Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14](O)=O)[CH2:9][C:10](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>C(O)CO.O>[NH:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:24]=[C:10]1[CH2:9][N:8]([CH2:13][C:14]1[NH:24][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Reactant: Nc1ccccc1N
Solvent: OCCO
Solvent: O
Product: c1ccc(CN(Cc2nc3ccccc3[nH]2)Cc2nc3ccccc3[nH]2)cc1
Temperature: 190 °C
Reaction time: 4 h

Procedure:
A mixture of 4.00 g (17.9 mmol) N-benzyliminodiacetic acid and 3.86 g (35.8 mmol) o-phenylene diamine in 30 ml ethylene glycol was stirred at 190° C. for 4 hours. The water produced during was distilled off continuously. At the end of the reaction, the reaction mixture was allowed to cool down to room temperature and then poured in 150 ml water. The obtained slurry was triturated for 30 min, filtered, washed with water (3×30 ml) and dried at 60° C. under reduced pressure for 48 hours. Yield 4.94 g (75.0%). 1H NMR (250 MHz, DMSO-d6), δ 3.72 (s, 2H), 3.92 (s, 4H), 7.13–7.57 (m, 13H), 12.37 (Br. s, 2H). +CI MS (m/z): [368]. (+CI-MS is Positive Chemical Ionisation Mass Spectroscopy).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:16][CH:15]=[C:14]([Br:31])[CH:13]=2.[Cl:32][CH2:33][C:34](Cl)=O>ClCCl>[Br:31][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:19]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:34]([CH2:33][Cl:32])=[N:8][C:9]=3[CH:10]=[N:11][C:12]=2[CH:13]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2cc(Br)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3cc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
Triethylamine (26.7 g, 264 mmol) was added to a solution of tert-butyl 3-[(3-amino-7-bromoquinolin-4-yl)amino]propylcarbamate (52.17 g, 132.0 mmol) in dichloromethane (370 mL). Chloroacetyl chloride (15.65 g, 138.6 mmol) was added, and the reaction was stirred overnight at ambient temperature. The solvent was removed under reduced pressure, and the residue was stirred in ethanol (1 L) overnight at ambient temperature. The solvent was removed under reduced pressure, and the residue was dissolved in chloroform. The resulting solution was washed twice with water, concentrated under reduced pressure, and dried under high vacuum to provide 41.63 g of tert-butyl 3-[7-bromo-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:28]([O:32][C:33]([NH:35][CH2:36][C:37]([OH:39])=O)=[O:34])([CH3:31])([CH3:30])[CH3:29].CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[C:28]([O:32][C:33](=[O:34])[NH:35][CH2:36][C:37](=[O:39])[N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)CNC(=O)OC(C)(C)C)c1ccncc1
Reaction time: 1 h

Procedure:
A solution of 1.1 eq. of 4-(methylamino)pyridine (180, Aldrich, 19,551-0) in anhydrous DMF was stirred under an atmosphere of argon as 1.1 eq. of HOBT and 2.0 eq of DIPEA were added followed by 1.0 eq of N-(tert-butoxycarbonyl)glycine (Bachem, A-1730). The mixture was stirred for 1 hr, cooled in an ice-bath and 1.1 eq. of EDC.HCl was added. The reaction was stirred and allowed to reach rt overnight. Water was added to the reaction mixture and the solvents were evaporated under high vacuum. The residue was dissolved in ethyl acetate, washed with 0.15 M citric acid, sat. aq. NaHCO3, brine and dried over anhydrous Na2SO4. To afford 181.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[C:30](O)(=[O:32])[CH3:31].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[C:30]([N:26]1[CH2:27][CH2:28][CH:23]([N:22]([CH3:29])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([Br:1])[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:24][CH2:25]1)(=[O:32])[CH3:31]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Reactant: CC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Product: CC(=O)N1CCC(N(C)c2cc(Br)cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c2C)CC1
Reaction time: 8 h
Yield: 66.7 %

