Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:36])=[C:5]([C:27]([O:34]C)=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])=[C:9]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:8]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:31][O:30][C:29]1[C:3](=[O:2])[C:4]([CH3:36])=[C:5]([CH2:6][C:7]2[CH:20]=[CH:19][C:10]([C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[O:12])=[C:9]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:8]=2)[C:27](=[O:34])[C:28]=1[O:32][CH3:33]
Reactant: COc1c(C)c(Cc2ccc(C(=O)N3CCOCC3)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)N3CCOCC3)c(-c3cccnc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
N-[4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoyl]morpholine (8 mg, 0.0162 mmol) was dissolved in a mixed solvent of acetonitrile (3 ml) and water (1 ml), then CAN (26 mg, 0.0483 mmol) was added thereto at room temperature and the mixture was stirred for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (4.5 mg, 0.0097 mmol, 60%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:3][C:2]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[CH:25]=[O:26])=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: O=Cc1cccc(B(O)O)c1
Product: CN1CCN(Cc2cc3nc(-c4cccc(C=O)c4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 3-formyl phenyl boronic acid in General Procedure A. Purification on silica yielded 3-[6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-benzaldehyde. This was then treated with sodium borohydride in methanol to give the desired compound.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Br:34][C:35]1[S:36][C:37]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:38]([C:40]([OH:42])=O)[N:39]=1.[NH2:51][C:52]1[CH:53]=[N:54][N:55]([CH3:74])[C:56]=1[N:57]1[CH2:63][C:62]([F:65])([F:64])[CH2:61][CH:60]([NH:66][C:67](=[O:73])[O:68][C:69]([CH3:72])([CH3:71])[CH3:70])[CH2:59][CH2:58]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:47]([O:46][C:44]([NH:43][C:37]1[S:36][C:35]([Br:34])=[N:39][C:38]=1[C:40]([NH:51][C:52]1[CH:53]=[N:54][N:55]([CH3:74])[C:56]=1[N:57]1[CH2:63][C:62]([F:65])([F:64])[CH2:61][CH:60]([NH:66][C:67](=[O:73])[O:68][C:69]([CH3:70])([CH3:71])[CH3:72])[CH2:59][CH2:58]1)=[O:42])=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: Cn1ncc(N)c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (2.5 g, 6.67 mmol) in ethanol (100 mL) and water (10 mL) was added ammonium chloride (3.5 g, 65.0 mmol) and iron powder (3.0 g, 53.7 mmol). The reaction mixture was heated at 100° C. for 2.5 hr, before being cooled down at room temperature, filtered through Celite®, washed with MeOH and the filtrate concentrated under reduced pressure. The residue was dissolved in DCM (200 mL), quenched with a saturated solution of sodium hydrogencarbonate (300 mL) and a 10% solution of sodium sulfite (100 mL) and the mixture stirred for 30 min. The layers were separated and the aqueous layer extracted with DCM (100 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave tert-butyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate as an orange foam (2.12 g). A solution of PyBOP (1.92 g, 3.70 mmol) and 2-bromo-5-(tert-butoxycarbonyl-amino)thiazole-4-carboxylic acid (795 mg, 2.46 mmol) in DCM (50 mL) was stirred at room temperature for 15 min. tert-Butyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate (850 mg, 2.46 mmol) and DIPEA (2.0 mL, 11.4 mmol) were added and the mixture stirred at room temperature for 18 hr. The reaction mixture was diluted with DCM (50 mL) and washed with a saturated solution of sodium hydrogencarbonate (100 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 1-(4-(5-(tert-butoxycabonyl-amino)-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate as a pale yellow foam (1.35 g, 77% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 8.37 (s, 1H), 7.65 (s, 1H), 4.88 (s, 1H), 4.04 (s, 1H), 3.77 (s, 3H), 3.63-3.43 (m, 2H), 3.38-3.24 (m, 2H), 2.52-2.40 (m, 2H), 2.13-2.05 (m, 1H), 1.99 (s, 1H), 1.53 (s, 9H), 1.43 (s, 9H).
