Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH:5]([OH:36])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:35]=[CH:34][C:14]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][C:24]3=[O:25])[CH2:19][CH2:18]2)=[O:16])=[CH:13][CH:12]=1)[CH3:2].[CH3:39][N:40]=[C:41]=[O:42]>C(#N)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH:5]([O:36][C:41]([NH:40][CH3:39])=[O:42])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][C:24]3=[O:25])[CH2:21][CH2:22]2)=[O:16])=[CH:34][CH:35]=1)[CH3:38]
Reactant: CCN(CC)CC(O)CCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: CN=C=O
Solvent: CC#N
Product: CCN(CC)CC(CCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1)OC(=O)NC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-{1-[4-(6-Diethylamino-5-hydroxyhexyloxy)benzoyl}-4-piperidinyl}-3,4-dihydrocarbostyril (0.7 g) and methyl isocyanate (0.24 ml) are dissolved in acetonitril (20 ml), and thereto is added trifuroboran ethyl ether complex (0.35 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated and purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to give 1-{1-[4-(6-diethylamino-5-methylaminocarbonyloxyhexyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (314 mg) as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:15])[N:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][N:30]([C:34]4[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[N:38][CH:39]=4)[CH2:31]3)=[CH:26][CH:25]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CO>[NH2:15][C:4]1[N:3]=[C:2]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][N:30]([C:34]4[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[N:38][CH:39]=4)[CH2:31]3)=[CH:26][CH:25]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=1
Reactant: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(c2ccc(C#N)nc2)CC3)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(c3ccc(C#N)nc3)CC4)nc(N)n2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.075 g, 0.33 mmol), 5-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carbonitrile (0.12 g, 0.33 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (1:1) complex (0.01 g, 0.02 mmol) and potassium carbonate (0.14 g, 0.99 mmol) in 1,4-dioxane (2 mL), and water (1 mL) was heated at 120° C. for 2 h. After cooled to r.t., the mixture was diluted with MeOH, filtered, concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with 10% MeOH in DCM to give the desired product. The product was further purified by RP-LCMS (pH=10) to afford the desired product (0.10 g, yield: 71%). Analytic LCMS (M+H)+: m/z=427.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][C:18]2[S:19][C:20]([C:28]([CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])=[C:21]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:21]1[N:22]=[C:18]([NH:17][C:15](=[O:16])[CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[S:19][C:20]=1[C:28]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CN1CCNCC1)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
Compound 560 (428 mg, 0.849 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added thereto at 0° C., followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was reslurried with diethyl ether to afford the entitled Compound 561 (263 mg, 77%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[Cu][C:18]#[N:19].CN1C(=O)CCC1.O>C(OCC)C>[CH3:15][C:11]1([CH3:16])[CH2:12][CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([C:18]#[N:19])=[N:7][CH:6]=2)[CH2:10]1
Reactant: N#C[Cu]
Reactant: CC1(C)CCCC(Oc2ccc(Cl)nc2)C1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1(C)CCCC(Oc2ccc(C#N)nc2)C1
Temperature: 190 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
