Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>>[C:12]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[N:8]=1)(=[O:16])[CH:13]([CH3:14])[CH3:15]
Reactant: COc1ccc2c(C(=O)C(C)C)n[nH]c2c1
Reactant: CC(C)(C)C(=O)CBr
Product: COc1ccc2c(C(=O)C(C)C)nn(CC(=O)C(C)(C)C)c2c1

Procedure:
Reaction of 1-(6-methoxy-1H-indazol-3-yl)-2-methylpropan-1-one with 1-bromo-3,3-dimethylbutan-2-one using a procedure similar to that described in Example 3 Step A gave the title compound. Recrystallization from 2:1 hexanes and EtOAc gave fine needles. 1H NMR (CDCl3, 500 MHz) δ 8.25 (d, 8.9 Hz, 1H), 6.98 (dd, 2.0 & 8.9 Hz, 1H), 6.52 (d, 1.8 Hz, 1H), 5.37 (s, 2H), 3.87 (s, 3H), 3.86 (heptet, 6.9 Hz, 1H), 1.36 (s, 9H), 1.27 (d, 6.8 Hz, 6H). LC-MS: 3.70 min. (m/Z=317.1, 339.1).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1[N:10]=[C:9](Cl)[C:8]([F:12])=[C:7]([Cl:13])[N:6]=1>C1COCC1>[Cl:13][C:7]1[C:8]([F:12])=[C:9]([O:2][CH3:1])[N:10]=[C:5]([CH3:4])[N:6]=1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C)nc(Cl)c1F
Temperature: 5 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
3.21 g of sodium methoxide are added to a solution of 9.8 g of 2-methyl-4,6-dichloro-5-fluoropyrimidine in 80 ml of THF cooled to 5° C. in an ice bath. The ice bath is removed. The suspension is stirred at ambient temperature for 3 hours. The reaction medium is cooled to 5° C. in an ice bath. 20 ml of water and 100 ml of ethyl acetate are added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give 9 g of 4-chloro-5-fluoro-6-methoxy-2-methylpyrimidine in the form of a colorless oil which crystallizes, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:17]([NH2:21])[CH:18]([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]=[C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[N:24]1[CH2:33][CH2:34][CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:17]([NH:21][CH2:35][CH2:34][CH2:33][N:24]1[C:25](=[O:32])[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]1=[O:22])[CH:18]([CH3:19])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)C(N)c1nc2ccccc2n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)C(NCCCN1C(=O)c2ccccc2C1=O)c1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(1-benzyl-1H-benzimidazol-2-yl)-2-methyl-propylamine (160 mg, 0.56 mmol) and 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde (114 mg, 0.56 mmol) in dry DCM (3 ml) at room temperature, was added sodium triacetoxyborohydride (119 mg, 0.56 mmol). After 10 minutes, acetic acid (34 μl, 0.56 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography to give material that was used in Example 5g.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH2:17])[N:16]=3)[CH:11]=[CH:12][N:13]=2)[C:4]([CH3:18])=[N:3]1.ClC1C2N(N=C(N)N=2)C=CN=1.CN1C(C)=C(B(O)O)C(C)=N1.Cl[C:42]1[CH:50]=[C:49]2[C:45]([C:46]([CH3:53])([CH3:52])[C:47](=[O:51])[NH:48]2)=[CH:44][CH:43]=1>>[CH3:52][C:46]1([CH3:53])[C:45]2[C:49](=[CH:50][C:42]([NH:17][C:15]3[N:16]=[C:9]4[C:8]([C:5]5[C:4]([CH3:18])=[N:3][N:2]([CH3:1])[C:6]=5[CH3:7])=[N:13][CH:12]=[CH:11][N:10]4[N:14]=3)=[CH:43][CH:44]=2)[NH:48][C:47]1=[O:51]
Reactant: CC1(C)C(=O)Nc2cc(Cl)ccc21
Reactant: Cc1nn(C)c(C)c1-c1nccn2nc(N)nc12
Agent: Cc1nn(C)c(C)c1B(O)O
Agent: Nc1nc2c(Cl)nccn2n1
Product: Cc1nn(C)c(C)c1-c1nccn2nc(Nc3ccc4c(c3)NC(=O)C4(C)C)nc12

