Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]#[N:17])=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH2:25][C:26]([NH:28][NH2:29])=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[N:17]=[C:26]([CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:28][N:29]=2)=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#N)sc1C(=O)NCc1ccccc1
Reactant: NNC(=O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Cc1nc(-c2n[nH]c(Cc3ccccc3)n2)sc1C(=O)NCc1ccccc1
Yield: 13.8 %

Procedure:
A mixture of N-benzyl-2-cyano-4-methylthiazole-5-carboxamide (0.085 g, 0.33 mmol), phenylacetic hydrazide (0.02 g, 0.13 mmol) and potassium carbonate (0.037 g, 0.27 mmol) in 1-butanol (2 mL) was subjected to a microwave irradiation (150° C., 100 W) for 30 minutes. The reaction mixture was purified by column chromatography (0-10% methanol in dichloromethane). Less polar fractions were combined and concentrated in vacuo. The residue was purified by preparative thin layer chromatography plate (60% ethyl acetate in hexanes) to afford the title compound as a yellow solid (0.007 g, 15%): mp 235-237° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.87 (t, J=5.6 Hz, 1H), 7.38-7.21 (m, 11H), 4.43 (d, J=5.6 Hz, 2H), 4.15 (s, 2H), 2.61 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 160.8, 156.8, 155.4, 139.1, 136.4, 128.6, 128.6, 128.3, 127.2, 126.8, 42.7, 31.7, 17.0; MS (ES+) m/z 390.3 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][C:16]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]3[C:17]=2[CH2:18][C:19](=[O:26])[NH:20]3)[C:7]1=[O:27].[OH-].[Li+]>O.O1CCOCC1>[Cl:25][C:23]1[CH:22]=[C:21]2[C:17]([CH2:18][C:19](=[O:26])[NH:20]2)=[C:16]([CH2:15][N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]([CH2:5][CH2:4][C:3]([OH:28])=[O:2])[C:7]2=[O:27])[CH:24]=1
Reactant: COC(=O)CCn1c(=O)n(Cc2cc(Cl)cc3c2CC(=O)N3)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCn1c(=O)n(Cc2cc(Cl)cc3c2CC(=O)N3)c2ccccc21
Reaction time: 1 h
Yield: 33.3 %

Procedure:
3-[3-(6-Chloro-2-oxo-2,3-dihydro-1H-indol-4-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-propionic acid methyl ester (34 mg 0.09 mmol) is dissolved in dioxane water (2 mL/2 mL) and lithium hydroxide (18 mg, 0.45 mmol) is added in one portion. The reaction is stirred for one hour then the solvents evaporated in vacuo. The crude material is purified by preparative reverse phase LC to give the title compound (12 mg 0.03 mmol, 36%). LCMS (ESMS): m/z 387.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([CH:21]=C)[N:12]2[CH:17]([CH3:18])[CH2:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:29].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([CH:21]=[O:29])[N:12]2[CH:17]([CH3:18])[CH2:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1c(C(=O)OCC)c(OCc2ccccc2)c2n1C(C)CN(C)C2=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C=O)C(C)CN(C)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 8-(benzyloxy)-2,4-dimethyl-1-oxo-6-vinyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (0.11 g, 0.29 mmol), osmium tetroxide (2.5% in t-butanol, 0.59 mL, 0.058 mmol), sodium periodate (0.19 g, 0.87 mmol) in aqueous THF (6 mL, 1:2 v/v) was stirred at room temperature for 4 hours. The reaction mixture was treated with 10% aqueous sodium sulfite and diluted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with a hexanes and ethyl acetate gradient to provide the titled product.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.O.N[C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15](NC2C=CC(N)=CC=2)=[CH:14][CH:13]=1>CC(C)=O>[CH:19]1[C:18]2[C:17](=[O:27])[C:16]3[C:25](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:24](=[O:26])[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(Nc2ccc(N)c3c2C(=O)c2ccccc2C3=O)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Reaction time: 0.55 h

