Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=1>CN(C)C=O.CC(C)=O.[Cu]>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: Cc1ccc(O)cn1
Agent: [Cu]
Agent: [K]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2cccc(C(F)(F)F)c2)cn1

Procedure:
3.68 g of a potassium salt of 5-hydroxy-2-methylpyridine was suspended in 10 ml of dimethylformamide, and 5.65 g of m-bromobenzotrifluoride and 300 mg of copper powders were added to the suspension, followed by allowing the mixture to react in a nitrogen stream at 120° C. for 15 hours while stirring. After cooling, the reaction mixture was diluted with 40 ml of acetone and filtered. The filtrate was immediately dried to solidify, and 100 ml of chloroform and 50 ml of water were added thereto. The mixture was adjusted to a pH of 9 with 5 N sodium hydroxide, and any insoluble matter was again separated by filtration. The resulting chloroform layer was dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 4.1 g of oily 5-(m-trifluoromethylphenoxy)-2-methylpyridine.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([O:16][CH2:17][C@@H:18]2[CH2:21][CH2:20][N:19]2C(OC(C)(C)C)=O)[CH:12]=[N:13][C:14]=1[Cl:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:9]1[CH:10]=[C:11]([O:16][CH2:17][C@@H:18]2[CH2:21][CH2:20][NH:19]2)[CH:12]=[N:13][C:14]=1[Cl:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(C(=O)c2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1)c1cc(OC[C@@H]2CCN2)cnc1Cl
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
5-benzoyl-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 107a is dissolved in CH2Cl2 (10 mL). The mixture is cooled to 0° C., TFA (10 mL) is added and the reaction is stirred for 45 minutes as it warms to room temperature. The mixture is concentrated in vacuo and taken up in a minimum amount of H2O. The aqueous mixture is basified with 15% NaOH and extracted with CH2Cl2 (200 mL), which is dried (MgSO4) and concentrated. The residue is chromatographed (silica gel) to afford the free amine. The isolated free amine is taken up in a minimum amount of Et2O, cooled to 0° C., and treated with HCl in EtOH to afford the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]Br.O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[Br:9]
Reactant: BrBr
Reactant: Nc1cccc(O)n1
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(O)ccc1Br
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
To a solution of 6-amino-pyridin-2-ol (5 g, 45.4 mmol) in glacial acetic acid (60 mL) was added bromine (2.33 mL, 45.4 mmol) under Ar atmosphere. The mixture was stirred for 20 minutes, then water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to dryness to obtain crude 6-amino-5-bromo-pyridin-2-ol (4.53 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[OH:11][CH:12]([C:50]1[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=1)[CH2:13][NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]=[C:36]([C@H:38](F)[C:39]4[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=4)[O:35][N:34]=3)=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:19][CH:18]=1.[CH3:56]I.[NH4+].[Cl-]>C1COCC1>[OH:11][CH:12]([C:50]1[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=1)[CH2:13][NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]=[C:36]([C@@H:38]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([F:47])([F:46])[F:48])=[CH:41][CH:40]=4)[CH3:56])[O:35][N:34]=3)=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Nc1ccc(CCNCC(O)c2cccnc2)cc1)c1ccc(-c2noc([C@H](F)c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](c1ccc(C(F)(F)F)cc1)c1nc(-c2ccc(S(=O)(=O)Nc3ccc(CCNCC(O)c4cccnc4)cc3)cc2)no1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
A 1.0M solution of lithium bis(trimethylsilyl)amide in THF (2.02 mL, 2.02 mmol) was added to a stirred solution of the ester from Example 110, Step A (400 mg, 1.83 mmol) in THF (8 ml) at -78° C. The solution was stirred at -78° C. for 10 min. Methyl iodide (120 μL, 1.93 mmol) was added. The solution was allowed to warm slowly to RT over 12 h. Saturated NH4Cl solution was added and the mixture extracted with diethyl ether (3×). The combined organic phase was washed with water (2×), brine, dried (MgSO4) and the solvent removed in vacuo. Flash chromatography (silica, 2-3% ethyl acetate-hexanes) afforded the title compound (234 mg, 55%) as a colorless liquid: 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 3.77 (q, J=7.1 Hz, 1H), 3.66 (s, 3H), 1.50 (d, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([N:8]1[C:12](=O)[CH2:11][CH2:10][C@@H:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].BrCC1C=CC=CC=1.Br[C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][CH:29]=1>>[CH2:17]([O:16][C:14](=[O:15])[C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:10][CH2:11][CH2:12][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][CH:29]=1)[CH3:18]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: CC(C)(C)Oc1ccc(Br)cc1
Agent: BrCc1ccccc1
Product: CCOC(=O)[C@@H](CCCc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C

