Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].CN1CCOCC1.ClC(OCC(C)C)=O.[F:29][C:30]([F:45])([F:44])[C:31]([NH:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[NH:40][CH2:39][CH2:38][CH2:37]2)=[O:32]>O1CCCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([N:40]2[C:41]3[C:36](=[CH:35][C:34]([NH:33][C:31](=[O:32])[C:30]([F:44])([F:45])[F:29])=[CH:43][CH:42]=3)[CH2:37][CH2:38][CH2:39]2)=[O:13])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Reactant: O=C(Nc1ccc2c(c1)CCCN2)C(F)(F)F
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: N#Cc1ccc(CCC(=O)N2CCCc3cc(NC(=O)C(F)(F)F)ccc32)cc1
Temperature: -20 °C

Procedure:
10 g (0.057 mol) of 3-(4-cyano-phenyl)propionic acid and 6.6 g (0.065 mol) of N-methyl-morpholine are dissolved in 250 ml tetrahydrofuran and cooled to −20° C. Then 8.2 g (0.06 mol) of isobutyl chloroformate are added dropwise. 13.9 g (0.057 mol) of 6-(trifluoroacetylamino)-1,2,3,4-tetrahydro-quinoline in 200 ml tetrahydrofuran are then added and the solution is left to heat up to ambient temperature overnight. It is then diluted with 200 ml of ethyl acetate and washed with 2×80 ml of 0.5 N hydrochloric acid and then 100 ml of sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][N+:8]([O-])=O)[CH2:3][C:4](=[O:6])[CH3:5].[N+](CC(=O)CCC)([O-])=O.N(C(OCC)=O)=NC(OCC)=O.C(P(CCCC)CCCC)CCC>>[CH3:1][C:2]([CH3:11])([CH2:3][C:4](=[O:6])[CH3:5])[C:7]#[N:8]
Reactant: CC(=O)CC(C)(C)C[N+](=O)[O-]
Agent: CCCC(=O)C[N+](=O)[O-]
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Product: CC(=O)CC(C)(C)C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4,4-Dimethyl-5-nitropentan-2-one was made according to the literature procedure; see Kloetzel, M. C. J. Am. Chem. Soc., 69, pp. 2271-2275 (1947). Under a nitrogen atmosphere, a solution of nitropentanone (9.55 g, 60.0 mmol) was cooled to 0° C. Diethyl azodicarboxylate (11.5 g, 66 mmol) and tributylphosphine (26.71 g, 132 mmol) were sequentially added. The reaction was stirred for one hour at 0° C. and then for one hour at room temperature. The solvent was removed under reduced pressure, and the residue was purified by chromatography on a HORIZON HPFC system (65I cartridge, eluting with dichloromethane). The resulting oil was treated with hexane; a precipitate formed and was removed by fitration. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on a HORIZON HPFC system (65I cartridge, eluting with 45% to 55% ethyl acetate in hexane) to provide 5.17 g of 2,2-dimethyl-4-oxopentanenitrile as a pale yellow oil.
Reaction SMILES: ClCCl.C(O)(=O)C.C(OC([N:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[NH:27][CH:26]=[C:25]3[Br:33])[CH2:16]1)=O)(C)(C)C>CO>[Br:33][C:25]1[C:24]2[C:29](=[CH:30][CH:31]=[C:22]([O:21][C@H:17]3[CH2:18][CH2:19][CH2:20][NH:15][CH2:16]3)[CH:23]=2)[C:28](=[O:32])[NH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(=O)[nH]cc(Br)c3c2)C1
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]cc(Br)c2cc(O[C@H]3CCCNC3)ccc12
Reaction time: 2 h

