Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[O:2]=[C:3]1[NH:8][CH2:7][C:6]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[O:5][CH2:4]1.[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)#[N:15]>N1C=CC=CC=1>[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:11]2[CH2:12][CH2:13][C:6]3([O:5][CH2:4][C:3](=[O:2])[NH:8][CH2:7]3)[CH2:9][CH2:10]2)=[O:21])=[CH:18][CH:17]=1)#[N:15]
Reactant: O=C1COC2(CCNCC2)CN1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Br
Solvent: c1ccncc1
Product: N#Cc1ccc(C(=O)N2CCC3(CC2)CNC(=O)CO3)cc1
Temperature: 25 °C

Procedure:
18.0 g (71.7 mmol) 3-oxo-1-oxa-4,9-diaza-spiro[5.5]undecane hydrobromide (prepared according to J. Med. Chem. 1983, 26, 855) were dissolved in 300 ml dry pyridine, and 11.9 g (71.9 mmol) 4-cyanobenzoyl chloride were added in small portions. The mixture was stirred over night at room temperature and evaporated under reduced pressure. The residue was dissolved in toluene, which was removed in vacuo. This process was repeated two times to remove remaining pyridine. It was treated with water and neutralized by addition of saturated aqueous sodium bicarbonate solution. The precipitate of the title compound was filtered with suction, washed with water, and dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:29]C)=[C:6]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=1[CH:15]=[N:16][NH:17]3)[C:9]([C:23]([F:26])([F:25])[F:24])([OH:22])[CH2:8][C:7]2([CH3:28])[CH3:27].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[C:11]2[CH:10]([NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[N:16][NH:17]4)[C:9]([C:23]([F:24])([F:25])[F:26])([OH:22])[CH2:8][C:7]([CH3:27])([CH3:28])[C:6]=2[C:5]([OH:29])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2[nH]ncc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]ncc23)c2c(Br)ccc(O)c21
Temperature: 25 °C
Reaction time: 19 h
Yield: 84.6 %

Procedure:
21 mg (0.043 mmol) of 8-bromo-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is mixed at room temperature with 0.4 ml of a 1 M BBr3 solution and stirred for 19 hours at room temperature. After the reaction mixture is mixed with ice, saturated sodium bicarbonate solution is added drop by drop, and it is diluted with ethyl acetate. The organic phases are washed neutral as usual, and the residue that remains after the solvent is spun in is chromatographed on silica gel (mobile solvent methanol/dichloromethane). 17.1 mg (83.8%) of the desired compound (together with the Desbrom compound) is isolated.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][CH:8]([C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][C:16](=O)[NH:15][C:14]=2[CH:20]=1)[CH3:9]>C1COCC1>[O:18]1[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([NH2:7])[CH3:9])=[CH:20][C:14]=2[NH:15][CH2:16][CH2:17]1
Reactant: CC(N)c1ccc2c(c1)NC(=O)CO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(N)c1ccc2c(c1)NCCO2
Temperature: 25 °C
Yield: 95 %

Procedure:
Lithium aluminum hydride (2.28 g, 60 mmol) was carefully added to a suspension of (±)-6-(1-aminoethyl)-4H-benzo[1,4]oxazin-3-one, Preparation 11 (3.84 g, 20 mmol) in THF (80 mL) at −78° C. The reaction mixture was stirred while warming to room temperature, then under reflux for 4 hours. The reaction mixture was then cooled to −78° C. and was quenched with water (2.3 mL), sodium hydroxide (10N) (2.3 mL), and water (4.6 mL). The resulting mixture was filtered and the resultant filtrate was concentrated in vacuo. The residual material was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and the resultant filtrate was concentrated in vacuo to provide the title compound (3.38 g, 95%) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:21])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:11][C:8]=2[C:9]=1[CH3:10].Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(O)C>[CH3:16][O:15][C:13]1[C:12]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:11][C:8]2[C:9]([CH3:10])=[C:4]([CH2:3][CH2:2][N:34]3[CH2:33][CH2:32][N:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH3:23])[CH2:36][CH2:35]3)[C:5](=[O:21])[O:6][C:7]=2[CH:14]=1
Reactant: COc1cc2oc(=O)c(CCCl)c(C)c2cc1OC(C)C
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCO
Product: COc1cc2oc(=O)c(CCN3CCN(c4ccccc4OC)CC3)c(C)c2cc1OC(C)C
Yield: 54 %