Reaction SMILES: C(NC1CCNC1)(=O)C.[CH2:10]([O:17][C:18]([NH:20][CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl[C:27]1[N:36]=[C:35]2[C:30]([C:31](=[O:42])[C:32]([C:39]([OH:41])=[O:40])=[CH:33][N:34]2[CH2:37][CH3:38])=[CH:29][C:28]=1[F:43]>>[CH2:10]([O:17][C:18]([NH:20][CH:21]1[CH2:25][CH2:24][N:23]([C:27]2[N:36]=[C:35]3[C:30]([C:31](=[O:42])[C:32]([C:39]([OH:41])=[O:40])=[CH:33][N:34]3[CH2:37][CH3:38])=[CH:29][C:28]=2[F:43])[CH2:22]1)=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(NC1CCNC1)OCc1ccccc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Agent: CC(=O)NC1CCNC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NC(=O)OCc4ccccc4)C3)nc21

Procedure:
In place of 3-acetylaminopyrrolidine, 3-benzyloxycarbonylaminopyrrolidine was allowed to react with 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid in the same manner as described in Example 1 to give 7-(3-benzyloxycarbonylamino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, which was used in the next step:
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:6][C:7]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][CH2:10]1)=[O:8]>>[CH3:15][C:13]1([CH3:16])[CH2:12][CH2:11][CH2:10][CH:9]([C:7]([OH:8])([CH2:2][CH:3]([CH3:5])[CH3:4])[CH3:6])[CH2:14]1
Reactant: CC(=O)C1CCCC(C)(C)C1
Reactant: CC(C)CBr
Product: CC(C)CC(C)(O)C1CCCC(C)(C)C1

Procedure:
The protocol of example 1 is carried out again with 1-bromo-2-methylpropane replacing bromoethane, and herbac replacing dehydroherbac.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[NH2:17]>C(O)(C)C>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1
Reactant: Clc1ncnc2ccc(Br)cc12
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CC(C)O
Product: Fc1cccc(COc2ccc(Nc3ncnc4ccc(Br)cc34)cc2Cl)c1
Yield: 85.9 %

Procedure:
6-bromo-4-chloro-quinazoline (1.36 g) and 3-chloro-4(m-fluoro-benzyloxy)-aniline (1.42 g) were dissolved into 50 mL of isopropanol. The mixture was reacted under reflux for 3 h, and a lot of yellow solid was deposited. The precipitated solid was filtered, and the filter cake was washed with cold ethanol and dried at 60° C. under vacuum overnight to obtain the 6-bromo-4-aminoquinazoline product (2.20 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7](Br)[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].C(OCC)(=O)C.C(OC)(C)(C)C.[CH3:28][N:29](C)C=O>[Cl-].[Na+].O.[C-]#N.[Zn+2].[C-]#N>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7]([C:28]#[N:29])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4]
Reactant: COC(=O)c1c(N)c(Br)cc2cn[nH]c12
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)c1c(N)c(C#N)cc2cn[nH]c12
Temperature: 180 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
To a solution of 500 mg (1.85 mmol) of 6-amino-5-bromo-1H-indazole-7-carboxylic acid methyl ester, prepared as in step a in example 16, in 10 mL of N,N-dimethylformamide under an atmosphere of argon is added 135 mg (1.15 mmol) of zinc cyanide and 206 mg (0.185 mmol) of tetrakis(triphenylphsophine)palladium. The reaction mixture is stirred in a microwave oven at 180° C. for 5 minutes. Then, a 1:1 v/v mixture of ethyl acetate and tertbutylmethyl ether and brine are added to the reaction and the phases are separated. The aqueous layer is extracted with tert-butylmethylether. The organic extracts are washed twice with brine, dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, hexane/ethyl acetate 2:1 to 1:1, gradient) to afford 380 mg of product (94%) as a yellowish solid; LC/MS:217/218 (M+H)+.
