Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[N:4][CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:10])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Cl)n1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cncc(Cl)n1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.18 g (1.1 mmol) 6-chloro-pyrazine-2-carboxylic acid, 0.15 g (1.1 mmol) 5-fluoro-2,3-dihydro-1H-indole, 0.31 mL (2.2 mmol) TEA in 3.0 mL DMF were mixed with 0.39 g (1.2 mmol) TBTU and stirred for 1 h at RT. The reaction mixture was mixed with water and stirred for 5 min. The precipitated solid was filtered, washed with water and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10]Cl.[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][N:16]1[CH2:17][CH2:18][CH:13]([OH:12])[CH2:14][CH2:15]1
Reactant: OC1CCNCC1
Reactant: ClCCOc1ccccc1Br
Product: OC1CCN(CCOc2ccccc2Br)CC1

Procedure:
The title compound was prepared from 1-bromo-2-(2-chloroethoxy)benzene and 4-hydroxypiperidine in a similar manner to Example 149 (b).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[NH:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15]
Reactant: BrCc1cccc(Br)c1
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C1NCCN1Cc1cccc(Br)c1
Yield: 43.7 %

Procedure:
3-Bromobenzyl bromide (1.0 g, 4.0 mmol) was added to a solution of 2-imidazolidone (1.03 g, 12.0 mmol) and potassium carbonate (1.66 g, 12.0 mmol) in 2-propanol (10 mL), and the reaction stirred at reflux for 40 h. The cooled solution was partitioned between EtOAc and water. Organics were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography (100% EtOAc) gave 446 mg (44%) of the title compound as a white solid. 1H NMR (400 MHz, MeOD-d4) δ 7.40-7.48 (m, 2H), 7.21-7.28 (m, 2H), 4.30 (s, 2H), 3.29-3.41 (m, 4H). [M+H] calc'd for C10H11BrN2O, 255, 257; found, 255, 257.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:33])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:31][CH:32]=5)=[CH:18]4)=[CH:13][C:12]=3[O:33][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: C=CCOC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Reactant: CCOC(=O)CCCCBr
Product: C=CCOC(=O)c1ccc(-c2ccc3cc(OCCCCC(=O)OCC)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Yield: 60.8 %

Procedure:
Following the procedure of Example 12(a), but reacting 2 g (4.5 mmol) of allyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 1.4 g (6.7 mmol) of ethyl 5-bromovalerate, 1.55 g (59%) of the expected compound was obtained, which compound had a melting point of 117°-8° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:30]3[CH2:35][O:34]C(C)(C)[O:32][CH2:31]3)[CH:29]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(=O)(O)[O-].[Na+]>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:29]=[C:28]([CH:30]([CH2:35][OH:34])[CH2:31][OH:32])[CH:27]=[N:26][CH:25]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(c2cncc(-c3nc(NCc4ccccc4)c4c(-c5ccccc5)ccn4n3)c2)CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCC(CO)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
To a solution of N-benzyl-2-(5-(2,2-dimethyl-1,3-dioxan-5-yl)pyridin-3-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (60.0 mg, 0.122 mmol) in methanol (15 mL) was added p-toluenesulfonic acid monohydrate (12.0 mg, 0.0610 mmol) and stirred at ambient temperature for 2 h. Reaction mixture was diluted with saturated sodium bicarbonate solution (50 mL) and extracted into DCM (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition B-73 as described in general methods) to get 2-(5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)propane-1,3-diol (35.0 mg, 63.5%). LCMS Condition B-12: retention time 2.00, [M+1]=452.2. HPLC Condition B-4: retention time 7.22, purity 97.89%. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.93-2.96 (m, 1H), 3.68-3.77 (m, 4H), 4.69 (br s, 2H), 4.80 (d, J=5.6 Hz, 2H), 6.69 (t, J=5.6 Hz, 1H), 6.79 (d, J=2.8 Hz, 1H), 7.23-7.27 (m, 1H), 7.32-7.41 (m, 5H), 7.46-7.55 (m, 4H), 7.90 (d, J=2.8 Hz, 1H), 8.36 (t, J=2.4 Hz, 1H), 8.51 (d, J=2.0 Hz, 1H), 9.19 (d, J=2.0 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25][CH2:24]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[H][H]>C(O)C.[C].[Pd]>[OH:1][CH:2]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25][CH2:24]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1
Reactant: O=C1CCc2cc(C(=O)CCCN3CCN(c4ccc([N+](=O)[O-])cc4)CC3)ccc2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCN(CCCC(O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1