Procedure:
A solution of (S)-3-(oxo-1,2-dihydroisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester (1 g, 2.9 mmol) and N-bromosuccinamide (516 mg, 2.9 mmol) in acetonitrile was stirred overnight at ambient temperature. The mixture was absorbed onto silica and flash chromatography (eluent: ethyl acetate) to give (S)-3-(4-bromo-1-oxo-1,2-dihydroisoquinblin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester (700 mg). Dichloromethane and trifluoroacetic acetic acid (3:1, 20 ml) were added to (S)-3-(4-bromo-1-oxo-1,2-dihydroisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester and the mixture stirred for 2 h, then concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column using methanol and eluted with 2M ammonia in methanol to afford crude (S)-4-bromo-6-(piperidin-3-yloxy)-2H-isoquinolin-1-one (530 mg), which was purified by prep-HPLC, El-MS: m/z=325.5 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:4]=2[C:5]([Cl:8])=[N:6][CH:7]=1.C1C=CC=CC=1.[Li]CCCC.[CH:29](=[O:31])[CH3:30]>C1COCC1.CCCCCC>[Cl:8][C:5]1[C:4]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:11][C:3]=2[C:2]([CH:29]([OH:31])[CH3:30])=[CH:7][N:6]=1
Reactant: CC=O
Reactant: Clc1ncc(Br)c2sc(-c3ccccc3)cc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(O)c1cnc(Cl)c2cc(-c3ccccc3)sc12
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
7-bromo-4-chloro-2-phenyl-thieno[3,2-c]pyridine 95 (130 mg, 0.40 mmol) was azeotroped to dryness from benzene and dissolved in THF (11 mL). Upon cooling to −78° C., the solution was treated dropwise with n-BuLi (168 μl of a 2.5 M solution in hexane, 0.42 mmol). After 2 min, acetaldehyde (50 μl, 0.89 mmol) was added and the resultant solution was stirred at −78° C. for 1 h. After this time, the reaction mixture was warmed to 0° C., quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (3×). The organic layers were dried over Na2SO4, filtered, and the filtrate was purified by silica gel column chromatography (eluent: hexane:EtOAc, 4:1) to give 96. 1H NMR (400 MHz, CDCl3) δ: 1.68 (d, J=6.5 Hz, 3H), 2.29 (bd, 1H), 5.22–5.29 (m, 1H), 7.38–7.49 (m, 3H), 7.69 (s, 1H), 7.73–7.78 (m, 2H), 8.13 (s, 1H). MS (EI) m/z (M+H+) 290.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:37](=O)[CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.C1COCC1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:32][CH2:33][N:34]([CH2:37][CH3:38])[CH2:35][CH2:36]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC=O
Reactant: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Nc3cc(Cl)cc(Cl)c3)c1)cn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCN1CCC(n2cc(C(=O)c3cccc(NC(=O)Nc4cc(Cl)cc(Cl)c4)c3)c3c(N)ncnc32)CC1
Reaction time: 3.5 h
Yield: 10.5 %

Procedure:
A solution of 1-[3-(4-Amino-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-3-(3,5-dichloro-phenyl)-urea (100 mg, 0.19 mmol) and acetaldehyde (8.4 mg, 0.19 mmol) in DMF/THF (20%, 10 mL) was stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (61 mg, 0.29 mmol) was added to the reaction mixture, stirred for 3.5 hours, and concentrated in vacuo. Purification by reverse phase preparative HPLC (HPLC method 2) provided the title compound as a white solid (11 mg, 10%). MS: 553.5 (MH+); HPLC Rf: 1.7 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]1[CH3:19])(=[O:3])N.C(=O)([O-])[O-:21].[Na+].[Na+]>Cl>[C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]1[CH3:19])([OH:21])=[O:3]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(C)C2)cc1
Agent: Cl
Agent: [Na+]
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
15.16 g of (2S,4S)-2-carbamoyl-4-(4-methoxybenzylthio)-1-methylpyrrolidine [prepared as described in step (i) above] were dissolved in 170 ml of 2N aqueous hydrochloric acid, and the solution was stirred in a bath kept at 110° C. for 3.5 hours. At the end of this time, the reaction mixture was cooled to room temperature, and its pH was adjusted to a value of 8.5 by the addition of sodium carbonate. The mixture was then concentrated by evaporation under reduced pressure, after which it was allowed to stand in a refrigerator to precipitate crystals. The precipitated crystals were collected by filtration and washed with a small amount of cold water. They were then dried, to give 10.4 g of the title compound. The mother liquor was then concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through CHP20P (75-150μ, Mitsubishi Chemical Industries, Ltd.), using 50% v/v aqueous methanol as the eluent, to afford a further 3.7 g of the title compound, as crystals melting at 185°-187.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5](C2CCCCO2)[C:6]=1[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:13]=[CH:14]2)=[CH:9][CH:8]=1.CO.[ClH:31]>O1CCOCC1>[ClH:31].[CH3:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:13]=[CH:14]2)=[CH:9][CH:8]=1
Reactant: Cc1cnn(C2CCCCO2)c1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cn[nH]c1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of N-(7-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide (43 mg, 0.11 mmol) in methanol (3 mL, 70 mmol) was added 4.0 M of hydrogen chloride in 1,4-dioxane (0.30 mL). The reaction mixture was stirred at 40° C. for 1 hour and then evaporated in vacuo. The residue was triturated with 0.5 mL N,N-dimethylformamide, and the resulting light yellow precipitate was collected, rinsed with ethyl acetate, and dried under vacuum to yield 17.3 mg (46%) of N-(7-(4-methyl-1H-pyrazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide hydrochloride. LCMS (ESI): RT (min)=3.816, M+H=293.0, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.22 (s, 1H), 8.44 (s, 1H), 8.27 (s, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.63 (s, 1H), 2.31 (s, 3H), 2.14-2.01 (m, 1H), 0.93-0.76 (m, 4H).
Reaction SMILES: CO.[N+:3]([C:6]1[CH:30]=[CH:29][C:9]([C:10]([NH:12][C:13]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:11])=[CH:8][CH:7]=1)([O-])=O>[C].[Pd].C(OCC)(=O)C>[NH2:3][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][C:13]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:11])=[CH:29][CH:30]=1
Reactant: O=C(Nc1cc(Oc2ccccc2)ccc1C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)O)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 108.6 %

