Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11](Br)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:19][N:20](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn]>[C:1]([O:5][C:6]([C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([C:19]#[N:20])=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ncc(Br)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: O
Product: CC(C)(C)OC(=O)c1ncc(C#N)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
To a solution of 5-bromo-3-nitro-pyridine-2-carboxylic acid tert-butyl ester (888 mg, 2.93 mmol) in DMF (8.8 ml) was added zinc cyanide (206 mg, 1.76 mmol) and zinc dust (2 mg, 0.03 mmol). The mixture was purged with nitrogen (3 times)bis(tri-tert-butylphosphine)palladium(0) (150 mg, 0.293 mmol) was added and the mixture was heated to 80° C. for 4 h. After cooling to 0° C. water was added and the mixture extracted with EtOAc, the combined organic layers were washed with half saturated aq. NaCl, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1:4) to provide the title compound as beige solid.
Reaction SMILES: [C:1]([O:6][OH:7])([CH2:4][CH3:5])([CH3:3])[CH3:2].[O:8]=[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].S(=O)(=O)(O)O>>[C:1]([O:6][O:7][C:9]1([O:8][O:6][C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CCC(C)(C)OO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCCCC1(OOC(C)(C)CC)OOC(C)(C)CC
Temperature: -10 °C

Procedure:
Ethyl 2,2-di(tertiary-amylperoxy)-1-cyclohexanecarboxylate was prepared by the addition of 92.64% TAHP (tertiary amyl hydroperoxide) (42.16 g, 0.3750 mol) to 95% ethyl 2-oxo-1-cyclohexanecarboxylate (17.92 g, 0.1000 mol) at room temperature in a three necked 250-mL round bottomed flask equipped with a thermometer and mechanical stirrer. The solution was cooled to −10° C. via a dry ice-acetone bath and 78% sulfuric acid (15.09, 0.1200 mol) was added dropwise to the solution with the temperature at −10° C. Upon completion of the addition of sulfuric acid, the solution was allowed to reach 5° C. where it was maintained by an ice-water bath for three hours with mechanical stirring. The reaction was transferred to a separatory funnel and the lower acidic aqueous layer separated and discarded. The organic layer was then washed with saturated NaCl solution until the aqueous washings had a pH of 4.5 or greater. The organic layer was then dried over MgSO4, filtered through a Buchner funnel and analyzed for purity by gas chromatography (53% by area). Purification by chromatography (silica gel, 95:5 petroleum ether/diethyl ether) afforded a liquid product: 13C NMR (75 MHz, CDCl3) δ 171.8 (C═O), 106.0 (O—C—O, cyclic), 81.1 (C—(CH3)2CH2), 81.0 (C(CH3)2CH2), 59.6 (O—CH2CH3), 44.0 (CH, cyclic), 3.16 (CH3—CH2—C), 31.5 (CH3CH2—C), 26.0 (CH2, cyclic), 23.6 (C(CH3)2, (2x)), 21.8 (CH2, cyclic), 22.0 (CH2, cyclic), 13.8 ((O—CH2CH3) (2X)), 8.0 ((CCH2CH3) (2x)); IR (neat) ν 1736, 1364, 1220, 872 cm−1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH2:16])[CH:15]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[S:29])[CH:23]=[C:24]([Cl:26])[CH:25]=1>C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]([NH:16][C:14]2[CH:15]=[C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:11]=[CH:12][C:13]=2[O:17][CH3:18])=[S:29])[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 1, Step B, 5-(1H-indol-2-yl)-2-methoxy-phenylamine (0.1765 g, 0.74 mmol) was mixed with 3,5-dichlorophenyl isothiocyanate (0.151 g, 0.74 mmol) in ethyl acetate (20 mL) and was heated briefly at 50° C. and then allowed to stand overnight at room temperature. The reaction mixture was concentrated to dryness, triturated with hexanes, and the insoluble material collected by filtration (0.169 g), mp 199-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[OH:24].C(S(C1C=C(C2C=C[C:44]([O:47]CCO)=[C:43]3[C:39]=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:39][CH2:43][CH2:44][OH:47]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCO)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(Cl)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCCO)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 218 by using an analogous procedure to that outlined in the preparation of Compound 215. 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1 H) 8.06 (m, 1 H) 8.01 (m, 2 H) 7.87 (t, J=8.0 Hz, 1 H) 7.63 (s, 1 H) 7.23 (d, J=8.32 Hz, 1 H) 7.16 (d, J=8.32 Hz, 1 H) 4.34 (t, J=6.32 Hz, 2 H) 3.72 (t, J=6.32 Hz, 2 H) 3.43 (q, J=7.32 Hz, 2 H) 2.02 (m, 2 H) 1.18 (t, J=7.32 Hz, 3 H). [M+H] calc'd for C22H22ClN2O4S, 445; found, 445.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[NH2:17][C:18]1[CH:35]=[CH:34][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:26]2)=[C:20]([O:36][CH3:37])[CH:19]=1.ClCCl.CO.N>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([NH:17][C:18]1[CH:35]=[CH:34][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:26]2)=[C:20]([O:36][CH3:37])[CH:19]=1)=[O:16]
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1cc(N)ccc1OCCN1CCC(C(N)=O)CC1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1CCC(C(N)=O)CC1

