Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][NH:4][C:3]1=[O:9].[CH2:10]=O.[BH4-].[Na+]>CO.ClCCl>[CH3:1][C@@H:2]1[N:7]([CH3:10])[C@@H:6]([CH3:8])[CH2:5][NH:4][C:3]1=[O:9]
Reactant: C[C@@H]1N[C@@H](C)CNC1=O
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1CNC(=O)[C@H](C)N1C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of (3S,5S)-3,5-dimethyl-2-piperazinone in methanol (12 mL) at room temperature was added formaldehyde (0.345 mL, 37% water solution, 4.6 mmol) followed by sodium borohydride (261 mg, 6.9 mmol). The reaction mixture was stirred for 2 h before being diluted with dichloromethane and washed with 1N NaOH solution. The aqueous layer was back extracted with CH2Cl2 three times, and the combined organic layers were washed with brine, dried (MgSO4) and evaporated to yield (3S,5S)-3,4,5-trimethyl-2-piperazinone (128 mg, 39%). LCMS: (M+H)+: 143.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12](/[C:16](/[C:35]3[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=3)=[C:17](/[C:20]3[CH:25]=[CH:24][C:23](B4OC(C)(C)C(C)(C)O4)=[CH:22][CH:21]=3)\[CH2:18][CH3:19])=[CH:13][CH:14]=2)[CH:9]=[N:8]1.I[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1.[OH-].[K+].C(Cl)Cl>O1CCOCC1.C(OCC)(=O)C>[N:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[C:23]1[CH:22]=[CH:21][C:20](/[C:17](/[CH2:18][CH3:19])=[C:16](\[C:35]2[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=2)/[C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[N:8]=[CH:9]3)=[CH:25][CH:24]=1
Reactant: Ic1ccccn1
Reactant: CC/C(=C(/c1ccc(C=O)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC/C(=C(/c1ccc(C=O)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccc(-c2ccccn2)cc1
Temperature: 70 °C
Yield: 40.9 %

Procedure:
A mixture of (E)-4-(1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-1-en-1-yl)benzaldehyde (220 mg, 0.39 mmol), 2-iodopyridine (0.062 mL, 0.58 mmol), and KOH (6M aq., 0.40 mL, 2.34 mmol) in 1,4-dioxane was degassed with nitrogen. PdCl2dppf.DCM (31 mg, 0.04 mmol) was added and the resulting mixture was heated to 70° C. overnight. The mixture was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with brine (3×), dried over sodium sulfate, and purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate/hexanes to afford 82 mg of the title compound as a yellow foam. LCMS: 514 (M+H)+.
Reaction SMILES: [Na].[O-]CC.[Na+].[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:17]([O:19][C:20](=[O:43])/[CH:21]=[CH:22]/[C@@H:23]1[CH2:27][C@@H:26]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:25][N:24]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH3:18].C(O)(=O)C>C(O)C>[C:39]([O:38][C:36]([N:24]1[CH2:25][C@H:26]([O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:30])[CH3:31])[CH2:27][C@H:23]1[CH:22]([CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:43])[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([O:14][CH2:15][CH3:16])=[O:13])=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCOC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CC(C(C(=O)OCC)C(=O)OCC)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To sodium metal (6.90 g, 0.30 mol), absolute ethanol (300 ml) was gradually added to prepare sodium ethoxide, and a solution of diethyl malonate (151.9 ml, 1.0 mol) in ethanol (500 ml) was dropwise added thereto at room temperature. A solution of (E)-3-[(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]-acrylic acid ethyl ester (400 g, 1.0 mol, compound of Reference Example 1-4) in ethanol (1500 ml) was further added thereto at the same temperature, and stirred overnight. After acetic acid (17.2 ml, 0.30 mol) was added thereto under cooling with ice, the reaction solution was concentrated under reduced pressure to obtain triethyl 2-[(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]-1,1,3-propanetricarboxylate (558.3 g) as a crude oil.
