Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[ClH:27].Cl.[NH2:29][CH2:30][CH2:31][O:32][NH2:33].N1C=CC=CC=1>C(O)C>[ClH:27].[ClH:27].[NH2:29][CH2:30][CH2:31][O:32][N:33]=[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:25]=[CH:26][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: NCCON
Reactant: O=C(CCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NCCON=C(CCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 4-[4-(4-fluorobenzoyl)-1-piperdinyl]-1-phenyl-1-butanone (5.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.21 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was stirred at 60° C., overnight, under nitrogen. The reaction mixture was evaporated, toluene was added and evaporated. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 2.3 g (34%) of product, mp 110°-115° C. (dec).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][OH:22].C(=O)(O)[O-].[Na+]>>[CH3:18][N:19]([CH:20]([OH:8])[CH2:21][O:22][CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH3:23]
Reactant: C1=COCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN(C)CCO
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)C(O)COC1CCCCO1
Reaction time: 2 h

Procedure:
10.0 mg of paratoluenesulphonic acid, 8.7 ml of dihydropyran, then 7.12 g of N,N-dimethylethanol-amine are mixed together at 20° C. The temperature is taken to 60° C., and after agitation for 2 hours the mixture is returned to 20° C. 0.5 g of sodium bicarbonate is then added. Agitation is continued for one hour. The tetrahydropyranyloxylated derivative is obtained which is immediately reacted.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.[CH3:12][CH:13]([NH2:15])[CH3:14].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:15][CH:13]([CH3:14])[CH3:12])[S:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: CC(C)N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2ccc(Br)cc2s1
Yield: 64 %

