Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[C:28]1([CH2:27][C:26]([NH:25][C@@H:24]2[C:23](=[O:35])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:19][S:20][C@H:21]23)=[O:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3ccccc3)CS[C@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(O)=S)=C(c3ccccc3)CS[C@H]12

Procedure:
A solution of 0.96 g (1.62 mmols) of 7β-phenylacetylamino-3-phenylthio-3-cephem-4-carboxylic acid diphenylmethyl ester and 0.26 ml (2.43 mmols) of anisole in 9.6 ml of methylene chloride is stirred with 1.24 ml (16.2 mmols) of trifluoroacetic acid for 30 minutes at 0° C. and the mixture is treated with 50 ml of cold toluene and evaporated in vacuo and the residue is dried in a high vacuum. The residue is digested with diethyl ether, filtered off, rinsed with the same solvent and dried in vacuo. 7β-Phenylacetylamino-3-phenylthio-3-cephem-4-carboxylic acid is obtained as a microcrystalline, colourless powder which can be recrystallised from acetone/methylene chloride/diethyl ether. Melting point 190° C. (decomposition). Thin layer chromatogram (silica gel): Rf ~0.60 (n-butanol/pyridine/acetic acid/H2O, 40:24:6:30); UV spectrum (ethanol): λmax =263 nm (ε=7000); 305 nm (ε=9000); IR spectrum (nujol): characteristic bands at 3.02; 5.59; 5.81; 6.01; 6.22 and 6.48μ.
Reaction SMILES: CS(O[CH:6]([CH3:15])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[O:8]([CH2:7][CH:6]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(COc1ccccc1)OS(C)(=O)=O
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(COc1ccccc1)N1CCNCC1

Procedure:
1-Phenoxy-2-propyl methane sulfonate (1 mole), anhydrous piperazine (4 moles) and potassium carbonate (2 moles) are added to 1000 ml methyl ethyl ketone. The mixture is refluxed during 45 hours, with stirring. The solvent is removed in vacuo and the residue is taken up into water and ether. The ethereal phase is again treated with a dilute aqueous hydrochloric acid solution and the aqueous phase is evaporated off. The resulting oil is taken up into a minimum amount of water. Sodium hydroxide (30 g) is added thereto, after which the material is extracted twice with ether. The ether is removed and the residual oil is distilled. B.p. = 104°-105° C./0.1 mm Hg. N.M.R.: consistent.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1.C(N)(=O)C>C(Cl)Cl.O.CCN(CC)CC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][S:22]([CH3:21])(=[O:24])=[O:23])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19]
Reactant: CN(C)c1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Reactant: CS(=O)(=O)Cl
Agent: CC(N)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN(C)c1cc(-c2ccc3nc(NS(C)(=O)=O)sc3c2)cnc1Cl
Reaction time: 8 h
Yield: 53 %