Procedure:
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid and 194 mg (0.66 mmol) of 1-[2-(4-amino-2-methoxyphenoxy)ethyl]piperidine-4-carboxylic acid amide. Yield: 310 mg (98% of theory); melting point: 150° C.; C25H25ClF3N3O4 (M=523.93); calc.: molecular ion peak (M+H)+: 524/526 (Cl); found: molecular ion peak (M+H)+: 524/526 (Cl); Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]2)=[S:19])=[C:10]([F:26])[CH:9]=1.[C:27](Cl)(Cl)=[S:28]>C(Cl)Cl>[Cl:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([N:17]=[C:18]2[N:20]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[C:27](=[S:28])[S:19]2)=[C:10]([F:26])[CH:9]=1
Reactant: S=C(Cl)Cl
Reactant: O=[N+]([O-])c1cc(NC(=S)N2CCCCN2)c(F)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(N=c2sc(=S)n3n2CCCC3)c(F)cc1Cl
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
While maintaining a reaction temperature of -5° C., 7.75 g (0.0850 mole) of pyridine was added dropwise to a stirred solution of 9.0 g (0.028 mole) of N-(4-chloro-2-fluoro-5-nitrophenylaminothiocarbonyl)perhydropyridazine in 250 mL of methylene chloride. To this mixture was added dropwise 3.25 g (0.0282 mole) of thiophosgene. This mixture was stirred at -5° C. for 30 minutes, then was allowed to warm to room temperature and was stirred for approximately 18 hours. The reaction mixture was washed with an aqueous, 5% hydrochloric acid solution followed by an aqueous, saturated sodium chloride solution. The washed reaction mixture was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving a solid residue. The residue was purified by recrystallization to yield 4.5 g of 9-(4-chloro-2-fluoro-5-nitrophenyl)imino-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-thione, mp 171°-173° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[Cl-].[NH4+]>[Fe].O1CCCC1.O>[CH3:1][C:2]1([CH3:21])[C:6]2[C:7]([O:11][C:12]3[N:13]=[CH:14][C:15]([NH2:18])=[CH:16][N:17]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC1(C)COc2cccc(Oc3ncc([N+](=O)[O-])cn3)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COc2cccc(Oc3ncc(N)cn3)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.2 %