Procedure:
1-18.4 g of cyanuric chloride was placed into a beaker. A small amount of crushed ice and water were added for pulping for 0.1-1 h; during which, 1-17.4 g of 1-amino-4-(p-aminoanilino) anthraquinone in 200 ml of acetone was added with the cyanuric chloride, condensed for 4-5 h, to obtain an anthraquinone dye comprising triazinyl group and amino group.
Reaction SMILES: C([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([CH:28]([OH:56])[C@@H:29]([NH:37][C:38](=[O:55])[C@H:39]([CH:52]([CH3:54])[CH3:53])[NH:40][C:41](=[O:51])[CH2:42][NH:43]C(OC(C)(C)C)=O)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])(OC(C)(C)C)=O.CO>ClCCl>[NH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([CH:28]([OH:56])[C@@H:29]([NH:37][C:38](=[O:55])[C@H:39]([CH:52]([CH3:54])[CH3:53])[NH:40][C:41](=[O:51])[CH2:42][NH2:43])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)CNC(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)[C@H](NC(=O)CN)C(=O)N[C@@H](Cc1ccccc1)C(O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)CN)C(C)C
Yield: 91 %

Procedure:
Using the procedure of Example 6F but replacing the resultant compound of Example 6E with the resultant compound of Example 140 provided, after silica gel chromatography using 10% methanol in dichloromethane, 48.7 mg (91%) of the desired compound as a white solid. 1H NMR (DMSO-d6) δ0.70-0.83 (four d, 12H), 1.78 (m, 1H), 1.96 (m, 1H), 2.62 (m, 2H), 2.74 (br d, 2H), 2.97 (m, 1H), 3.46-3.87 (m, 5H), 4.02 (m, 2H), 4.21 (m, 1H), 5.33 (br d, 1H), 7.08-7.26 (m, 10H), 7.57 (br d, 2H), 7.67 (br d, 1H), 7.86 (br d, 1H). Mass spectrum: (M+H)+ =583.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:16][NH2:17]>CCO>[CH3:16][NH:17][C:3]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])NCc1cccnc1
Reactant: CN
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCc1cccnc1
Yield: 76.8 %

Procedure:
In 50 ml of EtOH was dissolved 2.3 g (0.01 mole) of 1-methylthio-1-(3-pyridyimethyl)amino-2-nitroethylene with heating and, then, a solution of 1.2 g (0.015 mole) of 40% aqueous methylamine in 10 ml of EtOH was added dropwise over a period of 30 minutes while refluxing. The mixture was further refluxed for 2 hours, after which it was concentrated. The crystals were collected by filtration and recrystallized from acetonitrile to give 1.6 g of the title compound as white prisms.
Reaction SMILES: C([NH:8][C@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC(C)(C)C)=O.[ClH:36].CCOC(C)=O>C(OCC)(=O)C>[ClH:36].[C:14]([NH:13][CH2:12][CH2:11][CH2:10][C@@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=1)[CH3:28])=[O:25])[NH2:8])([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: C[C@@H](NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1)c1ccc(O)cc1

Procedure:
Prepared according to the method described in Example 1(b) above from (R)-N2 -(Boc)-N5 -(Cbz)-(S)-N-[1-(4-hydroxyphenyl)ethyl]ornithine amide (5.1 g; from step (a) above), ethyl acetate (100 mL) and HCl/EtOAc (100 mL) yielding, after isolation, 3.3 g of the sub-title compound as a tan solid.
Reaction SMILES: [NH2:1][NH2:2].OS(O)(=O)=O.[Br:8][C:9]1[C:10](=O)[O:11][C:12](=[O:14])[CH:13]=1>O>[Br:8][C:9]1[C:10](=[O:11])[NH:1][NH:2][C:12](=[O:14])[CH:13]=1
Reactant: NN
Reactant: O=C1C=C(Br)C(=O)O1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1cc(Br)c(=O)[nH][nH]1
Temperature: 90 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To a solution of NH2NH2.H2SO4 (362 mg, 2.8 mmol) in H2O (5 mL) was added dropwise 3-bromofuran-2,5-dione (500 mg, 2.8 mmol), and the mixture was stirred at 90° C. for 4 hours. After the reaction, the mixture was filtered to get 4-bromo-1,2-dihydropyridazine-3,6-dione (300 mg, yield: 56%). 1H-NMR (DMSO-d6, 400 MHz) δ 12.47 (s, 1H), 11.17 (s, 1H), 7.62 (s, 1H). MS (M+H)+:191/193.
Reaction SMILES: Cl.[NH2:2][OH:3].O.O.O.C([O-])(=O)C.[Na+].[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=1[C:20](=O)[CH3:21]>CCO.O.O>[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=1[C:20](=[N:2][OH:3])[CH3:21]
Reactant: CC(=O)c1c(O)cccc1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of hydroxylamine hydrochloride (756 mg, 10.9 mmol) and sodium acetate trihydrate (1.71 g, 12.6 mmol) dissolved in 23 ml of a mixture of EtOH/H2O (7/3) was added to a solution of 2′,6′-dihydroxyacetophenone (1.5 g, 9.9 mmol) in 12 ml of a 7/3 EtOH/H2O mixture. After refluxing and stirring under N2 for 2 hours, additional hydroxylamine hydrochloride (340 mg, 4.9 mmol) and sodium acetate trihydrate (570 mg, 4.19 mmol) dissolved in 7 ml of water were added and the reflux was continued for additional 30 minutes. After cooling down to room temperature, the volatiles were removed. Then water was added and the solid obtained was filtered, washed with water and dried. This afforded 1.3 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[CH:8][C:9]=1[CH3:10])=[O:4].Cl.[OH:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[CH2:19][CH2:20][NH2:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:13])[NH:21][CH2:20][CH2:19][C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([OH:15])[CH:17]=2)=[CH:8][C:9]=1[CH3:10])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1C
Reactant: NCCc1cccc(O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCCc2cccc(O)c2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 162.8 %