Add 6-chloro-3-(3,3-dimethylcyclohexyloxy)-pyridine (1.1 g, 4.59 mmol) and copper(I) cyanide (1.23 g, 13.8 mmol) to NMP (20 mL). Heat the mixture to 190° C. and stir overnight. Cool the mixture to room temperature, add water (30 mL) and diethyl ether (30 mL). Extract the aqueous phase with diethyl ether (3×20 mL). Wash the combined organic extracts with brine (20 mL), dry over Na2SO4, filter, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 60 min, 80 mL/min) to obtain the desired intermediate as a colorless oil (412 mg, 39%). MS (APCI+) m/z: 231 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[Na].C(S)C>CN(C=O)C>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:11][C:7]1=2
Reactant: COc1ccc2ccsc2c1
Agent: [Na]
Solvent: CCS
Solvent: CN(C)C=O
Product: Oc1ccc2ccsc2c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
Dissolve 6-methoxy-benzo[b]thiophene (J. Med. Chem. 32:2548, 1989; 26.1 g, 146 mmol) in DMF (500 mL). Add ethanethiol sodium salt (37 g, 440 mmol) and heats to 150° C. with stirring overnight. Add additional ethanethiol sodium salt (112.8 g, 152 mmol) and continue to heat at 150° C. overnight. Concentrate in vacuo to ¼ volume. Partition reaction mixture between ethyl acetate (500 mL) and water (500 mf), separate layers, wash organic layer with water (2×500 mL), brine (500 mL), and dry with magnesium sulfate. Filter and concentrate in vacuo to give 8 g of benzo[b]thiophen-6-ol. Back extract aqueous layers with ethyl acetate (3×1000 mL) wash organics with brine, and dry with magnesium sulfate. Concentrate in vacuo to obtain an additional 15 grams of benzo[b]thiophen-6-ol. Distill off remaining DMF to yield 22.7 g (100%) of benzo[b]thiophen-6-ol.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].C(OC([N:53]1[CH2:60][CH2:59][CH2:58][C@:54]1([CH3:61])[C:55](O)=[O:56])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:95]([OH:101])([C:97]([F:100])([F:99])[F:98])=[O:96]>ClCCl>[F:98][C:97]([F:100])([F:99])[C:95]([OH:101])=[O:96].[CH3:61][C@:54]1([C:55]([NH:37][C@H:36]([C:35]([N:34]([C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]2[CH2:23][CH2:24][CH2:25][C@H:21]2[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@@H:8]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:6])=[O:45])[CH3:42])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:56])[CH2:58][CH2:59][CH2:60][NH:53]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1)C(C)C
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a stirring solution of #114 (164 mg, 0.259 mmol, 1.0 eq.) and 1-(tert-butoxycarbonyl)-2-methyl-D-proline (71.3 mg, 0.311 mmol, 1.2 eq.) in 4 mL of dichloromethane, HATU (118 mg, 0.311 mmol, 1.2 eq.) was added followed by Hunig's base (0.180 mL, 1.04 mmol, 4 eq.). The reaction was allowed to stir at room temperature for -30 minutes. Reaction was reduced down. Reaction was taken up in 3.5 mL of dichloromethane and placed under nitrogen. To this stirring solution, TFA (1.5 mL, 20 mmol, 76 eq.) was added. The reaction was allowed to stir at room temperature for -1 hour. Reaction was reduced down and placed underneath high vacuum. Purification by (Method J*) affords #131 (119 mg, 54%) as a white solid. HPLC (Protocol A at 45° C.): m/z 744.5 [M+H+], retention time=7.342 minutes (purity >98%). 1H NMR (400 MHz, DMSO-d6), δ 9.08-9.18 (m), 8.79-8.89 (m), 8.76 (t), 8.54 (d), 8.29 (d), 7.14-7.31 (m), 4.70-4.79 (m), 4.57-4.66 (m), 4.45-4.55 (m), 3.96-4.04 (m), 3.74-3.80, 3.66 (d), 3.48-3.61 (m), 3.40-3.48 (m), 3.09-3.34 (m), 3.00-3.09 (m), 2.95-3.00 (m), 2.83-2.93 (m), 2.36-2.53 (m), 2.21-2.35 (m), 2.10-2.19 (m), 1.99-2.10 (m), 1.61-1.09 (m), 1.36-1.53 (m), 1.21-1.35 (m), 1.02-1.10 (m), 0.94-1.0 (m), 0.86-0.93 (m), 0.73-0.82 (m).