Procedure:
A microwave reaction vial was charged with 6-bromo-2-chlorobenzo[d]thiazole (300 mg, 1.21 mmol), propan-2-amine (75 mg, 1.27 mmol), triethylamine (183 mg, 1.81 mmol) and 2.4 mL DMF. The vial was sealed, and the mixture was irradiated in the microwave for 20 min at 150° C. The reaction mixture was concentrated twice from toluene and purified by silica gel chromatography (0-50% 90/10 CH2Cl2/MeOH in CH2Cl2), which provided 6-bromo-N-isopropylbenzo[d]thiazol-2-amine (210 mg, 64%) as a white solid. MS (ESI pos. ion) m/z calc'd for C10H11BrN2S: 271.2/273.2. found 271.0/273.0.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[F:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:26])[CH:25]=1.[CH:27](OC)=[O:28].C(=O)(O)[O-].[Na+]>C1COCC1>[F:26][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([F:19])[C:25]=1[CH:27]=[O:28]
Reactant: Fc1cncc(F)c1
Reactant: COC=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1c(F)cncc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon and at −70° C., 44 ml of 2.5 M n-butyllithium solution in n-hexane (110 mmol, 1.1 equivalent) were slowly added dropwise to 15.4 ml of diisopropylamine (110 mmol, 1.1 equivalent) in 23 ml of THF. The solution formed was warmed to 0° C. and stirred at this temperature for 30 min. The reaction mixture was then brought to −70° C. and diluted with 23 ml of THF, and 11.5 g of 3,5-difluoropyridine (100 mmol, 1 equivalent) dissolved in 72 ml of THF, were added dropwise. The mixture was stirred at −70° C. for 30 min. 12.4 ml of methyl formate (200 mmol, 2 equivalent), dissolved in 23 ml of THF, were then slowly added dropwise. After 1.5 h at −70° C., the reaction solution was quickly poured into 230 ml of saturated aqueous sodium bicarbonate solution and extracted with a total of 460 ml of ethyl acetate. The combined organic phases were washed twice with in each case 115 ml of saturated aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated using a rotary evaporator. This gave 11.6 g (81% of theory) of the title compound which were directly reacted further.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O-])(O)=O.[Na+].CI>CC(N(C)C)=O>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([O:14][CH3:23])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)C[C@@H](CCOCc1ccccc1)C(=O)O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: COC(=O)[C@H](CCOCc1ccccc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of (R)-2-(2-(benzyloxy)ethyl)-4-tert-butoxy-4-oxobutanoic acid (120 g, 388 mmol) in DMA (750 mL) was added NaHCO3 (65.2 g, 776 mmol) followed by MeI (36.4 mL, 582 mmol) and stirred overnight at room temperature. Additional NaHCO3 (130 g, 1.55 mol), and MeI (72.8 mL, 1.16 mol) were added and stirring was continuted for an additional 20 h. The mixture was filtered and the filtrate partitioned between MTBE (1.5 L) and H2O (1.5 L). The aqueous phase was separated and back-extracted with MTBE (1.0 L). The combined organics were washed with H2O (2×1.5 L), brine (1 L), dried over MgSO4, and filtered. The filtrate was concentrated to give a pale yellow oil containing (R)-4-tert-butyl 1-methyl 2-(2-(benzyloxy)ethyl)succinate (140 g, 379 mmol, 98% yield). Exact mass calculated for C18H26O5: 322.2, found: LCMS m/z=323.3, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 9 H), 1.82 (m, 1 H), 1.97 (m, 1 H), 2.42 (dd, J1=16.3, J2=5.3 Hz, 1 H), 2.63 (dd, J1=16.5, J2=9.0 Hz, 1 H), 2.96 (m, 1 H), 3.50 (t, J=6.2 Hz, 2 H), 3.65 (s, 3 H), 4.48 (s, 2 H), 7.32 (m, 5 H).
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH:19]=O)[N:15]3[CH3:18])=[C:11]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:10]=2)[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)([CH3:3])[CH3:2].[CH:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40])([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:31]([N:34]1[CH2:39][CH2:38][N:37]([CH2:19][C:14]2[N:15]([CH3:18])[C:16]3[C:12]([N:13]=2)=[C:11]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:10]=[C:9]([N:8]2[C:7]4[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=4[N:5]=[C:4]2[CH:1]([CH3:2])[CH3:3])[N:17]=3)[CH2:36][C:35]1=[O:40])([CH3:33])[CH3:32]
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC(C)N1CCNCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)C)C(=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A mixture of 2-(2-isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.15 g, 0.37 mmol), 1-isopropylpiperazin-2-one (0.078 g, 0.44 mmol) and 4 Å molecular sieves (0.372 g) in DCE (3 mL) was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.157 g, 0.74 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 10:90) to give 555 as an off-white solid (0.168 g, 84%). LCMS (Method I): RT=3.43 min, [M+H]+ 532.3. 1H NMR (400 MHz, DMSO-d): δ 7.93-7.89 (m, 1 H); 7.68-7.63 (m, 1 H); 7.28-7.23 (m, 2 H); 4.64-4.58 (m, 1 H); 4.29-4.21 (m, 4 H); 3.97-3.90 (m, 1 H); 3.90 (d, J=4.6 Hz, 2 H); 3.80 (s, 3 H); 3.78 (t, J=4.6 Hz, 4 H); 3.21-3.15 (m, 4 H); 2.78-2.75 (m, 2 H); 1.36 (d, J=6.8 Hz, 6 H); 1.05 (d, J=6.8 Hz, 6 H)
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:12]=1.Br[CH2:30][CH2:31][O:32][CH3:33]>CN(C)C=O.CO>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:30][CH2:31][O:32][CH3:33])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:12]=1
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(-c3ccc(F)cc3F)n2)n[nH]1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(-c3ccc(F)cc3F)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
Sodium hydride (17 mg, 60%) was added slowly to an ice-cooled solution of 1-(2,4-difluoro-phenyl)-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (150 mg) in 2 mL N,N-dimethylformamide (DMF). After stirred for 30 min, 1-Bromo-2-methoxy-ethane (59 mg) in 1 mL DMF was added cautiously by syringe. The mixture was warmed to room temperature and stirred overnight, then diluted with 1 mL methanol and directly sent to prep-HPLC. The product [1-(2,4-difluoro-phenyl)-6-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (40 mg) was obtained as a yellow solid. LC-MS m/e 411(MH+). 1H NMR (400 MHz, DMSO) 9.12(s, 1H), 7.81(s, 1H), 7.61(m, 1H), 7.43(t, 1H), 7.34(d, 1H), 7.25(t, 1H), 7.10(d, 1H), 6.85(d, 1H), 5.81(s, 1H), 4.23(m, 2H), 3.71(m, 2H), 3.32(s, 3H), 2.20(s, 3H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13](#[N:15])[CH3:14].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O-])=[O:22])=[C:19]([F:26])[CH:18]=1>C1COCC1.CCCCCC>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](=[O:22])[CH2:14][C:13]#[N:15])=[C:19]([F:26])[CH:18]=1
Reactant: CC#N
Reactant: O=C([O-])c1ccc(Cl)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: N#CCC(=O)c1ccc(Cl)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
A 1.6 M hexane solution of n-butyllithium (39.8 mL, 63.6 mmol) was added to a solution of diisopropylamine (9.45 mL, 66.3 mmol) in THF (100 mL) at −78° C. over 10 min. The resultant solution was stirred at 0° C. for 30 min and cooled to −78° C. Acetonitrile (3.32 mL, 63.6 mmol) dropwise. The mixture was stirred at −78° C. for 30 min and then added a solution of 4-chloro-2-fluorobenzoate (5.00 g, 26.5 mmol) in THF (5 mL) at −78° C. dropwise. After stirring for 1 h at −78° C., the reaction mixture was quenched with brine (20 mL), warmed to room temperature and adjusted to pH 1-2 with 1N aqueous HCl. Following addition of ethyl acetate (400 mL), the mixture was washed with water (40 mL), brine (40 mL), dried (MgSO4) and concentrated to provide 3-(4-chloro-2-fluorophenyl)-3-oxopropanenitrile as tan solid (5.10 g, 97%). MS (ES+) m/z: 198 (M+H).
Reaction SMILES: Cl.[OH:2][NH2:3].[Cl:4][C:5]1[N:6]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([C:14]=1[CH:15]=O)=[CH:12][CH:11]=[CH:10][CH:9]=2>N1C=CC=CC=1>[Cl:4][C:5]1[N:6]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[N:3][OH:2])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: O=Cc1c(Cl)nc(-c2ccccc2)c2ccccc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1c(Cl)nc(-c2ccccc2)c2ccccc12
Reaction time: 2 h
Yield: 76.3 %

