure:
Ethyl 1H-indazol-3-ylcarbamate (81 mg) and 1-(2-fluorophenyl)piperazine (Aldrich Co., 47 mg) were dissolved in dimethylformamide (2 ml), and the mixture was stirred with heating at 100° C. for 11 hr. After allowing to cool, water was added to the reaction mixture, and the precipitated solid was collected by filtration and dried to give 4-(2-fluorophenyl)-1-piperazinecarboxylic acid (1H-indazol-3-yl)amide (48 mg, yield 57%).
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.[Br:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][N:40]([CH2:43][C:44]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48][C:47]=3[CH3:54])=[O:45])[C:39](=[O:55])[CH:38]=2)=[N:33][CH:34]=1.C(OC1C=CN(CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1>>[Br:25][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:44](=[O:45])[CH2:43][N:40]2[CH:41]=[CH:42][C:37]([O:36][CH2:35][C:32]3[CH:31]=[CH:30][C:29]([Br:28])=[CH:34][N:33]=3)=[CH:38][C:39]2=[O:55])=[C:47]([CH3:54])[CH:48]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccc(Br)cn2)cc1=O
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Agent: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccc(Br)cn2)cc1=O
Yield: 88 %

Procedure:
1-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one is prepared following preparation 1d employing 4-(5-bromo-pyridin-2-ylmethoxy)-1-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 4a) instead of preparation 1c.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:16]=3[C:17]=1[Cl:18])=[O:12])[CH2:3]2>[Sn](Cl)Cl.CN(C=O)C>[ClH:18].[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:16]=3[C:17]=1[Cl:18])=[O:12])[CH2:3]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1sc2cc([N+](=O)[O-])ccc2c1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Product: Nc1ccc2c(Cl)c(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
83 mg (0.23 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-chloro-6-nitro-1-benzothiophene-2-carboxamide hydrochloride are dissolved in 1.5 ml of 2M tin(II) chloride solution in DMF and stirred at RT for 14 h. The reaction mixture is purified by preparative HPLC. The product fractions are concentrated, dissolved in a mixture of methanol and 4M HCl in dioxane, then again concentrated and dried under high vacuum. 53 mg (57.2% of theory) of the title compound are obtained.
Reaction SMILES: BrC1N=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=CC=1.C(C1CN(CC2C=CC(OC)=CC=2)C(=O)N1)(C)C.[CH3:42][C:43]1[C:44]([N:50]2[CH2:55][CH2:54][N:53]([C:56]([C:58]3[CH:59]=[CH:60][C:61]([N:64]4[CH:68]([CH:69]([CH3:71])[CH3:70])[CH2:67][N:66](CC5C=CC(OC)=CC=5)[C:65]4=[O:81])=[N:62][CH:63]=3)=[O:57])[CH2:52][CH2:51]2)=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=1>>[CH3:42][C:43]1[C:44]([N:50]2[CH2:51][CH2:52][N:53]([C:56]([C:58]3[CH:59]=[CH:60][C:61]([N:64]4[CH:68]([CH:69]([CH3:70])[CH3:71])[CH2:67][NH:66][C:65]4=[O:81])=[N:62][CH:63]=3)=[O:57])[CH2:54][CH2:55]2)=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=1
Reactant: COc1ccc(CN2CC(C(C)C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cn3)C2=O)cc1
Agent: COc1ccc(CN2CC(C(C)C)NC2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4C(C)C)nc3)CC2)c(C)c1

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (225 mg) described in Preparation Example 127 and 4-isopropyl-1-(4-methoxybenzyl)imidazolidin-2-one (149 mg) described in Preparation Example 210 and by the reaction and treatment in the same manner as in Example 505, the title compound (52 mg) was obtained via 3-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-4-isopropyl-1-(4-methoxybenzyl)imidazolidin-2-one.
Reaction SMILES: [NH2:1][C@@H:2]1[C:21](=[O:22])[N:4]2[C:5]([C:18]([OH:20])=[O:19])=[C:6]([CH2:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:7][S:8][C@H:3]12.CN(C)C(=O)C.[N:29]1([CH2:34][C:35](Cl)=[O:36])[CH:33]=[N:32][N:31]=[N:30]1.C(=O)([O-])O.[Na+:42]>ClCCl>[Na+:42].[Na+:42].[N:29]1([CH2:34][C:35]([NH:1][C@@H:2]2[C:21](=[O:22])[N:4]3[C:5]([C:18]([O-:20])=[O:19])=[C:6]([CH2:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:7][S:8][C@H:3]23)=[O:36])[CH:33]=[N:32][N:31]=[N:30]1.[N:29]1([CH2:34][C:35]([NH:1][C@@H:2]2[C:21](=[O:22])[N:4]3[C:5]([C:18]([O-:20])=[O:19])=[C:6]([CH2:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:7][S:8][C@H:3]23)=[O:36])[CH:33]=[N:32][N:31]=[N:30]1
Reactant: O=C(Cl)Cn1cnnn1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CCC(=O)O)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: O=C(O)CCC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cn3cnnn3)[C@H]2SC1