Reaction SMILES: Br[C:2]1[N:3]([C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH2:19])[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([C:2]1[N:3]([C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH2:19])[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ncnc2c1nc(Br)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1nc2c(N)ncnc2n1[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 90 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of 8-bromo-2'-deoxyadenosine (0.403 g, 1.22 mmol) in DMF (25 ml) was added sodium azide (0.278 g, 4.27 mmol), and the mixture stirred at 90° C. for 2 h. The solvent was removed and the residue was purified on silica gel (10% methanol/chloroform) to give 0.325 g (91%) of 8-azido-2'-deoxyadenosine: 1H NMR (Me2SO-d6)δ2.17 (m, 2H), 3.59 (m, 2H), 3.82 (m, 1H), 4.42 (m, 1H), 5.25 (m, 2H), 6.11 (m, 1H), 7.24 (br.s, 2H), 8.07 (s, 1H); UV (H2O) λmax 282.5 nm; FTIF (KBr) 2155 cm-1. 8-Azido-2'-deoxyadenosine was silylated by Procedure A (77% yield) and then reduced, dideoxygenated, and converted to 8-amino-2',3'-dideoxyadenosine (VIII) using in sequence Procedure D (79%), Procedure E (77%), and Procedure F (81%): mp 177°-179° C., 13C NMR (Me2SO-d6) δ26.0, 29.0, 63.1, 79.5, 83.9, 117.1, 148.4, 148.9, 151.4, 152.3; 1H NMR (Me2SO-d6) 2.16 (m, 4H), 3.61 (m, 2H), 4.11 (m, 1H), 5.54 (m, 1H), 6.10 (m, 1H), 6.40 (br.s, 2H), 6.52 (br.s, 2H), 7.89 (s, 1H); UV (H2O) λmax 273.5 nm (λ13950); FAB HRMS obsd (M+ +H) 251.1266, calcd for C10H14N6O2 251.1257.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH:5]([C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=1)[C:6]([NH:8][NH:9]C(OC(C)(C)C)=O)=[O:7]>C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH:5]([C:17]1[CH:18]=[C:19]([F:25])[C:20]([F:24])=[C:21]([F:23])[CH:22]=1)[C:6]([NH:8][NH2:9])=[O:7]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CCCl)c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NNC(=O)C(CCCl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 211.5 %

Procedure:
A solution of 4 N hydrogen chloride in ethyl acetate (20 mL) was added to tert-butyl N′-[4-chloro-2-(3,4,5-trifluorophenyl)butyryl]hydrazinecarboxylate (1.35 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride (1.18 g). A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride (552 mg) and triethylamine (0.95 mL) in ethanol (10 mL) was added to a solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (500 mg) and triethylamine (1 mL) in ethanol (10 mL) at room temperature, and the reaction solution was stirred at 80° C. for 21 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 131 mg of the title compound as a racemate. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:28]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([F:28])=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)F
Temperature: -5 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirred solution of N-benzyloxycarbonyl-L-leucine (0.50 g, 1.87 mmol) and pyridine (0.15 ml, 1.88 mmol) in anhydrous DCM (5 ml) kept under a N2 atmosphere was added cyanuric fluoride (0.51 ml, 5.64 mmol) at −15 to −10° C. A white precipitate formed. After stirring for 1 hr at −5° C., IR of the crude reaction mixture indicated formation of the acyl fluoride. After 2 hrs crushed ice was added along with DCM (10 ml). The organic layer was separated and the aqueous layer extracted with DCM (5 ml). The combined DCM layers were washed with ice-cold water (10 ml), dried (MgSO4) and concentrated under reduced pressure to afford a colourless oil (0.36 g, 73%) which was used in subsequent reactions without further purification: νmax(polyethylene card) 3317 (N—H), 1843 (acid fluoride); δH (200 MHz, CDCl3) 0.97 (6H, d, J 6.0, CH(CH3)2), 1.62–1.78 (3H, m, CH(CH3)2 & CH2CH(CH3)2), 4.54–4.61 (1H, m, NHCH), 5.02 (1H, m, NH), 5.14 (2H, s, CH2Ph), 7.36 (5H, s, Ar—H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1[CH:16]=[C:15](F)[CH:14]=[C:13]([CH3:18])[C:10]=1[CH:11]=[O:12].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[CH3:8][C:9]1[CH:16]=[C:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[C:13]([CH3:18])[C:10]=1[CH:11]=[O:12]
Reactant: Cc1cc(F)cc(C)c1C=O
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccccc2)cc(C)c1C=O
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
2.3 g (25 mmol) of phenol and 3.8 g (25 mmol) of 2,6-dimethyl-4-fluorobenzaldehyde were dissolved in 60 ml DMA, combined with 4.8 g (35 mmol) of K2CO3 and stirred at 150° C. for 5 min in a microwave (OEM Discoverer), filtered through basic Alox, washed with DMF and concentrated by rotary evaporation. Taken up in a mixture of acetonitrile/water. The substance crystallised, was filtered off and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][S:16][CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][S:16]([CH3:17])=[O:35])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCCC(C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(CCCS(C)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The 2-[1-[(4-chlorophenyl)sulfonyl]-2-methyl-5-(methylthio)pentyl]-1,4-difluorobenzene (Isomer 43-A) (180 mg, 0.430 mmol) obtained in Example 43 was dissolved in methylene chloride (10 ml). Under ice cooling, 3-chloroperbenzoic acid (89 mg, 0.52 mmol) was added, followed by stirring at room temperature for 14 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel chromatography (methylene chloride:methanol=40:1), whereby the title compound (172 mg, 92%) was obtained a colorless oil.
