Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH2:14][NH:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=O)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C(O)=C(F)C(F)=C(F)C=1F>CN(C=O)C>[NH:1]([C:8]1[N:13]=[C:12]([CH2:14][N:15]2[C:16](=[O:22])[CH2:17][CH2:18][C:19]2=[O:21])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)NCc1ccnc(Nc2ccccc2)n1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1Cc1ccnc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 46.9 %

Procedure:
1-[3-(Dimethylamino)propyl]3-ethylcarbodiimnide hydrochloride (4.44 g, 22 mmol) was added in one portion to a stirred mixture of 4-{[(2-anilinopyrimidin-4-yl)methyl]amino}-4-oxobutanoic acid (Method 13; 6.0 g, 20mmol) and pentafluorophenol (4.05 g, 22 mmol) in DMF (180 ml) under nitrogen. The reaction was stirred at ambient temperature under nitrogen for 20 hours and then the reaction mixture was concentrated by evaporation. The residue was partitioned between EtOAc and water. The layers were separated and the organic layer washed with water (2×) and saturated brine, dried (Na2SO4) and the volatiles removed by evaporation. The crude pentafluoroester was stirred in dry TBF (218 ml) under nitrogen at 0° C. and sodium hydride (528 mg of a 60 % dispersion in oil, 22 mmol) added in one portion. The reaction mixture was stirred at 0° C. for 15 minutes and then 72 hours at ambient temperature. Acetic acid (1.32 ml) was added and the reaction mixture was concentrated by evaporation. The residue was partitioned between EtOAc and water and the layers separated. The organic layer was washed with dilute aqueous sodium hydrogen carbonate solution (2×), water and saturated brine, dried (Na2SO4) and the volatiles removed by evaporation. The crude product was purified by chromatography eluting with EtOAc/isohexane (60:40 and then 100:0). The purified product was triturated with isohexane, collected by filtration and dried to give the title compound (2.65 g, 47%) as a white solid. NMR: 2.75 (s, 4H), 4.55 (s, 2H), 6.75 (d, 1H), 6.93 (t, 1H), 7.25 (t, 2H), 7.64 (d, 2H), 8.37 (d, 1H), 9.53 (s, 1H); m/z 283.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=O.[Cl-].[OH:15][NH3+:16].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=[N:16][OH:15]
Reactant: [NH3+]O
Reactant: Cc1ccccc1C(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(=NO)C(F)(F)F
Temperature: 0 °C
Yield: 66.4 %

Procedure:
3.7 g (0.020 mol) of 2,2,2-trifluoro-1-(2-methylphenyl)-ethanone are dissolved in 20 ml of ethanol at 80° C. To the solution are added dropwise 1.4 g (0.020 mol) of hydroxylammonium chloride and 2.7 g (0.033 mol) of sodium acetate dissolved in 10 ml of water. The reaction mixture is refluxed for 5 hours, poured into ice water, and extracted with ethyl acetate. The organic phase is washed with water and brine, dried over MgSO4, and concentrated, yielding 2.7 g of 2,2,2-trifluoro-1-(2-methylphenyl)-ethanone oxime as a white solid. The crude product is used in the next reaction step without further purification.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:19][C:20]1[CH:25]=[N:24][C:23](Cl)=[CH:22][N:21]=1>CN(C)C=O>[Cl:19][C:20]1[N:21]=[CH:22][C:23]([O:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:24][CH:25]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Temperature: 0 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (184 mg, 0.85 mmol) was dissolved in dry dimethylformamide (3 ml), cooled to 0° C. and treated with sodium hydride (60% in mineral oil, 36 mg, 0.89 mmol). The mixture was allowed to warm to room temperature over 30 minutes. A solution of 2,5-dichloropyrazine (D47) (139 mg, 0.94 mmol) in dry dimethylformamide (1 ml) was added and the mixture stirred at room temperature for 5 hours. The mixture was applied to a SCX column and washed with methanol then a mixture of 0.880 ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo to afford the title compound (268 mg); MS (ES+) m/e 330 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][N:25]([CH:30](C)C)[CH2:24]5)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]>CC(=O)C>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][N:25]([CH3:30])[CH2:24]5)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CN(C(C)C)C5)cc23)CC1
Solvent: CC(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CN(C)C5)cc23)CC1