Procedure:
To a solution of 3-methyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (0.1 g, 0.5 mmol) and 3-hydroxyphenethylamine hydrochloride (105 mg, 0.6 mmol) in DMF (5 ml) was added at rt triethylamine (0.21 ml, 1.5 mmol), HOBT (81 mg, 0.6 mmol) and HBTU (230 mg, 0.6 mmol). The mixture was stirred at rt for 1 h, then quenched with 1NHCl and extracted with EtOAc. The layers were separated. The organic layer was washed with brine, then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 15-65% EtOAc in hexane to afford the desired product (260 mg, 81% yield).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:10][C@@H:9]1[CH:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>CN(C)C=O.O1CCCC1>[CH2:19]([N:13]1[CH2:14][CH2:15][CH:11]([C@H:9]2[CH2:10][C@@H:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:12]1=[O:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@H]1C1CCNC1=O
Reactant: ClCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H]1C1CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.3 %

Procedure:
A solution (100 ml) of 8.816 g (39.1 mmol) of 3-[(1R,2S)-2-t-butoxycarbonylcylcopropyl]pyrrolidin-2-one in a 3:2 mixed solvent of tetrahydrofuran and dimethylformamide was added dropwise to 20 ml of a suspension of 1.72 g (43.0 mmol) of sodium hydride in dimethylformamide while cooling with ice, and the mixture was stirred at room temperature for 1.5 hours. Then, 40 ml of a tetrahydrofuran solution of 6.76 ml (58.7 mmol) of benzyl chloride was added dropwise thereto, followed by stirring for 3 hours. After completion of the reaction, a saturated ammonium chloride aqueous solution was added thereto, followed by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 5.710 g (44.8%) of 1-benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidin-2-one (isomer A1) as a colorless solid. Then, the column was eluted with a 1:1 mixed solvent of hexane and ethyl acetate to give 3.959 g (31.1%) of 1-benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidin-2-one (isomer B1) as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(Cl)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-6-methylbenzoicacid (339) (300 g, 1.76 mol, 1.0 eq) and DMF (0.5 mL) in DCM (500 mL) at RT, oxalyl chloride (249 g, 1.92 mol, 1.1 eq) was added slowly (over 5 min). The resulting mixture was stirred at RT for 2 h and then concentrated in vacuo to afford 2-chloro-6-methylbenzoyl chloride (340) which was used directly in the next step.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[CH2:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[I:37][C:38]1[CH:39]=[C:40]([CH:56]=[C:57]([C:61]([O:63][CH3:64])=[O:62])[C:58]=1[O:59][CH3:60])[C:41]([C:43]1[CH:48]=[C:47]([C:49]([O:51][CH3:52])=[O:50])[C:46]([O:53][CH3:54])=[C:45]([I:55])[CH:44]=1)=O>C1COCC1>[CH3:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[C:41]([C:43]1[CH:44]=[C:45]([I:55])[C:46]([O:53][CH3:54])=[C:47]([C:49]([O:51][CH3:52])=[O:50])[CH:48]=1)[C:40]1[CH:39]=[C:38]([I:37])[C:58]([O:59][CH3:60])=[C:57]([C:61]([O:63][CH3:64])=[O:62])[CH:56]=1
Reactant: COC(=O)c1cc(C(=O)c2cc(I)c(OC)c(C(=O)OC)c2)cc(I)c1OC
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC=C(c1cc(I)c(OC)c(C(=O)OC)c1)c1cc(I)c(OC)c(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.8 %

