Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C=O)C>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCOCC3)n2n1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 43 mg, 0.125 mmol) and morpholine (43 mg, 0.499 mmol) in DMF (0.5 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with DMF and then purified by preparatory HPLC (20-35% MeCN/H2O+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (22.4 mg, 45%). Melting point (242.8-242.9° C.). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6 H), 2.38 (s, 3 H), 3.69-3.78 (m, 4 H), 3.80-3.88 (m, 4 H), 6.18 (s, 1 H), 7.34 (s, 1 H), 7.60 (d, J=8.84 Hz, 2 H), 7.99 (d, J=8.84 Hz, 2 H), 10.87 (s, 1 H); ESI-MS: m/z 396.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH3:32])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[N:40]1([CH2:44]CN2C=C(C3C=CC(F)=C(C(F)(F)F)C=3)N=C2C2CCNCC2)[CH2:43][CH2:42][CH2:41]1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:44][N:40]4[CH2:43][CH2:42][CH2:41]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using 4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=515, obsd.=515).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:14])=[C:6]([C:8](=[O:13])[CH2:9][S:10]([CH3:12])=O)[CH:7]=1.FC(F)(F)C(O)=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH:9]([S:10][CH3:12])[C:8](=[O:13])[C:6]=2[CH:7]=1
Reactant: CS(=O)CC(=O)c1cc(Cl)ccc1O
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CSC1Oc2ccc(Cl)cc2C1=O

Procedure:
5-Chloro-2-hydroxy-1-[(methylsulfinyl)acetyl]benzene (6.0 g) and trifluoroacetic acid (6 g) are refluxed in benzene (50 ml) for one hour under nitrogen. The solvent is removed under reduced pressure to give a yellow oil, which crystallizes on standing. Recrystallization from ethanol gives white crystals. (3.0 g 54%) m.p. 76°-78° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH3:26])=[CH:21][CH:20]=1)=[O:15].C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.N1CCCC1>ClCCCl.C(OCC)(=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[S:4][C:3]3[C:14](=[O:15])[N:16]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([CH:25]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH3:26])=[CH:21][CH:20]=4)[C:40](=[O:42])[NH:1][C:2]=3[CH:6]=2)=[CH:8][CH:9]=1
Reactant: CC(c1ccc(CCNC(=O)c2sc(-c3ccc(F)cc3)cc2N)cc1)N1CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCNC1
Product: CC(c1ccc(CCn2c(=O)[nH]c3cc(-c4ccc(F)cc4)sc3c2=O)cc1)N1CCCC1
Reaction time: 3 h
Yield: 19.2 %

Procedure:
The obtained 3-amino-5-(4-fluorophenyl)-N-{2-[4-(1-pyrrolidin-1-ylethyl)phenyl]ethyl}thiophene-2-carboxamide (0.15 g) was suspended in 1,2-dichloroethane (5 ml), and triethylamine (0.067 ml) and triphosgene (0.080 g) were successively added with stirring. After 3 hr, pyrrolidine (0.8 ml) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=9:1 (volume ratio)→1:2 (volume ratio)) using NH-silica gel, and further recrystallized from ethyl acetate to give the title compound (0.024 g) as pale-yellow crystals.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:27]([NH2:29])=O)(=[O:23])=[O:22])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.Cl>ClCCl.O>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[CH:12]=[CH:11][C:10]=1[CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:25]=[C:26]([C:27]#[N:29])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])(=[O:23])=[O:22])(=[O:8])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C(N)=O)cc1S(=O)(=O)NCCc1ccc(C(C)C)cc1S(=O)(=O)NC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(C(C)C)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a stirred solution of 420 mg of 3-[[2-(2-tert-butylsulfamoyl-4-isopropylphenyl)ethyl]sulfamoyl]-4-methoxybenzamide in 30 mL of dichloromethane were added 0.48 mL of triethylamine and 0.245 mg of trifluoroacetic anhydride under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mL of triethylamine, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture were added water and 30 mL of 1 mol/L hydrochloric acid, and the mixture was extracted three times with 30 mL of dichloromethane. The organic layers were combined, washed with water, and brine, and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, ethyl acetate and hexane were added to the residue, and the crystal was collected by filtration to give 325 mg of N-tert-butyl-2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylbenzenesulfonamide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[C:8]([O:11][CH:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[CH3:9].C([O-])([O-])=O.[K+].[K+].CCN(CC)CC>CC(C)=O>[O:7]=[C:4]1[CH2:5][CH2:6][N:1]([CH2:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:2][CH2:3]1
Reactant: O=C1CCNCC1
Reactant: CC(=O)OC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1CCN(CC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.8 %