Procedure:
To a slurry of 6-(6-chloro-5-(dimethylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (60 mg, 197 μmol) in DCM (2 mL) was added methanesulfonyl chloride (400 μL, 5168 μmol), and pyridine (300 μL). After overnight, Et3N (0.3 mL) was added. After overnight, the mixture was diluted with H2O and stirred for several days. The mixture was filtered, washed with H2O to give a solid that is mostly the product (Rf 2.20), with small amount of Acetamide (Rf 3.39, m/e 347). The solid was washed with EtOAc, and hot EtOAc containing 5% MeOH to give the product as a brown solid (40 mg, 53%). MS (ESI, POS. ION) M/Z: calc'd for C15H15ClN4O2S2: 382.0. found: 383.0. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.84 (s, 6H) 3.03 (s, 3H) 7.41 (d, J=6.06 Hz, 1H) 7.66-7.87 (m, 2H) 8.26 (d, J=26.21 Hz, 2H) 12.90-13.23 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@H:28]([NH2:35])[C@@H:27]1[OH:36]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:35][C@@H:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][C@@H:27]2[OH:36])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and (1S,2R)-(−)-cis-1-amino-2-indanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:49])[C@@H:9]([CH3:48])[C:10]([NH:12][C@@H:13]([CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[C:14]([N:16]1[CH2:20][C@@H:19]([NH:21][C:22]([O:24][CH2:25][CH:26]2[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:18][C@H:17]1[C:39]([OH:41])=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:83]([NH2:90])[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1>CN(C=O)C>[CH:28]1[C:27]2[CH:26]([CH2:25][O:24][C:22](=[O:23])[NH:21][C@H:19]3[CH2:18][C@@H:17]([C:39](=[O:41])[NH:90][CH2:83][C:84]4[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=4)[N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:49])[CH3:48])[CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)[CH2:20]3)[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[CH:31]=[CH:30][CH:29]=1
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)NCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To (2S,4S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid (Intermediate 27) in DMF at 0° C. was added DIPEA (116 μL, 0.66 mmol) and HATU (93 mg, 0.24 mmol). The mixture was stirred at 0° C. for 15 minutes and then benzylamine (26.1 mg, 0.24 mmol) in DMF (0.5 mL) was added dropwise, the cooling bath removed and the reaction stirred for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined extracts were washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution, water, and brine and dried over anhydrous magnesium sulfate. Concentration gave ((3S,5S)-5-benzylcarbamoyl-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-pyrrolidin-3-yl)-carbamic acid 9H-fluoren-9-ylmethyl ester as a foam which was used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH3:12][C:10]([CH3:11])([CH3:13])[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:15]2)[CH:3]=1)=[O:14]
Reactant: C1=COCCC1
Reactant: CC(C)(C)C(=O)Nc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
N-(3-Hydroxy-phenyl)-2,2-dimethyl-propionamide (49 g, 0.254 mol) in dichloromethane (1 l) is treated with dihydropyrane (66 ml, 0.762 mol) and pyridinium p-toluenesulfonate (957 mg, 3.8 mmol). After stirring for 6 days at 25° C., the solvent is removed and the residue crystallized from EtOAc/hexanes to give 2,2-dimethyl-N-[3-(tetrahydro-pyran-2-yloxy)-phenyl]-propionamide.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:5][N:4]([C:6]2[CH:7]=[C:8]3[N:17]([CH3:18])[CH:16]=[CH:15][C:9]3=[N:10][C:11]=2[CH:12]([NH2:14])[CH3:13])[CH2:3]1.[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23](Cl)[N:22]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23]([NH:14][CH:12]([C:11]2[N:10]=[C:9]3[CH:15]=[CH:16][N:17]([CH3:18])[C:8]3=[CH:7][C:6]=2[N:4]2[CH2:5][C:2]([F:1])([F:19])[CH2:3]2)[CH3:13])[N:22]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: CC(N)c1nc2ccn(C)c2cc1N1CC(F)(F)C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CC(F)(F)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a 10 mL vial were added 1-(6-(3,3-difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (61 mg, 0.23 mmol) in DMF (2 mL) along with 2,4-diamino-6-chloropyrimidine-5-carbonitrile (38.8 mg, 0.229 mmol) and Et3N (0.064 mL, 0.46 mmol). The resulting yellow solution was heated to 90° C. and stirred for 5 hours. The reaction mixture was diluted with EtOAc and washed with saturated NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was precipitated with ether, filtered, and purified by silica gel column chromatography, eluting with 1:1 EtOAc/hexane to 100% EtOAc to 9:1 EtOAc/MeOH gradient. The resulting yellow foam was further purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium bicarbonate). The fractions containing the desired product were combined and lyophilized to give the title compound (racemate) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29-1.43 (m, 3 H), 3.74-3.85 (m, 3 H), 4.18-4.37 (m, 2 H), 4.41-4.59 (m, 2 H), 5.38-5.52 (m, 1 H), 6.39-6.56 (m, 3 H), 6.57-6.65 (m, 2 H), 6.68-6.76 (m, 1H), 7.39-7.45 (m, 1 H), 7.46-7.53 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H19F2N9, 400.2; found 400.4.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH2:20]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](Cl)=[O:37])=[CH:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:36]([C:29]3[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:28]=3)=[O:37])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1cn(Cc2ccccc2)c2ccccc12
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cn(Cc2ccccc2)c2ccccc12

