Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]([CH2:26][CH2:27][CH3:28])[C:12](=[O:25])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:36]([CH3:43])([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38]>CN(C=O)C>[CH2:40]([O:39][C:37](=[O:38])[C:36]([CH3:43])([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]([CH2:26][CH2:27][CH3:28])[C:12](=[O:25])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:14]=2)=[CH:4][CH:3]=1)[CH3:42])[CH3:41]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(CCc2ccc(O)cc2)nn(-c2ccc(C(F)(F)F)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1c(CCc2ccc(OC(C)(C)C(=O)OCC)cc2)nn(-c2ccc(C(F)(F)F)cc2)c1=O
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a mixture of 5-[2-(4-Hydroxyphenyl)ethyl]-4-propyl-2-(4-trifluoromethylphenyl)-2,4-dihydro-[1,2,4]triazol-3-one (0.10 g, 0.26 mmol) and cesium carbonate (0.16 g, 0.49 mmol) in anhydrous DMF (2.5 mL) was added ethyl 2-bromoisobutyrate (81.1 mg, 60.6 □L, 0.42 mmol). The reaction mixture was heated to 75° C. overnight. More ethyl 2-bromoisobutyrate (30.3 □L) was added and the mixture was stirred at 110° C. overnight and ambient temperature over the weekend. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with 5% aqueous lithium chloride solution, water, brine, dried and evaporated. Chromatotron chromatography (gradient of ethyl acetate in hexanes) gave the pure compound (94 mg, 70.7%): 1HNMR (400 MHz, CDCl3) δ 8.14 (m, 2H), 7.65 (m, 2 H,), 7.10 (m, 2H), 6.80 (m, 2H), 4.23 (m, 2H), 3.53 (m, 2 H), 3.05 (m, 2H), 2.83 (m, 2H), 1.70 (m, 2H), 1.57 (s, 6 H), 1.26 (m, 6H); ESMS m/z (relative intensity) 506.1 (M+H+, 100).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([NH:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=[N:10][C:9]([C:19]1[NH:23][C:22](=[O:24])[NH:21][N:20]=1)=[CH:8]2.CC1C=CC=C(C)N=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:33]([N:16]1[CH2:17][CH2:18][C@H:14]([NH:13][C:11]2[C:12]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[F:2])[CH:8]=[C:9]([C:19]3[NH:23][C:22](=[O:24])[NH:21][N:20]=3)[N:10]=2)[CH2:15]1)(=[O:36])[CH:34]=[CH2:35]
Reactant: C=CC(=O)Cl
Reactant: O=c1[nH]nc(-c2cc3cccc(F)c3c(N[C@H]3CCNC3)n2)[nH]1
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(F)c23)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 15.5 %

Procedure:
To a mixture of (S)-3-(8-fluoro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride (250 mg, 0.71 mmol) in DCM (15 mL) was added a solution of 2,6-dimethylpyridine (192 mg, 1.8 mmol) in DCM (1 mL). Acryloyl chloride (135 mg, 1.5 mmol) in DCM (1.35 mL) was added dropwise via syringe at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. Additional 2,6-dimethylpyridine (32 mg, 0.3 mmol) in DCM (0.32 mL) was added followed by acryloyl chloride (45 mg, 0.50 mmol) in DCM (0.45 mL). The reaction mixture was stirred at −10° C. for 20 minutes. The reaction was quenched with MeOH (1 mL) and the mixture was concentrated under vacuum. The crude product was purified by preparative HPLC to give the title compound as a white solid (40.58 mg, 15.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (s, 1H), 11.78 (s, 1H), 7.69-7.63 (m, 3H), 7.60-7.58 (m, 1H), 6.61-6.55 (m, 2H), 6.18-6.13 (m, 1H), 5.67-5.64 (m, 1H), 5.30-5.10 (m, 1H), 4.17-4.15 (m, 1H), 3.66-3.63 (m, 2H), 3.28-3.25 (m, 1H), 2.25-2.03 (m, 2H); ESI-MS m/z [M+H]+ 369.1.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19]>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)[CH:5]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C#N)cc2)cn1
Yield: 37 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 4-cyanophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (60 mg, 37%) which was obtained as a white solid. MS (ESI): m/e=327.0 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:39])C.[OH-].[Na+].Cl>C(O)C>[Cl:39][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16]([C:30]#[C:31][C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCCCN3CCOCC3)c2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCCCN3CCOCC3)c2)cc1Cl
Reaction time: 16 h

