Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:22][CH3:23])=[C:6]([CH:8]2[C:16](=[O:17])[CH:15]3[CH:10]([C:11]4([CH3:20])[O:18][C:14]3([CH3:19])[CH:13]=[CH:12]4)[C:9]2=[O:21])[CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[C:27]([F:34])[CH:26]=1.[F-].[Cs+]>COCCOC.ClCCl>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]([CH2:22][CH3:23])=[C:6]([CH:8]3[C:9](=[O:21])[CH:10]4[CH:15]([C:14]5([CH3:19])[O:18][C:11]4([CH3:20])[CH2:12][CH2:13]5)[C:16]3=[O:17])[CH:7]=2)=[C:27]([F:34])[CH:26]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: CCc1ccc(Br)cc1C1C(=O)C2C(C1=O)C1(C)C=CC2(C)O1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(Cl)cc2F)cc1C1C(=O)C2C(C1=O)C1(C)CCC2(C)O1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of (1RS,2SR,6RS,7SR)-4-(5-bromo-2-ethylphenyl)-1,7-dimethyl-10-oxatricyclo[5.2.1.02,6]dec-8-en-3,5-dione (113 mg, 0.3 mmol), 4-chloro-2-fluorophenylboronic acid (103 mg, 0.6 mmol) and cesium fluoride (449 mg, 3.0 mmol) in degassed 1,2-dimethoxyethane (1.5 ml) are stirred under nitrogen at room temperature for 40 minutes. [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (48 mg, 0.06 mmol) is added, followed by a further quantity of 1,2-dimethoxyethane (1 ml) and reaction mixture is heated to 80° C. for 18 hours. The mixture is cooled to room temperature, then diluted with dichloromethane and filtered through a small plug of diatomaceous earth. The filtrate is evaporated and the residue is purified by column chromatography on silica gel, to give (1RS,2SR,6RS,7SR)-4-(4′-chloro-4-ethyl-2′-fluorobiphen-3-yl)-1,7-dimethyl-10-oxatricyclo-[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[CH:42]=[C:43]([NH:44][C:13]([NH:12][C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]([C:22]([F:23])([F:24])[F:25])[CH:10]=2)=[O:21])[CH:45]=[CH:46][CH:47]=1
Reactant: O=C(Nc1cc(C(F)(F)F)nn1-c1ccccc1)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Yield: 53 %

Procedure:
The title compound was prepared as described in Example 159B, using phenyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate from the previous step (0.139 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50° C. for 6 hours, to afford 1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.116 g, 53%). 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.80 (s, 1H), 8.55 (s, 1H), 7.54-7.62 (m, 7H), 7.39 (m, 2H), 7.19 (d, 1H), 6.96 (d, 1H), 6.86 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H); LC-MS (ESI) m/z 551 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15])[CH:3]=O.[C:16]([O:23][CH3:24])(=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19].N1C=CC=CC=1>ClC(Cl)(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][CH:2]([CH2:5][CH2:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15])[CH:3]=[C:17]([C:16]([O:23][CH3:24])=[O:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CC(=O)OC
Reactant: CC1=C(CCC(C)C=O)C(C)(C)CCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=CC(C)CCC1=C(C)CCCC1(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
Under water-free conditions titanium(IV) chloride (91 g, 0.5 mol) in tetrachloromethane (120 ml) are added dropwise within 45 min to tetrahydrofuran at 0° C. The mixture is stirred for another 30 min at this temperature, then 2-Methyl-4-(2,6,6-trimethylcyclohex-1-enyl)butanal 4 (50 g, 0.24 mol) (M. Matsui et al., Agric. Biol. Chem. 50, 1475-1480, 1986) and dimethyl malonate (31.7 g, 0.24 mol) in tetrahydrofuran (50 ml) are added within 15 min at 0° C. followed by dropwise addition of pyridine (76 g) in tetrahydrofuran (240 ml) over 90 min at 0° C. The orange-brown suspension is stirred for 18 h at 25° C., then poured upon ice/water and extracted with tert-butyl methyl ether. The combined organic layers are washed with water and conc. NaCl and dried over MgSO4. After filtration and evaporation of the solvents the crude product (75 g) is short-path-distilled giving 62.5 g (81%) of 3a at 