Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:13])=O>>[CH:1]1([O:6][CH2:7][C:8]([Cl:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)COC1CCCC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)COC1CCCC1
Temperature: 70 °C

Procedure:
The product from Example 133B (0.33 g, 2.29 mmol) was taken up in thionyl chloride (4 mL, 54.8 mmol) and heated at 70° C. for 1 hour. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was taken up in CH2Cl2 (5 mL) and concentrated again to remove excess thionyl chloride. This was repeated twice more. The residue was dissolved in CH2Cl2 (2.5 mL) to provide a solution of the title compound that was used for the next step.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:35]([N:38]1[CH2:43][CH2:42][NH:41][C@H:40]([CH3:44])[CH2:39]1)([CH3:37])[CH3:36].C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:41]4[CH2:42][CH2:43][N:38]([CH:35]([CH3:37])[CH3:36])[CH2:39][C@H:40]4[CH3:44])[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: CC(C)N1CCN[C@H](C)C1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)C[C@H]4C)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (40.0 mg, 0.077 mmol) was added (R)-1-isopropyl-3-methylpiperazine (33.1 mg, 0.232 mmol) in 1,4-dioxane (1 mL) and triethylamine (15.7 mg, 22 μL, 0.155 mmol). The reaction mixture was stirred at 60° C. for 4 d, after which the reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C33H41ClN5O3S (M+H+): 622.3; Found: 622.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([C@H:13]1[CH2:15][C@@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:4].[CH:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:23][C:2]([F:1])([F:22])[C:3]([N:5]([CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:24][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)[CH2:11][CH2:12]1)[C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4]
Reactant: O=C(N(CC1CCNCC1)[C@H]1C[C@@H]1c1ccccc1)C(F)(F)F
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)c1ccc(CN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((1S,2R)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (243 mg, 0.745 mmol) in 1,2-dichloroethane (DCE) (4 mL) were added 4-formylbenzoic acid (134 mg, 0.894 mmol) and sodium triacetoxyborohydride (252 mg, 1.191 mmol), and the mixture was stirred at room temperature for 18 h. The reaction was quenched with water (4 mL) and extracted with CH2Cl2 (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 5% MeOH/EtOAc) to give 180 mg of product as pale yellow solid. MS: (M+H)+=461.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.32 (m, 2H), 1.35-1.47 (m, 1H), 1.53-1.82 (m, 3H), 1.88-2.05 (m, 2H), 2.81 (br. s., 2H), 3.09-3.22 (m, 2H), 3.26-3.41 (m, 2H), 3.27-3.43 (m, 2H), 7.09-7.35 (m, 5H), 7.39-7.50 (m, 2H), 7.86-7.94 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[CH:6]([C:10]#[N:11])[CH2:5]2.ClCCl.C(N(CC)CC)C.[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25]>O>[CH3:22][N:23]([CH3:28])[S:24](=[O:26])(=[O:25])[O:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[CH:6]([C:10]#[N:11])[CH2:5]2
Reactant: CN(C)S(=O)(=O)Cl
Reactant: N#CC1Cc2cc(O)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN(C)S(=O)(=O)Oc1ccc2c(c1)CC2C#N
Reaction time: 96 h

Procedure:
2 g (13.8 mmoles) of 3-hydroxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile are mixed into 40 mL of dichloromethane, 3.9 g (2 equivalents) of triethylamine and 1.63 mL (1. 1 equivalents) of dimethylsulphamoyl chloride. Stirring is carried out at 25° C. for 4 days. The reaction mixture is poured into water, extracted with dichloromethane, dried over MgSO4, filtered and evaporated to obtain an oil. This residue is purified by flash chromatography over 70 g of silica (eluant: dichloromethane/toluene: 50/50). The expected product is obtained in the form of a white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl[CH2:15][CH:16]([OH:25])[CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>C(O)C.O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:15][CH:16]([OH:25])[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OC(CCl)CCc1cccnc1
Reactant: Oc1ccc2c(c1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC(CCc1cccnc1)COc1ccc2c(c1)OCCO2
Yield: 33.7 %