Procedure:
(R)-2-tert-Butoxycarbonylamino-5-(4-tert-butoxy-phenyl)-pentanoic acid ethyl ester is prepared according to the procedure of Ding, Chuanyong.; Ma, Rujian.; Rong, Guobin. Preparation of w-Phenyl-(2S)—N-Boc-amino Acid Ethyl esters; Chinese Journal of Organic Chemistry Vol 26(12) 2006, 1694 &1695, replacing Ethyl Boc-L-pyroglutamate with Ethyl Boc-D-pyroglutamate & Bromomethyl-benzene with 1-Bromo-4-tert-butoxy-benzene in Example 2a, using preparation steps 2.2, 2.3, and 2.5; [M+H]+ 394
Reaction SMILES: C([C:5]([C:22](=[O:66])[C@H:23]([CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[NH:24][C:25](=[O:58])[C@H:26]([CH2:47][C:48](=[O:57])[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[NH:27][C:28](=[O:46])[CH2:29][CH2:30][NH:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[NH:40][O:41][C:42](=[O:44])[N:43]=2)=[CH:35][CH:34]=1)([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH2:21])[C:6]([O-:8])=[O:7])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:41]1[C:42](=[O:44])[N:43]=[C:39]([C:36]2[CH:35]=[CH:34][C:33]([C:32]([NH:31][CH2:30][CH2:29][C:28]([NH:27][C@H:26]([C:25]([NH:24][C@H:23]([C:22]([CH:5]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH2:21])[C:6]([OH:8])=[O:7])=[O:66])[CH2:59][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)=[O:58])[CH2:47][C:48](=[O:57])[O:49][CH2:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)=[O:46])=[O:45])=[CH:38][CH:37]=2)[NH:40]1
Reactant: CC(C)(C)C(OCCOCCOCCOCCN)(C(=O)[O-])C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CCNC(=O)c1ccc(-c2nc(=O)o[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCOCCOCCOCCOC(C(=O)O)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CCNC(=O)c1ccc(-c2nc(=O)o[nH]2)cc1

Procedure:
Compound 11 (0.2 g, crude, max. 0.22 mmol) was stirred in a mixture of DCM (5 mL) and TFA (3 mL). After 2 h the solution was concentrated and remains of TFA were removed by repeated concentration in toluene (3×5 mL). The product was purified by preparative HPLC-MS to give compound 12 in pure form (0.11 g, 56% over the three steps from 9).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[CH3:8][O:9][C:10]1[C:15]2[N:16]=[C:17]([NH:19][C:20](=[O:30])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH2:27]NC)[CH:22]=3)[S:18][C:14]=2[C:13]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:12][CH:11]=1.ClCCl.CO>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][N:24]=1)[C:20]([NH:19][C:17]1[S:18][C:14]2[C:13]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:12][CH:11]=[C:10]([O:9][CH3:8])[C:15]=2[N:16]=1)=[O:30]
Reactant: CNCc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COCCOCc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 48 %

Procedure:
2-Methoxyethanol (2.6 ml, 48 mmol) is treated at 0° C. with sodium hydride (38 mg, 0.95 mmol, 60% in mineral oil) and the remaining solution allowed to warm to ambient temperature over 1 h. N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylaminomethyl-isonicotinamide (200 mg, 0.48 mmol, dissolved in tetrahydrofurane (2.0 ml), is added and the mixture stirred at 80° C. for 15 h. The mixture is then evaporated to dryness, treated with saturated sodium carbonate (20 ml) and extracted four times with each 20 ml dichloromethane. The combined organic phases are dryed and evaporated. Flash chromatography (SiO2, eluent: dichloromethane/methanol 20:0 to 19:1) afforded the title compound as light yellow crystals (104 mg, 48% yield). MS: m/e=459 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][CH2:16][C@@H:15]([CH:18]([NH2:24])[C:19]3S[CH:21]=[CH:22][N:23]=3)[CH2:14]2)[C:9]([F:25])=[C:8]2[C:3]=1[C:4](=[O:33])[C:5]([C:30]([OH:32])=[O:31])=[CH:6][N:7]2[C@@H:26]1[CH2:28][C@@H:27]1[F:29].[C:34](#N)[CH3:35].NC1C(F)=C(F)C(F)=C2C=1C(=O)C(C(O)=O)=CN2[C@@H]1C[C@@H]1F>C(N(CC)CC)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][CH2:16][C@@H:15]([CH:18]([NH2:24])[C:19]3[CH:35]=[CH:34][CH:21]=[CH:22][N:23]=3)[CH2:14]2)[C:9]([F:25])=[C:8]2[C:3]=1[C:4](=[O:33])[C:5]([C:30]([OH:32])=[O:31])=[CH:6][N:7]2[C@@H:26]1[CH2:28][C@@H:27]1[F:29]
Reactant: Nc1c(F)c(N2CC[C@@H](C(N)c3nccs3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: CC#N
Agent: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Solvent: CCN(CC)CC
Product: Nc1c(F)c(N2CC[C@@H](C(N)c3ccccn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 67 %