Procedure:
Process A; starting materials: 3-(2-chloroethyl)-7-methoxy-4-methyl-6-(1-methylethoxy)-2H-1-benzopyran-2-one (Example 30) and 1-(2-methoxyphenyl)piperazine hydrochloride; yield 54%; m.p. 123°-125° C. (from ethanol).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nc(Sc3ccc(Cl)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(Cl)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.23 g of 4,5-bis(4-methoxyphenyl)-2-(4-chlorophenylthio)imidazole in 100 ml of dichloromethane. The reaction mixture is agitated for 3 hours at room temperature, the solution is washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus obtaining 3.90 g of 4,5-bis(4-methoxyphenyl)-2-(4-chlorophenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[C:25](Cl)(=[O:27])[CH3:26]>C1C=CC=CC=1>[C:25]([N:11]1[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[CH2:9][CH2:10]1)(=[O:27])[CH3:26]
Reactant: O=C(c1cccc(C(F)(F)F)c1)C1CCNCC1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)N1CCC(C(=O)c2cccc(C(F)(F)F)c2)CC1

Procedure:
To a solution of 32.1 g (0.125 mole) of 4-(m-trifluoromethylbenzoyl)piperidine in 75 ml of benzene and 21.2 g (0.2 mole) of Na2CO3, was added dropwise a solution of ten g (0.127 mole) of acetyl chloride in 75 ml of benzene. The mixture was refluxed for 2 hours. The mixture was filtered and the filtrate was concentrated under vacuum giving crude 1-acetyl-4-(m-trifluoromethylbenzoyl)piperidine. Yield 37.3 grams.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=2[CH2:7][N:8](C)[C:9](=O)C(F)(F)F)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[ClH:26]>CO.O.C1COCC1.O1CCOCC1>[ClH:26].[CH:1]1([S:4][C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=2[CH2:7][NH:8][CH3:9])[CH2:3][CH2:2]1
Reactant: CN(Cc1ccccc1SC1CC1)C(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1ccccc1SC1CC1
Temperature: 25 °C

Procedure:
To 1D (1.50 g, 4.67 mmol) in MeOH (23 mL) and water (5 mL) was added potassium carbonate (3.20 g, 23.4 mmol) and the reaction was refluxed for 45 min. After cooling to rt, the mixture was filtered and the filtrate was concentrated. The resulting residue was dissolved in ethyl acetate and washed with water and brine. The aqueous layer was back-extracted with ethyl acetate (5×). The combined organic layers were dried (MgSO4), filtered and concentrated to provide a yellow oil. The oil was dissolved in THF and 4N HCl in 1,4-dioxane (2.2 mL) was added. The resulting white solid was filtered to provide 1E (1.00 g). 1H NMR (400 MHz, CD3OD) δ ppm 1.03-1.21 (m, 2H), 1.30 (ddd, J=7.14, 4.50, 4.17 Hz, 2H), 2.80 (s, 3H), 2.84-3.03 (m, 1H), 2.86-3.05 (m, 1H), 4.41-4.65 (m, 2H), 7.59-7.93 (m, 3H), 8.06 (d, J=7.91 Hz, 1H). LC-MS: 226.10 (M+H)+.
Reaction SMILES: C(Cl)Cl.[CH3:4][C:5]([CH3:7])=O.N1([C:13]2[CH:34]=[CH:33][C:16]([CH2:17][CH2:18][C:19]([NH:21][CH:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])=[CH:15][CH:14]=2)C=CC=C1>>[N:21]1([C:19]([C:13]2[CH:14]=[CH:15][C:16]([CH2:17][CH2:18][C:19]([NH:21][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:20])=[CH:33][CH:34]=2)=[O:20])[CH:22]=[CH:7][CH:5]=[CH:4]1
Reactant: CCOC(=O)C(NC(=O)CCc1ccc(-n2cccc2)cc1)C(=O)OCC
Reactant: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)CCc1ccc(C(=O)n2cccc2)cc1)C(=O)OCC