Procedure:
A solution of benzo-1,4-dioxan-6-ol (0.15 g; Tetrahedron, 1995, 3197) in ethanol (20 ml) at room temperature was treated with a solution of sodium hydroxide (0.044 g) in water (5 ml) and was then heated at reflux. A solution of (±)-α-(chloromethyl)-3-pyridinepropanol (1.0 g) in ethanol (5 ml) was added dropwise to the latter and the resulting mixture heated at reflux for 1 hour. The reaction mixture was cooled and then water was added. The organic component was extracted with dichloromethane, the combined extracts dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate to give an oil (0.100 g).
Reaction SMILES: O.[OH-].[Na+].O.Cl.[NH2:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][SH:9].Cl[C:14](OC1C=CC=CC=1)=[O:15]>C1(C)C=CC=CC=1>[O:15]=[C:14]1[NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][S:9]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1N[C@H](C(=O)O)CS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A aqueous solution comprising 0.88 liter of water and 184.0 g of sodium hydroxide was dissolved 175.6 g of L-cysteine monohydrochloride monohydrate under ice-cooling, 0.35 liter of a toluene solution containing 313.2 g of phenyl chloroformate was added to the above solution within a range not exceeding 30° C. After stirring the mixture at room temperature for 2 hours, it was allowed to stand and the liquids were separated. The aqueous layer was washed with 0.35 liter of toluene, the layers were separated, and the aqueous layer was concentrated to give 139.84 g of (4R)-2-oxothiazolidin-4-carboxylic acid as colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Cl.O1CCOCC1>CC(O)=O.[Ni]>[NH2:10][CH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[CH:3][C:4]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1cc(CN2CCOCC2)c(C#N)c(=O)[nH]1
Agent: [Ni]
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1cc(CN2CCOCC2)c(CN)c(=O)[nH]1
Yield: 95.3 %

Procedure:
A clear solution of 6-methyl-4-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.60 g, 2.57 mmol) in HOAc (20 mL) was treated on an H-Cube apparatus (50 psi, 60° C., 1 mL/min., Raney Nickel cartridge) for 18 hr overnight. LCMS showed that the reaction was complete. The reaction was evaporated to dryness, taken up in a small volume of MeOH and treated with 4 N HCl in dioxane (5 mL, 20.00 mmol). The mixture was evaporated to dryness under vacuum (began to ppt. out during evaporation), triturated with Et2O, filtered and dried under vacuum to give the product 3-(aminomethyl)-6-methyl-4-(4-morpholinylmethyl)-2(1H)-pyridinone (0.76 g, 2.450 mmol, 95% yield) as a light grey solid. 1H NMR (400 MHz, DMSO-d6) δ 6.39 (s, 1H), 4.28 (s, 2H), 3.99 (s, 2H), 3.87 (br. s., 4H), 3.27 (br. s., 4H), 2.22 (s, 3H). MS(ES)+m/e 238.0 [M+H]+ (weak), 221.3 [M+H]+—NH3 (strong).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][O:20][CH2:19][CH2:18][NH:17]1)=[O:15])[CH3:12].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][O:20][CH2:19][CH2:18][N:17]1[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1COCCN1c1ccc(N)cc1

Procedure:
4-Fluoronitrobenzene and morpholine-3-carboxylic acid ethyl ester were allowed to undergo the reaction at 100° C. in DMSO in the presence of diisopropylethylamine, and then the resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 4-(4-aminophenyl)morpholine-3-carboxylic acid ethyl ester. ESI: 251.
Reaction SMILES: [Mg].Br[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH2:4][CH3:5].[C:14]([C:22]1[CH:39]=[CH:38][C:25]([N:26]([CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:24][CH:23]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1.O>[CH2:36]([N:33]([CH2:34][CH3:35])[CH2:32][CH2:31][N:26]([S:27]([CH3:30])(=[O:28])=[O:29])[C:25]1[CH:38]=[CH:39][C:22]([C:14]([OH:21])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:3]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH2:4][CH3:5])=[CH:23][CH:24]=1)[CH3:37]
Reactant: CCN(CC)CCN(c1ccc(C(=O)c2ccccc2)cc1)S(C)(=O)=O
Reactant: CCC(Br)c1ccc(OC)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(c1ccc(OC)cc1)C(O)(c1ccccc1)c1ccc(N(CCN(CC)CC)S(C)(=O)=O)cc1
Reaction time: 16 h