Procedure:
1.5 Gram of 6-{1-oxo-4-[4-(4-nitrophenyl)-piperazinyl]-butyl}-3,4-dihydrocarbostyril and 0.3 g of 5%-palladium-carbon were dispersed in 150 ml of ethanol and catalytically reduced under 2 kg/cm2 of hydrogen gas for 5 hours. The reaction mixture was filtered and the mother liquor was concentrated under a reduced pressure. The residue thus obtained was recrystallized from methanol to obtain 0.7 g of 6-{1-hydroxy-4-[4-(4-aminophenyl)-1-piperazinyl]butyl}- 3,4-dihydrocarbostyril in brown powdery crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][Mg+].[Br-]>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[CH2:14][CH2:15][C:16]([OH:18])([CH3:28])[CH3:17])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg+]
Reactant: CC(=O)CCN(Cc1ccc(Cl)cc1Cl)CC1CN(C(=O)OC(C)(C)C)C1
Agent: [Br-]
Solvent: CCOCC
Product: CC(C)(O)CCN(Cc1ccc(Cl)cc1Cl)CC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a solution of 3-{[(2,4-dichlorobenzyl)-(3-oxo-butyl)-amino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester (190 mg, 0.46 mmol) in Et2O (4 mL) is added MeMgBr (3.0 M in Et2O, 0.92 mmol). The resulting mixture is stirred at room temperature for one hour. The reaction is quenched with saturated ammonium chloride and extracted with EtOAc (3×). The combined organic extracts are dried (Na2SO4), filtered and concentrated. The crude product is purified by flash chromatography on silica gel eluting with 5% EtOH (10% NH4OH)/chloroform to yield 138 mg (70%) of 3-{[(2,4-dichlorobenzyl)-(3-hydroxy-3-methyl-butyl)-amino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, CD3OD) δH: 7.49-7.47 (2H, m), 7.36-7.34 (1H, m), 4.0-3.96 (2H, m), 3.67 (2H, s), 3.57-3.53 (2H, m), 2.9-2.82 (1H, m), 2.75-2.73 (2H, m), 2.67 (2H, t, J=7.0 Hz), 1.69 (2H, t, J=7.3 Hz), 1.46 (9H, s), 1.1 (6H, s). Mass spectrum (ion spray): m/z=431.2 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=O)[CH:2]=1.B.O1CCCC1.CO>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCc2cccnc2)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCCc2cccnc2)CC1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of 1.5 g of tert-butyl 4-[3-(pyridin-3-yl)propanoyl]piperazine-1-carboxylate in 25 mL of tetrahydrofuran was added 7 mL of a 1 M borane/tetrahydrofuran solution under ice-cooling. The mixture was heated to reflux for 6 hours, and then cooled to room temperature, and 10 mL of methanol was added thereto, followed by further heating to reflux for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and a mixture of a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate was added thereto. The aqueous layer was separated, and then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 1.43 g of tert-butyl 4-[3-(pyridin-3-yl)propyl]piperazine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)[CH:3]=1.C(N(CC)CC)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[N:1]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)[CH:3]=1)=[C:28]=[O:30]
Reactant: Nc1ccnc(Cc2n[nH]c(=O)c3ccccc23)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C=Nc1ccnc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 4-(4-amino-pyridin-2-ylmethyl)-2H-phthalazin-1-one (21) (0.40 g, 1.48 mmol) in anhydrous DCM (160 mL) and triethylamine (0.46 mL, 4.09 mmol), was added a dropwise preformed solution of triphosgene (0.27 g, 0.93 mmol) in anhydrous DCM (30 mL). The reaction was stirred for 6 hrs at room temperature. The reaction mixture was then concentrated to dryness in vacuo yielding a grey solid. Single peak in LC-MS analysis, (yield taken to be quantitative) no purification performed. m/z (LC-MS, ESP), RT=3.79 mins, (M+MeOH) 329.0.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:23][CH:24]([CH3:28])[CH2:25][CH2:26][OH:27])=[N:5][C:6]([CH2:21][CH3:22])=[C:7]([C:9]2[C:18]([O:19][CH3:20])=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)[N:8]=1)[CH3:2].I[CH2:30]C.IC>>[CH2:1]([C:3]1[C:4]([NH:23][CH:24]([CH3:28])[CH2:25][CH2:26][O:27][CH3:30])=[N:5][C:6]([CH2:21][CH3:22])=[C:7]([C:9]2[C:18]([O:19][CH3:20])=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)[N:8]=1)[CH3:2]
Reactant: CCI
Reactant: CCc1nc(-c2cc3c(cc2OC)CCCC3)c(CC)nc1NC(C)CCO
Solvent: CI
Product: CCc1nc(-c2cc3c(cc2OC)CCCC3)c(CC)nc1NC(C)CCOC
Yield: 87 %