Procedure:
3.0 mL of methanol, 2.0 mL of ethyl acetate and 4.0 mg of 5% palladium-carbon were added to 20 mg of 2-(4-nitrobenzamido)-4-phenoxybenzoic acid at room temperature and stirred under hydrogen atmosphere at 40° C. for 8 hours. Insoluble were removed by filtration, and the solvent was evaporated under reduced pressure to obtain 20 mg of 2-(4-aminobenzamido)-4-phenoxybenzoic acid as white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C1([O:18][C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=2)C=CC=CC=1.Cl>C1COCC1.C(OCC)(=O)C.O>[Br:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9])=[O:18]
Reactant: O=C(Oc1ccccc1)c1cccc(Br)c1
Reactant: O=C1CCc2sccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1cccc(Br)c1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 58 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL of THF was treated with NaH (60 percent, 1.5 g, 36 mmol). After the addition of 3-Bromo-benzoic acid phenyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (80 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(3-Bromo-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.5 g, 8.2 mmol) as brown solid in 58% yield.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH:12][C@@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.N>CN1C(=O)CCC1.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:15]3[CH2:16][CH2:17][C@@H:13]([OH:12])[CH2:14]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: O[C@@H]1CCNC1
Reactant: Fc1ccc2nnc(Cl)n2c1
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: O[C@@H]1CCN(c2nnc3ccc(F)cn23)C1
Temperature: 160 °C
Yield: 44 %

Procedure:
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and (R)-3-hydroxypyrrolidine (607 mg, 9.96 mmol) in NMP (4 mL) was heated in the microwave at 160° C. for 2 h. The reaction mixture was applied to an SCX-2 cartridge (70 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (170 mg, 44%). LCMS (Method 1): Rt 0.39 min, m/z 223 [MH+].
Reaction SMILES: [Si]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)(C)(C)C.C([Li])CCC.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1.O>C1COCC1.CCOC(C)=O>[S:6]1[C:7]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]3([O:25][CH2:15][CH2:16][O:17]3)[CH2:19][CH2:20]2)=[CH:8][N:9]=[CH:5]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C[Si](C)(C)c1nccs1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2cncs2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 88.7 %

