Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10](Cl)[CH:9]=2)[C:5](=[O:15])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:3]1=[O:27].C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C)C=O>[CH3:1][C:2]1([CH3:28])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:9]=2)[C:5](=[O:15])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:3]1=[O:27]
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc(Cl)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc(N2CCOCC2)c1
Temperature: 210 °C
Reaction time: 0.83 h

Procedure:
A sealed 2.5 ml tube containing 0.05 g of 5,5-dimethyl-1-(2-chloropyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione, 0.5 ml of dimethylformamide, 0.034 g of potassium carbonate and 0.021 ml of morpholine is placed in a Personal Chemistry Emrys Optimiser microwave oven. The mixture is irradiated with magnetic stirring at 210° C. for about 50 minutes. The reaction mixture is placed on a Bond Elut Varian cartridge of reference 1225-6053 containing 2 g of SCX phase conditioned with dimethylformamide. The cartridge is washed with methanol and then eluted with 2M ammoniacal methanol. The ammoniacal fractions are concentrated to dryness under reduced pressure. The residue thus obtained is purified by flash chromatography using a cartridge 16 mm in diameter packed with 2 g of conditioned 15-35 μm silica, and then eluted with a mixture (cyclohexane/ethyl acetate) (8/2) (v/v) at a flow rate of 10 ml/minute. The fractions between 160 and 260 ml are concentrated to dryness under reduced pressure. 0.01 g of 5,5-dimethyl-1-(2-morpholinopyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione is thus obtained in the form of a powder, the characteristics of which product are as follows:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:15][CH2:16][CH2:17][OH:18])(=[O:14])=[O:13].[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=1>>[NH2:41][C:38]1[N:39]=[CH:40][C:35]([C:21]2[CH:22]=[CH:23][C:24]([C:2]3[C:3]([S:12]([NH:15][CH2:16][CH2:17][OH:18])(=[O:14])=[O:13])=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=3)=[CH:25][C:20]=2[F:19])=[CH:36][N:37]=1
Reactant: O=S(=O)(NCCO)c1cc(C(F)(F)F)ccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3S(=O)(=O)NCCO)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-bromo-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzene-sulfonamide and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine. MS (ESI): mass calcd. for C19H16F4N4O3S, 456.09; m/z found, 457.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.57-8.53 (d, J=1.4, 2H), 8.38-8.35 (m, 1H), 8.00-7.96 (dd, J=8.1, 1.5, 1H), 7.63-7.60 (d, J=8.0, 1H), 7.59-7.54 (m, 1H), 7.38-7.36 (dd, J=6.1, 1.6, 1H), 7.36-7.34 (m, 1H), 3.51-3.45 (t, J=5.9, 2H), 2.95-2.86 (t, J=5.9, 2H).
Reaction SMILES: Br[CH:2]([CH2:8][C:9]([OH:11])=[O:10])[C:3](=[O:7])[C:4]([OH:6])=[O:5].[CH2:12]([SH:14])[CH3:13].C(N(CC)CC)C>ClCCl>[CH2:12]([S:14][CH:2]([CH2:8][C:9]([OH:11])=[O:10])[C:3](=[O:7])[C:4]([OH:6])=[O:5])[CH3:13]
Reactant: O=C(O)CC(Br)C(=O)C(=O)O
Reactant: CCS
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCSC(CC(=O)O)C(=O)C(=O)O

Procedure:
To a suspension of 1.00 g of 3-bromo-2-oxoglutaric acid in 20 ml of dichloromethane was added 0.33 ml of ethane thiol while stirring under ice-cooling, followed by addition of 1.83 ml of triehtylamine. The reaction mixture was stirred at room temperature for 3 hours, then the solvent was distilled off. The residue was distributed to ethyl acetate and 1N-HCl. The ethyl acetate layer was separated, washed with water and dried (Na2SO4), followed by distilling off the solvent to give 0.82 g of 3-ethylthio-2-oxoglutaric acid as a pale yellow oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[H][H].Cl>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)c1cccc2nc(-c3ccc(-c4ccncc4)cc3)oc12
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCNCC4)cc3)oc12
Yield: 3.3 %