Procedure:
To a solution of 2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-nitropyrimidine (Intermediate 64, 1.257 g) in a mixture tetrahydrofuran/water (30 ml/15.00 ml) iron (1.222 g, 21.88 mmol) and ammonium chloride (1.170 g, 21.88 mmol) were added. The reaction mixture was stirred at room temperature for 48 hours. The catalyst was filtered off, and the filtrate was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue was recrystallized from ethyl acetate to afford the title compound (768 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].[Br:22]N1C(=O)CCC1=O>ClCCl>[Br:22][C:21]1[N:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[NH:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Solvent: ClCCl
Product: COC(=O)Nc1nc2ccc(Sc3ccccc3)cn2c1Br

Procedure:
A suspension of 2-(methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine (300 mg., 1 mmole) in 20 ml. of dichloromethane is treated with N-bromosuccinimide (220 mg., 1.24 mmole). The resultant solution is stirred at room temperature for 48 hours. The precipitate is collected by filtration, washed with dichloromethane and dried to yield 3-bromo-2-(methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine m.p. 165°-168° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:27]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:14]=3)=[CH:5][CH:4]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(Cn4ccnc4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.4 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)-phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the solution were added imidazole (49 mg) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 18 hours, and to the mixture was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[(imidazol-1-yl)methyl]phenyl]-3-(4-methylphenyl)-cinnamamide (Compound 65) (90 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][C:12]=2[CH:11]=[C:10]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:9]=1.[CH3:35][NH2:36]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH:36][CH3:35])[CH2:13][C:12]=2[CH:11]=[C:10]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(-c4ccccc4F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3ccccc3F)c2O1

Procedure:
The title compound was prepared (0.065 g, 83%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp 204-206° C.
Reaction SMILES: [NH:1]([S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=O)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].C[O-].[Na+]>CO>[NH:1]([S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:22][OH:23])=[O:18])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCS(=O)(=O)Nc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(CCCCCS(=O)(=O)Nc1ccccc1)NO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69 %

Procedure:
To a mixture of ethyl 6-(anilinosulfonyl)hexanoate (64b) and hydroxylamine hydrochloride (0.43 g, 6.2 mmol) in methanol (5 ml) the 3.43 N solution of sodium methylate (2.62 ml, 9.0 mmol) in methanol was added and the reaction was stirred at ambient temperature for 40 min. The reaction mixture was poured into saturated NaH2PO4 (15 ml) and extracted with ethyl acetate. The extract was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was evaporated, the residue was washed with diethyl ether and crystallised from ethyl acetate. The title compound (0.3 g, 69%) was obtained as white crystals, m.p. 97-98° C. 1H NMR (DMSO-d6, HMDSO), δ: 1.02-1.78 (m, 6H, CH2); 1.90 (br t, 2H, J=6.4 Hz, CH2); 3.06 (t, 2H, J=7.0 Hz, CH2); 6.94-7.60 (m, 5H, arom.); 8.66 (br s, 1H, NH); 9.76 (br s, 1H, NH); 10.36 (br s, 1H, OH). HPLC analysis on Symmetry C8 column: impurities 3.5% (column size 3.9×150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5), 30:70; detector UV 220 nm; flow rate 1.1 ml/min; sample concentration 0.4 mg/ml). Anal. Calcd for C12H18N2O4S, %: C, 50.33; H, 6.34; N, 9.78; S, 11.20. Found, %: C, 50.10; H, 6.22; N, 9.83; S, 11.10.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccnc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnc(Cl)c1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-chloropyridin-4-amine (1.0 g, 7.78 mmol, 1.00 equiv) and N,N-Diisopropylethylamine (1.0 mL) in dichloromethane (30.0 mL). This was followed by the addition of a solution of 3-(trifluoromethyl)benzoyl chloride (2.6 g, crude) in dichloromethane (5.0 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0˜1:2). This resulted in 2.2 g (92%) of N-(2-chloropyridin-4-yl)-3-(trifluoromethyl)benzamide as a light-yellow syrup
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[CH:12]=[C:13]([CH3:33])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1.ClC(Cl)(Cl)C[O:37][C:38](=O)[NH:39][C:40]1[N:41]([C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=2)[N:42]=[C:43]([C:45]([CH3:49])([CH3:48])[CH2:46][F:47])[CH:44]=1>C(#N)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:23]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[N:15]=[CH:16][C:11]([NH:10][C:38]([NH:39][C:40]3[N:41]([C:50]4[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=4)[N:42]=[C:43]([C:45]([CH3:49])([CH3:48])[CH2:46][F:47])[CH:44]=3)=[O:37])=[CH:12][C:13]=2[CH3:33])[CH2:22][CH2:21]1)=[O:24]
Reactant: Cc1ccc(-n2nc(C(C)(C)CF)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Cc1cc(N)cnc1N1CCN(C(=O)c2c(F)cccc2F)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(-n2nc(C(C)(C)CF)cc2NC(=O)Nc2cnc(N3CCN(C(=O)c4c(F)cccc4F)CC3)c(C)c2)cc1
Temperature: 80 °C
Reaction time: 96 h
Yield: 48 %

