Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:25]CC4C=CC=CC=4)=O)=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.FC1N=CC(C2C=CC(OCCN3CCOCC3)=CC=2)=CC=1>C(#N)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]#[N:25])=[N:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Agent: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Solvent: CC#N
Product: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1

Procedure:
In another aspect, the invention relates to the process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide comprising the steps of reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; and reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:17]=[C:16]([CH:18]=[C:19]([F:21])[F:20])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C.[OH-].[Li+].Cl>C1COCC1>[F:20][C:19]([F:21])=[CH:18][C:16]1[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=[C:5]([CH:17]=1)[C:4]([OH:22])=[O:3]
Reactant: CCCN(C)C(=O)c1cc(C=C(F)F)cc(C(=O)OCC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C=C(F)F)cc(C(=O)O)c1
Yield: 43.7 %

Procedure:
Stir a solution of 5-(2,2-difluorovinyl)-N-methyl-N-propyl-isophthalamic acid ethyl ester (187 mg, 0.63 mmol), 1 N lithium hydroxide (2.5 mL, 2.5 mmol) and THF (2.5 mL) at room temperature overnight. Partition the reaction between ethyl acetate and water. Acidify the aqueous with 5 N HCl and extract with ethyl acetate. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 2:98 to 6:94 methanol:dichloromethane with 1% acetic acid) to give the title compound (78 mg, 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH2:6])=[O:5].[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18])[CH3:13]>N1C=CC=CC=1>[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH2:6])=[O:5])=[O:18])[CH3:13]
Reactant: Cc1cccc(N)c1C(N)=O
Reactant: CCOc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Product: CCOc1ccccc1C(=O)Nc1cccc(C)c1C(N)=O

Procedure:
A mixture of 2-amino-6-methylbenzamide (UK Patent Application No 1,276,359; 5.49 g, 0.0365 mol), 2-ethoxybenzoyl chloride (7.67 g, 0.0415 mol) and pyridine (100 ml) was stirred at room temperature for 20 hours. The solvent was then removed by evaporation under vacuum and the residue dissolved in dichioromethane (200 ml). The solution was washed with saturated aqueous sodium carbonate solution (200 ml) and the aqueous phase back-extracted with further dichioromethane (2×100 ml). The organic solutions were combined, washed successively with 2N hydrochloric acid (3×100 ml) and brine (100 ml), then dried (Na2SO4) and evaporated under vacuum to give the title compound, which recrystallized from ethyl acetate as a colourless solid (6.86g, 63%), m.p. 166-168° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[OH:12].[C:13](=[O:16])([O-])O.[Na+]>C(Cl)Cl.O1C=CCCC1.O1CCOCC1>[Br:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[O:12][CH:5]1[CH2:4][CH2:3][CH2:11][CH2:13][O:16]1
Reactant: O[C@H]1CCc2c(Br)cccc21
Reactant: O=C([O-])O
Agent: C1=COCCC1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Brc1cccc2c1CC[C@@H]2OC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In methylene chloride (16.2 mL), 3,4-dihydro-2H-pyran (10.6 mL) was dissolved. To the solution, a solution of 4M hydrogen chloride in 1,4-dioxane (31.1 μL) was added and (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that was commercially available or could be obtained by a known method was added. The resultant reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (60 mL) was added and extracted with methylene chloride (60 mL). The organic phase was washed with brine (60 mL) and dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5). From the eluted solution, the solvent was distilled off under reduced pressure to give the title compound (15 g).
Reaction SMILES: CN(C)[C:3](=O)[S:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH:13]=O.[OH-].[Na+].ClC[C:21]#[N:22]>O.CO>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[CH:13]=[C:3]([C:21]#[N:22])[S:4][C:5]=2[CH:10]=1
Reactant: COc1ccc(C=O)c(SC(=O)N(C)C)c1
Reactant: N#CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2cc(C#N)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
(Ref: Gallagher, T; Pardoe, D. A.; Porter, R.; Tetrahedron Lett.; 2000, 41(28), 5415–5418.) To a solution of S-(2-formyl-5-methoxyphenyl) dimethylthiocarbamate (1.08 g, 4.5 mmol) in water (4 mL) and methanol (8 mL) was added sodium hydroxide (199 mg, 4.9 mmol), this was heated to reflux for 16 hours. The reaction was cooled to room temperature and chloroacetonitrile (0.28 mL, 4.5 mmol) was added in one portion and the mixture the stirred at room temperature for 1 hour. The methanol was removed in vacuo, and water (10 mL) added. The aqueous layer was extracted with diethyl ether (3×20 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography with a gradient of 0–30% ethyl acetate in iso-hexane to give the title compound as a colourless solid (390 mg, 46%); δH (300 MHz, CDCl3) 7.80–7.70 (1H, m, ArH), 7.29 (2H, m, ArH), 7.11–7.01 (1H, m, ArH) and 3.85 (3H, s, OCH3). M+23=212.0. νmax/cm−1 [film] 2213.50 (m).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[N:23][C:22]([C:25]([OH:27])=O)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[NH3:36]>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:24]=[N:23][C:22]([C:25]([NH2:36])=[O:27])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: N
Reactant: C[C@@H](c1ccc(-c2ccc(C(=O)O)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C(N)=O)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylic acid and ammonia (32% in water) following a procedure analogous to that described in Example 203. Mass spectrum (ESI+): m/z=475 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([OH:26])[C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=1.Cl>O1CCOCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([OH:26])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1
Reactant: COC(=O)C(C)(O)c1ccc(OCc2nc3ccc(OC)cc3n2C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2nc(COc3ccc(C(C)(O)C(=O)O)cc3)n(C)c2c1
Yield: 103.9 %