Procedure:
2-TMS-thiazole (2.5 g, 15.89 mmol) was added to a solution of n-butyllithium (11.9 mL of 1.6 M solution in hexane, 19.07 mmol) in THF (20 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 0.5 h, a solution of 1,4-cyclohexanedione mono-ethylene ketal (2.48 g, 15.89 mmol) in THF (20 mL) was added to the lithiated compound solution via syringe and stirred for 1 h at −78° C. Water (5 mL) and EtOAc were added, and the reaction mixture was warmed to room temperature and extracted using EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and crystallized from EtOAc to yield 3.4 g of 8-(1,3-thiazol-5-yl)-1,4-dioxaspiro[4,5]decan-8-ol in 90% yield. MS (EI) calcd: (M+H)+=242.1; found: 242.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[SH:8].[CH:15](O)=O>>[CH2:13]([N:10]([CH2:11][CH3:12])[C:3]1[C:2]2[N:1]=[CH:15][S:8][C:7]=2[N:6]=[C:5]([CH3:9])[N:4]=1)[CH3:14]
Reactant: O=CO
Reactant: CCN(CC)c1nc(C)nc(S)c1N
Product: CCN(CC)c1nc(C)nc2scnc12

Procedure:
3 g of 5-amino-4-diethylamino-6-mercapto-2-methylpyrimidine was dissolved in 50 ml of 90% formic acid and refluxed for 2 hours. After the completion of the reaction, formic acid was distilled off under reduced pressure. The residue was added with 30 ml of water, and neutralized with ammonium hydroxide. This aqueous solution was extracted with 200 ml of ethyl acetate and the organic layer was dried over sodium sulphate anhydride. Then the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica-gel to obtain 7-diethylamino-5-methylthiazolo[5,4-d]pyrimidine (1.6 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9](Cl)[CH:8]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[O:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([C:22]3[CH:23]=[CH:24][O:20][CH:21]=3)[CH:8]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1
Reactant: OB(O)c1ccoc1
Reactant: N#Cc1ccc(-n2c(N)nc3ccccc32)cc1Cl
Product: N#Cc1ccc(-n2c(N)nc3ccccc32)cc1-c1ccoc1

Procedure:
2-Amino-1-[3-(3-furyl)-4-cyanophenyl]benzimidazole was prepared from 2-amino-1-[3-chloro-4-cyanophenyl]benzimidazole and 3-furylboronic acid by method B. mp 140°-144° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:45]1[N:46]=[C:47]([NH:50][CH:51]=[O:52])[S:48][CH:49]=1)[C:5]([NH:7][CH:8]1[C:43](=[O:44])[N:10]2[C:11]([C:27]([O:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[C:12]([CH2:16][O:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])[CH2:13][S:14](=O)[C@H:9]12)=[O:6].[I-].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.CC(C)=O>[CH3:1][O:2][N:3]=[C:4]([C:45]1[N:46]=[C:47]([NH:50][CH:51]=[O:52])[S:48][CH:49]=1)[C:5]([NH:7][CH:8]1[C:43](=[O:44])[N:10]2[C:11]([C:27]([O:29][CH:30]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[C:12]([CH2:16][O:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)N3CCN(C)CC3)CS(=O)[C@H]12)c1csc(NC=O)n1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)N3CCN(C)CC3)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 2.5 h

Procedure:
In a solution of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (1.5 g) in a mixture of tetrahydrofuran (30 ml) and acetone (15 ml) was dissolved sodium iodide (1.44 g) under ice-cooling and thereto was at a time added trifluoroacetic anhydride (2.04 ml) followed by stirring for 2.5 hours. The reaction mixture was evaporated and to the residue were added ethyl acetate and water. The ethyl acetate layer was separated, washed with 5% aqueous solution of sodium thiosulfate, and an aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal and then evaporated to give benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate.trifluoroacetate (syn isomer) (1.5 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].O.CCOC(C)=O>[O:7]1[CH2:10][CH2:11][O:12][CH:6]1[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[N:3][CH:4]=1
Reactant: OCCO
Reactant: O=Cc1ccc(F)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(C2OCCO2)cn1
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 64 %