Procedure:
Add DIEA (2 equiv.) to a solution of [4-(5-amino-3-methyl-pyridin-2-yl)-piperazin-1-yl]-(2,6-difluoro-phenyl)-methanone (400 mg, 1.205 mmol) and [5-(2-fluoro-1,1-dimethyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (1 equiv) in acetonitrile (12 mL). Stir the mixture at 80° C. in a sealed tube. After 4 days, remove solvent. Dilute crude with DCM, extract with water, and dry over Na2SO4. Filter and remove solvent under reduced pressure. Subject solid to silica gel chromatography, eluting with hexane/acetone 3:1 to obtain 352 mg of 1-{6-[4-(2,6-difluoro-benzoyl)-piperazin-1-yl]-5-methyl-pyridin-3-yl}-3-[5-(2-fluoro-1,1-dimethyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-urea as a white solid (48% yield). ES+(m/z): 606 [M+1]
Reaction SMILES: [N+](C1C=CC(COC([NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]3[CH2:24][C@H:23]([S:25][C:26]4[C@H:27]([CH3:50])[C@@H:28]5[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]5[C:30]=4[C:31]([O:33]CC4C=CC([N+]([O-])=O)=CC=4)=[O:32])[CH2:22][N:21]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:19])[CH2:14]2)=O)=CC=1)([O-])=O.[ClH:66]>O1CCCC1.O>[ClH:66].[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]2[CH2:24][C@H:23]([S:25][C:26]3[C@H:27]([CH3:50])[C@@H:28]4[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]4[C:30]=3[C:31]([OH:33])=[O:32])[CH2:22][NH:21]2)=[O:19])[CH2:14]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC[C@H](N)C4)C3)[C@H](C)[C@H]12

Procedure:
1.0 g of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3S)-3-(4-nitrobenzyloxycarbonyl)aminopyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 30 ml of a 2:1 by volume mixture of tetrahydrofuran and water, after which 1.0 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through in at room temperature for 2 hours in the presence of 1.5 g of 10% w/w palladium-on-charcoal. The catalyst was filtered off, and the filtrate was washed with diethyl ether. The washed aqueous solution was concentrated by evaporation under reduced pressure, and the residue was purified by reverse phase column chromatography through 19 ml of Cosmo Sil 75C18 -PREP (a trade mark for a product of Nacalai Tesque), using water as the eluent. Those fractions containing the title compound were combined, concentrated by evaporation under reduced pressure and lyophilized to give 169 mg of the title compound as a powder.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[CH:22][C:23]([O:25][C@H:26]5[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]5)=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:38])C=CC=CC=1>CO>[O:38]=[C:9]1[C:10]2([C:20]3[CH:21]=[CH:22][C:23]([O:25][C@H:26]4[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]4)=[CH:24][C:19]=3[O:18][CH2:17]2)[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc3c(c2)OCC32C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc3c(c2)OCC32C(=O)Nc3ccccc32)C1
Temperature: 60 °C
Reaction time: 48 h
Yield: 69.6 %