Procedure:
55.5 g Hydroxyamine hydrochloride is added to 53.6 g 3-chloro-1-phenyl-isoquinoline-4-aldehyde in 150 ml pyridine at 0° C. The resulting mixture is left to stand at room temperature for 2 hours. Then, successively, the solvent is removed in vacuo, the residue is partioned between water and toluene, the toluenic phase is dried and concentrated. 43.2 g 3-chloro-1-phenyl-isoquinoline-4-aldoxime having a melting point from 151° to 154° C. are obtained.
Reaction SMILES: SCCCS[C:6](=[O:28])[CH2:7][C:8]1([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)(=O)C>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][C:8]1([CH2:7][CH2:6][OH:28])[C:9]2[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=2[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]1=2
Reactant: CN(C)CCC1(CC(=O)SCCCS)c2ccccc2CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCC1(CCO)c2ccccc2CCc2ccccc21
Temperature: 0 °C

Procedure:
To a solution of [5-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]-thioacetic acid-S-(3 mercapto-propyl)ester (104), 3.1 g, 7.5 mmol) in 50 mL of THF, maintained under an argon atmosphere, was added lithium aluminum hydride (37.5 mL of a 1M solution in THF; 37.5 mmol) dropwise. The clear solution was refluxed for 5 hours and then cooled to 0° C. The mixture was diluted with ethyl acetate and quenched with 10% sodium hydroxide. The resulting slurry was filtered over celite and the organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried the over sodium sulfate, filtered, and evaporated to dryness. The resulting oil was purified by chromatography on silica gel (95:5:0.5 of methylene chloride:methanol:ammonium hydroxide). The product fractions were evaporated to dryness to yield the title product. as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4](Cl)[N:3]=1.[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.CN1CCCC1=O.Cl>C(OCC)C.O1CCOCC1>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[N:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Nc1nc(Cl)nc(Cl)c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: C1COCCO1
Product: N#Cc1ccc(Nc2nc(N)c(Cl)c(Cl)n2)cc1
Temperature: 145 °C
Yield: 6.8 %

