Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)[C:7](=[O:23])[NH:6][C:5]1=[O:24].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>CN(C)C=O>[CH3:25][N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][CH:3]=[C:4]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH2:16][N:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)[CH:12]=4)[C:7](=[O:23])[NH:6][C:5]3=[O:24])=[CH:34][CH:33]=2)[CH2:30][CH2:31]1
Reactant: COC=C1C(=O)NC(=O)c2ccc(OCCN3CCOCC3)cc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(OCCN5CCOCC5)cc43)cc2)CC1
Temperature: 110 °C
Yield: 41.8 %

Procedure:
A mixture of 4-methoxymethylene-6-(2-morpholin-4-yl-ethoxy)-4H-isoquinoline-1,3-dione (115 mg, 0.35 mmole), N,N-dimethylformamide (1 mL) and 4-(4-methyl-piperazin-1-yl)-phenylamine (66 mg, 0.35 mmole) is stirred and heated at 110° C. for one hour, cooled in the refrigerator. The reaction mixture is evaporated to dryness, taken up in 5% methanol in chloroform and passed through a short pad of Florisil eluting with 5% methanol in chloroform. The eluate is evaporated in vacuo and treated with ether, filtered and dried to give a yellow solid 72 mg (42%), mp 142-143° C.; MS (ES+): m/z 492.2 (M+H).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].Cl[S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9]>ClC1C=CC=CC=1>[CH3:6][S:3]([N:2]([CH3:1])[S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])(=[O:5])=[O:4]
Reactant: CNS(C)(=O)=O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Clc1ccccc1
Product: CN(S(C)(=O)=O)S(=O)(=O)N=C=O

Procedure:
151 g (1.38 moles) of methanesulfonic acid methyl amide are dissolved in 500 ml of chlorobenzene, a solution of 215 g (1.52 moles) of chlorosulfonyl-isocyanate in 200 ml of chlorobenzene is added within 10 minutes at room temperature, the whole is subsequently heated at 120° - 125°C for 4 hours with agitation, and finally, the methanesulfonyl-methylamino-sulfonylisocyanate is isolated by distillation. The yield is 173 g (59 %), boiling point 94° - 98°C/0.1 torr.
Reaction SMILES: [C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2].[C:24]1([CH3:36])[CH:29]=[CH:28][C:27]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1>CC(C)=O>[C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH:22][C:34]([NH:33][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:36])=[CH:25][CH:26]=1)(=[O:32])=[O:31])=[O:35])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1N
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1NC(=O)NS(=O)(=O)c1ccc(C)cc1
Temperature: 50 °C
Yield: 29 %

Procedure:
To a suspension of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (1.0 g.; 0.00304 mole) in acetone (5 ml.) is added p-toluenesulfonyl isocyanate (0.6 g.; 0.00304 mole). The suspension is heated to 50° C. and vacuum filtered. The precipitate is washed with acetone and ether and then dried to afford 0.4 g. (29% yield) of 3-(3-carbomethoxythioureido)-4-(3-p-toluenesulfonylureido)benzophenone, m.p. 191°-192° C., dec.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[C:8](=[O:14])[CH2:7]2.[Cl-].[NH4+]>C(O)C.O.ClCCl.[Fe]>[NH2:15][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[N:9]([CH2:11][CH2:12][CH3:13])[C:8](=[O:14])[CH2:7]2
Reactant: CCCN1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCCN1C(=O)Cc2cc(N)cc(F)c21
Temperature: 25 °C