Procedure:
3-(R)-[1-Tert-butoxycarbonylamino-1-(2-pyridyl)methyl]pyrrolidine [F1] (339 mg, 1.22 mmol) was added to an acetonitrile suspension (10 ml) of 5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (316 mg, 1.00 mmol), and the mixture was heated under reflux for 14 hours in the presence of triethylamine (0.5 ml). After cooling, the solvent of the reaction solution was evaporated under a reduced pressure. The resulting residue was dissolved in chloroform (150 ml), this was washed with 10% citric acid (80 ml) and saturated brine (80 ml) and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was mixed with concentrated hydrochloric acid (10 ml) under ice-cooling, further mixed with 1 mol/l hydrochloric acid aqueous solution (5 ml) at room temperature and then washed with chloroform (50 ml×4), and the insoluble matter was removed by filtration. This hydrochloric acid aqueous solution was adjusted to as alkaline liquid property by adding 10 mol/l sodium hydroxide aqueous solution. This suspension was adjusted to a liquid property of pH 7.4 by adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then extracted with chloroform (150 ml×4). The resulting organic layer was dried anhydrous sodium sulfate and the solvent was evaporated under a reduced pressure to obtain the crude title compound as light yellow crystals. This was purified by recrystallizing from ethanol to obtain 316 mg (67%) of the title compound. 1H-NMR (400 MHz, 0.1 mol/1 NaOD) δ: 1.45-1.47 (2 H, m), 1.75-1.17 (1 N, m), 2.25-2.27 (1 H, m), 2.48-2.50 (1 H, m), 2.97-3.00 (1 H, m), 3.30-3.83 (5 H, m), 4.76 (1 H, br. d, J=62.50 Hz), 7.35-7.44 (2 H, m), 8.52 (1 H, t, J=7.81 Hz), 8.12 (1 H, s), 8.46 (1 H, d, J=4.39 Hz). Melting point: 194-196° C. Elemental analysis: for 0.5H2O. 0.5EtOH.C23H22F3N5O3 Calcd.: C, 57.03; H, 5.18; N, 13.85. Found: C, 57.03; H, 5.11; N, 13.85.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]([OH:16])=O)=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:38]1[C:46]2[C:41](=[C:42]([CH2:47][NH2:48])[CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14](=[O:16])[NH:48][CH2:47][C:42]2[CH:43]=[CH:44][CH:45]=[C:46]3[C:41]=2[CH:40]=[CH:39][NH:38]3)=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1C(F)(F)F
Reactant: NCc1cccc2[nH]ccc12
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ccc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
To a solution of 3-Trifluoromethyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (570 mg, 2.24 mmol) in anhydrous DMF (10 mL) was added triethylamine (1.25 mL, 8.96 mmol), EDC (520 mg, 2.69 mmol), HOBT (360 mg, 2.69 mmol), and C-(1H-Indol-4-yl)-methylamine (390 mg, 2.69 mmol). The mixture was stirred at room temperature 3 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-70% EtOAc in hexane to afford the desired product (0.27 g, 31% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O-])(=O)CC([O-])=O.C(C(CC)(O[Mg+2])C)C.S(=O)(=O)(O)O>C1C=CC=CC=1>[CH3:26][C:12]([C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=1)=[O:13]
Reactant: O=C([O-])CC(=O)[O-]
Reactant: O=C(Cl)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: CCC(C)(CC)O[Mg+2]
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 130 °C

Procedure:
70 g of 3,5-dibenzyloxy-benzoyl-chloride in dry benzene were slowly added to a solution of diethyl ethoxy-magnesium-malonate prepared in known manner. The reaction mixture was refluxed overnight, and after cooling 300 ml of benzene and 200 ml of 5-N sulphuric acid were added to hydrolyze the mixture. The benzene phase was washed 3 times with water and dried with magnesium sulphate. The benzene was evaporated and the excess of diethyl malonate distilled off under reduced pressure. To the residue 400 ml of dioxane, 80 ml of water and 40 ml of conc. hydrochloric acid were added. The reaction mixture was heated for 24 hours on an oil bath at 130°C. After evaporation a brown oil remained, which crystallized on standing. Recrystallized from ethanol: M.p. 60°-61°C.
Reaction SMILES: C([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:41][O:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:11]([NH:13][CH:14]2[C:39](=[O:40])[N:16]3[C:17]([C:23]([O:25][CH:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])=[C:18]([CH:21]=[CH2:22])[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:3][C:4]1[N:9]=[C:8]([C:10](=[N:41][O:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:11]([NH:13][CH:14]2[C:39](=[O:40])[N:16]3[C:17]([C:23]([O:25][CH:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])=[C:18]([CH:21]=[CH2:22])[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cccc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cccc(N)n3)[C@H]2SC1
Temperature: 35 °C
Yield: 97.7 %

