Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13](Br)=[CH:12][N:11]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH:28]1([Zn+])[CH2:30][CH2:29]1>C1COCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:28]2[CH2:30][CH2:29]2)=[CH:12][N:11]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Zn+]C1CC1
Reactant: CCCCc1ccc(-n2cc(Br)c(=O)c(OCc3ccccc3)c2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCc1ccc(-n2cc(OCc3ccccc3)c(=O)c(C3CC3)c2)cc1
Temperature: 60 °C

Procedure:
3-(Benzyloxy)-5-bromo-1-(4-butylphenyl)pyridin-4(1H)-one (37 mg, 0.09 mmol) was treated with 1,-bis(diphenylphosphino)ferrocene dichloro palladium(il) dichloromethane complex (6.6 mg, 0.009 mmol) and cyclopropylzinc bromide (0.54 mL of a 0.5 M solution in THF, 0.27 mmol). The reaction vessel was purged with N2, sealed, and heated at 60° C. for 1 h, after which it was concentrated under a stream of N2 and purified by flash chromatography (4 g Si02, 0-55% ethyl acetate/hexanes) to provide 3-(benzyloxy)-1-(4-butylphenyl)-5-cyclopropylpyridin-4(1H)-one. LC/MS (M+H)+ 374.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:45])[N:15]([CH3:44])[C@@H:16]([C:28](=[O:43])[N:29]([C@@H:31]([C:39](=[O:42])[NH:40][CH3:41])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:30])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:44][N:15]([C@@H:16]([C:28](=[O:43])[N:29]([CH3:30])[C@@H:31]([C:39](=[O:42])[NH:40][CH3:41])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:14]([CH:11]1[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]1)=[O:45]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)C1CCC(N)CC1
Reaction time: 0.08 h
Yield: 49.3 %

Procedure:
To a solution of (4-[N-Methyl-N-{(1R)-1-(N-methyl-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)-ethyl}-carbamoyl]cyclohexyl)carbamic acid tert-butyl ester (240 mg, 0.38 mmol) in 1 ml dichloromethane was added 0.5 ml trifluoroacetic acid and the mixture was stirred for 5 min. Sodium bicarbonate was added until gas evolution has ceased, and the mixture was extracted with dichloromethane (3×15 ml). The combined organic phases were washed with brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (16 g) with dichloromethane/methanol (4:1). The obtained product was dissolved in 3 ml of methanol and added 40 ml of water and 0.5 ml of acetic acid and lyophilized to give 99 mg of the title compound.
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[N:3]=[C-:2]1.[H-].[Na+].[CH2:9]([O:11][C:12](=[O:30])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[CH2:28]Br)[CH:15]=1)[CH3:10].[O:31]1CCOCC1>>[CH2:9]([O:11][C:12](=[O:30])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[CH2:28][N:3]2[CH2:4][CH2:5][O:1][C:2]2=[O:31])[CH:15]=1)[CH3:10]
Reactant: C1COCCO1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C)cc2CBr)c1
Reactant: O=C1CO[C-]=N1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1cccc(Oc2ccc(C)cc2CN2CCOC2=O)c1
Reaction time: 0.17 h