Procedure:
To a stirred suspension of 4-piperidone (10.0 g, 65.0 mmol) and bromobenzyl acetate (14.9 g, 65.2 mmol) in acetone (100 ml) was added K2CO3 (9.0 g) and Et3N (9.1 ml, 65.2 mmol). The reaction mixture was stirred at room temperature for two days, and then the solvent was evaporated. The residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The organic extracts were combined and dried over Na2SO4. The solvent was evaporated to afford the title compound (13.3 g, 53.8 mmol, 83%) as a thick oil. 1H NMR (300 MHz, CDCl3) δ 7.33-7.37 (m, 5H), 5.18 (s, 2H), 3.42 (s, 2H), 2.91 (t, J=6.1 Hz, 4H), 2.50 (t, J=6.1 Hz, 4H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)=[C:7]([N+:20]([O-])=O)[CH:6]=1)(=[O:4])=[O:3].C(O)(=O)C.[H][H]>[Pd].[OH-].[Na+]>[Cl:17][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[Cl:16])[O:9][C:8]1[CH:18]=[CH:19][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][C:7]=1[NH2:20]
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)c(N)c1
Yield: 149.5 %

Procedure:
A slurry of 10.5 g (0.0290 mole) of 4-(4-(methylsulfonyl)-2-nitrophenoxy)-1,2-dichlorobenzene and 350 ml of glacial acetic acid was placed in a Parr bottle and 0.5 g of 5% palladium on carbon added under nitrogen. The mixture was placed on a Parr hydrogenator apparatus and the desired reduction carried out with 50 pounds per square inch (psi) of hydrogen. Two batches of equal size were run and the catalyst removed by filtration. The solvent was removed in vacuo leaving crude product which was slurried in aqueous NaOH to remove any residual acetic acid. The aqueous layer was decanted from the product which was dried, to obtain 14.4 g (74.8% yield) of product. Recrystallization from ethanol and water afforded purified 2-(3,4-dichlorophenoxy)-5-(methylsulfonyl)benzenamine, mp 119°-121° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](OC(=O)C(C)(C)C)[N:6]=[C:5]2[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[NH:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:3]=2)[NH:7][N:6]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(C)(C)C(=O)On1nc(-c2ccc[nH]2)c2cc(N)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]nc(-c3ccc[nH]3)c2c1)c1ccncc1
Yield: 104.1 %

Procedure:
2,2-Dimethyl-propionic acid 5-amino-3-(1H-pyrrol-2-yl)-indazol-1-yl ester (0.38 mmol) was coupled with isonicotinoyl chloride (0.4 mmol) (Aldrich, Milwaukee, Wis.) and triethylamine in DCM at 0° C. to give 120 mg of the titled compound as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2)o1
Yield: 40 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (5.00 g, 23.0 mmol) was converted using 4-fluorobenzoic acid instead of o-toluic acid to the title compound (recrystallisation from tert-butylmethylether, 2.98 g, 40%) which was obtained as an off-white solid. MS: m/e=322.2 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:22])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1.Cl[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH2:22][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Reactant: CC(C)OC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)CC(CN)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl amine trifluoroacetate (prepared in example 1) and i-propyl chloroformate in a manner analogous to the procedure described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]#[N:15])=[C:12]([C:16]([O:18]CC)=[O:17])[CH:11]=[N:10]1.[OH-:21].[K+]>C(O)C>[C:16]([C:12]1[CH:11]=[N:10][N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:13]=1[C:14]([NH2:15])=[O:21])([OH:18])=[O:17]
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C#N
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1c(C(=O)O)cnn1-c1ccc(Cl)cc1Cl

