Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:12][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:10])[F:11]
Reactant: FC(F)(F)c1ccccc1S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1ccccc1C(F)(F)F
Reaction time: 12 h
Yield: 88.3 %

Procedure:
Dissolve 2-trifluoromethyl-benzenethiol (10 g, 56 mmol), potassium carbonate (25 g, 180 mmol), iodomethane (11 mL, 177 mmol) in DMF (100 mL). Stir for 12 hours. Filter the suspension through a pad of silica gel and elute with ethyl acetate (500 mL). Evaporate half of the solvent and wash the remaining solution with 10% aqueous LiCl (100 mL). Dry with MgSO4 and evaporate solvent. Chromatograph the residue on a SiO2 column eluting with hexane to give 9.5 g of 1-methylsulfanyl-2-trifluoromethyl-benzene (88%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>N1C=CC=CC=1>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2])=[O:18]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)CCCCCBr
Solvent: c1ccncc1
Product: O=C(CCCCCBr)Nc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
To a solution of 2-nitroaniline (13.82 g, 100 mmol) in pyridine (120 mL) at 0° C. was dropwise added 6-bromohexanoyl chloride (22.6 mL, 32 g, 150 mmol) over 15 minutes. The resulting mixture was stirred for 1.5 hours at the same temperature, then poured into ice-water (500 mL) and extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with aqueous citric acid solution (2×100 mL), water (100 mL) and brine (50 mL). After removal of the solvent, the crude product was passed through a silica gel pad (100 g) and washed with 1:1 mixture of hexane and diethyl ether. Concentration of the appropriate fractions gave 28.4 g of 2 as yellow solid. LC-MS (M++1) 315
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.F[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O.O>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(Br)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Brc1ccc(-n2ccc3ccccc32)cc1
Temperature: 25 °C

Procedure:
A solution of 1H-indole (3.0 g, 25.6 mmol), 4-fluorobromobenzene (4.48 g, 25.6 mmol), potassium fluoride (40% wt on alumina; 3.0 g) and 18-crown-6 (690 mg, 2.56 mmol) in anhydrous DMSO (30 mL) was heated at 150° C. for 24 hours, and then cooled to room temperature. The reaction mixture was poured into water (50 mL) and extracted with diethyl ether (3×50 mL). The combined organic extract was washed with water (2×30 mL), brine (3×30 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 20% ethyl acetate/hexane as eluent, afforded the title compound has a pale yellow solid (5.5 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[CH2:10][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:10][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1
Reactant: COc1ccc(Cl)c(CSc2nc(C)cc(O)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)nc(SCc2cc(O)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a solution of the 2-{[(2-chloro-5-methoxyphenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (1.0 g, 3.36 mmol) compound in anhydrous dichloromethane at 0° C., 1 M solution of boron tribromide (0.844 g, 3.36 mmol) was added. The reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was quenched with sodium bicarbonate solution and the solid was filtered. The crude solid was purified by using dichloromethane and methanol (1:10) to provide the product 2-{[(2-chloro-5-hydroxyphenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (0.62 g, 65% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 4.34 (s, 2H), 5.98 (bs, 1H), 6.66 (d, J=8.8 Hz, 1H), 6.97 (s, 1H), 7.20 (d, J=8.8 Hz, 1H); M+ 283.06.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)[CH2:2][CH3:3].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH3:3]
Reactant: OB(O)c1ccccc1
Reactant: CCCNC(=O)c1ccc(Br)cc1
Product: CCCNC(=O)c1ccc(-c2ccccc2)cc1
Yield: 71 %

Procedure:
Using Preparation Method 2, N-n-propyl-4-bromobenzamide from Example 9A was reacted with phenylboronic acid. The resulting reaction mixture was purified using SiO2 with CH2Cl2/Petroleum Ether 80:20 to CH2Cl2/AcOH 80:20 to give a white solid (71%). NMR 1H (ppm, CDCl3): 7.82 (d, J3=8.32 Hz, 2H), 7.63 (d, J3=8.69 Hz, 2H), 7.59 (d, J3=7.14 Hz, 2H), 7.45 (t, J3=7.09 Hz, 2H), 7.39-7.34 (m, 1H), 6.14 (br. s., 1H), 3.47-3.41 (m, 2H), 1.65 (sext., J3=7.18 Hz, 2H), 0.99 (t, J3=7.37 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O>[Cl:8][C:6]1[CH:7]=[C:2]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=1
Reactant: CN1CCNCC1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Solvent: O
Product: CN1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1