170° C./0.07 mbar. Analytical data: 1H NMR (400 MHz, CDCl3): δ 0.95 (s, 6 H), 1.1 (d, 3 H), 1.4-1.5 (4 H), 1.5-1.6 (2 H), 1.58 (s, 3 H), 1.8-2.0 (2 H), 2.5 (m, 1 H), 3.8 (s, 3 H), 3.85 (s, 3 H), 6.85 (d, 1 H) ppm. 13C-NMR (400 MHz, CDCl3): δ 19.45 (t), 19.55 (q), 19.75 (q), 26.4 (t), 28.5 (q), 32.7 (t), 34.8 (s), 35.7 (d), 36.8 (t), 39.7 (t), 52.1 (q), 52.2 (q), 126.7 (s), 127.1 (s), 136.8 (s), 154.9 (d), 164.4 (s), 166.0 (s). MS (EI): m/z (%) 322 (M+, 10), 307 ([M-15]+, 2), 275 (6), 259 (7), 243 (16), 215 (11), 200 (18), 187 (19), 175 (20), 173 (16), 172 (100), 153 (22), 145 (28), 140 (70), 137 (27), 135 (34), 123 (60), 122 (28), 121 (42), 109 (35), 108 (34), 95 (62), 93 (36), 81 (44), 79 (33), 55 (36), 41 (35). IR (film): 2950 (m), 2926 (m), 2865 (m), 1725 (s), 1642 (w), 1454 (w), 1433 (m), 1363 (w), 1327 (w), 1246 (s), 1221 (s), 1204 (s), 1168 (w), 1104 (w), 1054 (m), 991 (w), 945 (w), 925 (w), 833 (w), 762 (w).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:17](O)=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19]>>[CH3:19][C:13]1[C:12]2[N:11]=[C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=3)[O:8][C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Cc1cccc(O)c1N
Product: Cc1cccc2oc(-c3ccc(N)cc3)nc12
Temperature: 160 °C

Procedure:
To a suspension of 4-amino-benzoic acid (2.0 g, 14.5 mmol) in PPA (˜85 g) was added 2-amino-m-cresol (1.8 g, 15.3 mmol). The reaction was heated to 160° C. for 14 h, then carefully quenched in aqueous sodium carbonate (˜50% saturated) at room temperature. Ethyl acetate was added, and the organic layer was washed with water and brine, and dried over sodium sulfate. The crude product was obtained was subsequently purified by flash column chromatography on silica gel eluting with ethyl acetate in hexanes to afford the desired product, 4-(4-methyl-benzooxazol-2-yl)-phenylamine as a light pink solid, 1.8 g (56%). LC-MS m/z=225 [C14H12N2O+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]([CH3:24])([CH3:23])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[CH3:23][C:17]1([CH3:24])[CH2:18][C:19]([CH3:21])([CH3:22])[CH2:20][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:16]1
Reactant: CC1(C)C=C(c2ccc(OCc3ccccc3)cc2)CC(C)(C)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2ccc(O)cc2)CC(C)(C)C1
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To 10% Pd/C (0.17 g) under N2 was added 1-benzyloxy-4-(3,3,5,5-tetramethyl-cyclohex-1-enyl)-benzene (1.7 g, 5.3 mmol), prepared by a substantially similar procedure to that of Step 1 of Example 18, in MeOH (15 mL) and EtOAc (15 mL). This mixture was stirred under H2 (1 atm) overnight. The reaction mixture was filtered through celite. The filtrate was concentrated to give the title compound as a white solid (1.19 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].O>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2cccc(Cl)n2)C1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To 1,1-dimethylethyl(4RS,5RS)-5-(6-chloro-2-pyridyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate (677 mg, 1.46 mmol) in methanol (3.5 ml) was added 0.5N sodium hydroxide methanol solution (3.5 ml, 1.75 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added water (50 ml), and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from diisopropyl ether-hexane to give the title compound (550 mg, 57%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([F:11])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][C:6]=1[F:11]
Reactant: COC(=O)c1ccc(Br)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of 4-bromo-3-fluoro-benzoic acid methyl ester (5.3 g, 22.9 mmol) in dry THF (60 mL) was added diisobutylaluminum hydride (30 mL) dropwise, This mixture was stirred overnight at room temperature until the starting material had been consumed, quenched with saturated aqueous potassium tartrate solution and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to give white solid product (4.3 g, 92%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:13]=1[NH2:14].CC1C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Cl-].[Ca+2]>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[N:14][C:13]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:12]=2[CH3:11])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CC(=O)c1cccc(Br)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(=Nc1c(C)cc(C)cc1C)c1cccc(Br)n1