Reaction SMILES: NC(N)=O.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>>[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:33]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[Cl:25])=[O:34])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)(=O)CC2)c1O
Reactant: O=C=Nc1ccccc1Cl
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Cl)Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)(=O)CC2)c1O
Yield: 325.9 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyaniline (62 mg, 0.018 mmol) and 2-chlorophenylisocyanate (34 mg, 0.22 mmol) were coupled to form the desired urea (29 mg, 32%). LC-MS (m/z) 496.0 (M+).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[C:14]([CH2:26][CH2:27][CH3:28])([CH2:23][CH2:24][CH3:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.[OH-].[Na+:32]>C(#N)C.O>[O:30]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[C:14]([CH2:26][CH2:27][CH3:28])([CH2:23][CH2:24][CH3:25])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[O-:22])=[N:3]1.[Na+:32]
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.6 %

Procedure:
A suspension of the product of Example 1H (55 mg, 0.13 mmol) in 1:1 acetonitrile-water was treated with 1N NaOH solution (130 μL 0.13 mmol) and stirred at 25° C. for 2 hours. The solution was then lyophilized to afford the title compound (59 mg, 100%) a fluffy white solid. 1H NMR (300 MHz, DMSO-d6): δ 5.52 (s, 1 H), 8.06 (d, J=7.72 Hz, 1 H), 7.64 (d, J=7.72 Hz, 1 H), 7.49 (m, 3 H), 7.30 (m, 3 H), 2.10 (m, 2 H), 1.67 (m, 2 H), 0.88 (m, 2 H), 0.59 (m, 8 H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:7]=2[CH:32]=1.C1(=O)[NH:37]C(=O)C2=CC=CC=C12.[K]>CN(C=O)C>[NH2:37][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[NH:8][C:7]=2[CH:32]=1
Reactant: CCCN(CCC)CCCCc1nc2ccc(CCl)cc2n1S(=O)(=O)c1ccc(C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCc1nc2ccc(CN)cc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.4 %

Procedure:
The compound (113 mg) obtained in Example 2-3 was dissolved in DMF (2.0 ml) and added with potassium phthalimide (69.0 mg) and the whole was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform, followed by washing with water. After extraction with chloroform, the organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was dried under vacuum, and the dried product was dissolved in a 40% methylamine/methanol solution (1.5 ml), followed by stirring overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform, followed by washing with water and a 1 mol/l sodium hydroxide aqueous solution. After extraction with chloroform, the extract was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (39.8 mg) as a brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH2:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:14]([OH:16])=[O:15])=[CH:21][CH:20]=1)[CH3:18]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2cc(C(=O)O)cnc2OCC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2) and B-(4-ethylphenyl)-boronic acid, (CAN 63139-21-9) as starting materials; LC-MS (UV peak area/ESI) 95.8%, 324.0859 (M−H)−.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][CH3:40])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([O:23]CC4C=CC([N+]([O-])=O)=CC=4)=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].CO.O>[C].[Pd].O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][CH3:40])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 85.7 %

Procedure:
A suspension of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 2.4 g.), 10% palladium carbon (1.0 g.), methanol (24 ml.), water (3.6 ml.) and tetrahydrofuran (48 ml.) was subjected to catalytic reduction under ordinary pressure at room temperature. After removing insoluble substance by filtration, the filtrate was concentrated in vacuo. Water and ethyl acetate were added to the residue, and adjusted to pH 8 with a saturated aqueous solution of sodium bicarbonate. The insoluble substance was removed by filtration, and the aqueous layer was separated. Ethyl acetate was added to the solution, adjusted to pH 2.0 with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution and extract were combined together, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo, and the residue was triturated with diethyl ether and collected by filtration to give 7-[2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.6 g.).