Reaction SMILES: C1COCC1.Cl[C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([Cl:17])=[CH:9][N:8]=1.[H-].[Na+].[CH3:20][O:21][N:22]=[C:23]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][OH:31]>O>[CH3:20][O:21][N:22]=[C:23]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][O:31][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([Cl:17])=[CH:9][N:8]=1
Reactant: FC(F)(F)c1cc(Cl)cnc1Cl
Reactant: CON=C(c1cc(C)on1)c1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(c1cc(C)on1)c1ccccc1COc1ncc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
THF (3 ml), 2,5-dichloro-3-trifluoromethylpyridine (0.32 g, 1.5 mmol) and 60% sodium hydride (0.05 g, 1.2 mmol) were added to 2-hydroxymethylphenyl 5-methylisoxazol-3-yl ketone O-methyloxime (0.25 g, 1.0 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ether (150 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(5-chloro-3-trifluoromethyl-2-pyridyloxymethyl)phenyl 5-methylisoxazol-3-yl ketone O-methyloxime (0.41 g, yield: 96.3%) as colorless crystals.
Reaction SMILES: O.O.P([O-])([O-])(O)=O.[Na+].[Na+].O.O.P([O-])(O)(O)=O.[Na+].[C:18]([NH:21][CH:22]([CH2:27][C:28]1[CH:33]=[C:32]([CH3:34])[C:31]([NH2:35])=[C:30]([Cl:36])[CH:29]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:20])[CH3:19].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O.CC(C)=O>[C:18]([NH:21][C@H:22]([CH2:27][C:28]1[CH:33]=[C:32]([CH3:34])[C:31]([NH2:35])=[C:30]([Cl:36])[CH:29]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:20])[CH3:19]
Reactant: COC(=O)C(Cc1cc(C)c(N)c(Cl)c1)NC(C)=O
Agent: O=C([O-])[O-]
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)[C@@H](Cc1cc(C)c(N)c(Cl)c1)NC(C)=O
Temperature: 37 °C

Procedure:
22 mL Alcalase 2.4 L FG (Novozymes ANS; DK 2880 Bagsvaerd) were added to a solution of 27.3 g (178 mmol) disodium hydrogen phosphate dihydrate in 1000 mL water at 37° C. and the pH was adjusted to 7.5 by the addition of sodium dihydrogen phosphate dihydrate. Then 21.1 g (74 mmol) methyl 2-acetylamino-3-(4-amino-3-chloro-5-methyl-phenyl)-propionate dissolved in 210 mL acetone was added dropwise with stirring at 37° C. The pH of the reaction mixture was kept constantly in the range from pH 7.4 to pH 7.6 by the addition of 1 M NaOH. After the addition had ended the mixture was stirred for 3 h at 37° C. The reaction mixture was combined with 500 ml 15% potassium carbonate solution and extracted twice with 250 ml dichloromethane. The combined organic extracts were dried over sodium sulphate, evaporated down under reduced pressure and purified by column chromatography over silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21].[OH-].[Na+].C(O)(=O)C>O.C(O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[N:20][OH:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(COc2ccc(C=O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1ccc(COc2ccc(C=NO)cc2)cc1
Temperature: 88 °C
Yield: 84.1 %

Procedure:
To a suspension of 4-(4-methoxy-benzyloxy)-benzaldehyde (26.5 g, 110 mmol) in water/ethanol (260 mL, 9:1) was added hydroxylamine hydrochloride (9.06 g, 131 mmol) followed by dropwise addition of a 3.2M NaOH solution in ethanol/water (88 mL; 262 mmol). After addition was complete, the reaction mixture was heated to 88° C. for 4.5 h and then cooled to rt. The pH of the reaction mixture was adjusted to 5.5 with glacial acetic acid. 4-(4-methoxy-benzyloxy)-benzaldehyde oxime (23.8 g, 84%) was isolated as a white solid by filtration and air drying.