Procedure:
The 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(piperidine-4-yl)amino)benzamide (0.2 g, 0.447 mmol) dissolved in DMSO (2 mL) and acetic acid (0.054 g, 0.896 mmol) were added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (0.342 g, 0.672 mmol) was added to it and stirring was continued for overnight. After completion, reaction mass was poured into ice, and extracted using 10% MeOH/DCM. Combined organic layers were dried, concentrated to provide crude material, which then purified with column chromatography using silica (100-200 mesh size) to afford the desired compound (0.15 g, 17%). LCMS: 503.20 (M+1)+; HPLC: 96.06% (@ 254 nm) (Rt; 5.143; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.48 (s, 1H), 8.21 (t, 1H, J=4.8 Hz), 7.23 (d, 1H, J=1.6 Hz), 7.04 (d, 1H, J=1.6 Hz), 5.85 (s, 1H), 4.32 (d, 1H, J=12.4 Hz), 4.23 (d, 2H, J=4.8 Hz), 3.77 (d, 1H, J=13.2 Hz), 2.98 (t, 2H, J=11.2 Hz), 2.54 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H), 2.10 (s, 3H), 1.97 (s, 3H), 1.53-1.60 (m, 4H), 1.38-1.41 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:22]1[C:10]2[CH2:9][CH2:8][C:7]3[C:12]([C:11]1=2)=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc2c(c1)C=CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)C1=C(CC2)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
A solution of 7-nitro-3,4-dihydronaphthalene (9.18 g; 0.052 mol) (from Preparation 2) in CH2Cl2 (600 ml) was cooled to 0° C. and treated with m-CPBA, 57-85%, (13.86 g, approx. 0.056 mol, approx. 1.1 equiv). The reaction mixture was allowed to stir for 48 h, slowly warming to room temperature. The mixture was treated with aqueous NaHCO3 (300 ml) and the organic layer was separated. The organic layer was extracted with additional aqueous NaHCO3, washed with aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure to give 1,2-epoxy-7-nitro-3,4-dihydronaphthalene (9.94, 100%) as a white solid which was used in the next step without further purification. Rf (silica gel): 0.56(70% hexane: 30% EtOAc); 1H NMR (300 MHZ, CDCl3) 8.24 (s, 1H), 8.08 (dd, J=1.8 and 8.1 H 1H), 7.23 (d, J=8.1 Hz, 1H), 3.92 (d, J=4.2 Hz, 1H), 3.77 (s, 1H), 2.87-2.62 (m, 2H), 2.47 (dd, J=6.6 and 14.4 Hz, 1H), 1.78 (dt, J=5.7 and 14.1 Hz, 1H), 13C NMR (75 MHZ, CDCl3) 146.5, 144.7, 134.5, 129.4, 124.4, 123.4, 54.7, 51.8, 24.5, 21.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[C:25](=[O:27])=[O:26].[OH-].[Na+]>CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.CCCCCC.O.O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:25]([OH:27])=[O:26])=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: FC(F)(F)c1ccn(-c2ncccc2Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCc1ccccc1
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 15 g of 3-chloro-2-(3-trifluoromethyl-1H-pyrazol-1-yl)pyridine and 150 ml of tetrahydrofuran was added dropwise 39 ml of a 2.0 mol/L lithium diisopropylamide solution in heptane/tetrahydrofuran/ethylbenzene at −78° C., and then stirred at −78° C. for 15 minutes. Carbon dioxide was introduced into the mixture at such a rate that the inner temperature was retained at −60° C. or lower. After the mixture turned yellow, it was further stirred at −78° C. for 10 minutes. After the temperature of the reaction mixture was allowed to rise to room temperature, 200 ml of water and 200 ml of hexane were poured. The aqueous layer was adjusted to pH 10-12 by an addition of a 2N aqueous sodium hydroxide solution and then layers were separated. The organic layer was extracted with a 0.5N aqueous sodium hydroxide solution. The aqueous layers were combined, washed with diethyl ether, adjusted to around pH 3 by an addition of 2N hydrochloric acid, and then extracted with methyl tert-butyl ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 16.08 g of 1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazole-5-carboxylic acid of the formula:
Reaction SMILES: O.[NH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+:11]>C1(C)C=CC=CC=1>[NH2:2][C:3]1[CH:4]=[C:5]([O-:9])[CH:6]=[CH:7][CH:8]=1.[Na+:11]
Reactant: Nc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cccc([O-])c1

Procedure:
Another three-necked flask equipped with a Dean-Stark water separator, condenser, nitrogen inlet and outlet, thermometer and a mechanical stirrer is charged with 261.91 grams (2.4 moles) of meta-aminophenol, 192 grams (2.4 moles) of 50% aqueous sodium hydroxide and 720 milliliters of toluene. The mixture is heated at 100°-140° C. for three hours to remove all of the water and toluene and provide sodium meta-aminophenolate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(OCC)(=O)C.Cl>O1CCCC1.O>[CH2:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1/[CH:14]=[CH:13]/[CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCc1ccccc1C=CCCCC(=O)OC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCc1ccccc1/C=C/CCCCO