Procedure:
{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (200 mg; 0.33 mmol) was dissolved in ethanol (10 mL), and aqueous 1N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h, acidified with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness, and purified by prep. HPLC (method A). Yield: 46 mg. HPLC-MS: m/z: 572.3 (M+); Rt: 2.03 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=2)[C:5](=[O:18])[CH:4]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:15]([C:11]1[S:10][C:9]([N:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]2=[O:18])=[N:13][C:12]=1[CH3:14])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: COc1ccn(-c2nc(C)c(C(=O)O)s2)c(=O)c1
Product: COc1ccn(-c2nc(C)c(C(=O)NCc3ccccc3)s2)c(=O)c1
Yield: 17 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-methoxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a colorless solid in 17% yield: mp 205-208° C. (hexane/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.78 (t, J=6.0 Hz, 1H), 8.59 (d, J=8.1 Hz, 1H), 7.35-7.17 (m, 5H), 6.33 (dd, J=8.1, 2.7 Hz, 1H), 6.11 (d, J=2.7 Hz, 1H), 4.38 (d, J=6.0 Hz, 2H), 3.81 (s, 3H), 2.54 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 168.6, 161.9, 161.6, 153.9, 150.3, 139.9, 132.0, 128.7, 127.2, 123.7, 104.2, 86.5, 56.8, 43.1, 17.5; MS (ES+) m/z 356.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[C:18]1([C:24]2[CH:25]=[CH:26][C:27]([O:30][C@@H:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:11][C@@H:10]3[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:28][CH:29]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(-c2ccccc2)cc1
Yield: 33.4 %

Procedure:
A solution of (±) N-tert-butoxycarbonyl-1,2-iminoindane (5 g, 22 mmol), 4-phenylphenol (3.73 g, 22 mmol) and pyridinium p-toluenesulfonate (108 mg) in chloroform (150 ml) was heated at reflux for 2 h. On cooling, the solution was washed sequentially with 10% aq. NaOH, water and then brine. After drying over MgSO4, solvents were removed in vacuo and the resultant brown oil subjected to column chromatography on silica gel eluting with 20% diethyl ether in hexanes to afford the title compound (2.95 g).
Reaction SMILES: [C:1]([C:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])O[C:6]=1[CH3:13])([O:3][CH3:4])=[O:2].[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([N:19]2[C:8]([CH3:12])=[CH:9][C:10](=[O:11])[C:5]([C:1]([O:3][CH3:4])=[O:2])=[C:6]2[CH3:13])=[CH:17][CH:16]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)c1c(C)oc(C)cc1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(C)n(-c2ccc(Cl)cc2)c(C)cc1=O
Yield: 46.8 %

Procedure:
40 g of 3-carbomethoxy-2,6-dimethylpyr-4-one and 30.2 g of 4-chloroaniline are dissolved in 400 ml of toluene along with 400 mg of p-toluenesulfonic acid monohydrate. The reaction mixture is refluxed for 4 hours. The solvent is removed and the product crystallized from ether to yield 30 g of N-(4-chlorophenyl)-3-carbomethoxy-2,6-dimethylpyrid-4-one (m.p. 189°-90°).
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:54]1[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=1)CCC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:54]2[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(-c2cccnc2)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Yield: 73.4 %