Procedure:
Iron powder (0.855 g, 15.3 mmol) is added in small portions to 7-fluoro-5-nitro-1-propyl-1,3-dihydro-indol-2-one (0.910 g, 3.82 mmol) and ammonium chloride (2.02 g, 38.2 mmol) in ethanol (60 ml) and water (30 ml) at 90° C. The reaction mixture is stirred vigorously and heated for 60 min, cooled to room temperature, and diluted with dichloromethane (300 ml). The mixture is filtered through celite, the organic layer separated and washed with water and brine, dried over sodium sulfate and evaporated to give the title compound as a dark brown solid. HPLC r.t. 3.03 min; MS for C11H13FN2O m/z 209.0 (M+H)+.
Reaction SMILES: CC(C)(O[C:5]([NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[O:16])[C:9]1=[O:23])=[O:6])C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:49][C:50]1[CH:59]=[C:58]2[C:53]([C:54]([N:61]3[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]3)=[CH:55][C:56]([NH2:60])=[N:57]2)=[CH:52][CH:51]=1>>[NH2:60][C:56]1[CH:55]=[C:54]([N:61]2[CH2:62][CH2:63][N:64]([C:5]([NH:7][C@H:8]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([O:17][CH2:18][C:19]([F:20])([F:21])[F:22])=[O:16])[C:9]3=[O:23])=[O:6])[CH2:65][CH2:66]2)[C:53]2[C:58](=[CH:59][C:50]([Cl:49])=[CH:51][CH:52]=2)[N:57]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(C(=O)OCC(F)(F)F)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C(=O)OCC(F)(F)F)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 213, (3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-carboxylic acid, 2,2,2-trifluoroethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a white solid. LC-MS: 543 (M++1). 1H NMR (DMSO+TFA): δ 1.32–1.45 (m, 1H), 1.56˜1.90 (m, 5H), 3.26 (m, 4H), 3.54–3.66 (m, 5H), 4.15 (m, 1H), 4.68 (br.d, 1H), 4.83 (m, 2H), 6.32 (s, 1H), 7.42 (dd, 1H), 7.60 (d, 1H), 7.90 (d, 1H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH:25]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:29]3[CH:30]=[CH:31][N:32]=[C:28]3[CH:25]([CH3:27])[CH3:26])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:8][CH:9]=1
Reactant: CC(C)c1ncc[nH]1
Reactant: Cc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1OCCCc1oc(-n2ccnc2C(C)C)nc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 1 h

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]oxazole (1.00 g), 2-isopropylimidazole (661 mg), potassium carbonate (830 mg) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 1 hour. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (10 ml×2). The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-(2-isopropyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole was obtained as an oil (333 mg, 28%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>CN(C1C=CN=CC=1)C.C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:26](=[O:29])[CH2:27][CH3:28])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 5 °C

Procedure:
N4-(3-bromophenyl)quinazoline-4,6-diamine (100 mg, 0.32 mmol), pyridine (0.3 mL), and DMAP (20 mg) were dissolved in 10 mL of anhydrous THF. The solution was cooled to 5° C. Propionyl chloride (33 mg, 0.35 mmol) was added to the reaction flask dropwise. Ice bath removed was removed, and the reaction mixture was stirred at room temperature and filtered. The filtrate was dried in vacuo to give a yellow solid. The yellow solid was dissolved in ethyl acetate, washed once with saturated Na2CO3, then with 10% acetic acid, and then with brine. The organic phase was dried, filtered, and stripped of solvent in vacuo to give a crude product which was purified by TLC to give the title compound as a whitish product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:12][CH3:13])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.C=O.[OH-].[K+].[CH2:18](O)C>C(O)=O>[CH2:12]([CH:9]1[C:5]2[C:6](=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:18][NH:11][CH2:10]1)[CH3:13]
Reactant: CCC(CN)c1cccc(OC)c1
Reactant: CCO
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Product: CCC1CNCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(3-methoxyphenyl)-1-butanamine (25 g, 131 mmol, prepared according to the procedure described in J. Med. Chem. 1990, 33, 153-160) in formic acid (120 mL) at room temperature was treated with paraformaldehyde (4.18 g, 131 mmol), stirred for 16 hours, treated with 25% KOH (30 mL) and ethanol (100 mL), and refluxed for 2.5 hours. The mixture was cooled to room temperature, extracted with dichloromethane, and the combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane to provide the desired product.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[C:2]([NH:1][C:2]([CH3:7])([C:3]([OH:5])=[O:4])[CH3:6])([CH3:7])([CH3:6])[CH3:3]
Reactant: CC(C)(N)C(=O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)NC(C)(C)C(=O)O
Yield: 104.4 %