Procedure:
To a suspension of benzhydryl 7-[2-(6-formamidopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (4.8 g) in methanol (300 ml) was added conc. hydrochloric acid (2.88 ml), and the mixture was stirred at 35° C. for an hour. The reaction mixture was adjusted to pH 5.5 with 5% aqueous sodium bicarbonate, and the methanol was removed by distillation under reduced pressure, followed by extraction with ethyl acetate (300 ml). The extract was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave benzhydryl 7-[2-(6-aminopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (4.5 g), mp 125°-129° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(OCc1ccccc1)C1CCC(O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCC(C(=O)OCc2ccccc2)CC1
Reaction time: 2 h

Procedure:
To a solution of benzyl 4-hydroxycyclohexane carboxylate (32.1 g, 137.2 mmol) in 400 mL of dichloromethane was added pyridinium chlorochromate (68.8 g, 274.0 mmol) in portions over 10 minutes. After two hours, the reaction was filtered through a large plug of silica gel eluting with 30% ethyl acetate in hexane to afford benzyl 4-oxocyclohexane carboxylate as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([CH2:38][C:39]2[CH:48]=[CH:47][C:42]([C:43]([NH:45]O)=[NH:44])=[CH:41][CH:40]=2)[CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32][C:31]2=[O:37])(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([C:43]3[N:44]=[C:4]([CH2:3][O:2][CH3:1])[O:6][N:45]=3)=[CH:47][CH:48]=2)[CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32][C:31]2=[O:37])(=[O:27])=[O:28])=[CH:22][CH:21]=1
Reactant: COCC(=O)O
Reactant: N=C(NO)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COCc1nc(-c2ccc(CN(C3CCCCNC3=O)S(=O)(=O)c3ccc(Cl)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
To a solution of methoxyacetic acid (86 μl, 1.10 mmol) in 5 ml dimethylformamide were added 1,1′-carbonyl-diimidazole (0.18 g, 1.10 mmol). The mixture was stirred at room temperature for 10 minutes, heated to 40° C. for a few minutes and cooled to room temperature. 4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine (0.45 g, 1.00 mmol) was added and the mixture was stirred at 100° C. for 5 hours and then poured into water. Filtration and chromatography on silicagel with ethylacetate/heptane (1/1 to 4/1) yielded 0.46 g (90%) 4-chloro-N-[4-(5-methoxymethyl-[1,2,4]oxadiazol-3-yl)-benzyl]-N-(2-oxo-azepan-3-yl)-benzenesulfonamide as white solid, MS: m/e (%)=505.0 (MH+, 100).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>>[Cl:47][C:42]1[CH:41]=[C:40]([C:27]2([CH2:26][NH:25][C:22](=[O:24])[C:3]3[C:2]([F:1])=[C:7]([S:8][C:9]4[S:13][C:12]([NH:14][C:15]5[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=5)=[N:11][CH:10]=4)[CH:6]=[CH:5][N:4]=3)[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:31][CH2:32]2)[CH:45]=[CH:44][C:43]=1[Cl:46]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(Cl)c(Cl)c2)CC1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccc(Cl)c(Cl)c5)CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and tert-butyl 4-(aminomethyl)-4-(3,4-dichlorophenyl)piperidine-1-carboxylate (amine intermediate “K”) were reacted to give the title compound. LC/MS (M+H)+: 703. Ret. time: 2.20 min. (Condition I).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:18][CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:34](Cl)(=[O:36])[CH3:35]>N1C=CC=CC=1>[C:34]([NH:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:18][CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:36])[CH3:35]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3C#N)c2)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a solution of N-{3-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.44 mmol) produced in Example 1 (iv) in pyridine (2 mL) was added acetyl chloride (41 μL, 0.57 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was suspended in ethyl acetate (20 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (127 mg, 58%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:19]2[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:21][CH2:20]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
To a solution of 5-bromo-2-chloropyrimidine (50.0 g, 258 mmol) and 1-tert-butoxycarbonylpiperazine (72.2 g, 387 mmol) in 1,4-dioxane (500 mL) was added potassium carbonate (67.8 g, 491 mmol), and the mixture was stirred under reflux for 1.5 h. The reaction was cooled to RT, quenched by water (500 mL) and extracted with diethyl ether (1000 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified with silica gel chromatography (petroleum ether:ethyl acetate=8:1-4:1) to give the title compound (70.5 g, 80%) as a white solid. MS (ES+) C13H19BrN4O2 requires: 342. found: 243 [M+H−100]+.