Procedure:
To a solution containing the product from Example 92D (0.50 g, 0.70 mmol) in N,N-dimethylformamide (7.0 mL) were added lithium chloride (0.30 g, 7.08 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.150 g, 0.214 mmol), and 3-tributylstannylpyridine (0.776 g, 2.11 mmol), and the mixture was heated to 100° C. for 18 hours. The reaction was filtered, diluted with ethyl acetate and washed with water, and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with chloroform and ending with 25% ethyl acetate in chloroform to give the title compound (0.365 g).
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3].[I-].[K+].[C:29]([NH:32][C:33]1[S:34][CH:35]=[C:36]([CH2:38]Cl)[N:37]=1)(=[O:31])[CH3:30]>>[C:29]([NH:32][C:33]1[S:34][CH:35]=[C:36]([CH2:38][O:22][C:16]2[CH:15]=[C:14]3[C:19]([C:10]([NH:9][C:8]4[CH:23]=[CH:24][C:25]([CH3:26])=[C:6]([O:5][C:2](=[O:4])[CH3:3])[CH:7]=4)=[N:11][CH:12]=[N:13]3)=[CH:18][C:17]=2[O:20][CH3:21])[N:37]=1)(=[O:31])[CH3:30]
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Reactant: CC(=O)Nc1nc(CCl)cs1
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1csc(NC(C)=O)n1
Yield: 41.9 %

Procedure:
Using an analogous procedure to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (400 mg) was reacted in the presence of catalytic potassium iodide with 2-acetamido-4-chloromethylthiazole (252 mg) to give 7-(2-acetamidothiazol-4-ylmethoxy)-4-(3-acetoxy-4-methylanilino)-6-methoxyquinazoline (220 mg, 42%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH:7]([NH2:10])([CH3:9])[CH3:8]>>[CH:7]([NH:10][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([CH3:9])[CH3:8]
Reactant: CC(C)N
Reactant: C=CC(=O)OC
Product: COC(=O)CCNC(C)C
Yield: 84.9 %

Procedure:
8.6 g of methyl acrylate are added dropwise to 5.9 g of isopropylamine under ice-cooling and stirring. The mixture is further stirred at room temperature for 5 hours. Then, the reaction mixture is distilled under reduced pressure. 12.3 g of methyl 3-isopropylaminopropionate are thereby obtained as a colorless oil. Yield: 84.5%
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13]1(=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15](=[O:22])[O:14]1>>[CH3:8][C:1]1[CH:2]=[C:3]([CH3:7])[CH:4]=[CH:5][C:6]=1[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:13]([OH:23])=[O:14])=[O:22]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
An ice/salt cold mixture of m-xylene (114 g, 1073 mmol) was treated with aluminium chloride (59.4 g, 446 mmol) (in three portions), followed by 2-benzofuran-1,3-dione (30 g, 203 mmol) (in three portions). The mixture was warmed to room temperature and stirred for 3 hours after which time the mixture turned to a thick white suspension. The mixture was heated to 55° C. for 2 hours, and cooled to room temperature. The thick mixture was slowly poured into ice cold 20% HCl and collected on filter paper. The filtered material was allowed to dry to give the desired product as a white solid (50 g, 97%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.98-8.07 (m, 1 H) 7.60-7.69 (m, 1 H) 7.51-7.59 (m, 1 H) 7.38-7.45 (m, 1 H) 7.01-7.13 (m, 2 H) 6.86-6.94 (m, 1 H) 2.61 (s, 3 H) 2.33 (s, 3 H); LC/MS (m/z) ES+=255 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[C:6](Cl)=[N:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11])[CH2:2][CH2:3][CH3:4].[CH2:14]([NH2:19])[CH2:15][CH2:16][CH2:17][CH3:18]>>[NH2:12][C:8]1[N:7]=[C:6]([NH:19][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:10]([CH3:11])[N:9]=1
Reactant: CCCCCN
Reactant: CCCCc1c(C)nc(N)nc1Cl
Product: CCCCCNc1nc(N)nc(C)c1CCCC
Yield: 78 %

Procedure:
A mixture of 5-butyl-4-chloro-6-methylpyrimidine-2-yl amine (100 mg, 0.5 mmol) and amylamine (2 ml) was refluxed for 11 hours. The reaction mixture was cooled and the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (MeOH:CHCl3=1:20) to give the object compound (98 mg, 78%) as an oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2].[CH2:10]([Li])CCC.C(NC(C)C)(C)C.CI>>[CH2:1]([C:3]([CH3:10])([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2]
Reactant: [Li]CCCC
Reactant: CCC(CC)C(=O)OC
Solvent: CC(C)NC(C)C
Solvent: CI
Product: CCC(C)(CC)C(=O)OC