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 1-benzylindole-3-carbonyl chloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-1-benzyl-1H-3-indolecarboxamide as a white powder, m.p. 139.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.14 (t, J=7.8 Hz, 1H), 8.04 (m, 2H), 7.93 (m, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.44-7.09 (m, 9H), 6.63 (s, 2H), 5.44 (s, 2H), 4.66 (t, J=6.6 Hz, 2H), 1.97-1.92 (m, 2H), 1.62-1.57 (m, 2H); MS (EI) m/e 488.2326 (488.2325 calcd for C30H28N6O).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:24][CH2:23][CH2:22][N:12]2[C:13]=1[C:14]1[N:15]=[N:16][C:17]([NH:20][NH2:21])=[CH:18][CH:19]=1.[CH:25]1([CH:28]=O)[CH2:27][CH2:26]1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[CH:25]1([C:28]2[N:16]3[N:15]=[C:14]([C:13]4[N:12]5[CH2:22][CH2:23][CH2:24][C:11]5=[N:10][C:9]=4[C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[CH:19]=[CH:18][C:17]3=[N:20][N:21]=2)[CH2:27][CH2:26]1
Reactant: O=CC1CC1
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3n2CCC3)nn1
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Fc1ccc(-c2nc3n(c2-c2ccc4nnc(C5CC5)n4n2)CCC3)c(F)c1
Temperature: 2 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
The 2-(2,4-difluorophenyl)-3-(6-hydrazinylpyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (5.00 g, 15.2 mmol, Example #35, Step E) was reacted with cyclopropanecarbaldehyde (1.60 g, 22.8 mmol) overnight at ambient temperature in DCM (300 mL). The reaction mixture was cooled to about 0-4° C. Iodobenzene diacetate (5.4 g, 16.75 mmol) was added and the reaction mixture stirred at about 0-4° C. for about 30 min and then at ambient temperature for about 3 h. The reaction mixture was partitioned between DCM and a saturated aqueous Na2CO3 solution. The aqueous phase was back-extracted with of DCM (2×50 mL). The combined organics were dried over MgSO4, filtered, concentrated and purified by chromatography on silica gel using DCM/MeOH (gradient, 100:0 to 95:5) and subsequently triturated with a 90:10 mixture of DCM/Et2O to give the title compound (3.7 g, 64%): LC/MS (Table 1, Method a) Rt=2.22 min; MS m/z: 379.3 (M+H)+; 1H NMR (CDCl3) δ 7.84 (d, 1H), 7.66 (m, 1H), 7.08-7.00 (m, 1H), 6.95-6.85 (m, 2H), 4.55-4.45 (m, 2H), 3.12-3.01 (m, 2H), 2.78 (m, 2H), 2.53-2.42 (m, 1H), 1.45-1.38 (m, 2H), 1.28-1.19 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([NH:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Cl)[CH:22]=1)([CH3:18])([CH3:17])[CH3:16].C(N(C(C)C)C(C)C)C>O1CCCC1.ClCCl>[C:15]([NH:19][C:20]([C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[CH2:27][N:11]1[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:29])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)NC(=O)c1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a solution of tert-butyl-1-homopiperazine carboxylate (0.25 g, 1.25 mmol) and N-tert-butyl-3-(chloromethyl)benzamide (0.470 g, 1.25 mmol) in tetrahydrofuran (4 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.88 mmol). The resultant mixture was stirred at 80° C. for 16 hours. The mixture was cooled to room temperature, diluted with dichloromethane (50 mL) and washed with saturated ammonium chloride (aqueous) and brine. The organic phase was dried (sodium sulfate), filtered and concentrated under vacuum. The residue was purified by column chromatography on silica (using a solvent gradient of dichloromethane/methanol) to afford the title compound (0.435 g) as a white solid. MS (ESI) m/z 389.9 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[Na+]>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[CH:10]=[CH:11][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1cnc2[nH]ccc2c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(F)cnc32)cc1
Yield: 0 %

Procedure:
A mixture of 1.30 g of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine, 1.6 g of 4-methylbenzenesulfonyl chloride, 3.40 g of sodium hydroxide dissolved in 16 cm3 of water, and 0.052 g of tetrabutylammonium hydrogen sulfate in 200 cm3 of toluene is stirred for about 24 hours in the region of 20° C. The mixture is diluted with 500 cm3 of ethyl acetate; the organic phase is washed with three times 200 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a column of silica [eluent: dichloromethane]. 1.90 μg of 4-chloro-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine are thus obtained in the form of a powder, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:20])([CH3:19])[CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1.[CH:21](O)=[O:22]>>[CH:21]([O:18][CH2:17][CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:10][CH:11]=1)([OH:20])[CH3:19])=[O:22]
Reactant: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: O=CO
Product: CC(O)(CCOC=O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
3 g. of 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol and 15 ml. of formic acid are warmed to 80° for 2 hours. The mixture is cooled and worked up in the customary manner to give 1-formyloxy-3-(2',4'-difluoro-4-biphenylyl)butan-3-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH:15](O)[O:14][C:13](=O)[C:7]=3[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1.O.[NH2:19][NH2:20]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH:15]=[N:20][NH:19][C:13](=[O:14])[C:7]=3[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1
Reactant: NN
Reactant: O=C1OC(O)c2c1c(O)nc1cc(Cl)ccc21
Solvent: O
Solvent: CS(C)=O
Product: O=c1[nH]ncc2c1c(O)nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 90 h