Procedure:
8-(1,3,5-Trimethylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, synthesized by reaction of 8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine with (1,3,5-trimethylpyrazol-4-yl)boronic acid following procedure 1, is coupled with 6-chloro-3,3-dimethyl-1,3-dihydro-indol-2-one under Buchwald Hartwig conditions using general procedure 2.
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O1CCCC1>[O:20]1[CH2:21][CH2:22][N:17]([CH:2]2[C:14]3[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=3)[CH2:18][CH2:19]1
Reactant: C1COCCN1
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Solvent: C1CCOC1
Product: O=c1[nH]c2c([nH]c1=O)C(N1CCOCC1)c1ccccc1-2
Reaction time: 20 h
Yield: 42.3 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione (0.50 g, 2.13 mmol) was suspended in 5 ml of dry tetrahydrofuran, while cooling in an ice bath. Morpholine(0.37 ml, 4.27 mmol) dissolved in 2 ml of dry tetrahydrofuran was added over 2 min. After 1 hour the ice bath was removed and stirring was continued for 20 hours at room temperature. The precipitate was filtered off and washed with tetrahydrofuran, 10% acetic acid, water and dried to give 0.365 g of the crude product. Recrystallization from ethanol afforded 0.257 g (42%) of the title compound. M.p. 265°-267° C. 1H-NMR (DMSO-d6, δ): 2.47 (m, 2H), 2.61 (m, 2H), 3.56 (m, 4H), 4.54 (s, 1H), 7.13 (t, 1H), 7.3 (t, 1H), 7.47 (d, 1H), 7.53 (d, 1H), 11.8 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.[C:14]1([Li])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO.[BH4-].[Na+]>C1COCC1>[NH3:3].[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1([CH:12]([NH2:13])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: [Li]c1ccccc1
Reactant: CC1CCCN1C1(C#N)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1CCCN1C1(C(N)c2ccccc2)CCCC1
Product: N
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of (±)-1-(2-methyl-1-pyrrolidinyl)cyclopentanecarbonitrile D39 (0.997 g; 5.6 mmol) in dry THF was cooled to −70° C. To this phenyllithium (1.7M in C6H14/ether, 1.1 equiv) was added slowly. The whole mixture was allowed to warm slowly to room temperature over 3 h with stirring under argon. Reaction cooled to 0° C. and methanol added followed by sodium borohydride (portionwise) and allowed to react at 20° C. overnight. The reaction was cooled to 0° C. and quenched with saturated sodium bicarbonate, extracted with ethyl acetate, dried (Na2SO4) and evaporated. The product was purified by chromatography on a 5 g SCX column eluting from 0-100% ethyl acetate in pet. ether, 0-10% methanol in ethyl acetate then 2% 0.880 ammonia in ethyl acetate to give the title compound as an oil (0.67 g; 46%) was obtained. Mass Spectrum (Electrospray LC/MS): Found 259 (MH+). C17H26N2 requires 258. Ret. time 1.19 min.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH3:16][C:17]1[NH:18][C:19](=[O:23])[CH2:20][S:21][CH:22]=1>C(#N)C>[CH3:16][C:17]1[NH:18][C:19](=[O:23])[CH2:20][S:21][C:22]=1[CH:14]1[CH:13]=[CH:12][N:11]([C:5]([O:4][CH2:3][C:2]([Cl:9])([Cl:8])[Cl:1])=[O:6])[N:10]=[CH:15]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC1=CSCC(=O)N1
Reactant: c1ccnnc1
Solvent: CC#N
Product: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)N=C2)SCC(=O)N1
Reaction time: 0.17 h
Yield: 63 %