Procedure:
6-Fluoronicotinaldehyde (21.96 g, 176 mmol) was suspended in toluene (340 mL) and ethylene glycol (10.4 mL, 186 mmol) and p-toluenesulfonic acid (Acros, 15% in acetic acid, 1.10 mL) were added. The flask was fitted with a Dean-Stark head and a reflux condenser, and placed in a preheated oil bath (120° C.) and the reaction was stirred. After 45 minutes, the reaction was cooled to room temperature. The reaction was diluted with saturated sodium bicarbonate (50 mL), water (150 mL) and EtOAc (150 mL). The layers were separated and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (600 mL fritted filter with about 3 inches of silica gel; DCM to 100:1 to 50:1 DCM/MeOH to 40:1 DCM/MeOH) to give 19.055 g of 5-(1,3-dioxolan-2-yl)-2-fluoropyridine. m/z (ESI, +ve ion) 170 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@H:12]1[C:16](=[O:17])[O:15][C:14]([CH3:19])([CH3:18])[O:13]1)C1C=CC=CC=1.C1CCC=CC=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(O)C.[Pd]>[F:30][C:29]([F:32])([F:31])[C:27]([O-:33])=[O:28].[CH3:18][C:14]1([CH3:19])[O:13][C@@H:12]([CH2:11][NH3+:10])[C:16](=[O:17])[O:15]1
Reactant: CC1(C)OC(=O)[C@H](CNC(=O)OCc2ccccc2)O1
Reactant: O=C(O)C(F)(F)F
Agent: [Pd]
Solvent: C1=CCCC=C1
Solvent: CCO
Product: CC1(C)OC(=O)[C@H](C[NH3+])O1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude (S)-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylmethyl)carbamic acid benzyl ester (976 mg, 3.5 mmol) was dissolved in ethanol (14 mL), and palladium (10% on activated charcoal, 300 mg) and 1,3-cyclohexadiene (2.8 g, 35 mmol) were added and the reaction was stirred for 1 hour at room temperature, and heated to 40° C. for 10 min. After filtration, TFA (0.4 g, 3.5 mmol) was added and the solvent was removed by evaporation to afford crude (S)-2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylmethylammonium trifluoroacetate as an oil.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[C:13]([F:20])[C:12]=2[N:21]2[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22]2)[CH2:5][CH2:4]1.[Cl:30][C:31]1[C:44]([N:45]=[C:46]=S)=[C:43]([Cl:48])[CH:42]=[CH:41][C:32]=1[CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].CC(C)N=C=NC(C)C>CN(C=O)C>[F:29][C:2]([F:1])([F:28])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([N:21]3[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22]3)=[C:13]([F:20])[C:14]3[N:18]([CH3:19])[C:46]([NH:45][C:44]4[C:43]([Cl:48])=[CH:42][CH:41]=[C:32]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:31]=4[Cl:30])=[N:17][C:15]=3[CH:16]=2)=[O:27])[CH2:5][CH2:4]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1c(N)cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC[C@@H](F)C2)c1F
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(N3CC[C@@H](F)C3)c(F)c21

Procedure:
The title compound is prepared in analogy to 1e from (R)—N-(trans-4-trifluoromethyl-cyclohexyl)-2-[3-fluoro-pyrrolidinyl]-3-fluoro-4-methylamino-5-amino-benzoic acid amide (215 mg, 0.51 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (162 mg, 0.51 mmol), DIC (80 μL) and DMF (4.0 mL).
Reaction SMILES: [Na].[C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=[O:5].[CH:13]12[CH:21]=[CH:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][CH2:15][CH:14]2[C:22](Cl)=[O:23]>>[C:4]([O:6][C:22]([CH:14]1[CH2:15][CH2:16][CH:17]2[CH:18]=[CH:19][CH:13]1[CH2:21][CH2:20]2)=[O:23])(=[O:5])[CH2:3][C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: O=C(Cl)C1CCC2C=CC1CC2
Agent: [Na]
Product: CC(C)(C)OC(=O)CC(=O)OC(=O)C1CCC2C=CC1CC2
Yield: 80.9 %

Procedure:
To a solution of sodium salt of mono-tert-butyl malonate (20.4 g) prepared according to the same procedure as in Example 4, bicyclo[3,2,2]non-8-ene-2-carbonyl chloride (18.5 g) obtained in Preparation Example 3 is slowly added, and the reaction mixture is reacted at −20° C. in a nitrogen atmosphere for 1 hour, and further reacted at 55° C. for 8 hours. Then, the mixture is worked up as in the procedure of Example 1, to obtain 25 g of the pure title compound (purity: 99%, yield: 82%).