Procedure:
To 2-oxazolidone (0.06 g, 0.70 mmol) in 1,4-dioxane (10 mL) was added sodium hydride (60% in mineral oil; 0.03 g, 0.65 mmol), and the mixture was stirred for 10 minutes. [3-(2-Bromomethyl-4-methyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.17 g, 0.43 mmol) was added in 1,4-dioxane, and the reaction was stirred for 1 hour at room temperature. After work-up, the crude material was purified by preparative HPLC to give the desired product (0.10 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([C:18](=[SiH2:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@@:14]([C:25]([CH3:28])([CH3:27])[CH3:26])([OH:15])[C@H:12]2[OH:13])=[C:4]([NH2:29])[N:3]=1.[CH3:30]N(C=O)C.[H-].[Na+]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([C:18](=[SiH2:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[C@@:14]([C:25]([CH3:28])([CH3:27])[CH3:26])([OH:15])[C@H:12]2[O:13][CH3:30])=[C:4]([NH2:29])[N:3]=1
Reactant: CC(C)(C)OC(=[SiH2])[C@H]1O[C@@H](n2cnc3c(N)nc(N)nc32)[C@H](O)[C@@]1(O)C(C)(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CO[C@H]1[C@H](n2cnc3c(N)nc(N)nc32)O[C@H](C(=[SiH2])OC(C)(C)C)[C@]1(O)C(C)(C)C
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
To a stirred −20° C. solution of (62) (2.11 g, 5 mmol) in anhydrous DMF (40 ml) methyl iodide (0.93 ml, 15 mmol) was added followed by sodium hydride as a 60% mineral oil suspension (0.3 g, 7.5 mmol). The reaction mixture was stirred for 1.5 h at −20° C. and quenched with ammonium chloride (1.5 g). The resulting suspension was partitioned between chloroform (75 ml) and water (50 ml). The aqueous layer was washed with additional chloroform. The combined chloroform extracts were washed with 50 ml of water and the aqueous layer was extract back with chloroform. The resulting organic solution was dried over magnesium sulfate, filtered and the solvent was removed in vacuo. Crystallization from dichloromethane-hexane mixture (1:1) afforded (63) as colorless crystals. Yield 1.92 g (88%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[O:14])[CH2:9][CH2:8]3.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:22]=1[C:23](Cl)=[O:24]>>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[C:22]=1[C:23]([NH:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[O:14])[CH2:9][CH2:8]3)=[O:24]
Reactant: O=C(Cl)c1c(F)cccc1C(F)(F)F
Reactant: Nc1sc2c(c1C(=O)c1ccco1)CC1CCC2O1
Product: O=C(Nc1sc2c(c1C(=O)c1ccco1)CC1CCC2O1)c1c(F)cccc1C(F)(F)F

Procedure:
The title compound was prepared from the product of Example 15A and commercially available 2-fluoro-6-trifluoromethyl-benzoyl chloride according to the procedure described for Example 1C. 1H NMR (CDCl3, 300 MHz) δ 1.63-1.71 (m, 1H), 2.13-2.17 m, 4H), 3.26 (dd, J=16.3, 5.1Hz, 1H), 4.71 (dd, J=4.9, 4.9Hz, 1H), 5.14-5.15 (m, 1H), 6.58-6.60 (m, 1H), 7.16-7.17 (m, 1H), 7.35-7.41 (m, 1H), 7.55-7.64 (m, 3H), 11.13 (br s, 1H); MS (ESI+) m/z 466 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1O[C:9]1([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[C:10](=O)[CH3:11].O.[NH2:21][NH2:22]>C(O)C>[CH3:11][C:10]1[NH:22][N:21]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:9]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: CC(=O)C1(c2ccncc2)OC1c1ccccc1C
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1ccccc1-c1n[nH]c(C)c1-c1ccncc1

Procedure:
A solution of 4-(2-methylphenyl)-3-(4-pyridyl)-3,4-epoxy-2-butanone (step 2) (0.11 g, 0.434 mmol) and hydrazine hydrate (0.043 g, 0.868 mmol) in ethyl alcohol (50 ml) was heated at reflux for 20 hours. The solvent was removed and the resulting residue was purified by chromatography to give 4-[5-methyl-3-(2-methylphenyl)-1H-pyrazol-4-yl]pyridine: Anal. Calc'd for C16H15N3 (249.32): C, 77.08; H, 6.06; N, 16.85. Found: C, 76.66; H, 5.91; N, 16.84.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[C:3]=1[NH:13][CH3:14].C1COCC1.Cl.[CH2:21]([S:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=O)[CH3:22].C(=O)([O-])O.[Na+]>O>[Cl:1][C:2]1[C:3]2[N:13]([CH3:14])[C:26]([C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[S:23][CH2:21][CH3:22])=[N:12][C:4]=2[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CNc1c(N)cc(C(F)(F)F)cc1Cl
Reactant: CCSc1ccccc1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cc(Cl)c2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
To a mixture of 3-chloro-N2-methyl-5-trifluoromethylbenzene-1,2-diamine (1.12 g) and THF (5 ml), 2-ethylsulfanylbenzoic acid hydrochloride (1.00 g) was added under ice-cooling, heated to room temperature, and stirred for 1 hour. Sodium hydrogen carbonate (0.46 g) was added thereto, and then the reaction mixture was allowed to stand overnight. The reaction mixture was heated to 66° C., and stirred under reflux for 1.5 hours. After the mixture was cooled to room temperature, 2-ethylsulfanylbenzoic acid hydrochloride (0.5 g) was added at room temperature. After the reaction mixture was allowed to stand at room temperature overnight, sodium hydrogen carbonate (1.00 g) was added, and stirred. The reaction mixture was ice-cooled, and then water was added under ice-cooling, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.48 g of 7-chloro-2-(2-ethylsulfanylphenyl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter referred to as Present Compound 71).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:18][NH2:19].C(=O)(O)[O-]>ClCCl.CN(C)C=O.N1C=CC=CC=1>[CH3:18][NH:19][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)=[O:10]
Reactant: O=C(O)c1ccnc(Cl)n1
Reactant: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1ccnc(Cl)n1
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To a solution of 2-chloro-pyrimidine-4-carboxylic acid (200 mg, 1.3 mmol) in dichloromethane (10 ml) cooled in an ice/water bath was added oxalyl chloride (0.7 ml) and dimethylformamide (3 drops). The reaction was incomplete after 45 minutes so a further portion of oxalyl chloride was added (0.7 ml) and the reaction allowed to proceed at room temperature for a further hour. The reaction was then concentrated and to the crude acid chloride was added pyridine (0.1 ml) and methylamine hydrochloride (0.16 g, 1.9 mmol). After stirring for 3 hours a further portion of both reagents were added and the reaction left to stir overnight. To the reaction was added dilute bicarbonate solution and the mixture was extracted with dichloromethane. The organic liquors were concentrated to furnish the title compound as a yellow solid (150 mg). 1H NMR (400 MHz, DMSO-d6): 9.01 (1H, d), 8.99-8.88 (1H, m), 8.01 (1H, d), 2.83 (3H, d).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)[N:3]=1.[F:18][C:19]1[C:20]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23]>>[F:18][C:19]1[C:20]([C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[C:21]([C:22]([N:14]2[CH2:13][CH:12]3[CH:16]([CH2:17][N:10]([C:4]4[N:5]=[C:6]([CH3:9])[C:7]([CH3:8])=[C:2]([CH3:1])[N:3]=4)[CH2:11]3)[CH2:15]2)=[O:23])[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1nc(N2CC3CNCC3C2)nc(C)c1C
Reactant: O=C(O)c1cccc(F)c1-c1ncccn1
Product: Cc1nc(N2CC3CN(C(=O)c4cccc(F)c4-c4ncccn4)CC3C2)nc(C)c1C