Temperature: 25 °C

Procedure:
In argon atmosphere, a mixture of 3.70 g (18.50 mmol) of 1-(6-bromopyridin-2-yl)ethanone, 2.49 g (18.50 mmol) of 2,4,6-trimethylaniline, 50 mg of TsOH, and 150 ml of toluene was refluxed for 2.5 h using a Soxhlet apparatus with an extraction thimble filled with anhydrous CaCl2. The resulting mixture was cooled to ambient temperature, passed through a short layer of silica gel 60 (40-63 um), and then evaporated to dryness. Yield 5.59 g (95%) of dark-red solid. Anal. calc. for C16H17BrN2: C, 60.58; H, 5.40; N, 8.83. Found: C, 60.70; H, 5.56; N, 8.77. 1H NMR (CDCl3): δ 7.98 (dd, J=7.1 Hz, J=1.4 Hz, 1H, 3-H in pyridine), 7.63-7.71 (m, 2H, 4, 5-H in pyridine), 6.76 (s, 2H, 3, 5-H in mesityl), 2.70 (s, 3H, MeC═N), 2.20 (s, 3H, 4-Me in mesityl), 2.15 (s, 6H, 2, 6-Me in mesityl).
Reaction SMILES: [CH3:1]C1C=C(O)C=CC=1O.[O-2].[La+3].[O-2].[O-2].[La+3].CC1C(C)=C(C=CC=1O)O.[CH3:25][C:26]1[C:27]([OH:35])=[C:28]([CH3:34])[C:29]([CH3:33])=[C:30]([CH:32]=1)[OH:31]>CO>[CH3:25][C:26]1[C:27]([OH:35])=[C:28]([CH3:34])[C:29]([CH3:33])=[C:30]([OH:31])[C:32]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: Cc1cc(O)ccc1O
Agent: Cc1c(O)ccc(O)c1C
Agent: [La+3]
Agent: [O-2]
Solvent: CO
Product: Cc1c(C)c(O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into an autoclave (inner volume: 9 ml, made of SUS 316, equipped with a manometer) were charged 0.098 g of methylhydroquinone, 3.491 g of methanol and 7 mg of lanthanum oxide (manufactured by High Purity Chemicals Co.). The reaction was started by elevating the temperature up to 350° C. with sand bath. The pressure during the reaction was 18 MPa. After 2 hours, the autoclave was quickly cooled and the reaction solution was taken out from the autoclave when the temperature was cooled back to the room temperature. The measurement according to the process described above revealed that the conversion of methylhydroquinone was 32% by mole, the selectivity of dimethylhydroquinone was 80% by mole, the selectivity of trimethylhydroquinone was 10% by mole and no tetramethylhydroquinone was produced.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14].OO>C(O)(=O)C>[CH:3]1[C:2]([F:1])=[CH:10][C:9]2[NH:8][C:7]([O:14][C:6](=[O:12])[C:5]=2[CH:4]=1)=[O:11]
Reactant: O=S(=O)(O)O
Reactant: O=C1Nc2cc(F)ccc2C1=O
Agent: OO
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(F)ccc2c(=O)o1
Temperature: 25 °C

Procedure:
41 parts of 6-fluoroisatin are suspended in 500 parts of glacial acetic acid and 15 parts of concentrated sulfuric acid and 100 parts of 30 percent strength hydrogen peroxide solution are added at 30° C. A slightly exothermic reaction is observed and at 40°-45° C. a clear solution is temporarily produced. The temperature is not allowed to rise above 50° C., and after one hour the mixture is cooled to room temperature. The precipitate is filtered off and washed. 38 parts of 7-fluoroisatoic anhydride are obtained; melting point 229°-231° C., with decomposition.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH2:21][N:22]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:23][CH2:24][C:25](O)=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[N:50](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CO.N.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH2:1]([O:19][CH2:20][CH2:21][N:22]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:23][CH2:24][C:25]([NH2:50])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCOCCN(CCOCCCCCCCC/C=C\CCCCCCCC)CCC(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCC/C=C\CCCCCCCCOCCN(CCOCCCCCCCC/C=C\CCCCCCCC)CCC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