Procedure:
A mixture of methyl 4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactate (0.15 g), concentrated hydrochloric acid (2 ml) and dioxane (2 ml) was heated at reflux for 3 hours. The reaction mixture was concentrated and the water of the residue was removed by azeotropic distillation in dioxane and the crystals were isolated by filtration to afford the title compound (0.15 g, mp 216-218° C.).
Reaction SMILES: C([Mg]Br)C.Br[C:6]1[N:10]([CH3:11])[CH:9]=[N:8][CH:7]=1.[Cl:12][C:13]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:21]([Cl:29])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:30]([C:32]3[O:36][N:35]=[C:34]([CH3:37])[CH:33]=3)=[O:31])[CH:19]=2)[N:14]=1>C(Cl)Cl>[Cl:12][C:13]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:21]([Cl:29])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:30]([C:6]3[N:10]([CH3:11])[CH:9]=[N:8][CH:7]=3)([C:32]3[O:36][N:35]=[C:34]([CH3:37])[CH:33]=3)[OH:31])[CH:19]=2)[N:14]=1
Reactant: Cc1cc(C(=O)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)on1
Reactant: Cn1cncc1Br
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cc1cc(C(O)(c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)c2cncn2C)on1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethylmagnesium bromide (3 M in Et2O, 0.064 mL, 0.193 mmol) was added dropwise to a solution of 5-bromo-1-methyl-1H-imidazole (31.0 mg, 0.193 mmol) in DCM (1 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes, then was cooled to 0° C. A solution of (2,4-dichloro-3-phenylquinolin-6-yl)(3-methylisoxazol-5-yl)methanone (49.2 mg, 0.128 mmol, Intermediate 3: step b) in DCM (2 mL) was added via cannula. The mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous NH4Cl and was diluted with water. The mixture was extracted three times with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by RP-HPLC (10-90% CH3CN—H2O, 0.1% TFA) to afford the title compound along with the intended product (2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(3-methylisoxazol-5-yl)methanol. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.06 (d, J=9.05 Hz, 1H), 7.92 (d, J=8.80 Hz, 1H), 7.47-7.63 (m, 3H), 7.36-7.47 (m, 2H), 6.53 (br. s., 1H), 6.34 (s, 1H), 2.23-2.38 (m, 2H), 2.20 (s, 3H), 0.76 (t, J=7.21 Hz, 3H); MS m/e 413.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([SH:26])[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.Br[CH2:32][CH2:33][O:34][CH3:35].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([S:26][CH2:32][CH2:33][O:34][CH3:35])[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(S)cc(C(F)(F)F)c1
Reactant: COCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCCSc1cc(C(=O)N(C)c2cnccc2-c2ccc(F)cc2OC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-3-mercapto-N-methyl-5-(trifluoromethyl)benzamide (0.065 g, 149 μmol, example 216, intermediate a) in acetonitrile (2 mL) was treated with 1-bromo-2-methoxyethane (24.8 mg, 16.8 μL, 179 μmol) and DIPEA (38.5 mg, 52.0 μL, 298 μmol) and stirred at room temperature for 5 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (0.04 g; 54%). MS (ESI): m/z=495.14 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:10])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[C:17](OC(=O)C)(=[O:19])[CH3:18].[OH-].[Na+]>CO>[C:17]([NH:1][CH2:2][C:3]1([OH:10])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)(=[O:19])[CH3:18]
Reactant: CN1CCC(O)(CN)CC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NCC1(O)CCN(C)CC1
Yield: 90 %