Reaction SMILES: [CH2:1]([C:3]([CH3:5])=[O:4])[CH3:2].CO.[OH-].[K+].[CH3:10][C:11]1[C:15]([CH3:17])([CH3:16])[CH:14]([CH2:18][CH:19]=O)[CH2:13][CH:12]=1.S(=O)(=O)(O)O>O>[CH3:2][C:1](=[CH:19][CH2:18][CH:14]1[CH2:13][CH:12]=[C:11]([CH3:10])[C:15]1([CH3:17])[CH3:16])[C:3](=[O:4])[CH3:5]
Reactant: CC1=CCC(CC=O)C1(C)C
Reactant: CCC(C)=O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)C(C)=CCC1CC=C(C)C1(C)C
Reaction time: 21 h

Procedure:
To a stirred solution of 400 g (6.1 moles) of methyl ethyl ketone, 1025 g (32 moles) of methanol, 30.5 g (0.54 mole) of potassium hydroxide and 380 g of water cooled to -5° to -10° C was added 152 g (1.0 mole) of campholenic aldehyde over 15-30 minutes. The mixture was maintained at 0° to -10° C for 24-36 hours and then at 25°-35° C for 18-24 hours. The mixture was neutralized by addition of 36.8 g of 62.5% sulfuric acid and the unreacted methyl ethyl ketone and excess methanol were removed by atmospheric distillation. The residual liquid was added to 200 ml of hexane and 200 ml of water. The aqueous layer was drawn off and the hexane layer was washed with 200 ml of brine. The hexane was removed by atmospheric distillation and the oil fractionally distilled under vacuum to give 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl) pent-3-en-2-one and two other isomers in a ratio of ca. 86:6:8 by glc. Yield 140.3 g (85% theory); bp 102°-105° C (1.3 mm); nD20 1.4888; mol wt. 206 (ms); nmr, 0.8δ (3H, s), 1.0 (3H, s), 1.6 (3H, broad s), 1.8 (3H, broad s), 2.3 (3H, s, acetyl CH3), 5.3 (1H, broad multiplet, olefinic H), 6.7 (1H, complex, β-olefinic H of an α,β-unsaturated carbonyl system); ir, 3030, 1670, 1635, 790 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]1[NH:33][C:32](=[O:34])[N:31]2[C:35]([CH3:41])=[N:36][C:37]([CH2:38][CH2:39][CH3:40])=[C:30]2[N:29]=1)[CH3:16]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:14])[S:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:15][CH3:16])=[C:19]([C:28]3[NH:33][C:32](=[O:34])[N:31]4[C:35]([CH3:41])=[N:36][C:37]([CH2:38][CH2:39][CH3:40])=[C:30]4[N:29]=3)[CH:20]=2)(=[O:25])=[O:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Reactant: CNCCc1ccc(OC)c(OC)c1
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)N(C)CCc4ccc(OC)c(OC)c4)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
143 mg (0.73 mmol) of N-(3,4-dimethoxyphenylethyl)-N-methylamine are added to a solution of 100 mg (0.24 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-α][1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 2 hours. After chromatographic purification (dichloromethane/methanol=95:5), 138 mg (98%) of N-[2-(3,4-dimethoxy-phenyl)-ethyl]-4-ethoxy-N-methyl-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-α][1,3,5]triazin-2-yl)-benzenesulfonamide are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=1.[OH-].[Na+].[C:16](=S)=[S:17].N[C@H](C(O)=O)C[CH2:22][S:23][CH3:24]>CN(C=O)C.O>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][N:10]=[C:9]([N:13]=[C:22]([S:17][CH3:16])[S:23][CH3:24])[CH:8]=1
Reactant: Nc1cc(-c2cnccn2)ncn1
Reactant: CSCC[C@H](N)C(=O)O
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CSC(=Nc1cc(-c2cnccn2)ncn1)SC
Reaction time: 1.5 h
Yield: 43.7 %

Procedure:
To a solution of 6-(pyrazin-2-yl)pyrimidin-4-amine (0.2 g, 1.155 mmol) in DMF was added NaOH (0.115 mL, 2.310 mmol), CS2 (0.174 mL, 2.89 mmol), NaOH (0.115 mL, 2.310 mmol) and Met (0.181 mL, 2.89 mmol) at 15 min intervals. Stirring was continued for 1.5 h and the mixture was poured into water. The orange solid was separated, washed with water, dried to give a bright yellow solid (0.14 g, 0.505 mmol, 44%). MS (LC/MS) R.T.=3.19; [M+H]+=278.19.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>ClCCl>[C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13](=[O:15])[NH:23][CH2:22][CH:19]2[CH2:21][CH2:20]2)[CH:11]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NNc1cccc(C(=O)O)c1