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1H-isoindol-5-yl]-1H-indole-7-carboxamide, substituting formaldehyde (6 mg, 0.198 mmol) for 2-propanone to afford 1.2 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[C:18]([O:17][C:15]([N:9]1[CH2:14][CH2:13][N:12]([C:2]2[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][N:3]=2)[CH2:11][CH2:10]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cncnc1Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ncncc2Cl)CC1

Procedure:
The pyrimidine from step (b) above (1.75 g, 1.2 mmol) and tert-butyl 1-piperazinecarboxylate (2.235 g, 0.012 mol, Aldrich) reacted under the conditions of Example 3a to give the title compound as an orange oil. MS (ESI, pos. ion) m/z: 299 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:4](/[CH:5]=[CH:6]\[C:7](=[O:12])[O:8][CH2:9][CH2:10][F:11])[CH:3]1[C:13]([OH:15])=[O:14].[C:17]([CH:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[CH:18]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:12])[O:8][CH2:9][CH2:10][F:11])[C@H:3]1[C:13]([O:15][CH:19]([C:17]#[CH:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)=[O:14]
Reactant: CC1(C)C(/C=C\C(=O)OCCF)C1C(=O)O
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: C#CC(OC(=O)[C@@H]1[C@H](/C=C\C(=O)OCCF)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Step F of Example 9, (IR, cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2-fluoroethoxy)-1-propenyl]-cyclopropane-carboxylic acid and α-ethynyl-3-phenoxy-benzyl alcohol were reacted to obtain α-ethynyl-3-phenoxy-benzyl (IR,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2-fluoroethoxy) -1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20= +47° ±1.5° (c=1% in CHCl3).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21]C3CCCCO3)[C:13](=[O:28])[N:12](COCC[Si](C)(C)C)[C:11]=2[N:10]=[C:9]1[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]([F:48])([F:47])[F:46])[CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:28])[NH:12][C:11]=2[N:10]=[C:9]1[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]([F:46])([F:48])[F:47])[CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2nc(Oc3cccc(OC(F)(F)F)c3)n(Cc3ccccc3)c2c(=O)n1CCCO
Temperature: 80 °C
Reaction time: 8 h
Yield: 123 %

Procedure:
To a solution of 7-benzyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (5.3 g, 7.68 mmol) in ethyl alcohol (20 mL) was added concentrated HCl (5 mL). The reaction was stirred at 80° C. overnight. The reaction was concentrated and the residue was neutralized with saturated sodium bicarbonate. This aqueous phase was extracted with ethyl acetate and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 7-benzyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (4.5 g, 100% yield) as white solid. 1H-NMR (DMSO-d6) δ 11.93(s, 1H), 7.62-7.57(t, 1H), 7.44-7.32(m, 8H), 5.42(s, 2H), 4.49-4.46(t, 1H), 3.89-3.86(t, 2H), 3.46-3.41(m, 2H), 1.72-1.65(m, 2H). LCMS retention time 2.560 min; LCMS MH+ 477.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14](Br)[S:15][C:16]=1[Br:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(O)(O)[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1>C(O)C.O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[S:15][C:16]=1[Br:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Br)sc(Br)c1NC(=O)OCc1ccccc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1c(-c2ccc(C)cc2)sc(Br)c1NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Palladium tetrakis-triphenylphosphine is added to a degassed solution of dibromide 155 and p-tolylboronic acid 175 in ethanol: water:toluene (2:1:1) and sodium carbonate. The resulting mixture is heated under N2 and stirred for 1 h at 80° C. The mixture is then cooled filtered through a 0.45 μm syringe filter and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provides 176.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]([OH:16])=O)[CH:8]=2)[NH:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[Cl:40][C:41]1[CH:42]=[C:43]([NH:48]/[C:49](/[NH2:52])=[N:50]/O)[CH:44]=[CH:45][C:46]=1[Cl:47].S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C>[Cl:40][C:41]1[CH:42]=[C:43]([NH:48][C:49]2[N:52]=[C:14]([CH2:13][O:12][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2](=[O:1])[CH2:11][CH2:10]4)[O:16][N:50]=2)[CH:44]=[CH:45][C:46]=1[Cl:47]
Reactant: O=C(O)COc1ccc2c(c1)CCC(=O)N2
Reactant: N/C(=N\O)Nc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(OCc3nc(Nc4ccc(Cl)c(Cl)c4)no3)ccc2N1
Temperature: 110 °C
Yield: 3.4 %