Procedure:
A 2.5 g. portion of ethyl 1-(2,4-dichlorophenyl)-5-cyano-4-pyrazolecarboxylate was reacted with 1 g. of potassium hydroxide in 60 ml. of 50% aqueous ethanol to obtain 1.2 g. of purified product, m.p. 239°-240° , with the following elemental analysis.
Reaction SMILES: CC1C=CC(C2C=NN(C)C=2)=C(C=1)C(O)=O.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:22]([CH:27]=1)[C:23]([O:25]C)=[O:24]>>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:22]([CH:27]=1)[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1cc(C)ccc1-c1ccccn1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccccn2)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using methyl 5-methyl-2-(pyridin-2-yl)benzoate. ESI-MS (m/z): 214 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7](Cl)=[O:8].[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20]([NH2:28])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.C(N(CC)C(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>ClCCl>[F:16][C:17]([F:29])([F:30])[C:18]1[CH:19]=[C:20]([NH:28][C:7]([C:6]2[CH:5]=[C:4]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:3][C:2]=2[CH3:1])=[O:8])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1
Reactant: Cc1oc(-c2ccccc2)cc1C(=O)Cl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(-c2ccccc2)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
2-Methyl-5-phenyl-furan-3-carbonyl chloride (0.025 g) was added to a solution of 3,5-bis-trifluoromethyl-phenylamine (0.024 g) and N,N-diisopropylethyl-amine (0.018 mL) in dichloromethane (5 mL). After stirring at room temperature for 1 day, the reaction underwent an aqueous acidic (dilute HCl, 2×5 mL) and basic (dilute NaHCO3, 2×5 mL) workup followed by washing with brine (saturated NaCl, 2×5 mL), drying over MgSO4, and concentration. The crude compound was purified by passing through a silica gel plug eluting with hexanes/ethyl acetate (2:1) to afford the title compound (0.035 g, 82% yield). ES-MS negative Q1 (m/z) 412.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:22]([O:24]CC)=O)[N:12]([CH3:21])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[NH3:27]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:22]([NH2:27])=[O:24])[N:12]([CH3:21])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Reactant: N
Solvent: CO
Product: Cn1c(C(N)=O)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared from ethyl 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole-2-carboxylate and 2 M NH3 in MeOH following the method of example 36, step B (method B). LC-MS: Rt=3.6 min. m/e=379.9 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[CH3:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([C:34]([CH3:35])=[CH:33][N:5]2[C:6]3[C:11](=[CH:10][C:9]([CH3:15])=[CH:8][CH:7]=3)[C:12]3[CH2:13][CH2:14][N:2]([CH3:1])[CH2:3][C:4]2=3)=[CH:37][CH:38]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Reactant: COc1ccc(C(C)=CBr)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=Cn2c3c(c4cc(C)ccc42)CCN(C)C3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.6 %

Procedure:
2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (73 mg, 0.36 mmol) was dissolved in DMF (6 mL). To this solution was added CuI (7 mg, 0.036 mmol), L-proline (8 mg, 0.073 mmol), K3PO4 (156 mg, 0.734 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 1-(1-bromoprop-1-en-2-yl)-4-methoxybenzene (100 mg, 0.44 mmol). The reaction mixture was heated at 80° C. for 18 h. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 22 mg of 9-(2-(4-methoxyphenyl)prop-1-enyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (DMSO) OXALATE SALT 7.60 (d, 2H), 7.30 (d, 1H), 7.10 (d, 1H), 7.0 (m, 4H), 4.20 (m, 2H), 3.80 (s, 3H), 3.40 (m, 2H), 2.95 (m, 2H), 2.82 (s, 3H), 2.40 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.[CH:15]1([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH2:28])[CH2:23]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:15]1([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:2]3[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=3)[CH2:23]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Reactant: N[C@@H]1CCCN(CC2CCCCC2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(CC3CCCCC3)C2)cn1
Temperature: 95 °C
Reaction time: 0.08 h
Yield: 58.3 %

Procedure:
Ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (4.70 g) and (3R)-1-(cyclohexylmethyl)-3-piperidinamine (4.77 g) were combined in 1,4-dioxane (80 mL) at ambient temperature. To this solution were added palladium(II) acetate (248 mg) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (652 mg) at the same temperature and the mixture was stirred for 5 minutes. To the resulting mixture was added cesium carbonate (10.1 g) and the mixture was heated at 95° C. for twenty-four hours. The reaction mixture was allowed to cool to ambient temperature and the insoluble solid was filtered off. The filtrate was concentrated in vacuo and the residue was extracted with chloroform (300 mL). The chloroform phase was washed with saturated sodium bicarbonate (100 mL) and brine (100 mL). The aqueous layer was reextracted with chloroform (100 mL). The organic phase were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by a flash column chromatography eluting with a gradient solvent system from EtOAc-Hexane(1:1 v/v) to EtOAc to afford ethyl (2E)-3-(5-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate (4.80 g) as a yellow amorphous solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1.[CH:24]1([CH2:30]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:13]4[CH2:20][CH2:21][CH2:22][O:23][C:12]=34)=[O:10])[CH2:3][CH2:2]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(NCC1CCNCC1)c1c2n(c3ccccc13)CCCO2
Reactant: BrCC1CCCCC1
Product: O=C(NCC1CCN(CC2CCCCC2)CC1)c1c2n(c3ccccc13)CCCO2
Reaction time: 8 h