Reactant: NCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNc1cccc(C(=O)NCC2CC2)c1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
The 4.40 g of unpurified 3-(2-tert-butoxycarbonylhydrazino)benzoic acid was dissolved in 80 ml of dichloromethane. To this mixture, 1.78 g of cyclopropylmethylamine and 3.45 g of 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloric acid salt were added and the resulting mixture was heated at reflux for 2 hours. After leaving the reaction mixture to cool to room temperature, the mixture was sequentially washed with 50 ml of water, 50 ml of 1N hydrochloric acid and then 50 ml of aqueous saturated sodium hydrogen carbonate solution, dried and concentrated to obtain 3.42 g of crude crystals. The crude crystals were recrystallized twice from ethyl acetate-hexane to obtain 1.29 g (yield 40%, three steps) of the captioned compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:13].[C:14]1(=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[O:15]1.CC1C=CC=CC=1>O>[O:15]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:1]1[C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:13]
Reactant: CCOC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CC[C@@H](N2C(=O)c3ccccc3C2=O)[C@H](O)C1

Procedure:
A mixture of 4.7 parts of ethyl trans-4-amino-3-hydroxy-1-piperidinecarboxylate, 3.7 parts of 1,3-dihydroisobenzofuran-1,3-dione and 45 parts of methylbenzene was stirred and refluxed for 2 hours using a water-separator. The reaction mixture was decanted from some insoluble tar. The methylbenzene-phase was evaporated in vacuo in a boiling water-bath. The residue was boiled in 2,2'-oxybispropane. After cooling, the solvent was decanted. The remaining oil solidified on scratching in 2,2'-oxybispropane. The product was filtered off and dissolved in dichloromethane. The solution was washed successively with a dilute hydrochloric acid solution, water a dilute sodium hydroxide solution and again water. The organic phase was dried, filtered and evaporated in vacuo. The residue solidified on scratching in 2,2'-oxybispropane. The product was filtered off and crystallized from 2-propanol, yielding 2.12 parts of ethyl trans-4(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3-hydroxy-1-piperidinecarboxylate; mp. 128.4° C. (intermediate 57).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1>C(O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10]([N:15]3[CH2:16][CH2:17][CH2:18][C@H:14]3[CH3:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccc(Br)cc2)C1
Reactant: C[C@@H]1CCCN1
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@@H]1CCCN1[C@H]1C[C@@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a solution of 3-(4-bromo-phenyl)-cyclobutanone (1 g, 4.44 mmol) in ethanol (20 mL) was added a solution of (R)-2-methylpyrrolidine (prepared according to the procedure that described in: R. Altenbach et al., WO 2004043458, and Y. Pu et al., Organic Process Research & Development, 9(1), 45-50, 2005) (0.75 g, 8.9 mmol) in toluene. Borane-pyridine complex (0.67 mL, 6.6 mmol) was added subsequently and stirred at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure to dryness and partitioned between ethyl acetate and H2O. The organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Chromatography of the residue eluting with a gradient of 1-2% (9:1 MeOH:concentrated NH4OH) in dichloromethane provided the title compound (680 mg, 52%) as the faster eluting component and the product from Example 1B (76 mg, 6%) as the slower eluting component. 1H NMR (300 MHz, CD3OD) δ 1.15 (d, J=6 Hz, 3 H), 1.46 (m, 1 H), 1.77 (m, 2 H), 1.99 (m, 1 H), 2.07 (m, 2 H), 2.34 (m, 1 H), 2.58 (m, 3 H), 3.04 (m, 2 H), 3.17 (m, 1 H), 7.17 (d, J=9 Hz, 2 H), 7.41 (d, J=9 Hz, 2 H); (DCl/NH3) m/z 294 (M+H)+.