Procedure:
Following the general procedure of Example 13 Step 3 and making non-critical variations but substituting (2S)-2-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]butan-1-ol with 3-{[3,6-diethyl-5-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-yl]amino}butan-1-ol (Example 39, 95 mg, 0.24 mmol) and iodoethane with iodomethane the reaction was carried out and gave 108 mg of a crude yellow oil. This material was purified by Biotage MPLC (40 g column, 20% ethyl acetate in heptane) to give 85 mg (87%) of 3,6-diethyl-N-(3-methoxy-1-methylpropyl)-5-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-amine as a clear oil. Rf 0.30 (5% acetone in toluene). IR (liq.) 2965, 2933, 2873, 1567, 1551, 1494, 1465, 1446, 1392, 1248, 1233, 1204, 1197, 1121, 1110 cm−1. OAMS supporting ions at: ESI+398.2.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][N:4]=1>O1CCOCC1.[Pd]>[NH2:9][C:8]1[C:3]([NH:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1COCCO1
Product: CNc1ncccc1N
Yield: 96.2 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 5.00 g of 2-methylamino-3nitropyridine (prepared as described in Preparation 104) were hydrogenated in 80 ml of 1,4-dioxane in the presence of 1.00 g of 10 % w/w palladium-on-charcoal. After working up the product as described in Example 6, 3.87 g of the title compound, melting at 90°-92° C. were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1[CH3:8].ClC1C=C(C=CC=1)C(OO)=[O:14].S([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:8][C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][N+:1]=1[O-:14]
Reactant: Cc1ccnc(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc[n+]([O-])c(C)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.9 %

Procedure:
To a solution of 2,4-lutidine (2.0 g, 18.7 mmol) in methylene chloride (100 mL) was added 3-chloroperoxybenzoic acid (5.07 g, 29.4 mmol), which was stirred for 20 minutes at room temperature. A small amount of saturated aqueous sodium hydrogen sulfite solution was added to the reaction solution, and the organic layer was separated after vigorous stirring. This organic layer was washed with 5 N aqueous sodium hydroxide solution (5.9 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure to obtain the title compound (1.54 g, 66.9%). The title compound was used in the following reaction without being purified.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25](F)[CH:24]=1)[CH3:20]>>[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([N:14]2[C:13]([C:12]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:9][O:10][C:11]=3[CH3:18])=[CH:17][N:16]=[CH:15]2)=[CH:25][CH:24]=1)[CH3:20]
Reactant: CCOC(=O)c1cccc(F)c1
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1c[nH]cn1
Product: CCOC(=O)c1ccc(-n2cncc2-c2c(-c3cccc(F)c3)noc2C)cc1
Yield: 53 %

Procedure:
As described for Example 1, 3-(3-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (3.89 g, 16.0 mmol) was converted, using 3-fluorobenzoic acid ethyl ester instead of 4-fluoroacetophenone, to the title compound (3.34 g, 53%) which was obtained as a yellow solid. MS: m/e=391.9[M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6](=[S:8])[NH2:7])#[N:2].[CH2:17]([O:19][C:20](=[O:26])[CH:21](Cl)[C:22]([CH3:24])=O)[CH3:18]>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[S:8][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:26])=[C:22]([CH3:24])[N:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])#[N:2]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(C)COc1ccc(C(N)=S)cc1C#N
Solvent: CO
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 25 °C
Yield: 68 %

Procedure:
Methanol (50 mL) was placed into a round bottom flask and 3-cyano-4-isobutoxy benzothioamide (5.0 g) was added, followed by addition of ethyl-2-chloroacetoacetate (4.25 g). The mixture was heated to reflux and maintained until reaction completion. After the reaction was completed, the mass was cooled to about 25° C. and maintained for about 30 minutes. The mass was then filtered and washed with methanol. The wet solid was dried at about 70° C. to a constant weight to yield 5.0 g of the title compound. Purity by HPLC: 84.9%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1Br
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Into a 1000-mL round-bottom flask, was placed a solution of 2-bromo-4-fluoro-1-nitrobenzene (30 g, 137.61 mmol, 1.00 equiv) in N,N-dimethylformamide (450 mL), piperidine (13.974 g, 162.68 mmol, 1.20 equiv), and potassium carbonate (56.718 g, 411.00 mmol, 2.99 equiv). The resulting solution was stirred overnight at 75° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 300 mL of dichloromethane. The resulting mixture was washed with 2×100 mL of water and 2×100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:50). This resulted in 19 g (49%) of 1-(3-bromo-4-nitrophenyl)piperidine as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1([CH2:20][C:21]2[O:25][C:24]([NH2:26])=[N:23][N:22]=2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][C:21]2[O:25][C:24]([NH:26][C:8](=[O:9])[CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:23][N:22]=2)[CH2:19][CH2:18]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Nc1nnc(CC2CC2)o1
Product: O=C(Nc1nnc(CC2CC2)o1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 158-159° C. and MS: m/e=334.3 (M+H+) was prepared in accordance with the general method of example 44a from 2,2-diphenylacetic acid chloride and 5-cyclopropylmethyl-[1,3,4]oxadiazol-2-ylamine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:37]=[C:24]4[C:25]([C:29]5[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=5)=[CH:26][CH:27]=[CH:28][N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]3[N:37]=[C:24]4[C:25]([C:29]5[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[CH:33][CH:34]=5)=[CH:26][CH:27]=[CH:28][N:23]4[N:22]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3nc4c(-c5ccc(C#N)cc5)cccn4n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)cc1