Procedure:
2,2,2-Trichloroethylchloroformate (3.44 ml) was added dropwise to a solution of pyridazine (1.44 ml) in dry acetonitrile (40 ml) under ice-cooling, and the mixture was stirred for 10 minutes. 5-Methyl-2H-1,4-thiazin-3(4H)-one (1.29 g) was added to the mixture. The reaction mixture was further stirred at ambient temperature for 1 hour. Then, the solvent was removed under reduced pressure and the residue was extracted with chloroform. The extract was washed with 2N hydrochloric acid and successively with water, was dried over mangnesium sulfate and the solvent was removed. The residue was chromatographed on silica gel (Wakogel C-200) column, using ethyl acetate-n-hexane (=1:1) as an eluant to give the titled compound (2.4 g, yield 63%) as white crystals.
Reaction SMILES: Cl.NC[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:14])[CH:5]=1.[C:15]([O:19][C:20]([O:22]C(OC(C)(C)C)=O)=O)([CH3:18])([CH3:17])[CH3:16].[CH2:30]([N:32](CC)CC)C>CO>[C:15]([O:19][C:20]([NH:32][CH2:30][C:5]1[C:6]([OH:14])=[C:7]([CH:12]=[CH:13][CH:4]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:22])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(CN)cc1O
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
Methyl 4-aminomethyl-2-hydroxybenzoate hydrochloride (10.9 g, 50 mmoles) was suspended in anhydrous methanol (200 mL) and di-tert-butyldicarbonate (10.9 g, 50 mmoles) and triethylamine (7.0 mL, 50 mmoles) were added. The solid rapidly dissolved with the slow evolution of gas. The reaction mixture was stirred at room temperature for 18 hours under dry nitrogen, then evaporated to dryness to afford a white amorphous mass. This mass was partitioned between ethyl acetate (200 mL) and water (100 mL). The layers were separated, and the ethyl acetate solution was dried over anhydrous sodium sulfate. The solution was filtered and evaporated to a white solid. This solid was crystallized from ethyl acetate/hexanes, filtered, and dried in vacuo to afford 13.7 g (97% yield) of methyl N-tert-butoxycarbonylaminomethyl-2-hydroxybenzoate (m.p. 95-96° C., open capillary, uncorrected).
Reaction SMILES: C[CH:2]1[O:4][CH:3]1[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][CH:8]=1.[C:14]([OH:19])(=[O:18])[C:15]([CH3:17])=[CH2:16].[CH2:20](N(CC)CC)C>C(Cl)Cl>[C:14]([O:19][CH2:2][CH:3]([OH:4])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:20])[CH:10]=[C:11]([CH3:13])[CH:12]=1)(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)O
Reactant: Cc1cccc(OCC2OC2C)c1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCC(O)COc1cc(C)cc(C)c1
Temperature: 60 °C
Yield: 472.5 %

Procedure:
In a two neck flask equipped with a condenser under nitrogen atmosphere were placed 10.00 g (0.0561 mol) of 3,5-dimethylphenoxymethyl oxirane, 5.07 g (0.059 mol) of methacrylic acid, 0.90 g (0.009 mol) of triethylamine and 30 mg of BHT. The reaction mixture was stirred at 60° C. 1H NMR showed reaction completion at 36 hours. Reaction mixtures was dissolved in methylene chloride and extracted with saturate solution of sodium hydroxide (NaOH) 3×25 ml, diluted solution of acid chloride (HCl) 2×25 ml, 2×25 ml of saturated solution of sodium bicarbonate (NaHCO3) and finally with brine 1×25 ml. Organic layer was dried over sodium sulfate (Na2SO4), filtered and vacuum dried. 11.24 grams (yield: 75%) of a amber viscous oil were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(OCC)C>CO.CCCCCC.[Cu](Br)Br>[CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8]
Reactant: CC1(C)C(=O)CCC1=O
Agent: Br[Cu]Br
Solvent: CCOCC
Solvent: CO
Solvent: CCCCCC
Product: CC1(C)C(=O)C=CC1=O
Temperature: 25 °C
Yield: 65 %