Procedure:
4.6 g of diethyl 4-aminobenzylacetamidomalonate in 104 ml of acetic acid are placed in a three-necked flask which is maintained under nitrogen. 7.02 g of sodium acetate are added, followed by 1.87 ml of 2,5-dimethoxytetrahydrofuran. The mixture is heated at 65° C. for 1 h 15 min, then cooled down and extracted with 100 ml of dichloromethane and 100 ml of distilled water. The aqueous phase is separated off after settling and then washed with 3 times 100 ml of dichloromethane. The organic phases are combined, washed with 100 ml of water and then with 100 ml of a saturated solution of NaCl, separated off after settling and then dried over magnesium sulphate; the phases are filtered and then evaporated to dryness under reduced pressure (50 kPa) in order to yield 6.2 g of a solid which is purifed by flash chromatography (eluent CH2Cl2/acetone 75/25 by volume). This results in 3.57 g of diethyl 4-(1-pyrrolyl)benzylacetamidomalonate in the form of a beige solid which melts at 110° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([CH2:27][CH2:28][CH2:29][CH3:30])[C:15]1=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([CH2:27][CH2:28][CH2:29][CH3:30])[C:15]1=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: CCCCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)nc21
Yield: 80.8 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-benzyloxy-1-butyl-7-chloro-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example O-2, 0.16 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) in 20 mL of acetonitrile. The solution was warmed to reflux for 17 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.14 g of the title compound as a solid
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH:14]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:13][CH2:12]3)O1.[OH:26]OS([O-])=O.[K+]>CC(C)=O.O>[OH:26][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:13][CH2:12]2
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)S(=O)(=O)NC1CCc2cc(O)ccc21
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
To a stirred solution of N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (1.5 g, 4.11 mmol) in acetone (15 mL) was added dropwise a solution of oxone (2.78 g, 4.52 mmol) in water (15 mL). The resulting mixture stirred for another 10 min before the reaction mixture quenched with Na2O5S2 solution and diluted with DCM. The organic layer was separated, washed with brine (2×) and dried on Na2SO4. Solvent evaporated in vacuo to afford the title compound as a white solid (1.05 g, 100%). MS (ESI): m/z [M−H]− 254.0
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]([NH2:16])[CH3:15].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]([NH:16][CH2:22][C:18]1[O:17][CH:21]=[CH:20][CH:19]=1)[CH3:15]
Reactant: O=Cc1ccco1
Reactant: CC(N)COc1ccc2ccccc2c1Cl
Product: CC(COc1ccc2ccccc2c1Cl)NCc1ccco1
Yield: 85 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]propan-2-amine and furan-2-carbaldehyde in 85% yield as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[S:17])[NH:4][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[SH:17][C:3]1[C:2]([NH:1][C:27]([C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[NH:18][CH:19]=[CH:20]3)=[O:28])=[CH:7][CH:6]=[C:5]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]2)[N:4]=1
Reactant: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C2(c3ccccc3)CC2)nc1S)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione (750 mg, 3.10 mmol), 1H-indole-5-carboxylic acid (499 mg, 3.10 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (474 mg, 3.10 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (593 mg, 3.10 mmol) in DMF (3.1 mL) was stirred at ambient temperature for 16 h. The reaction mixture was diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 2 times with 50 mL of water, separated, dried over sodium sulfate, and concentrated via rotovap to give N-(2-mercapto-6-(1-phenylcyclopropyl)pyridin-3-yl)-1H-indole-5-carboxamide. MS (ESI) m/z: Calculated: 385.1; Observed: 386.4 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[OH:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:36][C:35]6[CH:38]=[CH:39][CH:40]=[C:33]([OH:32])[CH:34]=6)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: O=Cc1cccc(O)c1
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Product: Oc1cccc(CN2CCc3[nH]c(-c4n[nH]c5cc(-c6cc(F)c(O)cc6CC(F)(F)F)ccc45)nc3C2)c1