Procedure:
2.8 g of lithiumaluminium hydride are added in portions, over a period of approximately one hour, to a solution, stirred under a nitrogen atmosphere, of 34.4 g of 6-(2-nonylphenyl)-5-hexenoic acid methyl ester (cf. EP-OL 0 123 543) in 300 ml of absolute tetrahydrofuran. After a further 10 minutes 30 ml of ethyl acetate and then 30 ml of water are added dropwise. The reaction mixture is acidified by the addition of 1N hydrochloric acid and extracted repeatedly with ethyl acetate. After the combined organic phases have been dried and concentrated by evaporation, the crude product that remains is purified by chromatography on silica gel with dichloromethane to yield the title compound in the form of a yellowish oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:17])[C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>>[O:28]1[CH2:27][CH:26]1[CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:17])[C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: Cn1c(C(F)(F)F)cnc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1c(C(F)(F)F)cnc1-c1ccc(OCC2CO2)cc1

Procedure:
25 g of the 2-(4-hydroxyphenyl)-1-methyl-5-(trifluoromethyl)-1H-imidazole obtained according to Example (20c) and 25 g of anhydrous potassium carbonate are suspended in 250 ml of epichlorohydrin and the mixture is heated under reflux for 10 minutes. The mixture is subsequently filtered and excess epichlorohydrin is removed in a rotary evaporator. The residue is dissolved in ether, the solution is stirred with silica gel and active carbon, the solution is filtered and hexane is added until crystallisation begins. After filtration, 2-[4-(2,3-epoxypropoxy)-phenyl]-1-methyl-5-(trifluoromethyl)-1H-imidazole is obtained in the form of a colourless crystallisate having a melting point of 99°-101°.
Reaction SMILES: Br.[NH2:2][C@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][C@H:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[NH2:2][C@H:3]1[C:9](=[O:10])[N:8]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][C@H:4]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Reactant: CCOC(=O)CBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)[C@H](N)[C@H](c2ccccc2)Sc2ccccc21
Temperature: 10 °C
Reaction time: 2 h

Procedure:
With 40 ml of dimethylformamide is mixed 3 g of cis-3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)- one hydrobromide in the same manner as in (iv) of Example 1, and 0.72 g of 60% sodium hydride is added to the mixture under ice-cooling. After the temperature is gradually elevated to room temperature, the mixture is stirred for 2 hours. After the temperature of the reaction mixture is again cooled to about 10° C., 5 ml of a dimethylformamide solution containing 1.1 ml of ethyl bromoacetate is added dropwise thereto. Then, the reaction temperature is elevated to room temperature, and the reaction mixture is stirred for 6 hours, followed by concentration under reduced pressure. By adding ice water and chloroform to the residue, the organic substance is extracted. The chloroform layer is washed with water and dried. Thereafter, the solvent is distilled off under reduced pressure. The purification of the obtained residue by silica gel chromatography gives 3.0 g of ethyl cis-3-amino-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:13]3[C:14](=[O:20])[CH:15](I)[CH2:16][CH2:17][CH2:18][C@@H:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[P:21]([O:28]CC)([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:13]3[C:14](=[O:20])[CH:15]([P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][C@@H:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C1C(I)CCC[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Product: CCOP(=O)(OCC)C1CCC[C@@H]2CCC[C@H](c3ccc(F)cc3)N2C1=O
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of (4R*,10aS*)-4-(4-fluorophenyl)-7-iodooctahydropyrido[1,2-a]azepin-6-one (208 mg) with triethyl phosphite (2 mL) was stirred at 120° C. for 1.5 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure to obtain 213 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1.N1C=CC=CC=1>O>[C:20](/[CH:19]=[CH:1]/[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])([OH:22])=[O:21]
Reactant: COC(=O)c1cc(C=O)cc(-n2cccc2)c1
Reactant: O=C(O)CC(=O)O
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC(=O)c1cc(/C=C/C(=O)O)cc(-n2cccc2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A mixture of methyl 3-formyl-5-(pyrrol-1-yl)benzoate (3.0 g), malonic acid (2.73 g), piperidine (0.3 ml) and pyridine (30 ml) was stirred for 1 hour at 80° C. After being cooled to room temperature, the reaction mixture was poured into water. The solution was acidified to pH 1 and extracted with ethyl acetate. The extract was washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with the mixture of chloroform and methanol (15:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-((E)-2-carboxyethenyl)-5-(pyrrol-1-yl)benzoate (2.43 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:31]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(N(Cc4ccccc4)Cc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc(C#Cc2ccc(C3(N(Cc4ccccc4)Cc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-dibenzylaminocyclopropyl)-phenylethynyl]-benzoate (Compound 113, 48.0 mg, 0.10 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 42.0 mg (93%) of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[O:19])=[CH:11][CH:10]=2)[C:7]2[CH:31]=[C:32]([Cl:39])[C:33]([C:35]([F:38])([F:37])[F:36])=[CH:34][C:6]=2[N:5]=1)[CH3:3].[C:40](Cl)(=[O:42])[CH3:41].O>C(Cl)Cl>[Cl:39][C:32]1[C:33]([C:35]([F:36])([F:38])[F:37])=[CH:34][C:6]2[N:5]=[C:4]([CH:2]([NH:1][C:40](=[O:42])[CH3:41])[CH3:3])[N:8]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)(=[O:23])=[O:22])=[O:19])=[CH:11][CH:10]=3)[C:7]=2[CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(C(C)N)nc4cc(C(F)(F)F)c(Cl)cc43)cc2)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC(C)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.8 %

