Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=1.[Br-].[CH2:25]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:26][CH3:27].CC(C)([O-])C.[K+].O>C1COCC1>[F:23][C:17]1[CH:16]=[C:15]([C:3]2[CH:4]=[CH:5][C:6]([CH:8]3[CH2:13][CH2:12][C:11](=[CH:25][CH2:26][CH3:27])[CH2:10][CH2:9]3)=[CH:7][C:2]=2[F:1])[CH:20]=[C:19]([F:21])[C:18]=1[F:22]
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(c2ccc(-c3cc(F)c(F)c(F)c3)c(F)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCC=C1CCC(c2ccc(-c3cc(F)c(F)c(F)c3)c(F)c2)CC1
Temperature: -10 °C

Procedure:
12.5 g of 4-(2,3',4',5'-tetrafluorobiphenyl-4-yl)cyclohexanone and 15.5 g of propyltriphenylphosphonium bromide were introduced into 150 ml of THF, and the mixture was cooled to -10° C. with stirring and under nitrogen. A solution of 4.5 g of potassium tert-butoxide in 150 ml of THF was then added dropwise with stirring at -10° C., and the mixture was then stirred at room temperature for a further 2 hours. The yellow suspension was then cooled to 10° C., and 200 ml of water were added. The organic phase was separated off, and the aqueous phase was extracted once with 100 ml of methyl tert-butyl ether. The combined organic extracts were washed once with 50 ml of water, dried using sodium sulfate, filtered and evaporated to a residue. The residue was purified by means of a silica-gel frit, and the eluate was evaporated to a residue, giving 3,4,5,2'-tetrafluoro-4'-(4-propylidenecyclohexyl)bi-phenyl.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]1[CH:26]=[CH:25][N:24]2[N:27]=[CH:28][C:29]([C:30]([N:32]3[CH:37]4[CH2:38][CH2:39][CH:33]3[CH2:34][N:35](C(OC(C)(C)C)=O)[CH2:36]4)=[O:31])=[C:23]2[CH:22]=1>C(Cl)Cl.CCOC(C)=O>[CH:33]12[N:32]([C:30]([C:29]3[CH:28]=[N:27][N:24]4[CH:25]=[CH:26][C:21]([N:17]5[CH2:18][CH2:19][CH2:20][C@@H:16]5[C:10]5[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=5[F:8])=[CH:22][C:23]=34)=[O:31])[CH:37]([CH2:38][CH2:39]1)[CH2:36][NH:35][CH2:34]2
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2C(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12)N1C2CCC1CNC2
Reaction time: 15 h
Yield: 15.4 %

Procedure:
TFA (1.2 mL) was added to a solution of tert-butyl 8-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (200 mg, 0.37 mmol) in DCM (2 mL) at 0° C. and stirring was continued at 20-35° C. for 15 h. The reaction mixture was concentrated under reduced pressure to afford the crude, which was diluted with EtOAc, washed with saturated NaHCO3 solution, dried over anhydrous sodium sulphate to afford the crude. The crude compound was purified by recrystallisation from mixture of DCM and n-Hexane to afford 25 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C.CN1CCCC1=O>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:24][NH2:25])=[O:22]
Reactant: O=C(Nc1cccc2c(Cl)ccnc12)c1c(Cl)cccc1Cl
Reactant: NN
Solvent: CN1CCCC1=O
Solvent: CCO
Solvent: O
Product: NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 100 °C
Yield: 87.6 %

Procedure:
A mixture of 4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (200 mg) and hydrazine monohydrate (285 mg) in ethanol (4 ml) and N-methylpyrrolidone (1 ml) was heated at 100° C. overnight. After cooling, the resulting precipitates were collected by filtration, and the residue was recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-hydrazinoquinoline (173 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:4]([NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][NH:14][C:4]1[CH:5]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=[C:2]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: CC(C)(C)CNc1cc(NCC(C)(C)C)nc(Cl)n1
Reactant: C1CNCCN1
Product: CC(C)(C)CNc1cc(NCC(C)(C)C)nc(N2CCNCC2)n1
Yield: 78.3 %