Procedure:
Magnesium turnings (10.0 g., 0.411 mole) are employed to prepare the Grignard reagent from 0.333 mole of p-(1-bromopropyl)anisole in 500 ml. of tetrahydrofuran which has been previously dried by distillation for lithium aluminum hydride. The Grignard reaction is initiated by adding a small portion of the p-(1-bromopropyl)anisole to a small portion of the magnesium turnings in a beaker and when the reaction commences as evidenced by a rise in temperature of the mixture it is transferred to the main reaction flask containing the remaining magnesium turnings and tetrahydrofuran solvent. A nitrogen atmosphere is maintained over the reaction mixture which is cooled at 0°-5°C. The main portion of the p-(1-bromopropyl)anisole dissolved in 700 ml. of similarly dried tetrahydrofuran is then added dropwise to the reaction flask during a period of 30 min. The mixture is then agitated overnight (16 hr.) with cooling and then employed for reaction in the same flask with the substituted benzoylmethanesulfonanilide reactant. 4'-Benzoyl-N-(2-diethylaminoethyl)methanesulfonanilide (25.0 g., 0.0667 mole) dissolved in 200 ml. of dried tetrahydrofuran is added dropwise during 45 min. to the reaction mixture with cooling and stirring which is continued for 24 hr. after the material has been added. The reaction product is then recovered by removing the excess magnesium by filtration and treatment of the filtrate first with water (18.0 g., 1.00 mole) and then with a solution of 50 g. of ammonium chloride in 500 ml. of water. Stirring is continued for 1/2 hr. and the organic layer is then separated and concentrated under reduced pressure. The residual oil is dissolved in ether, the solution washed first with water, the with saturated sodium chloride, and dried over magnesium sulfate. Excess hydrogen chloride gas is then introduced into the solution with stirring and the precipitated hydrochloride salt is collected on a filter and washed with ether; yield 35.2 g. (66%), m.p. 75°-140°C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:17][C:18](I)([F:20])[F:19].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:18]([F:20])([F:19])[F:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)I
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCN(Cc2ccccc2)CC1C(F)(F)F
Reaction time: 0.25 h