Procedure:
To a stirred solution of 2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)acetic acid (0.15 g, 0.67 mmol) were added HOBt (0.1 g, 0.74 mmol), EDC (0.15 g, 0.74 mmol) and DIPEA (0.22 g, 1.69 mmol). The resulting reaction mixture was stirred at room temperature for 30 min. (E)-1-(3,4-dichlorophenyl)-2-hydroxyguanidine (0.15 g, 0.67 mmol) in DMF was added to the above reaction mixture followed by sodium sulfate (0.48 g, 3.39 mmol) and the reaction mixture was heated at 110° C. for 12 h. The reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated. Purification was by preparative HPLC to give 6-((3-(3,4-dichlorophenylamino)-1,2,4-oxadiazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (9.3 mg, 7%). 1HNMR: 400 MHz, DMSO-d6: δ 2.42 (q, J=7.20 Hz, 2H), 2.85 (t, J=7.60 Hz, 2H), 5.41 (s, 2H), 6.78-6.87 (m, 2H), 6.94 (d, J=2.40 Hz, 1H), 7.41 (dd, J=2.80, 8.80 Hz, 1H), 7.59 (d, J=8.80 Hz, 1H), 7.71 (d, J=2.80 Hz, 1H), 9.96 (s, 1H), 10.39 (s, 1H). LCMS, RT 1.880 min; LCMS (ES-API), m/z 405.1.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:6](=[O+:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[C:4]([OH:16])[CH:3]=1.[C-:17]#[N:18].[K+]>CN(C)C=O>[C:17]([CH:14]1[C:15]2[C:2]([OH:1])=[CH:3][C:4]([OH:16])=[CH:5][C:6]=2[O:7][C:8]2[C:13]1=[CH:12][CH:11]=[CH:10][CH:9]=2)#[N:18]
Reactant: Oc1cc(O)c2cc3ccccc3[o+]c2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1c2ccccc2Oc2cc(O)cc(O)c21
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture of 15.5 g (50.0 mmol) of 1,3-dihydroxy-xanthenium bisulfam [R. K. M. Pillai et al, J. Org. Chem. 51, 717 (1986)] and 4.90 g (75.0 mmol) of potassium cyanide in 150 ml of dimethylformamide is kept at 130° C. for 2 hours. The solvent is then concentrated on a vacuum rotary evaporator and the residue is taken up in ethyl acetate. The ethyl acetate phase is washed with water, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Chromatography of the residue over silica gel using the mobile phase system hexane/ethyl acetate=3:1 and crystallization of the pure fractions from ethyl acetate gives 10.0 g (83%) of 9-cyano-1,3-dihydroxy-xanthene, melting point 211°-215° C. (compound (107), Table 1).
Reaction SMILES: [C@H:1]1([C:10]([OH:12])=[O:11])[CH2:6][CH2:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2:29].[Rh+2]>CO>[Rh:29].[C@H:1]1([C:10]([OH:12])=[O:11])[CH2:2][CH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]1
Reactant: [Rh+2]
Agent: CC(=O)[O-]
Agent: O=C(O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C(O)[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CO
Product: [Rh]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.885 g (5.14 mmol) of 1,4-trans-cyclohexane dicarboxylic acid acid and 0.517 g (1.17 mmol) of rhodium acetate dimer (Rh2 (CH3COO)4) were dissolved in 900 ml of methanol. After this was stirred for three days at the room temperature, this was kept still for a few days. Thereafter, its precipitation product was suction-filtered, rinsed sufficiently with methanol and then vacuum-dried for 60° C./4 hours, whereby 0.824 g of target substance was obtained.
Reaction SMILES: C([N:3](C=O)[CH2:4]/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].C(O)C>>[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[NH2:3][CH2:4]/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)/C=C/CN(C=O)C=O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C=C/CN