Procedure:
The reaction of 2-chloro-4,6-bis(2,2-dimethylpropylamino)pyrimidine with piperazine as described in Example 4 leads to the title product in a yield of 78.3%, m.p.: 132°-136° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>CN(C=O)C>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][S:29]([CH3:28])(=[O:31])=[O:30])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65), (0.19 g, 0.5 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (92 uL, 1.2 mmol) and triethylamine (0.2 mL, 1.5 mmol). The reaction mixture was stirred at 60° C. for 1 h, at 110° C. for 16 h, allowed to cool to room temperature and partitioned between EtOAc and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. Purification of the residue by silica gel chromatography (1:1 of EtOAc/hexanes) provided the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 467 (M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]#N)=[CH:5]2)[CH2:3][CH2:2]1.O.[PH2](=O)[O-:21].[Na+]>C(O)(=O)C.O.N1C=CC=CC=1.[Ni]>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([CH:17]=[O:21])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: N#Cc1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=Cc1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
The 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile (150 mg, 0.609 mmol) obtained in (B) was dissolved in a mixed solution of acetic acid, water and pyridine (1:1:2, 4 ml), added with Raney Nickel (catalytic amount) and sodium phosphinate monohydrate (258 mg, 2.44 mmol), and then the mixture was stirred overnight at 60° C. The reaction mixture was left stand for cooling and the catalyst was removed by filtration through a Celite layer and washed with hot ethanol. The reaction mixture was concentrated, then diluted with chloroform, and washed with aqueous copper sulfate. The organic layer was dried over anhydrous magnesium sulfate to obtain the title compound (97.0 mg, 64%) as pale yellow solid.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][CH2:9][NH:10][C:11](=[O:24])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[CH:8]([CH2:9][NH:10][C:11](=[O:24])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=1)=[O:7]
Reactant: CC(=O)Oc1ccc(COC(=O)NCCO)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(COC(=O)NCC=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of pyridine (1.15 mL) in 20 mL of CH2Cl2 was cooled in an ice bath and chromium trioxide (711 mg) was added in one portion. The mixture was stirred at the same temperature for 5 min and at room temperature for 1 h. A solution of 62 (300 mg, 1.18 mmol) in 10 mL of CH2Cl2 was added in one portion and the mixture was stirred for 45 min at room temperature. The solution was decanted, diluted with 100 mL of CH2Cl2 and washed with aqueous NaHCO3 (2×75 mL), saturated NaCl (1×75 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude aldehyde which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 2.20 (s, 3H), 4.03 (s, 2H), 5.0 (s, 2H), 5.42 (broad s, 1H), 6.97 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 9.56 (s, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH2:21][CH2:22][CH3:23])(=O)=O.C([SiH](CCCCCCCC)CCCCCCCC)CCCCCCC.C(N(CC)CC)C.C1(PC2C=CC=CC=2)C=CC=CC=1.CN([CH:74]=[O:75])C>C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([CH:74]=[O:75])=[C:8]([CH2:21][CH2:22][CH3:23])[CH:9]=2)=[CH:15][CH:16]=1
Reactant: CN(C)C=O
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCC[SiH](CCCCCCCC)CCCCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of the triflate from Step 6 of Example 1 (3.98 g, 10 mmol), trioctylsilane (6.7 mL, 15 mmol), triethyl amine (7.0 mL, 25 mmol), palladium acetate (0.22 g, 0.5 mmol) and diphenylphosphine (0.21 g, 0.5 mmol) in DMF (60 mL) was stirred at 80° C. under an atmosphere of carbon monoxide (50 psi) for 5 h. The reaction was then diluted with ethyl acetate and water. The organic layer was washed with water and concentrated. The residue was purified by chromatography on silica gel to give the title product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:29][N:30]([CH3:40])[C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>>[CH3:29][N:30]([CH3:40])[C:31]1[N:32]([C:2]2[N:3]=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:14][CH:15]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH2:16]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1
Reactant: CN(C)c1nc2ccccc2[nH]1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1
Product: CN(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1