Procedure:
N-(4-Piperidylmethyl) 3,4-dihydro-2 H-[1,3]oxazino[3,2-a]indole- 10-carboxamide (E21) was alkylated with cyclohexylmethyl bromide using the method of Example 22 with a reaction time of 70 h at room temperature followed by 8 h at reflux temperature. The title compound (E23) was obtained as a white solid (31%) which was converted to its hydrochloride salt and crystallised from acetone/ether as a white solid mp 209°-210° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([S:12]([N:15]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:16]2[S:17][CH:18]=[CH:19][N:20]=2)(=[O:14])=[O:13])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.Br[C:31]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:32]=1[C:33]#[N:34].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:11]([S:12]([N:15]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:16]2[S:17][CH:18]=[CH:19][N:20]=2)(=[O:14])=[O:13])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:31]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:32]=3[C:33]#[N:34])[C:4]=2[CH:3]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc3c(cc2Cl)NCCO3)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc3c(cc2Cl)N(c2ccc(C(F)(F)F)cc2C#N)CCO3)cc1
Temperature: 25 °C

Procedure:
A 150-mL pressure vessel was charged with 6-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (2.32 g, 5.13 mmol), 2-bromo-5-(trifluoromethyl)benzonitrile (2.57 g, 10.27 mmol), Xantphos (0.594 g, 1.027 mmol), Pd2(dba)3 (0.470 g, 0.513 mmol), and cesium carbonate (5.02 g, 15.40 mmol). The vessel was flushed with Ar (g), then 1,4-dioxane (51.3 ml) was added. The vessel was sealed and placed in a 100° C. heating bath for 16 h. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (50-g Redi-Sep Gold column, 25-g silica gel loading column, 25-75% EtOAc/Heptane) to give 6-chloro-4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ=8.46 (d, J=2.1 Hz, 1 H), 8.15 (dd, J=1.8, 8.7 Hz, 1 H), 7.81 (d, J=8.5 Hz, 1 H), 7.50 (s, 1 H), 7.45 (d, J=3.6 Hz, 1 H), 7.32 (d, J=3.5 Hz, 1 H), 7.28-7.21 (m, 2 H), 6.90-6.78 (m, 3 H), 5.17 (s, 2 H), 4.40-4.34 (m, 2 H), 3.91-3.85 (m, 2 H), 3.71 (s, 3 H); m/z (ESI) 621.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:30]([N:37]1[CH2:42][CH2:41][CH:40](O)[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH2:30]([N:37]1[CH2:42][CH2:41][CH:40]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 17.5 h
Yield: 35 %

Procedure:
A chilled solution of 4-nitrophenol (1.14 g, 8.12 mmol), triphenyl phosphine (3.21, 12.2 mmol) and 1-benzyl-4-hydroxypiperidine (2.6 g, 14 mmol) in THF was treated with diisopropyl azodicarboxylate (DIAD) (2.4 mL, 12 mmol), stirred at ambient temperatures, under nitrogen, for 17.5 hours, poured into excess water and extracted with ethyl acetate. The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography with 30-40% ethyl acetate in hexane to give 1-benzyl-4-(4-nitro-phenoxy)-piperidine as a yellow semi-solid, 0.880 g (35% yield); Mass spectrum (+EI, [M+H]+) m/z 313. 1HNMR (500 MHz, DMSO-d6): δ8.11-8.15 (m, 2H), 7.24-7.30 (m, 4H), 7.18-7.22 (m, 1H), 7.10-7.14 (m, 2H), 4.53-4.59 (m, 1H), 3.45 (s, 2H), 2.60-2.64 (m, 2H), 2.20-2.26 (m, 2H), 1.91-1.95 (m, 2H), 1.58-1.67 ppm (m, 2H).