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C@H:7]([C:20]1[CH:21]=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:8]OS(C1C=CC(C)=CC=1)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[NH2:29][C:30]([CH3:42])([CH3:41])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1>CS(C)=O>[C:1]([Si:5]([CH3:27])([CH3:28])[O:6][C@H:7]([C:20]1[CH:21]=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:8][NH:29][C:30]([CH3:42])([CH3:41])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(Cl)nc2)cc1
Reactant: CC(C)(N)Cc1ccc([N+](=O)[O-])cc1
Solvent: CS(C)=O
Product: CC(C)(Cc1ccc([N+](=O)[O-])cc1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Yield: 63.5 %

Procedure:
A solution of (R)-toluene-4-sulfonic acid 2-(tert-butyl-dimethyl-silanyloxy)-2-(6-chloro-pyridin-3-yl)-ethyl ester (12.0 g) and 11.4 g of 2-amino-2-methyl-1-(4-nitrophenyl)propane (prepared by the method described in J. Milecki, et al. J. Med. Chem., 30, 1563 (1987)) in DMSO (30 mL) was stirred at 100° C. for 48 h. The reaction solution was partitioned between ethyl ether/water, the resulting organic layer washed with water (3×), brine, dried over sodium sulfate and concentrated in vacuo to afford an oil. Flash chromatography on silica gel (20% to 50% ethyl acetate/hexanes) afforded 8.0 g of the title compound (I-2f) as a golden oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@@H:14]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:40][CH:39]=1)[C:15]([N:17]([CH2:27][C:28]1[C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[S:31][CH:32]=1)[C@@H:18]([CH3:26])[CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[O:16]>>[S:31]1[CH:32]=[C:28]([CH2:27][N:17]([C@@H:18]([CH3:26])[CH:19]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])[C:15](=[O:16])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[CH:42][CH:43]=2)[C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]1=2
Reactant: CCNC(=O)NN(C)CC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 51 mg (0.29 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-6) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH3:12][S:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>CCO>[CH3:12][S:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: C1CNCCNC1
Solvent: CCO
Solvent: CC(=O)Cl
Product: CS(=O)(=O)c1ccc(CN2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
To a 2-neck, 2-L round bottom flask containing anhydrous EtOH (800 mL) and equipped with a mechanical stirrer and condenser was added acetyl chloride (20.2 mL, 0.267 mol, 1.1 equiv). The solution was stirred for 0.5 h and homopiperazine (24.3 g, 0.243 mol) was added, The mixture was heated to reflux for 2 h. The reaction mixture was cooled to 25° C., 4-(methylsulfonyl)benzyl chloride (25 g, 0.122 mol, 0.5 equiv) was added and the reaction mixture heated to reflux for 16 h. The reaction mixture was cooled to 25° C. and the solvent was removed under vacuum. The residue was diluted with EtOAc (500 mL) and was washed with 2N KOH (2×500 mL). The aqueous layer was extracted with EtOAc (1×500 mL). The organic phase was combined, washed with 2N KOH (1×300 mL), dried (MgSO4) and concentrated. The crude solid was washed with hot EtOAc to yield pure desired product (8.03 g, 32.7 g theoretical, 25%) as an off-white solid, TLC R1 0.04 (10% CH3OH—CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 9.82 (br s, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.60 (d, J=7.7 Hz, 2H), 3.80 (br s, 2H), 3.36 (br m, 2H), 3.07 (s, 3H), 2.93 (br s, 2H), 2.80 (br s, 2H), 2.12 (br m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([NH:32][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:33][CH:34]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of compound 10b (66 mg, 0.15 mmol) and pyridine (24 μL, 0.29 mmol) in DCM (5 mL) was added methanesulfonyl chloride (23 μL, 0.29 mmol). The resulting mixture was stirred at rt for 3 days. The mixture was then diluted with DCM (20 mL), and washed with 1 N HCl solution and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The orange solid obtained was washed with methanol (2×5 mL), and dried in vacuo to give the title compound 47. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 10.09-10.17 (m, 1H), 8.64-8.83 (br.s., 1H), 8.25 (br.s, 1H), 8.06-8.22 (m, 3H), 7.83-8.06 (m, 3H), 7.63-7.80 (m, 3H), 7.36-7.48 (m, 2H), 6.46 (d, J=5.9 Hz, 1H), 4.04-4.18 (m, 4H), 3.79-3.97 (m, 4H), 3.14 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H26N6O3S: 527.2 (M+H). Found 527.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>CS(C)=O.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10](=[CH:13][O:14][CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CO)cc1-c1ccccc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)[C@H](CCSC)NC(=O)C1=C(c2ccccc2)CC(=COCc2cccnc2)C=C1

Procedure:
The resultant compound from Example 16D (1.0 equivalent) is treated with sodium hydride (2.0 equivalents) in DMSO, then 3-chloromethylpyridine hydrochloride (1.0 equivalent) is added. When judged complete by TLC analysis, the reaction is diluted with water and ethyl acetate, the organic layer is dried and concentrated, and the crude title compound is purified by chromatography on silica gel.