Procedure:
4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)morpholine from Example 126 (75 mg) was reacted with N,N-dimethyl-1H-benzo[d]imidazol-2-amine via General Procedure D to produce 6.8 mg of 167 following reverse phase HPLC purification. MS (Q1) 530.2 (M)+
Reaction SMILES: [CH3:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[CH2:6][C:5]2[CH:11]=[C:12]([C:15]([O:17]C(C)(C)C)=O)[CH:13]=[CH:14][C:4]=2[NH:3]1.FC(F)(F)C(O)=O.[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[CH2:39][NH:40][CH3:41].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[CH2:39][N:40]([CH3:41])[C:15]([C:12]1[CH:13]=[CH:14][C:4]2[NH:3][C@H:2]([CH3:1])[C:8](=[O:9])[N:7]([CH3:10])[CH2:6][C:5]=2[CH:11]=1)=[O:17]
Reactant: C[C@H]1Nc2ccc(C(=O)OC(C)(C)C)cc2CN(C)C1=O
Reactant: CNCc1cc2ccccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1Nc2ccc(C(=O)N(C)Cc3cc4ccccc4n3C)cc2CN(C)C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.7 %

Procedure:
To a stirred solution of tert-butyl (2R)-2,4-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.75 g, 2.6 mmole) in CH2Cl2 (20 mL) was added trifluoroacetic acid (20 mL). After stirring at RT for 45 min the reaction was concentrated on the rotavap. The residue was redissolved in 4 N HCl in dioxane (50 mL), and the solution was concentrated to dryness. Trituration with Et2O, filtration, and drying under vacuo gave the crude carboxylic acid-hydrochloride salt as a white solid. To a stirred solution of this material in 1:1 DMF/CH2Cl2 (50 mL) was added 1-methyl-2-(methylaminomethyl)indole (0.42 g, 2.6 mmole), Et3N (0.73 mL, 5.2 mmole), HOBt.H2O (0.35 g, 2.6 mmole), and EDC.HCl (0.5 g, 2.6 mmole). After stirring for 18 h the reaction was concentrated on the rotavap, and the residue was taken up in EtOAc (50 mL). The solution was washed sequentially with H2O (50 mL), 1.0 N Na2CO3 (50 mL), and brine (50 mL), then was dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (EtOAc) gave the title compound (0.87 g, 86%) as a white solid: MS (ES) m/e 391.2 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:18])[NH:13]2)([OH:3])=O.CN1CCOCC1.ClC(OC)=O.[CH2:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32]>O.C(Cl)Cl>[CH2:31]([N:33]([C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:18])[NH:13]2)=[O:3])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32]
Reactant: O=C(O)CCCOc1cccc2c1CCC(=O)N2
Reactant: CCNc1ccccc1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CCN(C(=O)CCCOc1cccc2c1CCC(=O)N2)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.5 Grams of 5-(3-carboxy)propoxy-3,4-dihydrocarbostyril and 2.0 ml of N-methylmorpholine are added to 200 ml of methylene chloride, and then 1.0 ml of methyl chloroformate is added dropwise to said solution under external ice cooling and agitation while maintaining the internal temperature at 10°-20° C. After this dropwise addition, the mixture is further agitated at room temperature for 30 minutes and then added with 1.3 ml of