Procedure:
A 16.5 Kg portion of methyl 2-ethylbutyrate was reacted with 60 Kg of n-butyl lithium, diisopropylamine, and 19.1 Kg of methyl iodide to provide 17.4 Kg of methyl 2-ethyl-2-methylbutyrate. A 7.5 Kg portion of the ester thus formed was reacted with 3.25 Kg of acetonitrile and 5.03 g of sodium hydride in 33 liters of tetrahydrofuran to provide 1-ethyl-1-methylpropyl cyanomethyl ketone. The ketone thus formed was reacted with 4.35 Kg of hydroxylamine hydrochloride and 2.54 Kg of sodium hydroxide in 44 liters of water to provide 5.65 Kg of 5-amino-3-(1-ethyl-1-methylpropyl)isoxazole.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[OH:6])([O-])=O.C1COCC1.C([O-])=O.[NH4+]>[Pd].CO>[NH2:1][CH2:4][CH:5]([C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=1)[OH:6]
Reactant: O=[N+]([O-])CC(O)c1ccc(C(F)(F)F)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: NCC(O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
In a 250 mL round-bottomed flask, 2-nitro-1-(6-(trifluoromethyl)pyridin-3-yl)ethanol (2.4 g, 10.2 mmol) was combined with THF (40 ml) and methanol (40.0 ml) to give a colorless solution and placed under N2 atmosphere. 360 mg of 10% Pd/C was added. Ammonium formate (3.2 g, 50.8 mmol) was added. The reaction mixture was stirred at room temperature overnight. Complete by LCMS. The reaction mixture was purged with N2 and then filtered through Celite. The Celite filtercake was washed several times with methanol. The combined washes and filtrate was concentrated in vacuo. The residue was taken up in dichloromethane/0.01% NaOH and extracted 5 times with dichloromethane. The organic layers were dried over Na2SO4 and concentrated in vacuo. Product was still present in the aqueous phase so saturated NaCl was added to the aqueous phase and the aqueous phase was extracted 3 times with dichloromethane. The organic layers were dried over Na2SO4 and concentrated in vacuo. The combine product as a pale yellow solid was triturated with ether to get an off-white powder which was washed twice with ether/hexanes to afford 2-amino-1-(6-(trifluoromethyl)pyridin-3-yl)ethanol (1.05 g). (M+H)+=207 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.76 (dd, J=12.84, 7.93 Hz, 1H) 3.15 (dd, J=12.84, 3.78 Hz, 1H) 4.75 (dd, J=8.12, 3.97 Hz, 1H) 7.69 (d, J=8.31 Hz, 1H) 7.93 (dd, J=8.12, 1.70 Hz, 1H) 8.71 (d, J=1.51 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:13][Si](C=[N+]=[N-])(C)C>CC(C)=O.CCCCCC>[Cl:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,5-Dichloro-3-aminobenzoic acid, 206 mg (1.0 mmol), was dissolved in 4 ml of acetone, and 0.7 ml (1.4 mmol) of 2.0 M trimethylsilyl diazomethane solution in hexane was added to the solution. The mixture was stirred at room temperature for 1.5 hours. The solvent wad distilled off to give methyl 2,5-dichloro-3-aminobenzoate.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([Br:11])=[CH:6][C:3]=1[CH2:4]O.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(O)(=O)CC.[ClH:24]>C(OCC)(=O)C>[ClH:24].[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:4][C:3]2[CH:6]=[C:7]([Br:11])[CH:8]=[C:9]([Br:10])[C:2]=2[NH2:1])[CH2:15][CH2:14]1
Reactant: Nc1c(Br)cc(Br)cc1CO
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CCC(=O)O
Solvent: CCOC(C)=O
Product: CN1CCN(Cc2cc(Br)cc(Br)c2N)CC1
Temperature: 140 °C