Procedure:
To a flask under Argon was added 4-amino-2,5,6-trichloropyrimidine (0.08564 mol), 4-amino-benzonitrile (0.1071 mol), 1-methyl-2-pyrrolidinone (17 ml) and HCl in diethylether (1M; 85.6 ml). The mixture was placed in an oil bath at 130° C. under a stream of nitrogen until the ether was gone. An additional 10 ml of 1-methyl-2-pyrrolidinone was added. The mixture was heated at 145° C. for 16 hours under argon. 1,4-Dioxane was added. The mixture was refluxed, cooled, then filtered. The filtrate was evaporated. The residue was dissolved in CH2Cl2, washed with 1 N NaOH, then filtered. The solid was dissolved in 2-propanone, evaporated onto silica gel, and chromatographed using 1-3% 2-propanone in hexane as eluent. The pure fractions were collected and the solvent was evaporated, yielding 1.63 g (6.8%) of 4-[(4-amino-5,6-dichloro-2-pyrimidinyl)amino]benzonitrile (interm. 12).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N:4]1([CH2:3][CH2:2][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCN2CCCC2)cc1
Temperature: 60 °C
Yield: 54.5 %

Procedure:
A mixture of 1-(2-chloroethyl)pyrrolidine (1.19 g, 8.83 mmol), 4-hydroxybenzaldehyde (1.02 g, 8.33 mmol), and potassium carbonate (2.30 g, 16.7 mmol) in DMF (5 mL) was heated at 60° C. overnight. The reaction mixture was diluted with H2O and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed (50 mL brine), dried over Na2SO4, and concentrated. The crude material was purified on a silica gel column to yield 4-(2-(pyrrolidin-1-yl)ethoxy)benzaldehyde (996 mg, 53%). 1H NMR (CDCl3): δ 9.90 (s, 1H), 7.85 (d, 2H), 7.03 (d, 2H), 4.22 (t, 2H), 2.96 (t, 2H), 2.69 (m, 4H), 1.82 (m, 4H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][O:6][N:7]=[C:8]([C:24](=O)[CH2:25]Br)[C:9]([NH:11][CH:12]1[C:22](=[O:23])[N:14]2[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]12)=[O:10]>C(O)C>[NH2:1][C:2]1[S:3][CH:25]=[C:24]([C:8](=[N:7][O:6][CH3:5])[C:9]([NH:11][CH:12]2[C:22](=[O:23])[N:14]3[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[N:4]=1
Reactant: NC(N)=S
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
Thiourea (8.4 mg.) was added to a solution of 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 42 mg.) in ethanol (6 ml.) and stirred at room temperature for an hour and at 50° C. for 30 minutes. After removing ethanol from the reaction mixture in vacuo, water (5 ml.) was added to the residue and adjusted to pH 4.0 with 6 N-hydrochloric acid. The precipitates were collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 8 mg.). The filtrate was subjected to column chromatography on nonionic, adsorption resin "Diaion HP-20" (trademark: manufactured by Mitsubishi Chemical Industries Ltd., 5 ml.), washed with chilled water (5 ml.) and eluted with 20% aqueous isopropyl alcohol. The eluate was adjusted to pH 6.5 with 1 N aqueous sodium hydroxide under ice-cooling, and concentrated in vacuo. The residue was lyophilized to give sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 15 mg.).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:38][CH2:39][CH3:40])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:33]([O:35]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:2].O.[NH2:42][NH2:43]>CO>[CH2:1]([O:3][CH:4]([O:38][CH2:39][CH3:40])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:42][NH:43][C:33](=[O:35])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][C:24]([C:27]([N:28]([CH3:30])[CH3:29])=[O:31])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(=O)N(C)C)cc1)C(c1ccc(C(OCC)OCC)cc1)N2
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
Ethyl 2-(4-(diethoxymethyl)phenyl)-3-(4-(dimethylcarbamoyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (250 mg, 0.46 mmol) and hydrazine monohydrate (85%, 5 mL) were added in MeOH (15 mL) and the mixture was stirred room temperature for 5 h. The resulting mixture was concentrated under reduced pressure to a volume of 15 mL and then filtered; the filtrate was evaporated to give the title compound as a white solid (180 mg, yield 76%). LC-MS (ESI) m/z: 513 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:11].[Br:12][CH2:13][CH2:14][S:15][S:16][CH2:17][CH2:18]Br.[C:20](#[N:23])[CH2:21][CH3:22]>>[Br-:12].[Br-:12].[S:16]([CH2:17][CH2:18][N+:23]1[C:20]2[CH:6]=[CH:5][CH:10]=[CH:22][C:21]=2[N:2]([CH3:1])[C:3]=1[CH3:11])[S:15][CH2:14][CH2:13][N+:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]([CH3:1])[C:3]=1[CH3:11]
Reactant: Cc1nc2ccccc2n1C
Reactant: CCC#N
Reactant: BrCCSSCCBr
Product: Cc1n(C)c2ccccc2[n+]1CCSSCC[n+]1c(C)n(C)c2ccccc21
Product: [Br-]