N-ethylaniline, followed by additional 4-hour agitation at the same temperature. After the reaction, the reaction solution is added with water, and after liquid separation, the organic layer is washed with a dilute aqueous NaOH solution, diluted hydrochloric acid and water in that order and then dried with anhydrous Na2SO4. After filtering out the inorganic matter, the mother liquor is concentrated and the residue is recrystallized from ethanol, consequently obtaining 2.6 g of 5-[3-(N-ethylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals. m.p. 179.5°-180.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)[CH2:3][CH2:2]1.CN(C)C=O.[CH:21]1([C:25]2[C:33]([C:34](=[O:37])[NH:35][CH3:36])=[CH:32][C:28]([C:29](O)=[O:30])=[C:27]([CH3:38])[CH:26]=2)[CH2:24][CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.O>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([CH:4]3[CH2:3][CH2:2][N:1]([C:29]([C:28]4[C:27]([CH3:38])=[CH:26][C:25]([CH:21]5[CH2:24][CH2:23][CH2:22]5)=[C:33]([CH:32]=4)[C:34]([NH:35][CH3:36])=[O:37])=[O:30])[CH2:6][CH2:5]3)=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: CNC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Reactant: c1cc2[nH]ncc2cc1C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(C(=O)N2CCC(c3ccc4[nH]ncc4c3)CC2)c(C)cc1C1CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.7 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 5-(piperidin-4-yl)-1H-indazole (compound 62.5, 100 mg, 0.50 mmol) in N,N-dimethylformamide (3 mL) EDC.HCl (192 mg, 1.00 mmol), 4-dimethylaminopyridine (122 mg, 1.00 mmol) and 4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3, 122 mg, 0.49 mmol) were added and the resulting solution was stirred for 4 h at room temperature. The reaction was diluted with water (20 mL) and extracted with of ethyl acetate (2×25 mL). The combined organic layers were washed with brine (2×15 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate as the eluent, followed by additional purification by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (30% CH3CN up to 47% in 7 min, up to 100% in 3 min, down to 30% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield the title compound as a white solid (71.2 mg, 33%). m/z (ES+) 431 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:17]([OH:18])=[CH:16][C:15]([Br:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].[CH:20]([N:23]1[CH2:28][CH2:27][CH:26]([C:29](O)=[O:30])[CH2:25][CH2:24]1)([CH3:22])[CH3:21].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:19][C:15]1[CH:16]=[C:17]([OH:18])[C:2]([NH:1][C:29]([CH:26]2[CH2:27][CH2:28][N:23]([CH:20]([CH3:22])[CH3:21])[CH2:24][CH2:25]2)=[O:30])=[C:3]([C:4](=[O:5])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=2)[CH:14]=1
Reactant: CC(C)N1CCC(C(=O)O)CC1
Reactant: Nc1c(O)cc(Br)cc1C(=O)Nc1ccc(Cl)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N1CCC(C(=O)Nc2c(O)cc(Br)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 46 h
Yield: 59.3 %