Reaction SMILES: [H-].[Na+].C([O:5][CH2:6][CH3:7])=O.[CH3:8][C:9]1[S:10][C:11]2[C:17](=[O:18])C[CH2:15][CH2:14][C:12]=2[N:13]=1.Cl>CCOCC.CO.CCCCCC>[CH3:8][C:9]1[S:10][C:11]2[C:17](=[O:18])[CH:7]([CH:6]=[O:5])[CH2:15][CH2:14][C:12]=2[N:13]=1
Reactant: CCOC=O
Reactant: Cc1nc2c(s1)C(=O)CCC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: CCCCCC
Product: Cc1nc2c(s1)C(=O)C(C=O)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
To a suspension of hexane-washed NaH (1.1 g, 44.8 mmol) in dry Et2O (70 mL) was added dry MeOH (6.1 mL). After evolution of H2 had subsided, freshly distilled ethyl formate (7.3 mL, 6.7 g, 89.7 mmol) was added, followed by 2-methyl-5,6-dihydro-4H-benzothiazol-7-one (3.0 g, 17.9 mmol) in dry Et2O (12 mL). The reaction mixture was stirred at room temperature for 16 h. 10% aq HCl solution was added (150 mL) and the product was extracted with EtOAc (5×150 mL). The combined organic extracts were dried, filtered, and concentrated under vacuum to leave a brown oily crude product. Purification by flash column chromatography (20% EtOAc:hexane) afforded the pure title product as a yellow solid (2.30 g, 66%): mp 107-108° C. Anal. RP-HPLC: tR 12.6 min (0-60% MeCN, purity 100%). 1H-NMR (CDCl3): δ 9.90 (s, CHO), 7.20 (s, 1H, CH), 2.91 (t, 2H, J 7.1, CH2), 2.67 (s, 3H, CH3), 2.58 (t, 2H, J 7.1, CH2). 13C-NMR (CDCl3): δ 198.6, 186.3, 174.2, 165.7, 162.6, 131.0, 108.4, 27.0, 24.5, 20.7. MS: (ESI−) m/z 193.98 (M−H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[CH3:12].[NH2:13][C:14]1[N:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:12])[CH:4]=3)=[N:19][CH:18]=2)[CH2:25][CH2:24]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Cc1cc(CC(=O)O)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(Br)c(C)c3)nc2)CC1
Temperature: 25 °C

Procedure:
To a mixture of 2-(4-bromo-3-methylphenyl)acetic acid 24-5 (100 mg, 0.44 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (96 mg, 0.44 mmol) and HATU (200 mg, 0.53 mmol) in DMF (2 mL) was added DIEA (230 uL, 1.32 mmol) and the mixture was stirred at room temperature over night. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over Na2SO4 and the solvent was evaporated. The residue was subject to silica gel flash chromatography to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-bromo-3-methylphenyl)acetamide 159-1. MS m/z 431.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)/[C:19](/[NH2:22])=[N:20]/[OH:21])[C:8]2=[O:26])=[CH:4][CH:3]=1.[C:29](OCC)(OCC)(OCC)[CH3:30]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:25]=[CH:24][CH:23]=[C:18]([C:19]4[N:22]=[C:29]([CH3:30])[O:21][N:20]=4)[CH:17]=3)[C:8]2=[O:26])=[CH:27][CH:28]=1
Reactant: COc1nn(-c2cccc(/C(N)=N/O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Reactant: CCOC(C)(OCC)OCC
Agent: O=S(=O)(O)O
Product: COc1nn(-c2cccc(-c3noc(C)n3)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Yield: 25 %

Procedure:
According to Scheme 9 Step 2: A mixture of (Z)-3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-N′-hydroxybenzamidine (150 mg, 0.4 mmol), triethyl orthoacetate (2 mL) and of sulfuric acid (1 drop) was stirred at 100° C. 4 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 10 g prepacked column, cycloexane/ethyl acetate 80/20 to afford 4-(4-chlorobenzyl)-6-methoxy-2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 4.146 (40 mg, Yield=25%) as a white solid.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.Cl.[NH2:10][C@H:11]([C:15]([NH2:17])=[O:16])[CH2:12][CH2:13][CH3:14].[OH-].[Na+]>CO>[OH:16][C:15]1[C:11]([CH2:12][CH2:13][CH3:14])=[N:10][C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[N:17]=1