Procedure:
A mixture of N-{[(2-{4-[2-(1-aminoethyl)-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (step 3, 100 mg, 0.17 mmol) in CH2Cl2 (12 ml) was added acetyl chloride (0.01 ml, 0.18 mmol) and stirred at room temperature for 5 h. The mixture was added water (10 ml) and extracted with CH2Cl2 (20 ml). The organic layer was washed with brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with CH2Cl2/MeOH (10:1) to afford 59 mg (53%) of the title compound as white solids.
Reaction SMILES: C[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18]C(=O)OC(C)(C)C)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[ClH:26].O1CCOC[CH2:28]1>CO>[ClH:26].[CH3:28][N:12]([C:3]1[CH:2]=[N:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=1)[C@H:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[NH2:18]
Reactant: C1COCCO1
Reactant: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-{[3-methyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (480 mg, 1.332 mmol) in methanol (5 ml) was added HCl in 1,4-dioxane (4 M, 3.33 ml, 13.32 mmol). The reaction was stirred at room temperature overnight and then concentrated in vacuo, azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([OH:8])=[N:6][CH:7]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[N:6]([CH3:10])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(I)cnc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(I)cn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a stirred suspension of 5-iodo-3-methylpyridin-2-ol (Step 23.1) (1.67 g, 7.11 mmol) and K2CO3 (1.964 g, 14.21 mmol) in DMF (20 mL) was added MeI (0.666 mL, 10.66 mmol) at rt under Ar. The reaction mixture was stirred 1 hr at rt, concentrated, diluted with water, and extracted with EtOAc. The organic layers were combined and washed once with water, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 50-65) to afford the title product (1.40 g, 5.62 mmol, 79% yield) as a brown solid. tR: 3.31 min (HPLC 1); tR: 0.71 min (LC-MS 2); ESI-MS: 250 [M+H]+ (LC-MS 2); Rf=0.31 (hexane/EtOAc 1:1).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[C:22]([CH3:27])[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.O>[I:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)=[N:13][CH:14]=2)=[O:28])=[CH:21][C:22]=1[CH3:27]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(I)c(C)c3)cn2)CC1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NC(=O)c2ccc(N3CCC(C(=O)O)CC3)nc2)ccc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.6 %

Procedure:
A solution of 5′-(4-iodo-3-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester (200 mg, 0.39 mmol) in THF (10 mL) and H2O (2 mL) was treated with LiOH monohydrate (33 mg, 0.78 mmol). The mixture was stirred at room temperature for 24 h and then partitioned between EtOAc and H2O. The acidity of the water layer was adjusted to pH 5 by the addition of aqueous conc. HCl and solid Na2CO3. The water layer was separated and extracted once more with EtOAc. The EtOAc layers were combined, dried over Na2SO4, filtered and concentrated. The solid residue was suspended in CH2Cl2 then filtered and dried to afford the product (70 mg, Yield: 38%). HRMS m/z calcd for C19H20N3O3I [M+H]+: 466.0622. Found: 466.0619.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:12]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([NH:19][C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1nc2cccc(Cl)n2n1
Reactant: NC1CCCCCC1
Product: Nc1nc2cccc(NC3CCCCCC3)n2n1
Temperature: 180 °C
Yield: 59 %

Procedure:
The title compound was prepared following procedure described for intermediate A9, but starting from 5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A4), 2.88 g; 17.1 mmol; 1.0 eq.) and cycloheptylamine (14 mL) and heated at 180° C. for 1 h under microwave radiation to give the title compound as a beige oil (2.48 g; 59%). HPLC, Rt: 2.90 min. (purity 97.2%). LC/MS, M+(ESI): 292.9.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([CH3:12])=[C:14]([C:20]([F:21])([F:22])[F:23])[CH:15]=1)=[O:9]
Reactant: Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: Cc1ccc(NC(=O)c2cc(Cl)ccc2O)cc1C(F)(F)F
Yield: 80.2 %

Procedure:
Using 5-chlorosalicylic acid and 4-methyl-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.