Procedure:
Two grams of 4,6-dichloro-2-phenylpyrimidine is added in small portions to 10 ml. of N-methylpiperazine with slight warming and stirring. The resulting mixture is heated on a steam bath for several minutes, then poured into 250 ml. of water. The product (2.4 g., m.p. 81°-87°C.) is then recrystallized from n-pentane to afford 4-chloro-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine, m.p. 91°-92.5°C.
Reaction SMILES: O[CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][N:7]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].S(Cl)([Cl:21])=O>ClCCl>[Cl:21][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][N:7]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCc2c(CO)cccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(CCl)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a stirred solution of tert-butyl 4-(hydroxymethyl)indoline-1-carboxylate (230 mg, 0.92 mmol) in dichloromethane (3 mL), thionyl chloride (0.123 mL, 1.02 mmol) was added dropwise at 0° C. and stirred for 1 h. Then the mixture was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated under reduced pressure and dried under high vacuum to yield the title compound (217 mg, crude). The compound was directly used for the next step. [TLC Rf=0.86 (ethyl acetate/hexane 20:80)].
Reaction SMILES: C(OC([NH:11][C@H:12]([C:23]([O:25][CH2:26][C@@H:27]([C:35]([O:37]CC1C=CC=CC=1)=[O:36])[NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[O:24])[C@@H:13]([CH3:22])[O:14]CC1C=CC=CC=1)=O)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[NH2:11][C@H:12]([C:23]([O:25][CH2:26][C@@H:27]([C:35]([OH:37])=[O:36])[NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[O:24])[C@@H:13]([CH3:22])[OH:14]
Reactant: [H][H]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OCc1ccccc1)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H](N)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Yield: 93.9 %

Procedure:
Benzyl O-(N-benzyloxycarbonyl-O-benzyl-L-threonyl)-N-(trifluoroacetyl)-L-serinate (500 mg) was dissolved in acetic acid (10 ml) and the solution was hydrogenated over 10% palladium on activated carbon at 40 psi (500 mg) under 3 atomospheric pressure of hydrogen at room temperature for 1 hour. The mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in a small amount of methanol and the solution was diluted with diethyl ether to give a white precipitate. The precipitate was crystallized from aqueous methanol to give 230 mg of pure O-(L-threonyl)-N-(trifluoroacetyl)-L-serine as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:18])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2C1
Reactant: OCC1CCN(c2ccncc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.7 %

Procedure:
To a mixture of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (389 mg) and 4-hydroxymethyl-1-(pyridin-4-yl)piperidine (300 mg) in tetrahydrofuran (15 ml) and methylene chloride (5 ml) were added triphenylphosphine (450 mg) and diisopropyl azodicarboxylate (0.34 ml) and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:acetone=3:2-1:1, 1% triethylamine) and dried under reduced pressure to give the title compound (500 mg).
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.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:39])[CH2:35][CH:36]([CH3:37])[CH3:38])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 13 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-3-methylbutanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 10.79–10.51 (br, 1H), 8.85–8.67 (m, 1H), 8.01–7.81 (br, 1H), 7.70 (d, 1H, J=7.2 Hz), 7.47–7.14 (m, 11H), 6.89 (d, 1H, J=7.2 Hz), 5.03 (s, 1H), 3.53–3.26 (m, 4H), 2.96–2.80 (m, 2H), 2.78–2.52 (m, 3H), 2.44–2.14 (m, 2H), 2.26 (d, 2H, J=6.0 Hz), 2.14–1.94 (m, 3H), 1.94–1.76 (m, 2H), 1.10 (d, 6H, J=6.4 Hz); ESMS m/e: 512.3 (M+H)+; Anal. Calc. (HCl salt) C33H42ClN3O2.0.60CH2Cl2: C, 67.36; H, 7.27; N, 7.01. Found: C, 67.08; H, 7.57; N, 7.36.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:16]=[C:15]([NH:17][N:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)[CH:14]=[C:13]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd].C(O)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:16]=[C:15]([NH:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)[CH:14]=[C:13]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(CCOCc3ccccc3)n2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccc(CNNc2cc(N3CCOCC3)nc(CCOCc3ccccc3)n2)c1
Yield: 9600 %