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 42 and 3-fluoro-2-(pyrimidin-2-yl)benzoic acid. MS (ESI): mass calculated for C24H25FN6O, 432.21; m/z found 433.3 [M+H]+. 1H NMR (600 MHz, CDCl3): 8.41 (dd, J=4.7, 1.8, 2H), 7.66-7.54 (m, 2H), 7.34 (dd, J=7.4, 4.8, 2H), 3.94 (dd, J=12.1, 7.6, 2H), 3.80 (dd, J=11.5, 7.3, 1H), 3.74-3.46 (m, 4H), 3.31-3.01 (m, 3H), 2.40-2.13 (m, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)CCC1C=NC(C(C#N)(C)C)=C(Cl)C=1)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)CCc1cnc(C(C)(C)C#N)c(Cl)c1
Product: CC(C)(C)OC(=O)N1CCC(CCCCC(=O)O)CC1

Procedure:
The title compound was prepared analogously to step 5 of example B(29) where 4-(4-ethoxycarbonyl-butyl)-piperidine-1-carboxylic acid tert-butyl ester from step 3 above, was substituted in place of 3-[5-chloro-6-(cyano-dimethyl-methyl)-pyridin-3-yl]-propionic acid ethyl ester in that example. 1H NMR (400 MHz, CDCl3): δ 1.07-1.39 (m, 7H), 1.45 (s, 9H), 1.59-1.70 (m, 4H), 2.33-2.38 (m, 2H), 2.64-2.68 (m, 2H), 4.09-4.12 (m, 2H). ESIMS (MH−): 284.
Reaction SMILES: CC1(C)[O:6][C@H:5]2[C@@H:7]([C:25]3[O:29][N:28]=[C:27]([CH3:30])[N:26]=3)[O:8][C@@H:9]([N:10]3[CH:18]=[N:17][C:16]4[C:11]3=[N:12][CH:13]=[N:14][C:15]=4[NH:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C@@H:4]2[O:3]1.FC(F)(F)C(O)=O.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH:20]1([NH:19][C:15]2[N:14]=[CH:13][N:12]=[C:11]3[C:16]=2[N:17]=[CH:18][N:10]3[C@H:9]2[C@H:4]([OH:3])[C@H:5]([OH:6])[C@@H:7]([C:25]3[O:29][N:28]=[C:27]([CH3:30])[N:26]=3)[O:8]2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: Cc1noc([C@H]2O[C@@H](n3cnc4c(NC5CCCC5)ncnc43)[C@@H]3OC(C)(C)O[C@H]32)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1noc([C@H]2O[C@@H](n3cnc4c(NC5CCCC5)ncnc43)[C@H](O)[C@@H]2O)n1
Reaction time: 6 h
Yield: 73.6 %