Procedure:
2.4 g of 1,2-dimethylbenzimidazole, 2.1 g of bis(2-bromoethyl) disulfide and 6 ml of propionitrile were stirred at 100 C in a sealed 20 ml reactor for 8 h. After cooling, filtration, washing with 3 times 10 ml and drying under vacuum, 2.2 g of beige solid were recovered. The analyses showed that the product was in conformity with the expected structure.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][NH:4][C:3]1=[O:14]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][NH:4][C:3]1=[O:14]
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)NCC1C(=O)O
Yield: 100 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (801 mg, 4 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in TFA/DCM (trifluoroacetic acid/dichloromethane) (1:2, 9 ml) was stirred at room temperature for 6 hours. The solution was evaporated, the residue was co-evaporated with toluene and dried to give crude 3-methyl-2-oxo-4-imidazolidinecarboxylic acid (assume ˜4 mmol) which was used in the next step. LC/MS [M+H]+=145.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:22])[CH2:3]1.C(O)(=O)C.CO[CH:30]1[CH2:34][CH2:33][CH:32](OC)O1>Cl.O>[CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH:30]=[CH:34][CH:33]=[CH:32]5)=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:22])[CH2:3]1
Reactant: COC1CCC(OC)O1
Reactant: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(N)cc4)[nH]c3cc21
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(-n5cccc5)cc4)[nH]c3cc21
Reaction time: 20 h

Procedure:
3.06 g. 8,8-dimethyl-2-(4-aminophenyl)-5,6,7,8-tetrahydro-lH-imidazo[4,5-g]quinolin-6-one (see Example 38) were allowed to stand for 20 hours at 25° C. with 30 ml. glacial acetic acid, 5 ml. water, 2 drops of concentrated hydrochloric acid and 1.32 ml. 2,5-dimethoxytetrahydrofuran. The reaction mixture was then washed with 100 ml. water. After crystallisation from ethanol, there was obtained 0.8 g. of the title compound; m.p. 329 -350° C. (decomp.).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2([OH:33])[CH2:20][CH2:19][CH:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[CH2:17][CH:16]2[CH2:29][N:30]([CH3:32])[CH3:31])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[Cl:34]CCl.CCOCC>>[ClH:34].[CH3:31][N:30]([CH2:29][CH:16]1[CH2:17][CH:18]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[CH2:19][CH2:20][C:15]1([C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1)[OH:33])[CH3:32]
Reactant: ClCCl
Reactant: Cc1ccc(CC2CCC(O)(c3cccc(OCc4ccccc4)c3)C(CN(C)C)C2)cc1
Solvent: CCOCC
Product: Cc1ccc(CC2CCC(O)(c3cccc(O)c3)C(CN(C)C)C2)cc1
Product: Cl
Yield: 56 %

Procedure:
Compound (43) was hydrogenated corresponding to the conditions described in Example 23, step 2. The product was then taken up in 1:1 dichloromethane/ether and tetramethylchlorosilane/water was added. After recrystallisation from 2-butanone/water, compound (39) was obtained in a yield of 56% theoretical.