Procedure:
Compound 91, N-[2-(2-benzyloxy-ethyl)-6-morpholin-4-yl-pyrimidin-4-yl]-N′-(3-methyl-benzylidene)-hydrazine (109 mg., 0.25 mmol) was dissolved in ethanol (20 mL) and to the solution was added 10% palladium on carbon (200 mg.), three drops of glacial acetic acid, and the reaction was stirred at room temperature under 1 atmosphere of hydrogen for 4 hours. The reaction was passed through celite, evaporated and purified by column chromatography to give Compound 92, N-[2-(2-benzyloxy-ethyl)-6-morpholin-4-yl-pyrimidin-4-yl]-N′-(3-methyl-benzyl)-hydrazine (106 mg., 24 mmol).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=3)[C:12]([NH:21][S:22]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)(=[O:24])=[O:23])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:38]([O:41][C:42]([CH3:47])([CH3:46])[C:43](Cl)=[O:44])(=[O:40])[CH3:39]>ClCCl>[C:38]([O:41][C:42]([CH3:47])([CH3:46])[C:43]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=3)[C:12]([NH:21][S:22]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)(=[O:24])=[O:23])=[N:11]2)[CH:4]=1)=[O:44])(=[O:40])[CH3:39]
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)C(C)(C)OC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A stirring suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (40.5 g, 87 mmol) in dichloromethane (1000 mL) and triethylamine (36.4 mL, 262 mmol) was cooled down and then 2-chloro-1,1-dimethyl-2-oxoethyl acetate (12.52 mL, 87 mmol) was added dropwise. The reaction mixture was stirred at room temperature under nitrogen for 1 h and 20 min. It was then washed with 2M HCl (300 ml), NaHCO3 solution (300 ml), brine, dried over magnesium sulphate and filtered. The filtrate was evaporated in vacuo to give a white solid. The residue was dissolved in DCM and loaded onto a 1500 g silica column and eluted with 40-100% ethyl acetate in cyclohexane over 8 CV. The required fractions were combined and evaporated in vacuo to give the title compound in two batches (37.87 g, 73%) and (3.39 g) as white foams. HPLC showed that the latter batch was not pure, therefore it was purified again on a 120 g silica column using a gradient of 40-75% ethyl acetate in cyclohexane over 8 CV. The required fractions were combined and evaporated in vacuo to give the title compound (2.16 g, 4%) as a white foam.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[N:45]=[CH:44][C:43]3[C:38](=[C:39]([F:50])[CH:40]=[C:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:42]=3)[C:37]2=[O:51])=[CH:34][CH:33]=[CH:32][C:31]=1[B-](F)(F)F)(=[O:27])[CH3:26].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.C(O)CCC>[C:25]([O:28][CH2:29][C:30]1[C:31]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:32][CH:33]=[CH:34][C:35]=1[N:36]1[N:45]=[CH:44][C:43]2[C:38](=[C:39]([F:50])[CH:40]=[C:41]([C:46]([CH3:48])([CH3:47])[CH3:49])[CH:42]=2)[C:37]1=[O:51])(=[O:27])[CH3:26]
Reactant: CC(=O)OCc1c(-n2ncc3cc(C(C)(C)C)cc(F)c3c2=O)cccc1[B-](F)(F)F
Reactant: CCN1CCC(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCCCO
Product: CCN1CCC(c2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4COC(C)=O)nn(C)c3=O)nc2)CC1
Temperature: 100 °C
Yield: 62.1 %

Procedure:
In a 50 mL test tube, 6-chloro-4-(5-(1-ethylpiperidin-4-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (121 mg, 348 μmol, Eq: 1.00) and potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (165 mg, 348 μmol, Eq: 1.00) were combined with BuOH (4 ml) to give a orange solution. Water (1.00 ml) was added. X-PHOS (16.6 mg, 34.8 μmol, Eq: 0.1) and potassium phosphate tribasic (148 mg, 696 μmol, Eq: 2) were added. Bis(dibenzylideneacetone)palladium (10.0 mg, 17.4 μmol, Eq: 0.05) was added. The reaction mixture was purged with argon. The mixture was heated in an oil bath at 100° C. for 1.5 hours, then cooled to room temperature. The reaction mixture was poured into 75 mL H2O and extracted with twice with EtOAc. The organic layers were combined and dried over Na2SO4. Concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 50% to 100% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give a solid. The solid was triturated with Et2O to give 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-ethylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (147 mg, 62%). LC/MS-ESI observed [M+H]+ 680.
Reaction SMILES: Br[C:2]([CH3:18])([CH3:17])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[CH3:19][O-:20].[Na+]>CO>[CH3:17][C:2]1([CH3:18])[O:4][C:3]1([O:20][CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: CC(C)(Br)C(=O)c1ccc(N2CCCCC2)cc1
Agent: [Na+]
Solvent: CO
Product: COC1(c2ccc(N3CCCCC3)cc2)OC1(C)C

Procedure:
12.0 g (38.7 mmol) of 2-bromo-2-methyl-1-(4-piperidinophenyl)-propan-1-one are dissolved in 20 ml of methanol, and 7.0 g (46.4 mmol) of methanolic 30% strength sodium methylate solution are then added dropwise at room temperature. The methanol is then distilled off under reduced pressure. The residue is taken up in toluene, and the precipitated salt is filtered off. The solution is concentrated in vacuo. The brown residue, which is a slowly crystallising liquid, is directly further reacted.
Reaction SMILES: [OH:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:9]([C:15]4[CH:20]=[CH:19][C:18]([C:21]5([NH:25]C(=O)OC(C)(C)C)[CH2:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1.[ClH:39].CCOC(C)=O>CO.C(Cl)Cl>[ClH:39].[NH2:25][C:21]1([C:18]2[CH:17]=[CH:16][C:15]([C:9]3[C:8]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:7][C:6]4[C:5]5=[N:4][N:3]=[C:2]([OH:1])[N:14]5[CH:13]=[CH:12][C:11]=4[N:10]=3)=[CH:20][CH:19]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(O)nnc5c4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1(c2ccc(-c3nc4ccn5c(O)nnc5c4cc3-c3ccccc3)cc2)CCC1