The resulting 3-(bis(2-((Z)-octadec-9-enyloxy)ethyl)amino)propanoic acid (85 mg, 0.125 mmol) was dissolved in chloroform (3 mL), and stirred overnight at room temperature after adding 0(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; Aldrich; 95 mg, 0.251 mmol), a 7 mol/L ammonia methanol solution (0.090 mL, 0.627 mmol), and diisopropylethylamine (0.109 mL, 0.627 mmol). The aqueous layer was extracted with ethyl acetate after adding a saturated sodium bicarbonate aqueous solution to the reaction mixture. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 88/12) to give compound 84 (72.3 mg, 85.0%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17].O>CN(C)C=O>[CH2:16]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1)[CH3:17]
Reactant: OCC1CCCNC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring mixture of 3-piperidinemethanol (2 g) and potassium carbonate (6 g) in dry N,N-dimethylformamide (15 ml) was added iodoethane (1.53 ml). The reaction became warm and was cooled back to ambient temperature using a cold water bath. After 2 hours, the solvent was stripped, the residue treated with water and extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a phase separation cartridge and evaporated to give the title compound as a clear oil, yield 1.53 g, 61%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:11])[CH2:10][CH2:9]2)=[C:4]([F:12])[CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:23](=[O:24])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:9][CH2:10]2)=[C:4]([F:12])[CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1(c2ccc(Br)cc2F)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(c2ccc(Br)cc2F)CC1)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a cooled solution of 1-(4-bromo-2-fluorophenyl)cyclopropanamine (2.16 mmol) in DCM (10 mL) at 0° C., was added DIEA (0.75 mL, 4.32 mmol) and benzyl chloroformate (0.37 mL, 2.59 mmol). The reaction mixture was warmed to it and stirred for 1 h until LC/MS analysis indicated the reaction was complete. The reaction was quenched with HCl (1N) and extracted with DCM. Drying over MgSO4, yielded crude product which was purified by flash chromatography (gradient EtOAc/Hexanes (0-50%). HPLC-MS tR=1.31 min (UV254 nm); mass calculated for formula C17H15BrFNO2 363.02, observed LCMS m/z 363.9 (M+H)
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]([NH2:9])[CH3:8]>CO>[CH3:6][O:5][C:1](=[O:4])[CH2:2][CH2:3][NH:9][CH2:7][CH3:8]
Reactant: CCN
Reactant: C=CC(=O)OC
Solvent: CO
Product: CCNCCC(=O)OC
Temperature: -20 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
Methyl acrylate (5.22 g, 60.6 mmol) is dissolved in methanol (20 mL) and cooled to −20° C. Ethylamine (2 M in tetrahydrofuran, 47 mL, 94 mmol) is added via addition funnel and the reaction is allowed to stir at −20° C. for 2 hours. Solvents were then removed in vacuo and the residue is distilled under reduced pressure to afford the title compound as a colorless liquid (2.41 g, 30% yield). 1H NMR (CDCl3) 1.11 (t, 3H, J=7.02 Hz), 2.53 (t, 2H, J=6.58 Hz), 2.66 (q, 2H, J=7.02 Hz), 2.89 (t, 2H, J=6.58 Hz), 3.69 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:9])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[S:10]1[C:14]2[CH:15]=[C:16]([S:19](Cl)(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1>>[I:9][C:3]1[C:2]([NH:1][S:19]([C:16]2[CH:17]=[CH:18][C:13]3[N:12]=[CH:11][S:10][C:14]=3[CH:15]=2)(=[O:20])=[O:21])=[CH:7][CH:6]=[C:5]([Cl:8])[N:4]=1
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Reactant: Nc1ccc(Cl)nc1I
Product: O=S(=O)(Nc1ccc(Cl)nc1I)c1ccc2ncsc2c1

Procedure:
By working in a manner similar to that of Example 50, starting with 3-amino-2-iodo-6-chloropyridine and 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of an orange-colored solid (yield=33%).