Procedure:
α-Aminoisobutyric acid (6.18 g), tert-butyl acetate (200 ml) and 70% aqueous perchloric acid (9.45 g) were stirred at laboratory temperature for 7 days. The mixture was then cooled in an ice-water bath and extracted with 0.5N hydrochloric acid (4×50 ml). The combined aqueous extracts were immediately neutralised with solid sodium bicarbonate. The aqueous solution was extracted with diethyl ether (3×100 ml), the ether extracts pooled, dried over anhydrous sodium sulphate and the ether evaporated in vacuo to give tert-butyl α-methylalanine (4.98 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[O:26]=[C:27]1[NH:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([N:32]4[CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:28][C:27]4=[O:26])=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Product: CN1CCN(c2cc(N3CCc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5=O)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 14 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and tert-butyl 3-oxopiperazine-1-carboxylate (Aldrich, Cat. No. 641057). LCMS (M+H)+: m/z=523.2.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12]O)=[C:4]([CH2:14]O)[CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.C(N(CC)C(C)C)(C)C.[C:37]1([C:43]([NH2:56])([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C1C=CN=CC=1)C.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9])[CH2:12][N:56]([C:43]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:14]2
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(F)c(C(F)(F)F)cc1CO
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Fc1cc2c(cc1C(F)(F)F)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 1.56 mmol (4-fluoro-2-hydroxymethyl-5-trifluoromethyl-phenyl)-methanol and 0.08 mmol DMAP in 5 ml dichloromethane at 0° C. were added dropwise 3.28 mmol methanesulfonyl chloride and 6.25 mmol triethylamine. The mixture was stirred at 0° C. for 1 h, and then heated quenched with water. The mixture was extracted with dichloromethane and the organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in DMF and then 4.68 mmol N,N-diisopropylethylamine and 2.03 mmol triphenylmethylamine were added sequentially. The mixture was heated at 60° C. for 1 day and then at 80° C. for a further day. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: ethyl acetate/heptane) to afford the title compound as a white amorphous solid (23% yield). EI-MS (m/e): 370.1 ([M−Ph]+, 100%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.C([Li])CCC.CN(C)[CH:22]=[O:23].Cl>O1CCCC1>[F:14][C:2]([F:1])([F:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[S:9][C:10]([CH:22]=[O:23])=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)CCCCCc1cccs1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(CCCCCC(F)(F)F)s1
Temperature: -25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(6,6,6-trifluorohexyl)thiophene (3.33 g) in dry tetrahydrofuran (30 ml) at -25° C. under nitrogen, was added n-butyllithium (8.2 ml, 2.5M) dropwise and the solution stirred at -25° C. for 2 hours. Dry dimethylformamide (2.34 ml) was then added dropwise and the solution stirred for a further hour, allowed to warm to room temperature and stirred for half hour. The reaction mixture was poured onto 2N hydrochloric acid (100 ml), extracted with ether (2×100 ml), dried over MgSO4 and evaporated under reduced pressure to give a brown oil. The oil was distilled under reduced pressure to give a yellow oil b.p. 114° C./1 mm.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]([C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)=[O:22])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[N+:34]([C:37]1[CH:42]=CC(O)=[CH:39][CH:38]=1)([O-:36])=[O:35].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]([C:23]1[NH:27][CH:26]=[CH:25][N:24]=1)=[O:22])([O:6][C:7]1[CH:39]=[CH:38][C:37]([N+:34]([O-:36])=[O:35])=[CH:42][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CCCCCCCCCCCOC(=O)c1ncc[nH]1)OCC
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCCCCCCCCCOC(=O)c1ncc[nH]1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 16 (1.2 g, 3.0 mmol) dissolved in 25 mL of CH2Cl2 was added oxalyl chloride (0.65 n-flL, 7.5 mmol) dropwise at 0° C. The reaction mixture was allowed to slowly warm to room temperature. After stirring for 8 h, the mixture was concentrated to remove excess oxalyl chloride. The crude residue was redissolved in 20 mL of CH2Cl2, followed by the addition of 4-nitrophenol (414 mg, 3.0 mmol) and Et3N (0.80 mL, 6.0 mmol). After stirring at room temperature for 10 h, the reaction mixture was concentrated. The residue was purified by flash chromatography (hexane/EA=1:1) to give 601 mg (41%) of pure 17. 1H NMR (CDCl3, 500 MHz) δ 8.16 (d, J=9.0 Hz, 2H), 8.10 (s, 1H), 7.37 (s, 1H), 7.32 (d, J=9.0 Hz, 2H), 7.01 (s, 1H), 4.35 (t, J=6.5 Hz, 2H), 4.11 (m, 2H), 1.87 (m, 2H), 1.72 (m, 2H), 1.62 (m, 2H), 1.38-1.17 (br m, 20H). 31P NMR (CDCl3, 500 MHz) δ 30.49.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[O:17][C:18]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][C:32]5[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=5)[C:19]=4[C:20]=3[CH3:21])=[CH:10][C:8]=2[CH:9]=1)[CH3:2].C=O.[C:40](O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[O:17][C:18]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:40])[CH2:31][C:32]5[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=5)[C:19]=4[C:20]=3[CH3:21])=[CH:10][C:8]=2[CH:9]=1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCOCc1cc2cc(OCc3oc4cccc(OCCCNCc5cccnc5)c4c3C)ccc2o1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOCc1cc2cc(OCc3oc4cccc(OCCCN(C)Cc5cccnc5)c4c3C)ccc2o1