Reactant: CCC[C@H](N)C(N)=O
Reactant: O=C1CCCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc2c(nc1O)CCCC2
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
1,2-cyclohexanedione (5.4 g, 48 mM) was added all at once to a methanol solution (80 ml) of norvalineamide hydrochloride (6.1 g, 40 mM) at -30° C., and aqueous 12.5N NaOH (8 ml) was added dropwise thereto. The reaction mixture was stirred at -30° C. for 30 mins., cooling was removed, and the mixture stirred at room temperature for 3 hours. Conc. hydrochloric acid (10 ml) was added to the reaction mixture under ice-cooling, sodium bicarbonate (8 g) was added after 10 mins., the methanol then being distilled off in vacuo. The residue was extracted with chloroform, and the extract washed with water, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product as colorless crystals (3.8 g., yield: 50%, m.p.: 131°-133° C.).
Reaction SMILES: [Si](OC1C2C(=CC(C3C=CC(OC)=CC=3N)=CC=2)CC1)(C(C)(C)C)(C)C.BrC1C=CC(OCCN2CCCCC2)=CC=1.[Si]([O:50][CH:51]1[C:59]2[C:54](=[CH:55][C:56]([C:60]3[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][C:61]=3[NH:68][C:69]3[CH:74]=[CH:73][C:72]([O:75][CH2:76][CH2:77][N:78]4[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]4)=[CH:71][CH:70]=3)=[CH:57][CH:58]=2)[CH2:53][CH2:52]1)(C(C)(C)C)(C)C>>[CH3:67][O:66][C:63]1[CH:64]=[CH:65][C:60]([C:56]2[CH:55]=[C:54]3[C:59](=[CH:58][CH:57]=2)[CH:51]([OH:50])[CH2:52][CH2:53]3)=[C:61]([NH:68][C:69]2[CH:74]=[CH:73][C:72]([O:75][CH2:76][CH2:77][N:78]3[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]3)=[CH:71][CH:70]=2)[CH:62]=1
Reactant: COc1ccc(-c2ccc3c(c2)CCC3O[Si](C)(C)C(C)(C)C)c(Nc2ccc(OCCN3CCCCC3)cc2)c1
Agent: Brc1ccc(OCCN2CCCCC2)cc1
Agent: COc1ccc(-c2ccc3c(c2)CCC3O[Si](C)(C)C(C)(C)C)c(N)c1
Product: COc1ccc(-c2ccc3c(c2)CCC3O)c(Nc2ccc(OCCN3CCCCC3)cc2)c1
Yield: 69 %

Procedure:
Synthesized from 2-[1-(tert-butyldimethylsilyloxy)indan-5-yl]-5-methoxyphenylamine and 1-[2-(4-bromophenoxy)ethyl]piperidine according to an analogous synthetic method to Example 116, {2-[1-(tert-butyldimethylsilyloxy)indan-5-yl]-5-methoxyphenyl}[4-(2-piperidin-1-ylethoxy) phenyl]amine (1.1 g) was used according to an analogous synthetic method to Example 325 to provide the title compound (608 mg).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.C(O)=O.CCN(CC)CC.C([O:36][C:37]([C@@H:39]1[CH2:44][C@@H:43]2[C@@H:41]([CH2:42]2)[N:40]1[C:45](=[O:59])[CH2:46][N:47]1[C:51]2=[N:52][CH:53]=[CH:54][CH:55]=[C:50]2[C:49]([C:56](=[O:58])[CH3:57])=[N:48]1)=[O:38])C=C>CN(C=O)C.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[C:56]([C:49]1[C:50]2[C:51](=[N:52][CH:53]=[CH:54][CH:55]=2)[N:47]([CH2:46][C:45]([N:40]2[C@H:39]([C:37]([OH:38])=[O:36])[CH2:44][C@@H:43]3[C@H:41]2[CH2:42]3)=[O:59])[N:48]=1)(=[O:58])[CH3:57]
Reactant: C=CCOC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)Cn1nc(C(C)=O)c2cccnc21
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=CO