Procedure:
In dichloromethane (7 ml) was suspended 7β-amino-3-(3-carboxypropionyloxy)methyl-3-cephem-4-carboxylic acid (660 mg), followed by the addition of N,N-dimethylacetamide (0.7 ml). Then, under ice-cooling and stirring, a solution of (1H-tetrazol-1-yl)acetyl chloride (294 mg) in dichloromethane (2 ml) was added. The mixture was stirred at room temperature for 1 hour, after which time it was poured in an aqueous solution of sodium hydrogen carbonate and separated. The water layer was taken, washed with dichloromethane, made acidic with phosphoric acid and extracted with ethyl acetate. The extract was re-extracted with aqueous sodium hydrogen carbonate solution to bring the desired compound into the aqueous phase. This aqueous solution was purified by column-chromatography on Sephadex LH-20. The fractions containing the dominant product were pooled and lyophilized. The procedure provided 7β-[2-(1H-tetrazol-1-yl)acetamido]-3-(3-carboxypropionyloxy)methyl-3-cephem-4-carboxylic acid disodium salt.
Reaction SMILES: CN1CC[O:5]CC1.[CH2:8]1[CH2:13][CH2:12][CH:11]([N:14]=[C:15]=[N:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:10][CH2:9]1.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:15]([NH:14][CH:11]1[CH2:10][CH2:9][CH2:8][CH2:13][CH2:12]1)([NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:5]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 16 h

Procedure:
0.05 ml of N-methylmorpholine and 100 mg of DCCI are added, at -5°, to a solution of 470 mg of Z-Asn-Phe-Phe-[D-Trp(F) -Lys(Boc)-Thr(But)-Phe-OH, 165 mg of H-Gaba-OBzl p-toluenesulphonate (Example 1.7A) and 66 mg of N-hydroxybenzotriazole in 2 ml of dimethylformamide. After 16 hours at this temperature, the reaction mixture is worked up analogously to Example 7.1. Except for traces of dicyclohexylurea, the product is obtained in the pure form.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([O:15][CH2:14][CH2:13][CH2:12][NH:11][C:8]2[C:9](=[O:10])[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:6](=[O:22])(=[O:23])[C:7]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: CC(C)(C)N1C(=O)C(NCCCO)=C(c2ccccc2)S1(=O)=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A mixture of 2-tert-butyl-4-[(3-hydroxypropyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide (Example 49) (2.75 g, 8.12 mmol), 4-methylbenzenesulfonyl chloride (1.86 g, 9.74 mmol), DMAP (0.99 g, 8.12 mmol) and Na2CO3 (2.58 g, 24.35 mmol) in DCM (50 ml) was stirred at rt. After 2 h the mixture was filtered, evaporated and the residue purified by silica gel column chromatography (Horizons Biotage) using 5:1 DCM/petroleum ether 40-60° C. as eluent to give the title compound (2.34 g, 58%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.74 (d, 2H), 7.50-7.39 (m, 3H), 7.36 (d, 2H), 5.30 (t, 1H), 3.85 (t, 2H), 2.98 (q, 2H), 2.48 (s, 3H), 1.73 (s, 9H), 1.62 (qt, 2H); 13C NMR (125 MHz, CDCl3): δ 159.8, 145.4, 134.9, 132.9, 131.8, 130.2, 130.1, 129.0, 128.1, 124.9, 107.9, 67.2, 61.6, 40.3, 28.8, 27.8, 21.9; Mass Spectrum M+H+ 493.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13](=[O:20])[C:12]2=[CH:21][CH:22]=[CH:23][N:11]12>C1COCC1>[Br:1][C:23]1[N:11]2[N:10]([CH3:9])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13](=[O:20])[C:12]2=[CH:21][CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1c2ccccc2c(=O)c2cccn21
Solvent: C1CCOC1
Product: Cn1c2ccccc2c(=O)c2ccc(Br)n21
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
A solution of N-bromosuccinimide (3.5 g) in 50 mL of THF was added dropwise to a solution of 5-methylpyrrolo[1,2-b]cinnolin-10(5H)-one (3.8 g) in 70 mL of dry THF at 0° C. After 16 hours of stirring at room temperature, the solution was concentrated and the residue taken up in 200 mL of CHCl3. This solution was washed with H2O, dried over MgSO4, filtered and concentrated. The residue was purified by HPLC (silica, dichloromethane) to give 3.8 g of yellow crystals. This material was recrystallized from ether to give 3.6 g of pale yellow crystals, mp 103°-105° C.