Procedure:
NaN(TMS)2 (1 mL, 1 mmol) was added to an ice cold suspension of hexyltriphenylphosphonium bromide (0.427 g, 1 mmol) in THF (20 mL) and the solution was stirred for 30 min at 0° C. A solution of the benzophenone 39 (0.2 g, 0.33 mmol) in THF (5 mL) was added to the preformed ylide and the solution was stirred at rt overnight. The mixture was partitioned between 1 N HCl (100 mL) and ethyl acetate (100 mL). The organic layer was evaporated and flash chromatographed on SiO2 (230-400 mesh, 50.0 g), eluting with hexanes-ethyl acetate (5:1). The fractions which contained the product were pooled, evaporated, and chromatographed on silica gel (230-400 mesh, 20 g), eluting with hexanes-ethyl acetate (5:1), to give the product 40 (0.022 g, 9%) as an oil: 1H NMR (CDCl3, 300 MHz) δ 7.69 (s, 2H), 7.54 (d, J=2.0 Hz, 1H), 7.52 (d, J=2 Hz, 1H), 6.01 (t, J=7.6 Hz, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 2.05 (q, J=7.3 Hz, 2H), 1.42 (m, 2H), 1.25 (m, 2H), 0.85 (t, J=6.7 Hz, 3H); IR (neat) 2953, 2929, 1742, 1738, 1731, 1713 cm−1; HRFABMS calcd for C25H28I2O6 m/z 677.9975 (M+). Found: m/z 677.9954. Anal. (C25H28I2O60.5EtOAc), C, H.
Reaction SMILES: C(Cl)CCl.[F:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][C@@H:11]([CH2:15][CH2:16][C@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:18]([OH:20])=[O:19])[C:12](O)=[O:13])=[CH:8][CH:7]=1.[NH2:31][C@H:32]1[CH2:38][CH2:37][CH2:36][CH2:35][N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]1=[O:45]>CN(C=O)C.C(Cl)Cl>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@@H:17]([CH2:16][CH2:15][C@H:11]([CH2:10][C:9]2[CH:29]=[CH:30][C:6]([F:5])=[CH:7][CH:8]=2)[C:12](=[O:13])[NH:31][C@H:32]2[CH2:38][CH2:37][CH2:36][CH2:35][N:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]2=[O:45])[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=1
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccc(F)cc1)C(=O)O)Cc1ccc(F)cc1
Reactant: N[C@H]1CCCCN(c2ccccc2)C1=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(O)[C@H](CC[C@H](Cc1ccc(F)cc1)C(=O)N[C@H]1CCCCN(c2ccccc2)C1=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
EDC (16 mg, 0.083 mmol) was added to a 0° C. solution of (2R,5R)-2,5-Bis(4-fluorobenzyl)hexanedioic acid (30 mg, 0.083 mmol) in DMF (1 mL) and DCM (5 mL). The ice bath was removed and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated to remove most of the DCM. (S)-3-Amino-1-phenylazepan-2-one (21 mg, 0.085 mmol) was added followed by TEA (18.4 mg, 0.182 mmol). The reaction mixture was left to stir at rt for 3 hr. The reaction mixture was partitioned between EtOAc and 5% aqueous KHSO4. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (2R,5R)-2,5-bis(4-fluorobenzyl)-6-oxo-6-((S)-2-oxo-1-phenylazepan-3-ylamino)hexanoic acid (32 mg, 0.058 mmol, 71% yield) as a colorless syrup. Anal. Calcd. for C32H34F2N2O4 m/z 548.3. found: 549.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=O.[CH3:13][N:14]([CH3:30])[CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][C:22]3[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:16]1>>[CH3:13][N:14]([CH3:30])[CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][C:22]3[CH:28]=[C:27]([NH:29][C:3](=[O:5])[C:2]([CH3:1])=[CH:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:16]1
Reactant: CC(=Cc1ccccc1)C(=O)O
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Product: CC(=Cc1ccccc1)C(=O)Nc1ccc2nc(N3CCC(N(C)C)C3)sc2c1
Yield: 12.5 %