Procedure:
A mixture of 0.56 part of 2-amino-3,5-dibromobenzylalcohol, 1.0 part of N-methyl piperazine and 2 parts of propionic acid is heated at 140° C for 8 hours under stirring. Then, the propionic acid is distilled off under reduced pressure. The residue is extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. Evaporation of the solvent gives oily residue. The residue is chromotographed over silica gel. Ethyl acetate eluates are treated with ethanolic hydrochloric acid. This procedure gives N1 -methyl-N4 -(2-amino-3,5-dibromobenzyl)piperazine hydrochloride melting at 182° to 185° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([CH3:9])([CH3:8])[CH2:5][CH:6]=[CH2:7].[N:10]([C@@H:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]=[O:12]>C1COCC1>[CH3:8][C:4]([CH3:9])([CH2:5][CH:6]=[CH2:7])[CH2:3][N:2]([CH3:1])[C:11]([NH:10][C@@H:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12]
Reactant: C=CCCCCC[C@H](N=C=O)C(=O)OCC
Reactant: C=CCC(C)(C)CNC
Solvent: C1CCOC1
Product: C=CCCCCC[C@H](NC(=O)N(C)CC(C)(C)CC=C)C(=O)OCC
Reaction time: 1 h

Procedure:
N,2,2-trimethylpent-4-en-1-amine (0.847 g, 6.66 mmol) was added to a solution of ethyl (2S)-2-isocyanatonon-8-enoate (1.50 g, 6.66 mmol) and THF (10 ml), and the solution aws stirred for 1 hour. The reaction mixture was concentrated and purified by silica gel chromatography (gradient elution, 20-30% EtOAc in hexane) to give the title compound. LRMS (M+1)=353.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:5]([F:9])=[C:4]([F:10])[CH:3]=1
Reactant: Oc1cc(Br)cc(F)c1F
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(Br)cc(F)c2F)cc1
Temperature: 25 °C
Yield: 48.4 %

Procedure:
To a solution of 5-bromo-2,3-difluorophenol (1.0 g) in tetrahydrofuran (10 ml) under nitrogen was added sodium hydride, 60% dispersion in mineral oil (0.20 g). The solution was stirred at room temperature. After 30 minutes a solution of 4-methoxybenzylbromide (0.96 g) was added in tetrahydrofuran (7 ml). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was partitioned between dichloromethane and brine, then dried (MgSO4), the solvents were removed in vacuo to give a crude residue. This crude residue was purified using flash chromatography to give 5-bromo-1,2-difluoro-3-(4-methoxy-benzyloxy)-benzene (0.76 g).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][C@H:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)CC)C>ClCCl>[C:1]([NH:22][C@H:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
Tritylchloride (2.05 g. 7.36 mmol) was added to a solution of di-tert-butyl L-glutamate hydrochloride (2.15 g, 7.27 mmol) and triethylamine (5 mL, 36 mmol) in dichloromethane (20 mL). The solution was stirred for overnight (16 h) at room temperature. The solution was washed with sodium bicarbonate solution (3×10 mL) and water (2×5 mL). After drying over sodium sulphate, the solvent was evaporated. The crude product was purified by flash chromatography (ethyl acetate/n-hexane: 2/98 to 3/97) to give di-tert-butyl N-trityl-L-glutamate (3.2 g, 88%) as a white foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[CH:4][N:3]=1.[H-].[Na+].C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1.O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[O:9][C:17](=[O:18])[NH:8][C:6]=2[N:7]=1
Reactant: Nc1ncc(O)c(N)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc2oc(=O)[nH]c2n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2,4-Diamino-pyrimidin-5-ol (500 mg, 3.97 mmol) [prepared according to the method of Hull. J. Chem. Soc. 1956, 2033-2035] was suspended in DMF (10 mL). To this was added consecutively NaH (86.7 mg, 3.77 mmol) and CDI (707 mg, 4.36 mmol), and the reaction mixture was heated with vigorous stirring at 60° C. for 3 h. The mixture was cooled to ambient temperature, and then quenched with water (25 mL). The solvent and water were removed via rotary evaporation, and the residue was then triturated in water (5 mL). The solid was then collected by filtration and dried, affording 230 mg (38%): 1H NMR (400 MHz, d6-DMSO) δ 11.90 (br s, 1H), 7.72 (br s, 1H), 6.72 (s, 2H); Analysis calc'd for C5H4N4O2.0.2; H2O: C, 38.56; H, 2.85; N, 35.98. Found: C, 39.01; H, 2.71; N, 35.58; [M+H]+ m/z 153.