Procedure:
4-[2-(4-Piperidin-4-yl-phenylamino)-[1,2,4]triazolo[1,5-a]pyridine-8-yl]benzonitrile was prepared from 4-{4-[8-(4-cyano-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (0.181 g, 0.366 mmol) and trifluoroacetic acid (0.500 mL) in a manner analogous to Example 312 to give product (0.130 g, 90%). MP=228-232° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.70 (s, 1H), 8.85 (d, 1H), 8.40 (d, 2H), 8.00 (m, 3H), 7.62 (d, 2H), 7.15 (m, 3H), 3.05 (m, 2H), 2.60 (br m, 4H), 1.65 (m, 2H), 1.45 (m, 2H). MS=395 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[F:20][C:21]([F:31])([F:30])[C@H:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[NH2:23]>>[F:31][C:21]([F:20])([F:30])[C@@H:22]([NH:23][C:8]([C:5]1[CH:4]=[C:3]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: N[C@@H](c1cccnc1)C(F)(F)F
Reactant: O=C(O)c1cc(Cc2ccc(F)cc2)c(Cl)cn1
Agent: Cl
Product: O=C(N[C@@H](c1cccnc1)C(F)(F)F)c1cc(Cc2ccc(F)cc2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-(4-fluorobenzyl)-pyridine-2-carboxylic acid and (αS)-α-(trifluoromethyl)-3-pyridinemethanamine hydrochloride (1:1) (CAN 749839-26-7) as starting materials and isolated (23 mg, 71%) as colorless oil; MS (ESI, m/z): 424.2 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([Br:13])=[CH:8][N:7]=1)=O)C.[NH3:14].CO>>[Br:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:6]([C:4]([NH2:14])=[O:3])=[N:7][CH:8]=1
Reactant: CCOC(=O)c1ncc(Br)cc1C
Reactant: N
Solvent: CO
Product: Cc1cc(Br)cnc1C(N)=O

Procedure:
5-Bromo-3-methyl-pyridine-2-carboxylic acid ethyl ester (2.44 g, 10 mmol) was dissolved in NH3/MeOH (50 ml) and heated to reflux for 3 days. The reaction mixture was concentrated to give the desired product as a pink solid (2.05 g, 9.6 mmol).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:34][N:33]=[C:32]([CH3:35])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:11]([CH3:18])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[O:34][N:33]=[C:32]([CH3:35])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:17]
Reactant: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C)c1cc2c(cc1C)NC(=O)CC(c1cccc(-c3cc(C)no3)c1)=N2

Procedure:
The title compound was prepared from (5-(ethyl-methyl-amino)-4-methyl-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M86) (0.38 g, 0.75 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (160 mg, 55%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[C:18]([CH3:19])=[CH:17][C:10]([O:11][C@@H:12]2[CH2:15][C@H:14]([NH2:16])[CH2:13]2)=[CH:9][C:8]=1[CH3:20].C(N(CC)CC)C>ClCCl>[Br:6][C:7]1[C:18]([CH3:19])=[CH:17][C:10]([O:11][C@@H:12]2[CH2:15][C@H:14]([NH:16][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:13]2)=[CH:9][C:8]=1[CH3:20]
Reactant: Cc1cc(O[C@H]2C[C@@H](N)C2)cc(C)c1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(O[C@H]2C[C@@H](NS(C)(=O)=O)C2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methanesulfonyl chloride (0.16 mL), cis-3-(4-Bromo-3,5-dimethylphenoxy)cyclobutanamine (300 mg) and triethylamine (0.3 mL) are stirred at 0° C. in dry dichloromethane (25 mL). After 10 min, the reaction mixture is warmed to ambient temperature. After stirring for 3 hours, the mixture is diluted with dichloromethane, washed with 10% aqueous solution of KHSO4, then with 10% aqueous solution of K2CO3. The organic phase was passed through a phase separator and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→50:50) to give the title compound. Yield: 200 mg.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].[ClH:18].[CH3:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][NH2:29])=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[ClH:18].[CH3:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][NH:29][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: Cc1ncccc1OCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3cccnc3C)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 16.3 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(2-methylpyridin-3-yloxy)ethylamine hydrochloride (547 mg) and sodium hydrogencarbonate (1.02 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(2-methylpyridin-3-yloxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile dihydrochloride (87 mg).