Procedure:
2-(4-(Pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide (135 mg, 0.43 mmol) and platinum (IV) oxide monohydrate (70 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by chromatography (dichloromethane:methanol=8:1) to give the solid. The solid was acidified by hydrochloride acid. 4.6 mg of 2-(4-(piperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained. Yield: 3%. 1H-NMR (400 MHz, CD3OD-d4) δ 1.89 (m, 2H), 2.03 (m, 2H), 2.95 (m, 1H), 3.09-3.12 (m, 2H), 3.43-3.46 (m, 2H), 7.40-7.46 (m, 3H), 7.81 (t, J=8.4 Hz, 2H), 8.21 (d, J=8.0 Hz, 2H). LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1([CH3:39])[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]1[N:9]1[C:13](=[O:14])[CH2:12][C:11]([NH:15][C:16]2[CH:17]=[C:18]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:20])=[N:10]1.[C:40](OC(=O)C)(=[O:42])[CH3:41].[OH-].[Na+].Cl>C(Cl)(=O)C.CO>[Cl:1][C:2]1([CH3:39])[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]1[N:9]1[C:13](=[O:14])[CH2:12][C:11]([N:15]([C:16]2[CH:17]=[C:18]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:20])[C:40](=[O:42])[CH3:41])=[N:10]1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(OC)c(NC2=NN(C3C=CC(C)=CC3(C)Cl)C(=O)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)Cl
Solvent: CO
Product: CCCCCCCCCCCCOC(=O)c1ccc(OC)c(N(C(C)=O)C2=NN(C3C=CC(C)=CC3(C)Cl)C(=O)C2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dodecyl 3-{N-[1-(2-chloro-2,4-dimethylphenyl)-4,5-dihydro-5-oxo-1H-pyrazol-3-yl]-amino}-4-methoxy-benzoate (10.5 g, 18.9 mmol) was dissolved in acetyl chloride (50 ml) and acetic anhydride (35 ml) and the solution was heated under reflux for 1.5 hrs. The solution was cooled, then it was slowly poured into ice/water (750 ml) and the resulting sticky solid was extracted with ethyl acetate (2×100 ml). The combined extracts were dried (MgSO4) and evaporated to give an oil. Sodium hydroxide (0.8 g, 18.9 mmol) was added to a solution of the oil in methanol (80 ml) and the mixture was stirred at room temperature for 4 hrs. The solution was poured slowly into 3N hydrochloric acid (500 ml), the aqueous liquor was decanted off and the residue was dissolved in ethyl acetate (100 ml). The organic solution was dried (MgSO4) and evaporated to give a glass. The crude material was recrystallized from methanol (50 ml) to give pure product as a white solid, 5.8 g, 51%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH:13]=[CH:12][CH2:11][C@@H:10]2[N+:15]([O-])=O)=[CH:5][C:4]=1[O:18][CH3:19].C(O)(=O)C>C(O)C.[Zn]>[CH3:19][O:18][C:4]1[CH:5]=[C:6]([C@@H:9]2[C@H:10]([NH2:15])[CH2:11][CH:12]=[CH:13][CH2:14]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])cc1OC
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc([C@H]2CC=CC[C@H]2N)cc1OC
Yield: 32.4 %