Procedure:
Prepare according to Method B, using α-methylcinnamic acid (99 mg, 0.610 mmol) and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (162 mg, 0.618 mmol) to yield the title compound (31 mg, 12%). mass spectrum (m/e): 407.3 [M+H], 405.2 [M−H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][NH:23]2)=[CH:19][C:18]=1B1OCC(C)(C)CO1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][NH:23]2)=[CH:19][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: COc1cc(Br)ccc1C1(CO)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(CO)CCC4)c(OC)c3)cc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a mixture of [1-(4-bromo-2-methoxyphenyl)cyclobutyl]methanol (180 mg, 0.660 mmol) in dioxane (10 mL) and water (4 mL) was added methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (213 mg, 0.660 mmol), Pd (dppf)Cl2 (48 mg, 0.070 mmol) and potassium carbonate (273 mg, 2.00 mmol). The reaction mixture was purged with nitrogen for 3 minutes and stirred at 80° C. for 2 hours. The mixture was extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (220 mg, 83%) as a brown solid. It was used for next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:26]([OH:28])=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[C:29]([O:34][CH3:35])(=[O:33])[C@H:30]([CH3:32])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:30]([CH3:32])[C:29]([O:34][CH3:35])=[O:33])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: COC(=O)[C@H](C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
DTAD (11.48 g, 49.9 mmol) was added portion-wise to an ice-cooled solution of 4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-ol (7.36 g, 20 mmol), (S)-methyl lactate (2.29 ml, 24 mmol) and triphenylphosphine (13.1 g, 49.9 mmol) in DCM (200 ml). The mixture was stirred at room temperature for 1 hour. The mixture was extracted with 2N hydrochloric acid (2×50 ml). The hydrochloric layers were combined and washed with DCM. The pH of the solution was adjusted to pH 9 by slow addition of concentrated aqueous ammonia while cooling. This aqueous solution was extracted with DCM (2×100 ml). These DCM layers were combined, washed with water and brine and dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 4% methanol in DCM) to give methyl (2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate as a yellowish solid (7.35 g, 80%); NMR Spectrum (CDCl3) 1.80 (d, 3H), 3.85 (s, 3H), 5.15 (q, 1H), 5.76 (s, 2H), 6.79 (d, 1H), 6.85 (d, 1H), 7.18 (m, 1H), 7.43 (d, 1H), 7.50 (d, 1H), 7.63-7.54 (m, 2H), 7.70 (dd, 1H), 8.11 (s, 1H), 8.38 (s, 1H), 8.59 (br d, 1H), 8.63 (s, 1H); Mass spectrum MH+ 455.
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[Mo:10](=[O:13])(=[O:12])=[O:11].O.O.O.O.O.O.O.[O-:21]S([O-])(=O)=O.[Mg+2]>O>[O-:11][Mo:10]([O-:21])(=[O:13])=[O:12].[N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3]
Reactant: O=[Mo](=O)=O
Reactant: O=S(=O)([O-])[O-]
Agent: Nc1nc(N)nc(N)n1
Agent: [Mg+2]
Solvent: O
Product: O=[Mo](=O)([O-])[O-]
Temperature: 105 °C
Yield: 98.03 %

Procedure:
Melaminium octamolybdate having a 2/1 molybdate/melamine molar ratio was prepared by the following procedure. 10.00 grams of melamine, 22.83 grams of molybdenum trioxide, 39.09 grams of epsom salt (MgSO4.7H2O) and 300 milliliters of water were added to a 500 milliliter round-bottom flask fitted with a water-cooled condenser. The mixture was refluxed at about 105° C. for 2 hours while being stirred continuously, cooled to room temperature and filtered. A white crystalline product was recovered. The recovered product was washed with water and vacuum dried at 100° C. for 11/2 hours. The product was identified by infrared and x-ray diffraction analyses to be melaminium octamolybdate. 32.88 grams of the product were recovered, representing a yield of 98.03 percent of the theoretical yield.