Reaction SMILES: [Na].[CH3:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[C:3]([CH2:2][C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCCC(=O)CC(=O)C(=O)OCC
Temperature: 0 °C
Yield: 101.3 %

Procedure:
4.7 g of sodium metal was dissolved in 92 ml of ethanol. A mixture of 20 g of 2-heptanone and 26 g of diethyl oxalate was dropwise added thereto at 0° C. After the removing the ice bath, the reaction mixture was stirred at room temperature for 3 hours. After evaporation of the reaction mixture, 200 ml of water was added to the resulting syrup, and then an aqueous 10% hydrochloric acid was added with ice-cooling, the pH being adjusted to 1. After extraction with benzene (300 ml×3), the organic layer was washed with 100 ml of water, dried with Glauber's salt (Na2SO4). And concentrated to give ethyl hexanoylpyruvate as a liquid (38 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[NH:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])=[N:18]1>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([C:19]3[CH:20]=[CH:21][NH:17][N:18]=3)[CH:23]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(-c2cc[nH]n2)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Oc1cccc(Nc2nc(Nc3cccc(-c4cc[nH]n4)c3)ncc2F)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3-(1H-pyrazol-3-yl)aniline gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(1 H-pyrazol-3-yl)phenyl]-2,4-pyrimidinediamine. LCMS: purity: 84%; MS 363 (MH+)
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>C1(C)C(C)=CC=CC=1>[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)=[O:15]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Cc1ccccc1C
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)c1ccccc1Cl
Yield: 83.5 %

Procedure:
A solution of 10.9 g (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 17.5 g (0.10 mole) 2-chlorobenzoyl chloride was heated at reflux for 18 hours in 200 ml xylene. After concentration in vacuo, the resulting oil was triturated with cold hexane to give 14.9 g (85% yield) of crude product. Recrystallization from benzene/hexane gave a pure product; m.p. 142° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:26][C:27]1[CH:28]=[C:29]([NH:40][C:41]([C@H:43]2[C:52]3[C:47](=[CH:48][C:49]([O:53][CH3:54])=[CH:50][CH:51]=3)[CH2:46][CH2:45][NH:44]2)=[O:42])[CH:30]=[C:31]([F:39])[C:32]=1[C:33]([CH3:38])([CH3:37])[CH2:34][O:35][CH3:36].[C:55]([O:59][C:60](=[O:69])[CH2:61][C@@H:62]1[CH2:65][C@H:64]([C:66](O)=[O:67])[CH2:63]1)([CH3:58])([CH3:57])[CH3:56].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:26][C:27]1[CH:28]=[C:29]([NH:40][C:41]([C@H:43]2[C:52]3[C:47](=[CH:48][C:49]([O:53][CH3:54])=[CH:50][CH:51]=3)[CH2:46][CH2:45][N:44]2[C:66]([C@@H:64]2[CH2:63][C@H:62]([CH2:61][C:60]([O:59][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:69])[CH2:65]2)=[O:67])=[O:42])[CH:30]=[C:31]([F:39])[C:32]=1[C:33]([CH3:37])([CH3:38])[CH2:34][O:35][CH3:36]
Reactant: COCC(C)(C)c1c(F)cc(NC(=O)[C@@H]2NCCc3cc(OC)ccc32)cc1F
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COCC(C)(C)c1c(F)cc(NC(=O)[C@H]2c3ccc(OC)cc3CCN2C(=O)[C@H]2C[C@@H](CC(=O)OC(C)(C)C)C2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (114 mg, 0.30 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (120 mg, 0.27 mmol), cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (61.2 mg, 0.29 mmol) and DIEA (0.107 mL, 0.60 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl 2-(cis-3-((R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (120 mg, 0.200 mmol, 73.4%) as a colorless oil.