Reaction SMILES: Cl.[Cl:2][C:3]([Cl:20])([Cl:19])[CH2:4][O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH:10]([CH3:18])[CH:9]=1)=[O:7].CN(C)C1C=CC=CC=1.[S:30]([CH:34]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:35](O)=[O:36])([OH:33])(=[O:32])=[O:31].C(OOC(=O)O)C>ClCCl.C(N(CC)CC)C>[CH3:18][CH:10]1[CH:9]=[C:8]([C:6]([O:5][CH2:4][C:3]([Cl:2])([Cl:19])[Cl:20])=[O:7])[N:13]2[C:14](=[O:17])[CH:15]([NH:16][C:35](=[O:36])[CH:34]([S:30]([OH:33])(=[O:31])=[O:32])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:12]2[S:11]1
Reactant: O=C(O)C(c1ccccc1)S(=O)(=O)O
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Agent: CCOOC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(c3ccccc3)S(=O)(=O)O)[C@H]2S1

Procedure:
A suspension of 2,2,2-trichloroethyl-2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (6.9 g) in dried dichlormethane (70 ml) was homogenzied by adding triethylamine (1.48 g) and N,N-dimethylaniline (0.44 g) under stirring and ice-cooling and by stirring for 30 minutes at room temperature. A solution of triethylamine salt of mixed anhydride of 2-sulfo-2-phenylacetic acid with ethoxycarbonic acid (8.5 g) in dried dichloromethane (60 ml) was dropwise added over about 30 minutes under stirring and cooling at -20° to -25° C. to the above-mentioned solution, and the mixture was stirred for 1.5 hours at -10° to -15° C. and for 1 hour at room temperature. After the reaction, dichloromethane was removed at low temperature, and the residue was dissolved in ethyl acetate, after which the solution was washed with cooled 5% hydrochloric acid and three times with water, and then dried. The solvent was distilled off at low temperature to give 2,2,2-trichloroethyl 2-methyl-7-(2-sulfo-2-phenylacetamido)-3-cephem-4-carboxylate (11.5 g), amorphous.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:21]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH:22]([F:24])[F:23])=[C:17]([CH2:19]O)[CH:18]=1.C1C=CC(P([N:48]=[N+:49]=[N-:50])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[N:48]([CH2:19][C:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=1[CH:21]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH:22]([F:24])[F:23])=[N+:49]=[N-:50]
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CO)C(F)F)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(NC(c2ccc(Cl)cc2CN=[N+]=[N-])C(F)F)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
DBU (0.20 mL, 1.34 mmol) was added to a stirred solution of (5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}phenyl)methanol (0.439 g, 1.34 mmol) and DPPA (0.29 mL, 1.34 mmol) in THF (1.7 mL) at 0° C. and the mixture was warmed to ambient temperature. After 3 h the solution was partitioned between EtOAc (20 mL) and water (10 mL). The EtOAc layer was washed with 1M NaOH (10 mL) and brine (10 mL), dried (Na2SO4) and reduced in vacuo to give N-{1-[2-(azidomethyl)-4-chlorophenyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.463 g) as an oil: MS 353.5 (M+1).