Procedure:
A mixture of the compound of Example 42 (25.3 mg), formalin (37%, 5.7 μl), acetic acid (12 μl) and sodium cyanoborohydride (6.4 mg) was stirred in MeOH (2 ml) at room temperature for 1.5 hours. MeOH was evaporated to dryness, the residue was purified by silica gel TLC (dichloromethane-MeOH=10:1) to give the title compound as a colorless oil (23.4 mg). FAB-MS: m/z 515 (MH+); 1H-NMR (CDCl3): δ 1.26 (3H, t, J=7 Hz), 2.03 (2H, quintet, J=6.5 Hz), 2.25 (3H, s), 2.27 (3H, s), 2.61 (2H, t, J=7 Hz), 3.55 (2H, s), 3.61 (2H, q, J=7 Hz), 4.10 (2H, t, J=6 Hz), 4.57 (2H, s), 5.09 (2H, s), 6.58 (1H, d, J=8 Hz), 6.63 (1H, s), 6.97 (1H, dd, J=9 Hz, 2.5 Hz), 7.0-7.2 (4H, m), 7.37 (1H, d, J=9 Hz), 7.64 (1H, dt, 7.5 Hz, 1.5 Hz), 8.42 (1H, dd, J=5 Hz, 1.5 Hz), 8.51 (1H, d, J=1.5 Hz).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][N:7]1[C:11]2[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1>C(O)(=O)C.[C].[Pd]>[CH3:6][N:7]1[C:11]2[CH2:12][CH:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:15][C:10]=2[N:9]=[CH:8]1
Reactant: COC(=O)c1ccc2ncn(C)c2c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)C1CCc2ncn(C)c2C1
Yield: 91.9 %