Procedure:
40 g of (±)-cis-1,2-dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene (compound H1) are dissolved in 400 ml of ethanol and 40 g of zinc powder are added. After heating to boiling temperature, 65 ml of glacial acetic acid are added dropwise. Afterwards, the reaction mixture is filtrated and concentrated. The residue is redissolved in diluted hydrochloric acid and extracted with toluene. The aqueous layer is alkalized using 6 N solution of sodium hydroxide and extracted several times with toluene. The combined organic phases of the alkalic extraction are dried using sodium sulfate and concentrated. The residue is chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate/triethylamine in the ratio 6/3/1. 11.5 g of the title compound are obtained.
Reaction SMILES: [CH2:1]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH3:4].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]2([CH:40]=O)[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1>C1COCC1>[CH3:34][O:33][C:31]1[CH:30]=[C:29]([C:35]2([CH:40]=[CH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:36][CH2:37][CH2:38][CH2:39]2)[CH:28]=[C:27]([O:26][CH3:25])[CH:32]=1
Reactant: CCCCC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(OC)cc(C2(C=O)CCCC2)c1
Solvent: C1CCOC1
Product: CCCCC=CC1(c2cc(OC)cc(OC)c2)CCCC1
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To the above slurry of (butylmethylene) triphenylphosphorane at 10° C. under an argon atmosphere was added dropwise a solution of (3,5-dimethoxyphenyl)cyclopentane carboxaldehyde (1 equiv.) in dry THF (0.21M). The reaction was stirred for 45 min and upon completion was quenched by the addition of saturated aqueous ammonium chloride. The organic layer was separated and the aqueous phase was extracted twice with diethyl ether. The combined organic layer was washed with brine, dried over MgSO4 and the solvent was evaporated under reduced pressure to give an oil. The crude product was purified through a short column of silica gel using 5% diethyl ether-petroleum ether as eluent to afford the title compound in 96% yield.
Reaction SMILES: C[O:2][C:3](=S)[NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:14]3[S:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[CH:15]=3)[CH:13]=1)[NH:10][N:9]=[CH:8]2.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH2:32]>C(O)C>[S:18]1[C:14]([C:12]2[CH:13]=[C:5]([NH:4][C:3]([NH:32][CH2:31][CH2:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[O:2])[CH:6]=[C:7]3[C:11]=2[NH:10][N:9]=[CH:8]3)=[CH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]1=2
Reactant: COC(=S)Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Reactant: NCCc1ccccn1
Solvent: CCO
Product: O=C(NCCc1ccccn1)Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
A mixture of 7-benzo[b]thiophen-2-yl-1H-indazole-5-yl-thiocarbamic acid methyl ester (Preparation #14, 25.0 mg, 0.074 mmol) and 2-pyridin-2-yl-ethylamine (23 mg, 0.185 mmol) in ethanol (2 mL) was stirred at about 50° C. for about 8 hours. The solvent was removed under reduced pressure and the product was purified by crystallization in ethanol to give 1-(7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-3-(2-pyridin-2-yl-ethyl)-urea (12 mg, 39% yield); RP HPLC (Table 1, Method e) Rt=1.82 min; MS m/z: (M−H)− 412.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12](=[O:33])[C@@H:13]([C@H:23](O)[C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:10][O:11][C:12](=[O:33])[C@@H:13]([CH:23]([F:7])[C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](CCCc1ccccc1)C(F)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
(Diethylamino)sulfur trifluoride (2.0 ml, 15.2 mmol) was added to a ice cold solution of (R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid methyl ester (4a) (0.85 g, 2.5 mmol) in dry methylene chloride (15 ml) and the reaction mixture was stirred overnight while warming to room temperature. The reaction was quenched with aqueous NaHCO3 solution and extracted with methylene chloride. The organic extracts were dried over Na2SO4 and concentrated under reduced pressure. Column chromatography on silica eluting with a mixture of ethyl acetate and methylene chloride gave the title compound as a off-white solid (230 mg). 1H NMR (CDCl3) δ 1.90–1.58 (m, 4H), 2.78–2.57 (m, 2H), 3.28–3.10 (m, 1H), 3.75 (s, 3H), 3.74–3.45 (m, 8H), 5.40–5.12 (m, 1H), 7.35–7.18 (m, 5H);
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:6]=1[C:7](=[O:16])[CH2:8][CH2:9][S:10]2)(=[O:3])[CH3:2].[C:17]([NH:20]C1C=CC(C)=C2C=1C(=O)CCS2)(=[O:19])[CH3:18]>>[C:17]([NH:20][CH:8]1[C:7](=[O:16])[C:6]2[C:11](=[C:12]([Cl:15])[CH:13]=[CH:14][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])[S:10][CH2:9]1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1ccc(Cl)c2c1C(=O)CCS2
Reactant: CC(=O)Nc1ccc(C)c2c1C(=O)CCS2
Product: CC(=O)Nc1ccc(Cl)c2c1C(=O)C(NC(C)=O)CS2