Procedure:
4-aminomethyl-4-hydroxy-1-methylpiperidine (2.95 g, 0.02 mole), potassium carbonate (6.5 g, 0.047 mole) and acetic anhydride (8.5 g, 0.08 mole) in methanol were mixed at room temperature for two hours. Sodium hydroxide was added for neutralization and the solution extracted with chloroform. After evaporation, a yellow oil was obtained which was identified as 4-acetamidomethyl-4-hydroxy-1-methylpiperidine (3.4 g, 0.018 mole, 91% yield).
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][CH:11]2[CH2:15][CH2:14][CH:13]([CH2:16][CH3:17])[C:12]2=[CH2:18])=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:29])C=1.[OH-].[Ca+2].[OH-]>O>[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][CH:11]2[CH2:15][CH2:14][CH:13]([CH2:16][CH3:17])[C:12]32[O:29][CH2:18]3)=[CH:8][CH:7]=1
Reactant: C=C1C(CC)CCC1Cc1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC1CCC(Cc2ccc(Cl)cc2)C12CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into 100 ml of chloroform, 8.0 g of 2-(4-chlorobenzyl)-5-ethyl-1-methylenecyclopentane (the compound No. 129 shown in Table 3) were dissolved, and then 11.6 g of m-chloroperbenzoic acid were added to the thus formed mixture within 5 min, and the whole mixture was stirred for 2 hours at room temperature. In the next place, 11 g of calcium hydroxide were added to the mixture under cooling with iced water, and the whole mixture was stirred for 30 min at room temperature.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:14]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[I:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)Nc1ccsc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccsc1I
Yield: 92.3 %

Procedure:
In a manner analogous to Campaigne, E. and Monroe, P. A. J.A.C.S., 76, 2447-2450 (1954), to a boiling solution of (tert-butoxy)-N-(3-thiophenyl)carboxamide (21.0 g, 0.1 mol) in methylene chloride (400 mL) add N-iodosuccinimide (23.7 g, 0.1 mol) in small portions. Set the heating bath to 65° C. for 20 min. Take the reaction to room temperature, evaporate the solvent and purify the crude by flash chromatography (Silica gel-Hexane/EtOAc 9:1) to obtain 30.0 g (88%) of (tert-Butoxy)-N-(2-iodo(3-thiophenyl))carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.N1C=CC=CC=1.[CH3:31][N:32]1[CH:36]=[C:35]([C:37](Cl)=[O:38])[CH:34]=[N:33]1>ClCCl>[CH:21]1([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:37]([C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)=[O:38])[CH:3]=[CH:4][C:5]=2[CH3:24])[CH:17]=3)=[O:20])[CH2:22][CH2:23]1
Reactant: Cn1cc(C(=O)Cl)cn1
Reactant: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cnn(C)c2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.6 %