Procedure:
2-Amino-5-bromo-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide (5.14 g) and 2.83 g of 1-isopropylpiperidine-4-carboxylic acid were dissolved in 75 ml of N,N-dimethylformamide, then 4.33 g of 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride and 3.04 g of 1-hydroxybenzotriazole were added thereto and the mixture was stirred at room temperature for 46 hours. The reaction solution was added to 750 ml of 1% aqueous solution of sodium bicarbonate and 200 ml of ethyl acetate were added thereto. Ethyl acetate was evaporated therefrom in vacuo and the resulting solid was collected by filtration and washed with water. The resulting solid was suspended in 100 ml of methanol and 10 ml of water and the suspension was stirred for one night. The resulting precipitate was collected by filtration and dried in vacuo to give 4.41 g of 4′-bromo-2′-[(5-chloro-2-pyridyl)carbamoyl]-6′-hydroxy-1-isopropylpiperidine-4-carboxanilide.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][C:18]3[CH:19]=[N:20][C:21]([N+:24]([O-])=O)=[CH:22][CH:23]=3)[CH:14]=[CH:13][N:12]=2)=[O:9])[CH2:4]1.[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([O:17][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8]([N:5]3[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:27])[CH3:1])[CH2:4]3)=[O:9])[CH:16]=2)=[CH:23][CH:22]=1
Reactant: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(N)nc3)ccn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
A solution of (R)-3-(dimethylamino)-N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide (0.720 g, 1.934 mmol) in MeOH (10 mL) and THF (10 mL) was treated with NH4Cl (3.10 g, 58.0 mmol) followed by zinc dust (1.264 g, 19.34 mmol) and the mixture stirred at RT for 0.5 h. The mixture was diluted with EtOAc, the solids removed via filtration and washed with EtOAc. The filtrate was re-filtered and concentrated to dryness to afford (R)—N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide (600 mg, 91%). MS (ESI) m/z: 343.2 (M+H+).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[S:12]1[CH:16]=[C:15]([CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[NH2:19])[N:14]=[CH:13]1.C1COCC1.[C:28]1([C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N+]=[N-])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)(=O)C>C(O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[C:28]1([CH:34]([O:21][C:20](=[O:22])[C@H:18]([CH2:17][C:15]2[N:14]=[CH:13][S:12][CH:16]=2)[NH2:19])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: N[C@@H](Cc1cscn1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N[C@@H](Cc1cscn1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a solution of 38.85 g of the compound (43) (112.8 mmol) in ethanol (200 ml)-THF (600 ml) was added diphenyldiazomethane (39 g, 201 mmol) little, by little over 30 min. at room temperature with stirring. After the reaction mixture was stirred for 1 h at room temperature, to the mixture was added diphenyldiazomethane (10 g, 51.5 mmol) and the resulting mixture was stirred for 1 h. To the reaction mixture was added acetic acid (0.1 ml) for quenching the excess reagent and the mixture was concentrated in vacuo. The residue (92 g) was crystallized by adding ether (1 L) to give 49.05 g (96.1%) of the compound (44).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].F[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:32]3[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=3)[CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCNC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCN(c2ccc(C#N)cc2)C3)cc1
Temperature: 130 °C
Reaction time: 48 h
Yield: 43.1 %

Procedure:
To a suspension of 1-(2-chlorophenyl)-2-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 2, 80.0 mg, 0.236 mmol) and K2CO3 (97.9 mg, 0.708 mmol) in 2 mL DMF was added 4-fluorobenzonitrile (86.0 mg, 0.472 mmol) under argon. The mixture was heated at 130° C. with stirring for 48 h. The mixture was cooled to rt, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified on silica gel eluting with 1:3 EtOAc/hexanes to give a solid (44.7 mg, 43%): Rf=0.32 (1:2 EtOAc/hexanes).
Reaction SMILES: C(N)CC1C=CC=CC=1.FC(F)(F)C(Cl)=O.[F:17][C:18]([F:30])([F:29])[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1.C1C2C(=CC=CC=2)C=CN=1.[OH-].[Na+].[Cl:43][CH:44]([Cl:48])[C:45](Cl)=[O:46]>O.C(Cl)Cl>[Cl:43][CH:44]([Cl:48])[C:45]([N:20]1[CH2:21][CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]1[C:18]([F:17])([F:29])[F:30])=[O:46]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: FC(F)(F)C1NCCc2ccccc21
Agent: NCCc1ccccc1
Agent: O=C(Cl)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: c1ccc2cnccc2c1
Product: O=C(C(Cl)Cl)N1CCc2ccccc2C1C(F)(F)F

Procedure:
By procedures described in Example 1 (Method A), phenethylamine and trifluoroacetyl chloride were converted to 1-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 3.5 g of this isoquinoline compound, 20 ml 10% sodium hydroxide and 50 ml methylene chloride. With this mixture stirred, 2 ml dichloroacetyl chloride was added dropwise to the mixture. The mixture was stirred for 2 minutes, then water was added. The organic extract was dried with magnesium sulfate, stripped of solvent, and subjected to Kugelrohr distillation (130° C. @ 0.1 mm Hg) to provide a product having the elemental analysis reported in Table I.