Procedure:
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and 3-hydroxybenzaldehyde (56.6 mg, 0.46 mmol) using the method of Example 51. The crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 26.1% yield, 30 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:28]([O:38][CH3:39])[N:27]=3)=[N:24][N:25]=[C:18]12>CN(C=O)C.C(OCC)(=O)C.[Cl-].[NH4+]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][C:17]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:28]([O:38][CH3:39])[N:27]=3)=[N:24][N:25]=[C:18]12
Reactant: Oc1ccc(F)c(F)c1
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Oc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To a mixture of 3,4-difluorophenol (59 mg) and potassium carbonate (0.18 g) in DMF (4 mL) was added ethyl 8-chloro-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (0.18 g) at room temperature, and the mixture was stirred at 100° C. for 30 min. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate and saturated aqueous ammonium chloride solution, the mixture was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.11 g).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:32][O:33][CH3:34])[C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25]Cl)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1.[CH3:35][N:36]1[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]1.C(OCC)(=O)C>CN(C)C=O>[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:32][O:33][CH3:34])[C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([O-:29])=[O:28])=[C:22]([CH2:25][N+:36]4([CH3:35])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12)c1nsc(N)n1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCNCC3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (syn isomer) in N,N-dimethylformamide (150 ml) was added 1-methyl-4-tert-butoxycarbonylpiperazine (30 g). After being stirred at room temperature for 30 minutes, the mixture was added dropwise to ethyl acetate (1.5 l). The resulting precipitate was collected by filtration, washed with ethyl acetate and diisopropyl ether. To a solution of the above precipitate in a mixture of methylene chloride (60 ml) and anisole (20 ml) was added dropwise trifluoroacetic acid (40 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours and added to diisopropyl ether (1.5 l) under stirring. The resultant precipitate was collected by filtration and dissolved in aqueous sodium bicarbonate, and the solution was adjusted to pH 4.0 with hydrochloric acid and subjected to column chromatography on "Diaion HP-20" (Trademark: prepared by Mitsubishi Chemical Industries) with 5% aqueous isopropyl alcohol as an eluent. The eluate was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (12.00 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])(C)(C)C.CCCCCC.Br[C:20]1[S:24][C:23]([C:25]2[N:29]3[N:30]=[C:31]([CH3:39])[CH:32]=[C:33]([CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[C:28]3=[N:27][C:26]=2[CH3:40])=[C:22]([CH3:41])[CH:21]=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[CH3:1][C:2]1[S:3][C:4]([C:20]2[S:24][C:23]([C:25]3[N:29]4[N:30]=[C:31]([CH3:39])[CH:32]=[C:33]([CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[C:28]4=[N:27][C:26]=3[CH3:40])=[C:22]([CH3:41])[CH:21]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1csc(C)n1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4sc(C)nc4C)cc3C)c(C)nc12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a −78° C. mixture of 2,4-dimethylthiazole (0.23 g, 2.04 mmol) and THF (3 mL) is added 1.6 M t-Bu-Li in hexane (1.30 mL, 2.09 mmol). The mixture is stirred at −78° C. for 15 minutes. 0.5 M ZnCl2 in THF (4.3 mL, 2.14 mmol) is added and the solution warmed to ambient temperature. 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 1.02 mmol) and PdCl2(dppf) (0.037 g, 0.051 mmol) is added and mixture is stirred at 65° C. overnight, diluted with EtOAc (20 mL), washed with 10% citric acid (15 mL), water (15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated. The residue is purified by silica gel chromatography (0%-15% EtOAc/hexane gradient) furnish the title compound (0.21 g, 0.49 mmol, 49%). 1H NMR (CDCl3), δ 0.87 (t, J=7.5 Hz, 6H), 1.73-1.91 (m, 4H), 2.14 (s, 3H), 2.49 (s, 3H), 2.52 (s, 3H), 2.57 (s, 3H), 2.66 (s, 3H), 3.28-3.38 (m, 1H), 6.68 (s, 1H), 7.00 (s, 1H). LC/MS (m/z): calcd. for C23H28N4S2 (M+H)+: 425.3; found: 425.2.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH:36]2[CH3:42].C([O-])(O)=O.[Na+]>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH:36]4[CH3:42])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CC1c2cccc(N)c2C(=O)N1C
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)C4C)n2)c(OC)c1)OCC
Yield: 34.3 %

Procedure:
The title compound was prepared according to the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (230.1 mg, 0.5071 mmol) and 7-amino-2,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (Compound 157A, 95.1 mg, 0.540 mmol) in TFE (5 mL). The reaction mixture poured into a separatory funnel containing saturated NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was adsorbed onto a pre-filled solid loading cartridge [RediSepRf 2.5 gram] and purified using an ISCO Combiflash unit [RediSepRf 4 gram silica], eluting first with 40-100% EtOAc:Heptane and then 0-15% MeOH:CH2Cl2. The product was purified again by MDP [under basic conditions; ammonium bicarbonate buffer (pH 9)] to afford title product as a white solid (103.1 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 9.13 (s, 1H), 8.39 (s, 1H), 7.64-8.90 (m, 1H), 7.41 (br s, 2H), 7.18 (d, J=7.3 Hz, 1H), 7.05 (s, 1H), 6.91 (d, J=7.8 Hz, 1H), 4.55 (q, J=6.5 Hz, 1H), 3.91-4.06 (m, 4H), 3.74 (s, 3H), 3.29 (d, J=22.5 Hz, 2H), 2.99 (s, 3H), 1.40 (d, J=6.6 Hz, 3H), 1.20 (t, J=7.1 Hz, 6H). MS (ES+): m/z 594.17 (100) [MH+]. HPLC: tR=1.59 min (TOF, polar—3 min).