Procedure:
A solution of ethyl (2E)-4-(diformylamino)but-2-enoate (XV) (0.89 mg, 4.8 mmol) in a mixture trifluoroacetic acid-ethanol (absolute) (2:1, 10 mL) was stirred under reflux overnight (the reaction was followed by LC-MS and stopped when complete conversion was achieved). The solvent was evaporated under vacuum to obtain compound ethyl (2E)-4-aminobut-2-enoate trifluoroacetate (IV) as brown oil (undetermined yield), which was used without further purification in the next step.
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH:13]=2)[N:8]([CH3:30])[C:7](=[O:31])[C:6]=1[C:32]([O:34]C)=O)(=O)C.[NH3:36]>C1COCC1.CO>[NH2:4][C:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[CH:13]=2)[N:8]([CH3:30])[C:7](=[O:31])[C:6]=1[C:32]([NH2:36])=[O:34]
Reactant: N
Reactant: COC(=O)c1c(NC(C)=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(=O)c(C(N)=O)c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the product of EXAMPLE 91 (30 mg) in THF (1 mL) was added 3 mL of NH3 in methanol (7 M). The reaction stirred for about 15 hours at room temperature before it was concentrated. The residue was dissolved in CH2Cl2 and washed with water. The solution was dried (Na2SO4) and concentrated. The concentrated residue was purified by preparative TLC on silica gel eluted with 100% EtOAc affording the title compound. HPLC/MS: 473.0 (M+1), 475.0 (M+3); Rt=4.19 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:27][CH:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[OH-].[Na+]>C1OCCOC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:25][CH:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[CH2:27]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(F)cc4C)C3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(F)ccc1NC1CN(c2ncc(Cl)cc2C(=O)NC2(c3ccc(C(=O)O)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-(1-(5-chloro-2-(3-((4-fluoro-2-methylphenyl)amino)azetidin-1-yl)nicotinamido)cyclopropyl)benzoate (D168) (105 mg, 0.206 mmol) in a mixture 1-4 dioxane/water (3 ml/1 ml), 1N NaOH (0.309 ml) was added. The reaction mixture was stirred at room temperature overnight. Organic solvent was evaporated in vacuo and the reaction mixture was acidified with 2N HCl (pH=5-6). The solid obtained was filtered off and dried to afford the title (E34) (65 mg
Reaction SMILES: C([N:8]1[CH2:15][CH:14]2[CH:10]([CH:11]([CH3:20])[C:12]3[C:18]([CH3:19])=[CH:17][S:16][C:13]=32)[CH2:9]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CC(Cl)OC(Cl)=O>ClC(Cl)C>[CH3:19][C:18]1[C:12]2[CH:11]([CH3:20])[CH:10]3[CH:14]([C:13]=2[S:16][CH:17]=1)[CH2:15][NH:8][CH2:9]3
Reactant: Cc1csc2c1C(C)C1CN(Cc3ccccc3)CC21
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Product: Cc1csc2c1C(C)C1CNCC21
Temperature: 22 °C
Reaction time: 1 h