Procedure:
The reaction was carried out in the same manner as in Example 12-(1), except that 477 mg of the compound prepared in (1) above was used instead of 5-acetylamino-8-methyl-4-thiochromanone of Example 12-(1). The reaction product was post-treated to produce 171 mg of the title compound. NMR(CDCl3)δ: 2.08(3H, s), 2.20(3H, s), 3.20(1H, d, J=13 Hz), 3.51(1H, dd, J=13.9 Hz), 4.7-4.9(1H, m), 7.50(1H, d, J=9.2 Hz), 8.54(1H, d, J=9.2 Hz)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([CH:11]=1)[NH2:10])(=[O:4])=[O:3].[Cl:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:13][CH2:14][C:15]([NH:10][C:9]1[CH:11]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=1[CH3:12])=[O:16]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(S(C)(=O)=O)cc1N
Product: Cc1ccc(S(C)(=O)=O)cc1NC(=O)CCl

Procedure:
The subtitle compound was prepared from 5-methanesulphonyl-2-methylaniline (0.82 g) and chloroacetyl chloride (0.72 ml) by the method of Example 33 step (iii) as a beige solid. Yield: 0.61 g
Reaction SMILES: [Na+].[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O-:25])(=O)=[O:23])=[CH:18][CH:17]=1.S(Cl)([Cl:28])=O>>[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([Cl:28])(=[O:25])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Thionyl chloride (50 mL) is added to the title B compound, 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonic acid sodium salt (18.1 g, 52.46 mmol) at 0° C. After 10 min, the ice bath is removed and the mixture is stirred at RT for 30 min. An additional 50 mL of thionyl chloride is added, followed by about 1 mL of DMF. The solid dissolves within 10 min. Stirring is continued for an additional 2.5 h and the mixture is then concentrated under vacuum. The resulting yellow solid is partitioned between 250 mL of water and 250 mL of EtOAc (warm). The organic layer is further washed with water (3×250 mL), 0.1 N aqueous NaOH (4×250 mL) and brine (1×250 mL). The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to give 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl chloride as a yellow solid: ESI-MS 363.99 [M+1]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[NH3:13]>>[N:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([NH2:13])=[O:2])=[CH:7][CH:8]=1
Reactant: COC(=O)CCc1ccncc1
Reactant: N
Product: NC(=O)CCc1ccncc1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
The crude ester was dissolved in 250 mL of 7.1M methanolic ammonia solution and was stirred at room temperature for 65 hours. After the solvent and excess ammonia were removed by distillation under reduced pressure. The residue was dissolved in 150 mL of 1N HCl and extracted with dichloromethane to remove residual triphenylphosphine oxide. The aqueous phase was basified with 40 mL of 4N NaOH and then was extracted with ethyl acetate (5×300 mL). The dried (Na2SO4) extracts were evaporated to furnish 6 g of the amide. The aqueous layer was concentrated to dryness and triturated with tetrahydrofuran (4×100 mL) and evaporation of the tetrahydrofuran extracts yielded an additional 5 g of amide. The combined crude products were dried, triturated with ether and the solids were filtered to yield 10.7 g of 4-pyridinpPropanamide, mp 164°-166° C.
Reaction SMILES: C(N)C([NH2:4])C.[C:6]([O:15][CH3:16])(=[O:14])[C:7]([CH2:9][C:10](OC)=[O:11])=[CH2:8]>>[C:6]([CH:7]1[CH2:8][NH:4][C:10](=[O:11])[CH2:9]1)([O:15][CH3:16])=[O:14]
Reactant: CC(N)CN
Reactant: C=C(CC(=O)OC)C(=O)OC
Product: COC(=O)C1CNC(=O)C1
Temperature: 140 °C

Procedure:
Equimolar amounts of N-allyl, N-methyl, propylene diamine prepared as described above and Dimethyl Itaconate are charged to a reaction vessel and heated slowly with agitation to 130°-150° C. After the exotherm subsides, the reaction mixture is maintained at 140° C. for 3 hours. The reaction product 1-(N-allyl, N-methyl aminopropyl)-4-carbomethoxy pyrrolidone is isolated by distillation.
Reaction SMILES: [N:1]1([CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([N+:14]([O-])=O)[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.S1C=CC=C1.N.[H][H]>CO.[Pt]>[N:1]1([CH:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [H][H]
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1[N+](=O)[O-]
Agent: [Pt]
Agent: N
Solvent: c1ccsc1
Solvent: CO
Product: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1N
Yield: 99 %