Procedure:
A mixture of N-{9-[(3aR,4R,6S,6aR)-2,2-dimethyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl}-N-cyclopentylamine (63 mg), trifluoroacetic acid (1 ml) and water (0.1 ml) was stirred at 0° for 6 h and then diluted with ethyl acetate (20 ml). The mixture was neutralised with sodium bicarbonate solution and the aqueous phase was extracted with ethyl acetate (2×10 ml). The combined organic extracts were washed with water (8 ml) and brine (10 ml) and dried (MgSO4). After concentration in vacuo the residue was purified by flahs column chromatography on silica gel, eluting with ethyl acetate:methanol (19:1) to give the title compound as a white foam (42 mg).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[Br:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>>[Br-:10].[CH2:1]([N+:5]1[CH:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(CCCBr)cc1
Reactant: CCCCn1ccnc1
Product: CCCC[n+]1ccn(CCCc2ccc(OC)cc2)c1
Product: [Br-]
Temperature: 140 °C

Procedure:
A mixture of 2.5 g (0.02 mole) of 1-butyl-1H-imidazole and 4.61 g (0.02 mole) of 1-(3-bromopropyl)-4-methoxybenzene is heated at 140° C. for about 1.5 hours. Follow the progress of the reaction by thin-layer chromatography on silica gel (methanol: 1M sodium chloride, 95:5). At the completion of the reaction, the cooled reaction product is triturated thoroughly with ether and on drying, provides the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.O.[CH3:19]O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([O:13][CH3:19])=[O:12]
Reactant: CO
Reactant: O=C(O)Cc1c(F)cc(F)cc1F
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)Cc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2,4,6-trifluorobenzeneacetic acid (5.00 g, 26.3 mmol) in methanol (25 mL) was stirred at ambient temperature, and thionyl chloride (6 mL, ˜3 eq.) was added dropwise, causing the temperature of the reaction mixture to reach 60° C. The reaction mixture was allowed to cool to ambient temperature and was stirred for 3 h. Water (25 mL) was added with ice cooling. The mixture was extracted with ethyl acetate (2×100 mL). The combined organic phases were sequentially washed with water (2×), saturated aqueous sodium bicarbonate solution and brine, and then dried (MgSO4). Concentration provided the title compound as a clear oil (5.38 g).
Reaction SMILES: [O-:1]Cl=O.[Na+].[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([C@@H:19]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=3)[CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:9][CH2:8][CH2:7][CH2:6]1.CC(=CC)C>O.CC(O)(C)C>[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([C@@H:19]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([OH:1])=[O:32])=[CH:33][CH:34]=3)[CH2:20][C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccc(C=O)cc2)cc1OC1CCCC1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc([C@H](Cc2ccncc2)c2ccc(C(=O)O)cc2)cc1OC1CCCC1
Yield: 101.8 %

Procedure:
A solution of NaClO2 (149 mg, 1.64 mmol) and NaH2PO4 ·H2O (227 mg, 1.64 mmol) in water (1 mL) was added to a solution of aldehyde from Step 3 (508 mg, 1.27 mmol) and 2-methyl-2-butene (0.94 mL, 8.9 mmol) in t-BuOH (6 mL). The reaction mixture was stirred at room temperature for 19 hours before 25% aqueous NH4OAc was added. The mixture was then extracted twice with EtOAc. The organic phase was washed with brine, dried (MgSO4) and evaporated to afford the title compound as a white solid (540 mg). 1H NMR (400 MHz, CDCl3): δ 1.55 (m, 2H), 1.75 (m, 6H), 3.35 (m, 2H), 3.80 (s, 3H), 4.20 (t, 1H), 4.60 (m, 1H), 6.60 (s, 1H), 6.65 (d, 1H), 6.75 (d, 1H), 7.00 (d, 2H), 7.25 (d, 2H), 8.00 (d, 2H), 8.45 (d, 2H).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[O:25][CH2:26][CH2:27][O:28][CH3:29])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>>[CH3:29][O:28][CH2:27][CH2:26][O:25][C:14]1[CH:15]=[C:16]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[CH:17]=[CH:18][C:13]=1[NH:12][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:34]3[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=3)[C:7]=2[N:8]=1
Reactant: COCCOc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COCCOc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(-c3cnn(C)c3)c2n1