Procedure:
Copper (II) bromide (63.4 g, 0.28 mol) was added to a stirred solution of the dione 2 (17.9 g, 0.14 mol) in methanol (280 ml) at room temperature, under an atmosphere of nitrogen. The reaction was heated under reflux for 90 minutes and then cooled to room temperature. The mixture was then filtered through celite, washing with dichloromethane (3×250 ml) and evaporated in vacuo. Flash chromatography (SiO2, 50% diethyl ether in hexane) gave the enedione 3 (11.3 g, 91.0 mmol, 64%) as a yellow oil; δH (300 MHz, CDCl3) 7.22 (2H, s, CH═CH), 1.17 (3H, s, CH3), 1.15 (3H, s, CH3); δC (75.5 MHz, CDCl3) 207.7 (s), 147.1 (d), 46.4 (s), 19.5 (q).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([Cl:15])[C:12]([N+:16]([O-:18])=[O:17])=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C1COCC1>[CH2:1]([S:8][C:9]1[N:10]=[C:11]([NH:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:12]([N+:16]([O-:18])=[O:17])=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(Cl)nc(SCc2ccccc2)nc1Cl
Reactant: NC1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1c(Cl)nc(SCc2ccccc2)nc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
To a solution of 2-(benzylthio)-4,6-dichloro-5-nitropyrimidine (WO 01/58906 A1) (9 g, 28.5 mmol) in THF (60 mL) and DIEA (9.9 mL, 7.36 g, 57 mmol, 2 equiv.) was added drop wise a solution of 4-aminotetrahydropyran (2.77 g, 27.4 mmol, 0.96 equiv.) in THF (20 mL) over 15 min. The reaction mixture was stirred at room temperature for 18 h. The solvent was then removed in vacuo and the residue purified by column chromatography (silica gel, elution with 4/1 hexanes/ethyl acetate) to afford, after evaporation and drying, the desired product as a yellow solid (7.59 g, 70% yield). 1H NMR (300 MHz, CDCl3) δ, ppm: 7.86 (br d, J=6.8 Hz, 1H), 7.42-7.36 (m, 2H), 7.36-7.27 (m, 3H), 4.38 (s, 2H), 4.31-4.20 (m, 1H), 3.96 (dt, J=11.7, 3.5 Hz, 2H), 3.47 (ddd, J=11.7, 11.3, 2.2 Hz, 2H), 1.92 (br dd, J=12.4, 2.2 Hz, 2H), 1.66-1.52 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[OH2:7].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(O)CCC>[S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)([O-:17])(=[O:16])=[O:15].[CH3:8][CH2:9][CH:10]([O:7][C:2]([CH2:3][CH2:4][CH2:5][NH3+:1])=[O:6])[CH3:11]
Reactant: O=C1CCCN1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Solvent: CCCCO
Product: CCC(C)OC(=O)CCC[NH3+]
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 60 °C

Procedure:
Into a reactor flask equipped with magnetic stirrer, thermometer, nitrogen inlet tube, and Dean-Stark trap were placed 47.0 parts of 2-pyrrolidinone (4-butanelactam), 109.4 parts of para-toluenesulfonic acid monohydrate, and 197.4 parts of butanol. The aforesaid mixture was placed under nitrogen atmosphere, heated to reflux to azeotropically remove any water present, and maintained at reflux until a constant acid value was attained. (The acid value was determined by the procedure described in Example I, above.) The reaction mixture was allowed to cool to 60° C. followed by the addition of 280.8 parts of methanol over a five-minute period. The mixture was stirred and filtered to yield the [(3-butoxycarbonyl)propyl]ammonium tosylate. The aforesaid latent acid catalyst had a solids content of 30 percent in methanol and isobutanol.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.[N:21]1[N:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]2=[C:23]([C:30](O)=[O:31])[CH:22]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:30]([C:23]1[CH:22]=[N:21][N:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]=12)=[O:31]
Reactant: O=C(O)c1cnn2cccnc12
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a solution of (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (80.0 mg, 0.259 mmol) in DMF (5 ml) was added pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (42.3 mg, 0.259 mmol), HOBT.H2O (39.7 mg, 0.259 mmol) and HBTU (98.0 mg, 0.259 mmol). Finally DIPEA (0.136 ml, 0.778 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. DMF was evaporated in vacuo then 5 ml of DCM added and washed with saturated aq. NaHCO3 solution (5 ml), dried on a phase separation cartridge and evaporated in vacuo. The crude material was dissolved in MeCN/DMSO 1:1 and purified by MDAP. The desired fractions were collected and concentrated in vacuo to give the title compound as a white solid (105 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:15][NH2:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27].O1CCOCC1.CCOCC>CO>[ClH:27].[N:11]1([CH:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=2)[CH2:15][NH2:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: NCC(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of 4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (185 mg; 0.5 mmol; 1.0 eq.) and 4M hydrogen chloride in dioxane (1.8 ml; 7.4 mmol; 15 eq.) in Methanol (3.00 ml) was stirred at room temperature overnight. Ether was added to the reaction mixture. The precipitate was filtered, washed with ether and dried to yield 2-piperazin-1-yl-2-(4-trifluoromethyl-phenyl)-ethylamine hydrochloride salt as off-white solid in 67% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.[NH2:19][CH2:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1>>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:19][CH2:20][CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: NCCc1c[nH]c2ccccc12
Product: CP(C)(=O)c1ccc(Nc2cc(NCCc3c[nH]c4ccccc34)ncn2)cc1