Procedure:
(a-3) A mixture of 3.4 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-2-nitrobenzenamine, 1 part of a solution of thiophene in methanol 4%, 80 parts of methanol and 80 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 2.64 parts (99%) of 4-[(1H-imidazol-1-yl)-phenylmethyl]-1,2-benzenediamine as a residue (int. 126), or alternatively
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][N:19]=1>>[NH2:17][C:18]1[N:23]=[C:22]([C:24]([NH:14][CH:12]([C:9]2[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=2)[CH3:13])=[O:25])[CH:21]=[CH:20][N:19]=1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: Nc1nccc(C(=O)O)n1
Agent: Cl
Product: CC(NC(=O)c1ccnc(N)n1)c1ccc(OCC(F)(F)F)nc1
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield (98 mg, a white solid) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (92 mg, 0.36 mmol, Amine-1, single enantiomer) and 2-aminopyrimidine-4-carboxylic acid (50 mg, 0.36 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])[CH:7]=[CH:6][N:5]=1.[SH:16][C:17]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=1>C(O)C.[OH-].[Na+]>[Cl:15][CH2:14][CH2:13][CH2:12][S:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][S:16][C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)[C:9]=1[CH3:10]
Reactant: Cc1c(SCCCCl)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 55 °C
Reaction time: 3.5 h

Procedure:
One equivalent of 2-chloromethyl-4-(3-chloropropylthio)-3-methylpyridine hydrochloride (dissolved in 10 ml of water) is added dropwise at 40° C. in the course of 20 min. to a solution of 2-mercapto-1H-benzimidazole (1.5 g/10 mmol) in 40 ml of ethanol and 21 ml of 1 N sodium hydroxide solution. The mixture is then stirred for 2-3 h at 50-60° C. and a further 3-4 h at room temperature, ethanol is distilled off on a rotary evaporator (1 kPa/40° C.), the residue is extracted 3 times with 20 ml of dichloromethane each time, and the extracts are washed with 0.1 N sodium hydroxide solution, dried over potassium carbonate and concentrated completely in vacuo. For purification, the crude product is chromatographed on silica gel (dichloromethane/methanol 20:1); the collected pure fractions are jointly concentrated in vacuo and the residue is crystallized from dichloromethane/diisopropyl ether. It is then recrystallized from methanol/toluene. Yield 2.67 g (74%) of the title compound as a colorless solid of m.p. 112-114° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25].C(N(CC)CC)C>ClCCl>[Cl:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([C:18]#[N:19])=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH:8]=[N:7][CH:6]=3)[N:10]2[CH3:21])=[CH:15][CH:14]=1
Reactant: CCCC(=O)Cl
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)NCc1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e, 0.060 g, 0.202 mmol) in dichloromethane (2 mL) is added butyryl chloride (0.024 g, 0.222 mmol) and triethylamine (0.056 mL, 0.405 mmol), and the reaction is stirred at room temperature for 30 min. The reaction mixture is diluted with dichloromethane and washed with water. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) to afford N-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-butyramide as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 0.98 (t, J=7.5 Hz, 3H), 1.65-1.77 (m, 2H), 2.29 (t, J=7.5 Hz, 2H), 3.82 (s, 3H), 4.57 (s, 2H), 7.38 (dd, J=8.6, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 8.09 (t, J=2.1 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 367.1327 [(M+H)+ Calcd for C20H20N4OCl: 367.1326].
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].[O:12]=[C:13]([N:27]1[CH2:32][CH2:31][N:30]2[C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=[C:29]2[CH2:28]1)[CH2:14][C@H:15]([NH2:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25]>C(O)(C)C.C(Cl)(Cl)Cl>[C:1]([O-:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].[O:12]=[C:13]([N:27]1[CH2:32][CH2:31][N:30]2[C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=[C:29]2[CH2:28]1)[CH2:14][C@H:15]([NH2:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25]
Reactant: O=C(O)c1cc(O)ccc1O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=C([O-])c1cc(O)ccc1O

Procedure:
The gentisic acid salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was formed by mixing gentisic acid (0.113 g), (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (0.300 g) in a mixture of isopropylalcohol (0.6 mL) and chloroform (1.5 mL), followed by stirring at reflux temperature for 2 h. The solvent was distilled out at reduced pressure to obtain solid gentisate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine as an amorphous solid. [Wt.: 0.410 g, % purity: 98.9%, XRD=amorphous FIG. (2)].