Procedure:
To a solution of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (53.8 mg, 0.144 mmol) in methylene chloride (2.0 mL, 31 mmol) was added pyridine (0.10 mL, 1.2 mmol) and 1-methyl-1H-pyrazole-4-carbonyl chloride (27.7 mg, 0.192 mmol). The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was then poured into 50 mL dichloromethane, washed with aqueous NaHCO3, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 37.1 mg (61%) of N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-1-methyl-1H-pyrazole-4-carboxamide. LCMS (ESI): RT (Min)=4.307, M+H=426.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.80 (s, 1H), 9.19 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.01 (d, J=4.9 Hz, 2H), 7.93 (d, J=8.6 Hz, 1H), 7.70 (dd, J=10.3, 4.6 Hz, 3H), 7.30 (d, J=8.0 Hz, 1H), 3.89 (s, 3H), 2.25 (s, 3H), 2.19-1.98 (m, 1H), 0.85 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[N:40][CH:41]=1)=[C:34]=[O:35]>ClCCl.C1(C)C=CC=CC=1>[CH3:43][O:42][C:39]1[N:40]=[CH:41][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:37][CH:38]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: COc1ccc(N=C=O)cn1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (74.3 ul, 0.53 mmol) (Aldrich), followed by the addition of solution of 5-isocyanato-2-methoxy-pyridine (1.28 mL, 0.26 mmol) in toluene (from Example 62a supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (6-methoxy-pyridin-3-yl)-amide as a white solid. (Yield 55 mg, 49.1%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([CH2:9][C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1)=[O:2].FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[CH:1]([NH:3][C:4]1[S:5][C:6]([CH2:9][C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1)=[O:2]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cnc(NC=O)s3)[C@H]2SC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cnc(NC=O)s3)[C@H]2SC1
Reaction time: 0.25 h
Yield: 72.8 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-formamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (11.48 g) in methylene chloride (57.4 ml) and anisole (15 ml) was added 2,2,2-trifluoroacetic acid (46 ml) under ice-cooling, and the mixture was stirred at 7° to 8° C. for 15 minutes. After the reaction mixture was poured into diisopropyl ether (600 ml), it was stirred under ice-cooling for 20 minutes, followed by collecting the insoluble substance by filtration and washing it with diisopropyl ether. This substance (11.4 g) was suspended in water (150 ml), adjusted to pH 6.5 with sodium bicarbonate and then treated with charcoal. The resultant filtrate was adjusted to pH 2.0 with 10% hydrochloric acid, and the precipitated substance was collected by filtration, washed with water and then dried to give 7-[2-(2-formamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (5.88 g), mp 200° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:15]=[CH:14][C:13]([C:16]3[O:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:12][C:10]=2[NH2:11])=[CH:4][CH:3]=1.[CH:25](=O)[CH3:26].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[C:13]1[CH:14]=[CH:15][C:9]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:25]([CH3:26])=[N:11][C:10]=2[CH:12]=1
Reactant: CC=O
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
To a solution of 2-(2-(4-fluorophenyl)aminoanilin-5-yl)benzoxazole (see Working Example 34-1) (38.0 mg, 0.119 mmol) in dimethylformamide (2 mL) was added an aqueous solution of acetaldehyde (approx. 90%, 22.6 μL, 0.360 mmol) and oxone (73.2 mg, 0.119 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (20.0 mg, 49% yield) as light brown crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][C:21]([OH:27])=[CH:20]5)=[N:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.Cl[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35].[OH-].[Na+]>CN(C=O)C>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][O:27][C:21]1[CH:22]=[N:23][C:24]2[C:19]([CH:20]=1)=[CH:18][C:17]([CH2:16][C:13]1[N:11]3[N:12]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=[CH:9][C:10]3=[N:15][N:14]=1)=[CH:26][CH:25]=2
Reactant: Oc1cnc2ccc(Cc3nnc4ccc(-c5ccccc5)nn34)cc2c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1cnc2ccc(Cc3nnc4ccc(-c5ccccc5)nn34)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinolin-3-ol (0.05 g, 0.1 mmol) was dissolved in DMF (8 mL). SODIUM HYDRIDE (0.01 g, 0.3 mmol) was added and allowed to stir for 1 h at rt. 2-chloro-N,N-dimethylethanamine hydrochloride (0.06 g, 0.4 mmol), which was free-based using 5 N NaOH then extracted with ether, was added. The resulting mixture was continued to stir for 20 h at rt. Solvent was removed in vacuo. The crude material was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-026, 12 g SiO2, solvent system: DCM:MeOH(2M NH3)=95%:5%, Flow=30 mL/min) to afford the title compound MS m/z: 425.3 (M+H). Calc'd. for C25H24N6O−424.49.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:14][C@H:13]([OH:15])[CH:12]=[CH:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1CC(=O)C=C1)(=O)C.N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:9][C@H:10]1[CH2:14][C:13](=[O:15])[CH:12]=[CH:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O[C@@H]1C=C[C@@H](O)C1)c1ccccc1
Agent: CC(=O)OC1C=CC(=O)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1C=C[C@@H](OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.5 %

Procedure:
38 milligrams of the (S)-trans-3-benzoyloxy-5-hydroxycyclopent-1-ene obtained by the method of (1), above, was added in 15 milliliters of methylene chloride to a chromic acid-pyridine complex prepared from 100 milligrams of chromic anhydride and 159 milligrams of pyridine, following which the mixture was stirred for 20 minutes at room temperature. The organic layer was then separated, successively washed in a 5% aqueous NaOH solution, 5% aqueous HCl solution and water and dried, after which the solvent was distilled off to obtain 22 milligrams of 4(S)-benzoyloxycyclopent-2-en-1-one having a Δε226 = -14° and exhibiting the same IR, NMR and mass as those of the product obtained in Example 9. The yield was 58%.