Procedure:
The compound is prepared as in Example 59 by reacting 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with Tryptamine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[O:7]=[CH:8][C:9]([Cl:12])([Cl:11])[Cl:10].C(N(CC)CC)C>CCOCC>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:8]([OH:7])[C:9]([Cl:12])([Cl:11])[Cl:10]
Reactant: Cn1cccc1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cn1cccc1C(O)C(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 102.4 %

Procedure:
To a solution of N-methylpyrrole (1.62 g, 20 mmol) in ether (10 ml) was added a solution of chloral (3.24 g, 22 mmol) in ether (10 ml). To this was added Amberlyst (160 mg) and the mixture was stirred under reflux for 18 hours. After cooling to room temperature and adding triethylamine (0.3 ml), the mixture was stirred for 5 minutes and filtered through a layer of Celite. The filtrate was concentrated under reduced pressure to afford the crude adduct 1-methyl-2-(2',2',2'-trichloro-1'-hydroxyethyl)pyrrole (4.68 g) as pale brown prisms.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.Cl.[NH2:41][O:42][CH3:43].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:43][O:42][N:41]=[C:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:6][CH2:7]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=NOC)CC2)c2ncnn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), (aminooxy)methane hydrochloride (0.32 g) and pyridine (10 mL) was stirred at 100° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.15 g, 71%).
Reaction SMILES: [Br:1][C:2]1[C:12]2[C:13]3[C:5]([CH:6]=[CH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[C:14]1([C:20]2O[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:23]3[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:12]2[C:13]3[C:5]([C:6]4[C:20]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[C:28]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]5=[C:22]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:7]=4[C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c3c(cccc13)C=C2
Reactant: c1ccc(-c2oc(-c3ccccc3)c3ccccc23)cc1
Solvent: Cc1ccccc1C
Product: Brc1ccc2c3c(cccc13)-c1c-2c(-c2ccccc2)c2ccccc2c1-c1ccccc1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
200 ml of xylene were added to 5-bromoacenaphthylene (14.5 g, 62.8 mmol) and diphenylisobenzofuran (17.1 g, 63.3 mmol) and the mixture was stirred under reflux of xylene for 5 hours. After the mixture was cooled to room temperature, the solvent was distilled off. Then, 26 ml of trifluoroacetic anhydride and 260 ml of chloroform were added thereto, followed by stirring under reflux for 1 hour. After the mixture was cooled to room temperature, the solvent was distilled off. The obtained residue was purified by silica gel chromatography (mobile phase; toluene:heptane=1:3), whereby 16 g of 4-bromo-7,12-diphenylbenzo[k]fluoranthene were obtained as a yellow solid.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC(CBr)[C:20]#[N:21].[CH2:24](N(CC)CC)[CH3:25]>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:25][CH2:24][N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][CH:8]2[C:20]#[N:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC(Br)CBr
Reactant: c1ccc(CNCCNc2ccccc2)cc1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#CC1CN(Cc2ccccc2)CCN1c1ccccc1

Procedure:
In a manner similar to Preparation 1, react N-phenyl-N'-(phenylmethyl)-1,2-ethanediamine (0.41 g, 1.8 mmol) with 2,3-dibromopropanenitrile (0.77 g, 3.6 mmol) in toluene (5 mL) with triethylamine (0.73 g, 0.72 mmol) to obtain the title compound.