Product: CC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)O)c2ncccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Allyl palladium chloride dimer (0.084 g, 0.231 mmol) and 2-di-tert-butylphosphino-2′-methylbiphenyl (0.288 g, 0.923 mmol) were dissolved in DMF (7.69 mL) under an argon atmosphere. The reaction mixture was stirred at RT for 10 min. After cooling the reaction mixture to 10° C., formic acid (0.513 mL, 13.38 mmol) was added followed by Et3N (1.86 mL, 13.38 mmol) and a solution of (1R,3S,5R)-2-[2-(3-acetyl-pyrazolo[3,4-b]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid allyl ester (1 g, 2.3 mmol) in DMF (15.4 mL). The reaction mixture was stirred at 10° C. for 1 h. DMF was evaporated. The residue was poured into NH4Cl (sat. aq. solution) and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH and filtered over a PL-Thiol cartridge. The filtrate was concentrated and the crude residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5% to 80% CH3CN in H2O in 20 min, CH3CN and H2O containing 0.1% TFA) and the pure fractions were combined and lyophilized. White solid. MS (LCMS): 328.9 [M+H]+, 351.0 [MH+Na]; tR (HPLC conditions c): 1.84 min. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.66 (dd, J=4.52, 1.59 Hz, 1H), 8.58 (m, J=6.36 Hz, 1H), 7.35-7.50 (m, 1H), 8.54-8.61 (m, 1H), 5.88 (d, J=16.87 Hz, 1H), 5.55 (d, J=17.12 Hz, 1H), 4.14-4.24 (m, 1H), 3.75-3.83 (m, 1H), 2.64 (s, 3H), 2.26-2.36 (m, 1H), 2.10-2.23 (m, 1H), 1.80-1.95 (m, 1H), 0.95-1.07 (m, 1H), 0.67-0.81 (m, 1H).
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:10][C:5]2=[N:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Cl:23][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:3][N:4]=[C:5]2[CH2:10]1)=[O:12]
Reactant: C1COCCN1
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)nnc2C1
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nnc2N2CCOCC2)C1
Temperature: 110 °C

Procedure:
3-Bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.075 g, 0.183 mmol, e.g. see Example 1 for methods of preparation) was treated with morpholine (1.5 mL) and heated in a microwave reactor at 110° C. for a total of 7 hours. The solvent was evaporated under reduced vacuum and the residue was purified by mass-directed automated (preparative) HPLC (MDAP) and triturated with isohexane to afford 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-morpholinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.012 g) as white solid.
Reaction SMILES: F[C:2](F)(F)[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.Cl[C:14]1[CH:19]=[C:18](Cl)[CH:17]=[CH:16][C:15]=1[NH:21][NH2:22].[OH-].[Na+]>C(O)(=O)C.O>[C:15]1([N:21]2[C:5](=[O:7])[CH2:4][C:3]([C:2]3[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=3)=[N:22]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: NNc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2)=NN1c1ccccc1
Yield: 171.5 %

Procedure:
To a mixture of ethyl trifluoroacetoacetate (5.0 g, 27.2 mmol) in acetic acid (50 mL) was added 2,4-dichlorophenylhydrazine (4.82 g, 27.2 mmol). The reaction mixture was refluxed for 22 hours and then was diluted with water (50 mL), neutralized with 2N NaOH and extracted with EtOAc (3×50 mL). The EtOAc extracts were combined, dried over Na2 SO4, filtered and concentrated to afford 5.51 g (70%) of 2,4-dihydro-2-(2,4-dichlorophenyl)-5-trifluoromethyl-3H-pyrazol-3-one (Formula III: R1 =2,4-Cl2 --Ph; R2 =CF3 ; R3 =H).