Procedure:
A solution of 3.39 g of methyl 1-methylbenzimidazole-6-carboxylate sulfate in 70 ml of acetic acid was catalytically hydrogenated at 90° C. for 6 hours under 60 atms using 1.9 g of 5% palladium carbon as a catalyst. Ater the catalyst was filtered off and the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the concentrate followed by extraction with 0.5 N HCl. The aqueous phase was rendered alkaline with potassium carbonate and extracted with chloroform. The chloroform phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2.10 g (92%) of methyl 1-methyl-4,5,6,7-tetrahydrobenzimidazole-6-carboxylate.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:48][O:49][CH2:50][CH:51]=[CH2:52])[C:10]([NH:12][CH:13]2[C:46](=[O:47])[N:15]3[C:16]([C:30]([O:32][CH:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])=[C:17]([CH2:20][S:21]/[CH:22]=[CH:23]\[C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.O1CCCC1.O>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:48][O:49][CH2:50][CH:51]=[CH2:52])[C:10]([NH:12][CH:13]2[C:46](=[O:47])[N:15]3[C:16]([C:30]([O:32][CH:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[O:31])=[C:17]([CH2:20][S:21]/[CH:22]=[CH:23]\[C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CS/C=C\c3cccnc3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CS/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Temperature: 35 °C
Reaction time: 0.83 h
Yield: 95 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (23.5 g) in methanol (950 ml) was added conc. hydrochloric acid (12.7 ml) at ambient temperature. The mixture was stirred for 50 minutes at 35° C. The mixture was concentrated in vacuo to give a residue, which was dissolved in a mixture of ethyl acetate, tetrahydrofuran and water. The mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and concentrated in vacuo, and the residue was triturated in diisopropyl ether to give benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (21.5 g)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:6][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH2:17][C:16]3[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=3)=[C:2]([F:1])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccc(F)cc1)c1ccc(OCc2ccc(F)cc2)c(F)c1
Temperature: 65 °C
Yield: 75.2 %

Procedure:
A mixture of 3-fluoro-4-hydroxybenzoic acid (4.68 g, 30 mmol), 4-fluorobenzyl bromide (17.0 g, 90 mmol) and potassium carbonate (8.3 g, 60 mmol) in THF:water (1:1, 100 mL) was heated at 65° C. for 48 h. After cooling to room temperature the mixture was extracted with ethyl acetate (2×100 mL) and the combined extracts washed with brine (100 mL) and dried over sodium sulfate. Filtration and evaporation gave a residue which was crystallised from ether:heptane to afford the title compound (8.4 g, 75%) as a white solid. MS: m/e=372.0 (M+).
Reaction SMILES: [C:1]1([C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH2:21][OH:22])[CH:16]=[CH:17][CH:18]=3)=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:39]O)(C)(C)C.C(O)(=O)C(C(C(O)=O)O)O>ClCCl.C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:29]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([C@@H:19]4[O:39][C@H:20]4[CH2:21][OH:22])[CH:16]=[CH:17][CH:18]=3)=[N:9]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OO
Reactant: OCC=Cc1cccc(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: OC[C@@H]1O[C@H]1c1cccc(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reaction time: 0.17 h

Procedure:
L-(+)-Dimethyl tartrate (1.85 g) was added in dry dichloromethane (10 ml) dropwise to a stirred solution of titanium (IV) isopropoxide (3.1 ml) in dry dichloromethane (30 ml) at -20° to -25° C. under nitrogen. The solution was stirred for 10 minutes and a solution of 3-[3-(2-triphenylmethyl-2H-tetrazol-5-yl)phenyl]-2-propenol (4.5 g) in dry dichloromethane (20 ml) was added, followed by a 3.7M solution of t-butylhydroperoxide in toluene (6.7 ml), both at -20° to -25° C. The pale orange solution was left to stand in a freezer for 3 hours. To the stirred solution was added aqueous tartaric acid (10%; 50 ml) and the mixture stirred for 1 hour, filtered and separated. The dichloromethane layer was dried over magnesium sulphate filtered and evaporated under reduced pressure to give a yellow oil. The oil was dissolved in carbon tetrachloride, washed with water, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a pale yellow oil. The oil was chromatographed on a silica gel column using diethyl ether and hexane (2:1) and the required fractions evaporated under reduced pressure to give a colourless crystalline solid.