Procedure:
The title compound was prepared according to the method described for Example 95 using 8-chloro-N-(2-(2-methoxyethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Preparation 116) and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: Cl.[CH:2](=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]CC.[CH3:13][CH2:14][O:15][C:16]([CH2:18]Br)=[O:17].S(=O)(=O)(O)O>[Zn].C1C=CC=CC=1>[CH2:14]([O:15][C:16](=[O:17])[CH2:18][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:13]
Reactant: CCCCCCCCCC=O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: c1ccccc1
Product: CCCCCCCC(O)CC(=O)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
7.8 g of zinc activated by a hydrochloric acid and 25 ml of benzene were placed in a circulation device incorporating the Dean and Stark device. The solution was circulated while heated. To the resultant solution, a mixed solution of 15.6 g (100 mmol) of decanal and 18.4 g (110 mmol) of bromoacetic acid ethyl was dropped. After six hours, the solution was cooled to room temperature. A 50%(w/w) sulfuric acid was added to divide the solvent, and the organic layer was separated. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent: hexane/ethyl acetate=2/8). As a result, a 3-hydroxydecanoic acid ethyl ester was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][NH:6][C:5](=[O:9])[N:4]=1.[C:10]([NH:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)(=[O:12])[CH3:11].N1C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][N:6]([C:18]2[CH:19]=[C:14]([NH:13][C:10](=[O:12])[CH3:11])[CH:15]=[CH:16][CH:17]=2)[C:5](=[O:9])[N:4]=1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: COc1cn[nH]c(=O)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1cnn(-c2cccc(NC(C)=O)c2)c(=O)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
According to Scheme 6 Step 1: To a stirred solution of 5-methoxy-1,2,4-triazin-3(2H)-one (1 g, 7.9 mmol) in DMF (5 mL) were successively added the 3-acetamidophenylboronic acid (1.4 g, 7.9 mmol), copper(II) acetate (1.4 g, 7.9 mmol) and pyridine (1.2 g, 7.9 mmol). The mixture was stirred overnight at 60° C. The reaction mixture was quenched with a saturated sodium bicarbonate solution and extracted with ethyl acetate (×3). The combined organic layers were washed successively with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 70 g column, CH2Cl2/MeOH 98/2 to afford (0.493 g, 24%) of N-(3-(5-methoxy-3-oxo-1,2,4-triazin-2(3H)-yl)phenyl)acetamide
Reaction SMILES: C(O[C:6](=[O:33])[C@@H:7]([NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.C(OC(=O)[C@@H]([NH2:48])CC1C=CC=CC=1)(C)(C)C.C1(O[C:57](=O)[NH:58][C:59]2[CH:64]=CC(OC3C=CC(Cl)=CC=3)=CC=2)C=CC=CC=1.Cl>CS(C)=O.CCOC(C)=O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])[NH:15][C@@H:7]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([NH:48][CH2:64][CH2:59][NH:58][CH3:57])=[O:33])=[CH:24][CH:23]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(Nc1ccc(Oc2ccc(Cl)cc2)cc1)Oc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CNCCNC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
(S)-2-{3-[4-(4-Chloro-phenoxy)-phenyl]-ureido}-3-phenyl-propionic acid tert-butyl ester. To a stirred solution of (S)-2-amino-3-phenyl-propionic acid tert-butyl ester (0.2 g, 0.9 mmol) in DMSO (2 mL) was added [4-(4-chloro-phenoxy)-phenyl]-carbamic acid phenyl ester (0.3 g, 0.9 mmol). The mixture was stirred at rt overnight. EtOAc (80 mL) was then added, along with 0.1 N HCl (5 mL). The organic layer was washed sequentially with H2O (10 mL), 1 N NaOH (10 mL) and brine (20 mL), and dried (MgSO4). The solvent was removed. Purification by column chromatography [0–20% of (1% NH4OH/MeOH)/CH2Cl2] afforded 0.35 g (83%) of the desired product. MS (electrospray): mass calculated for C26H27ClN2O4, 466.17; m/z found, 411.1 [M−tBu+H]+. 1H NMR (400 MHz, CDCl3): 7.22–7.13 (m, 5H), 7.10–7.07 (m, 4H), 6.82–6.78 (m, 4H), 6.70 (s, 1H), 4.66 (s, 1H), 3.03 (dd, J=13.9, 6.06 Hz, 1H), 2.94 (dd, J=13.8, 6.07 Hz, 1H), 1.37 (s, 9H).