Procedure:
1-benzylpiperidin-4-one (12 g, 63.5 mmole) was added to the stirred suspension of sodium hydride (3.0 g, 127.0 mmole) in tetrahydrofuran (100 ml) at −5° C. The reaction mixture was stirred for 15 min, trifluoromethyl iodide (25 g, 127.0 mmole) was bubbled over a period of 4 hr at −5° C. and stirring continued for 1 hr. The resulting mixture was stirred for 16 hr at ambient temperature, saturated sodium sulphate solution (20 ml) was added and diluted with ethyl acetate (200 ml). Ethyl acetate layer was separated, dried (Na2SO4) and concentrated to furnish crude product, which was purified through column chromatography. Elute from hexane afforded l-benzyl-3-trifluoromethylpiperidin-4-one as oil and 20% ethyl acetate in hexane gave the unreacted 1-benzylpiperidin-4-one (9.5 g). Yield 2.1 g (44%, based on reacted 1-benzyl piperidin-4-one), C13H14F3NO, m/z 258 (M+1), PMR (CDCl3): 2.54 (2H, m, H6), 3.02 (2H, m, H2), 3.6 (3H, m, H3 & H5), 4.36 (2H, s, N—CH2), 7.28 (5H, m, ArH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:14]O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.N>[Zn].C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: ON=C(c1ccccn1)c1ccccn1
Agent: N
Agent: [Zn]
Solvent: CCO
Product: NC(c1ccccn1)c1ccccn1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To pyridyl ketone oxime (3 g, 15.1 mmol) was added ethanol (15 ml), concentrated ammonia solution (15 mL) and NH4OAc (1.21 g, 15.8 mmol). The solution was warmed until reflux. To this solution was added 4.64 g Zn in small portions. After the addition of all Zn, the mixture was refluxed for 1 h. and allowed to cool to ambient temperature. The solution was filtered and water (15 ml) was added. Solid NaOH was added until PH>>10 and the solution was extracted with CH2Cl2 (3×20 ml). The organic layers were dried over Na2SO4 and evaporated until dryness. Bis(pyridin-2-yl)methylamine (2.39 g, 12.9 mmol) was obtained as a colourless oil in 86% yield, showing the following analytical characteristics:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=1)[CH:12]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=1)[CH2:12][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)cc1CN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyrrolidine (4 mL, 48.5 mmol) was added to a solution of 5-chloro-2-nitrobenzaldehyde (6 g, 32.2 mmol) in dichloromethane (150 mL) and the solution was stirred at room temperature for 30 minutes. The solution was then cooled in ice, and sodium triacetoxyborohydride (10.3 g, 48.5 mmol) was added portionwise. Once addition was complete, the reaction was stirred at room temperature for 4 hours. The reaction was washed with sodium carbonate solution, dried over MgSO4 and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using ethyl acetate:pentane (86:14) to afford the title compound as a pale yellow solid, 6.3 g.
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:16][C@H:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[NH:10][C:7]1[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=1)=[O:24]
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 60 mg, 0.21 mmol) in DMF (3 ml) was added 2-(trifluoromethyl)benzoic acid (CAS number 433-97-6; 60 mg, 0.21 mmol), TBTU (0.082 g, 0.25 mmol) and DIPEA (0.1 g, 0.84 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction was diluted with water (25 ml) and extracted with ethyl acetate (30 ml×3). The organics were washed with water (50 ml), brine (25 ml), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-45% ethyl acetate/n-hexane) to afford the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=3)[C:33]2=[O:47])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:29]=[C:22]3[CH2:23][N:24]([CH3:28])[C:25](=[O:27])[CH2:26][N:21]3[N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[C:42]([C:37]1[CH:38]=[C:39]2[C:34](=[C:35]([F:46])[CH:36]=1)[C:33](=[O:47])[N:32]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:29]=[C:22]5[CH2:23][N:24]([CH3:28])[C:25](=[O:27])[CH2:26][N:21]5[N:20]=4)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:41]=[CH:40]2)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CC(=O)N(C)C4)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2cc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)nn2CC1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a solution of 146f (110 mg, 0.172 mmol) in THF/i-propanol/water (4/2/2 mL) was added lithium hydroxide (21 mg, 0.86 mmol). The mixture was stirred at 30° C. for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was dried and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 146 as a white solid (45 mg, 44%). MS-ESI: [M+H]+ 599.2. 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.41 (s, 1H), 8.08 (d, J=2.5 Hz, 1H), 7.91 (d, J=1.5 Hz, 1H), 7.78 (d, J=13.0 Hz, 1H), 7.51 (d, J=5.0 Hz, 1H), 7.42 (d, J=2.5 Hz, 1H), 6.08 (s, 1H), 4.91-4.89 (m, 1H), 4.62 (s, 2H), 4.57 (s, 2H), 4.45-4.43 (m, 2H), 3.61 (s, 3H), 2.98 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]C(C)(C)C)=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.[NH2:29][C:30]1[N:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][N:39]([C:42](=[O:44])[CH3:43])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[C:42]([N:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:15](=[O:17])[CH2:14][C:11]3[CH:12]=[N:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[N:9][CH:10]=3)=[N:35][CH:34]=2)[CH2:41][CH2:40]1)(=[O:44])[CH3:43]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Cc1cc(-c2ncc(CC(=O)OC(C)(C)C)cn2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(-c4ccnc(C)c4)nc3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 2-(2-(2-methylpyridin-4-yl)pyrimidin-5-yl)acetate 183-4 (35 mg, 0.12 mmol) and TFA (0.5 mL) in DCM (3 mL) was stirred at room temperature for 2 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2-(2-(2-methylpyridin-4-yl)pyrimidin-5-yl)acetic acid 183-5, was dissolved in DMF (2 mL). 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone (35 mg, 0.16 mmol) and DIEA (107 uL, 0.61 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (70 mg, 0.18 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2-(2-methylpyridin-4-yl)pyrimidin-5-yl)acetamide 183. MS m/z 433.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.47(s, 2H), 8.50(d, 1H), 8.22(s, 1H), 8.14(d, 1H), 7.97(d, 1H), 7.87(d, 1H), 7.38(dd, 1H), 3.83(s, 2H), 3.68(t, 2H), 3.64(t, 2H), 3.15(t, 2H), 3.09(t, 2H), 2.58(s, 3H), 2.09(s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[F:12][C:13]([F:19])([F:18])[S:14]([OH:17])(=[O:16])=[O:15].[N:20](OCCC(C)C)=O>CO>[O-:17][S:14]([C:13]([F:19])([F:18])[F:12])(=[O:16])=[O:15].[OH:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N+:1]#[N:20]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)CCON=O
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: CO
Product: N#[N+]c1ccc([N+](=O)[O-])cc1O
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C

Procedure:
To an ice cooled solution containing 5 parts of 2-amino-5-nitrophenol and 9.6 parts of trifluoromethane sulfonic acid in 150 parts of methanol was slowly added 3.9 parts of isoamyl nitrite to complete diazotization. The solution was filtered and the filtrate was poured into 700 parts of ethyl ether. The precipitate was collected, washed with ether and dried under vacuum to give 4.5 parts of product with purity >95%.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22]([Cl:27])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C(OC([NH:36]C1CCN(S(C2C3C(Cl)=CN=C(Cl)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22]([NH2:36])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Product: Cl
Product: Nc1ncc(Cl)c2c(S(=O)(=O)N3CC[C@@H](N)C3)cccc12

Procedure:
Intermediate 26b is used in the method of Example 39 instead of Intermediate 26 to obtain the title compound as hydrochloride.