Procedure:
The product of step h) (948 mg, 3.35 mmol) in dichloroethane (17 ml) was treated with K2CO3 (1.85 g, 13.4 mmol) and Ace-Cl (1.45 ml, 13.4 mmol) at 80° C. for 16 hours. Next, the reaction mixture was filtered, concentrated and the residue was dissolved in anhydrous MeOH (25 ml) and stirred for 1 hour at 22° C. The MeOH was concentrated and triturated with ether producing 733 mg (95%) of the subtitle compound. 1H NMR (300 MHz, d6-DMSO, ppm) 1.27 (d, J=7 Hz, 3H); 2.97-3.10 (m, 1H); 3.19-3.38 (m, 2H); 3.42-3.62 (m, 3H); 3.78-3.88 (m, 1H); 6.92 (d, J=5 Hz, 1H); 7.47 (d, J=5 Hz, 1H); 9.05 (br s, 1H); 9.38 (br s, 1H); MS calculated for C11H15NS+H 194, observed 194.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:11](O)(=[O:16])[CH2:12][CH2:13][CH:14]=[CH2:15].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:11](=[O:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: C=CCCC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: C=CCCC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a mixture of 3-nitroaniline (0.433 mmol)) and pent-4-enoic acid (1.30 mmol) in CH2Cl2 (4 mL) at ambient temperature was added HOBt (0.234 g, 1.73 mmol) and EDC (0.332 g, 1.73 mmol). The resulting mixture was stirred for 4 hours. The reaction mixture was cooled to 0° C. and quenched with H2O. The aqueous layer was extracted with CH2Cl2 thrice and the combined organic extracts were washed with saturated NaHCO3 followed by brine, dried over Na2SO4 and concentrated under reduced pressure to give (viC1).
Reaction SMILES: Cl[C:2]1([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.C(=[NH:29])(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].Cl>O1CCCC1.C1(C)C=CC=CC=1>[NH2:29][C:2]1([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1
Reactant: O=C(N1CCCCC1)C1(Cl)C=CC=CN1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: NC1(C(=O)N2CCCCC2)C=CC=CN1

Procedure:
Next, the 2-chloropyridinoyl-piperidine intermediate is reacted with benzophenone imine in the presence of tris(dibenzylidineacetone)-dipalladium(0) Pd2(dba)3) as a catalyst, and 2,2′-bis(diphenylphosphino)-1,1′binaphthyl (BINAP) and sodium t-butoxide in a suitable solvent, such as toluene, at reflux, to substitute the halo group with the benzophenone imino group. After work-up, this intermediate is typically reacted with hydrochloric acid in a suitable solvent, such as tetrahydrofuran, and then purified to give the corresponding 2-aminopyridinoyl-piperidine intermediate.
Reaction SMILES: C([O-])(=O)C.[C:5]([NH:8][CH:9]1[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][NH:11][CH2:10]1)(=[O:7])[CH3:6].[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(C(C)=O)C>[C:5]([NH:8][CH:9]1[CH2:10][N:11]([CH2:17][C:18]2[CH:25]=[CH:24][CH:23]=[C:20]([CH3:21])[CH:19]=2)[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15]1)(=[O:7])[CH3:6]
Reactant: CC(=O)NC1CNCCN(C)C1
Reactant: Cc1cccc(CCl)c1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: CC(=O)NC1CN(C)CCN(Cc2cccc(C)c2)C1
Reaction time: 16 h

Procedure:
A mixture of acetate of 6-acetylamino-1-methylhexahydro-1H-1,4-diazepine (3.0 g), 3-methylbenzyl chloride (3.5 g), potassium carbonate (17 g), sodium iodide (0.1 g) and methyl ethyl ketone (200 ml) is refluxed with stirring for 16 hours. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is chromatographed on silica gel with elution of chloroform-methanol (20:1). Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound as an oil.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[CH2:5]1)(=O)C.O1CCCC1.CO.O.[OH-].[Li+]>O>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C@H:6]2[CH2:7][CH2:8][CH2:9][NH:4][CH2:5]2)=[CH:15][CH:14]=1
Reactant: CC(=O)N1CCC[C@H](c2ccc(Br)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc([C@H]2CCCNC2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
To a solution of N-acetyl-(3R)-3-(4-bromophenyl)piperidine (2.88 g, 13.2 mmol) in mixture of tetrahydrofuran (24 ml), methanol (24 ml) and water (12 ml) was added lithium hydroxide monohydrate (3.8 g, 92.4 mmol) and stirred at 95° C. for 2 hours. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give (3R)-3-(4-bromophenyl)piperidine (2.3 g, 87%) as colorless crystals that was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25]>ClCCl>[CH2:24]([O:23][C:22]([NH:1][C:2]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1)=[O:26])[CH3:25]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1(c2ccc(C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-(1-aminocyclopropyl)benzoate (1.84 g) and triethylamine (2.82 mL) were dissolved in dichloromethane (40 mL), ethyl chlorocarbonate (1.01 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 min and at room temperature for 1 hr. After completion of the reaction, the solvent was evaporated, to the residue was added 0.5N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (0.86 g).