Procedure:
2.0 g (0.0079 mol) of (RS)-7-chloro-1,4-dihydroxy-1,3-dihydro-furo[3,4-c]quinolin-3-one were dissolved in 20 ml of dimethyl sulphoxide while gassing with argon. 0.40 g (0.0062 mol) of hydrazine hydrate was added thereto and the mixture was stirred at room temperature for 90 hrs. The suspension obtained was suction filtered and rinsed with ethyl acetate. Yield: 1.21 g (61%) of 8-chloro-5-hydroxy-3,4-dihydropyridazino[4,5-c]quinolin-4-one as yellow crystals; m.p. >350° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]([NH2:19])=[O:18].Br[C:21]1[N:26]=[C:25]([CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:16][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([NH:1][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])[N:26]=3)=[C:3]([C:17]([NH2:19])=[O:18])[N:4]=2)=[CH:12][CH:11]=1)([CH3:15])[CH3:14]
Reactant: OC(c1cccc(Br)n1)C(F)(F)F
Reactant: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(N)s2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(Nc3cccc(C(O)C(F)(F)F)n3)s2)cc1

Procedure:
The title compound was prepared as described in Example 9, Step 2 using 5-amino-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (Example 5, Step 3) (150 mg, 0.54 mmol), 1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethanol (138 mg, 0.54 mmol), Pd2(dba)3 (30 mg, 0.032 mmol), X-PHOS (77 mg, 0.16 mmol), potassium carbonate (82 mg, 0.60 mmol), and tert-amyl alcohol (1.2 ml) as starting materials. 1H NMR (600 MHz, d6-DMSO) δ 11.33 (s, 1H), 7.85 (d, 2H), 7.80 (t, 1H), 7.73 (s, 1H), 7.62 (s, 1H), 7.55 (d, 2H), 7.21 (d, 1H), 7.19 (d, 1H), 7.02 (d, 1H), 5.19 (m, 1H), 5.08 (s, 1H), 1.42 (s, 6H). LRMS (APCI) calc'd for C20H20F3N4O3S [M+H]+ 453.1, found 453.0.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][N:11]([CH2:44][CH:45](OCC)OCC)[C:12]([CH:14]([NH:27][C:28](=[O:43])[CH2:29][CH:30]([NH:32][C:33]([NH:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])[CH3:31])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C(C)(C)C)=[CH:18][CH:17]=3)=[O:13])[C:4]=2[N:3]=[CH:2]1>C(O)=O>[CH2:36]([NH:35][C:33]([N:32]1[CH:30]([CH3:31])[CH2:29][C:28](=[O:43])[N:27]2[CH:14]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[C:12](=[O:13])[N:11]([CH2:10][C:9]3[C:4]4[N:3]=[CH:2][S:1][C:5]=4[CH:6]=[CH:7][CH:8]=3)[CH2:44][CH:45]12)=[O:34])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(CN(Cc1cccc2scnc12)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)CC(C)NC(=O)NCc1ccccc1)OCC
Solvent: O=CO
Product: CC1CC(=O)N2C(Cc3ccc(O)cc3)C(=O)N(Cc3cccc4scnc34)CC2N1C(=O)NCc1ccccc1
Yield: 37.2 %

Procedure:
A solution of crude N-[1-[Benzothiazol-4-ylmethyl-(2,2-diethoxy-ethyl)-carbamoyl]-2-(4-tert-butoxy-phenyl)-ethyl]-3-(3-benzyl-ureido)-butyramide (3.55 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and hexane to give 8-Benzothiazol-4-ylmethyl-6-(4-hydroxy-benzyl)-2-methyl-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic acid benzylamide (1.05 g, 3 step yield: 32%). 1H NMR (CDCl3, 300 MHz) δ 9.25 (s, 1H), 7.4˜7.26 (m, 3H), 7.2 (d, J=7.01, 2H), 6.98 (t, J=8.0, 1H), 6.85 (m, 3H), 6.8 (t, J=7.0, 1H), 6.5 (d, J=8.76, 2H), 5.6 (m, 1H), 5.25 (t, J=4.7, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H), 3.5˜3.3 (m, 2H), 3.25˜3.1 (m, 2H), 2.2 (t, J=7.2, 2H) 1.45 (m, 3H) MS ESI 570 (M+H), 592 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[OH:26])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[NH4+].O.C.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>CC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[OH:26])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Product: C=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
Ammonium (Z)-7β-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4carboxylate (20 gm) was added to a mixture of water (250 ml) and acetone (80 ml) and warmed to 33–35° C. This aqueous solution was treated with activated charcoal and EDTA at 35° C. for 40 minutes. The carbon was filtered and the carbon bed was washed with water (70 ml). This aqueous acetone solution was cooled to −30° C. and a (10%) solution of aqueous sulphuric acid was added rapidly, stirred for 30 minutes and warmed to 0–2° C. The product thus obtained was filtered at 0–2° C., washed with cold-water (100 ml) and dried at 40–45° C. under vacuum for 5–6 hours to get (Z)-7β-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (6.0 gm, HPLC quality 89.0%, water content 4–5%).