Procedure:
A suspension of tert-butyl (3S)-3-{[1′-(diphenylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl]oxy}pyrrolidine-1-carboxylate (0.50 g, 0.85 mmol) in methanol (20 mL) was degassed by bubbling through nitrogen for one hour before palladium hydroxide on carbon (20%, 0.084 g) was added. The mixture was stirred under 120 psi hydrogen at 60° C. for 48 h. The mixture was filtered through a pad of celite, the filtrate was concentrated in vacuo. The obtained residue was recrystallized from ethyl acetate and hexanes to afford tert-butyl (3S)-3-[(2′-oxo-1,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)oxy]pyrrolidine-1-carboxylate (0.25 g, 70%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.01 (br s, 1H), 7.29-7.09 (m, 1H), 7.12 (d, J=7.0 Hz, 1H), 7.02 (dd, J=7.5, 0.8 Hz, 1H), 6.92 (d, J=7.7 Hz, 1H), 6.66 (d, J=8.3 Hz, 1H), 6.47 (d, J=2.1 Hz, 1H), 6.33 (dd, J=8.3, 2.1 Hz, 1H), 4.96 (d, J=9.1 Hz, 1H), 4.81 (s, 1H), 4.69 (d, J=9.1 Hz, 1H), 3.64-3.37 (m, 4H), 2.22-1.96 (m, 2H), 1.45 (s, 9H); MS (ES+) m/z 445.0 (M+23).
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-:13].[K+].[K+]>O>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH:12]=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=CN[C@@H]1C[C@H]1c1ccccc1
Reaction time: 8 h
Yield: 91 %

Procedure:
trans-2-Phenylcyclopropylamine hydrochloride (2.74 g, 16.15 mmol) was dissolved in water (50 ml), and the solution was alkalified with potassium carbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. To the residue was added formic acid (18.5 ml), and the mixture was ice-cooled, and acetic anhydride (7 ml) was added dropwise with stirring. The reaction mixture was stood at room temperature overnight, ice-cooled again. Water (7 ml) was added, and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with 5% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (2.36 g, yield 91%) as a pale-bistered solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.O[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:24]([O:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][C:17]([O:13][C:12]([C:9]2[CH:8]=[CH:7][C:6]3[CH2:5][CH2:4][CH2:3][C:2]([CH3:15])([CH3:1])[C:11]=3[CH:10]=2)=[O:14])=[CH:18][CH:19]=1)[CH3:25]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC1(C)CCCc2ccc(C(=O)O)cc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3)cc1

Procedure:
A solution of 220.7 mg (1.0804 mmol) of 8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthoic acid, 180.6 mg (1.0868 mmol) of ethyl 4-hydroxybenzoate, 227.3 mg (1.1034 mmol) of 1,3-dicyclohexylcarbodiimide and 22.9 mg (0.1874 mmol) of 4-dimethylaminopyridine in 15 ml of methylene chloride was stirred at room temperature for 18 h. The reaction mixture was then filtered and the residue washed with 10 ml of methylene chloride. The filtrate was concentrated in-vacuo and the resultant crude product purified by flash chromatography (silica; 5% ethyl acetate in hexanes) to give the title compound as a colorless oil. PMR (CDCl3): δ 1.35 (6H, s), 1.42 (3H, t, J~7.2 Hz), 1.68-1.76 (2H, m), 1.80-1.92 (2H, m), 2.85 (2H, t, J~6.1 Hz), 4.40 (2H, q, J~7.2 Hz), 7.18 (1H, d, J~ 8.0 Hz), 7.31 (2H, d, J~8.7 Hz), 7.89 (1H, dd, J~8.0 Hz, 1.6 Hz), 8.11-8.22 (3H, m).