Procedure:
To a solution of tert-butyl {1-[4-(3-hydroxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-6a) (1.14 g, 2.25 mmol) in MeOH (5 mL) and DCM (15 mL) was added a 4N solution of HCl in EtOAc (22 mL, 88 mmol) at room temperature. After 4 hours the reaction mixture was concentrated in vacuo to give 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-ol hydrochloride (1-16) as a yellow solid. HRMS (M+H)+: observed=408.1803, calculated=408.1819.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][CH3:7])[CH:3]=O.[CH3:8][C:9]([CH3:11])=[O:10]>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH3:1][C:2](=[CH:5][CH2:6][CH3:7])[CH:3]=[CH:8][C:9](=[O:10])[CH3:11]
Reactant: CC(C)=O
Reactant: CCC=C(C)C=O
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Product: CCC=C(C)C=CC(C)=O
Yield: 29.1 %

Procedure:
Into a 2 liter autoclave are charged 2-methyl-2-pentenal (196 grams), acetone (580 grams) and zinc acetate dihydrate. The reaction mixture is heated at 170°-180° C. for a period of 5 hours. After filtering the catalyst the organic layer is washed with 10% salt solution. Distillation and bulking fractions 4-8 gives 80.3 grams of product, B.P. 91°-98° C. at 5-7 mm Hg. pressure. The bulked fractions or separate fractions are useful for augmenting or enhancing the aroma or taste of the foodstuff.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][NH:23][O:24][CH3:25]>C(Cl)Cl.CN(C=O)C>[F:14][C:2]([F:1])([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]([N:23]([O:24][CH3:25])[CH3:22])=[O:5]
Reactant: CNOC
Reactant: O=C(O)C(F)(F)Oc1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)C(F)(F)Oc1ccc(F)cc1
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 2,2-difluoro-2-(4-fluorophenoxy)acetic acid (2.2 g, 10.6 mmol) in DCM (20 ml), were added oxalyl chloride (1.02 ml, 12 mmol) and a couple of drops of DMF and the reaction mixture was stirred for 2 h. The reaction mixture was evaporated to dryness and the yellowish residue was dissolved in DCM. The solvent was evaporated again and the residue was left under light vacuum (30 mm Hg) for 1 h. After dissolving the residue in DCM (20 ml), N,O-dimethyl hydroxylamine hydrochloride (1.24 g, 12.7 mmol) and TEA (25.4 mmol) were added. After stirring the reaction mixture overnight at rt, the heterogeneous mixture was washed with water and brine. After drying over sodium sulfate, the solvent was removed under vacuum to yield 2,2-difluoro-2-(4-fluorophenoxy)-N-methoxy-N-methylacetamide as an oil (2.05 g, 77%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]3[C:27]([C:28]4[O:32][N:31]=[C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:29]=4)=[CH:26][N:25](S(C4C=CC(C)=CC=4)(=O)=O)[C:22]3=[N:23][CH:24]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])([CH3:9])[CH3:8]>C1COCC1>[CH:7]([S:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]3[C:27]([C:28]4[O:32][N:31]=[C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:29]=4)=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)=[CH:17][CH:18]=1)(=[O:11])=[O:12])([CH3:9])[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(-c4ccccc4)no3)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(-c4cc(-c5ccccc5)no4)c3n2)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 67.2 %

Procedure:
2M Na2CO3 (136 μL, 0.272 mmol) was added to a stirred solution of 5-[2-(4-isopropylsulfonylphenyl)-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazin-7-yl]-3-phenyl-isoxazole (40.7 mg, 0.06798 mmol) in THF (4.6 mL) and the reaction stirred at ambient temperature for 64 hours. The reaction mixture was partitioned between EtOAc/brine and the layers separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated from MeCN and the precipitate isolated by filtration to give the title compound as a yellow solid (20.3 mg, 67% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.16 (s, 6H), 3.52 (t, 1H), 7.52-7.61 (m, 4H), 8.02-8.05 (m, 4H), 8.63 (d, 2H), 8.69 (s, 1H), 9.18 (s, 1H) and 13.00 (br s, 1H) ppm; MS (ES+) 445.1.