Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])[N:3]=1.[NH2:23][CH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:34]([O:33][C:32](=[O:38])[NH:31][CH:28]1[CH2:27][CH2:26][CH:25]([CH2:24][NH:23][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]([F:22])([F:21])[F:20])[N:3]=2)[CH2:30][CH2:29]1)([CH3:37])([CH3:35])[CH3:36]
Reactant: N#Cc1cnc(NCc2ccccc2OC(F)(F)F)nc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2C#N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
(4-Chloro-5-cyanopyrimidin-2-yl)-(2-trifluoromethoxy-benzyl)-amine (50 mg, 0.16 mmol) was dissolved in DMF (1 mL) and tert-butyl trans-4-aminomethylcyclohexylcarbamate (70 mg, 0.30 mmol) was added followed by DIPEA (53 μL, 0.30 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with EtOAc and washed with water (×3). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 76 mg (96%) of (4-{[5-cyano-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OC(NCCCC(OC1C(C)=CC=CC=1C)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: Cc1cccc(C)c1OC(=O)CCCNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)Oc1ccccc1

Procedure:
The title compound was prepared from N-(tert-butoxycarbonyl)-β-alanine and phenol in a similar manner as described for 2,6-dimethylphenyl 4-[(tert-butoxycarbonyl)amino]butanoate. Mass Spectrum (M-tert-Bu)+H+ 211.09.
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[C:15]1([S:21]([NH:24][C@@H:25]([CH2:33][NH2:34])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:35]N1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C.CCOC(C)=O>[C:29]([O:28][C:26](=[O:27])[C@@H:25]([NH:24][S:21]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:22])=[O:23])[CH2:33][NH:34][C:4](=[O:6])[C:3]1[CH:2]=[CH:10][C:9]([C:11]([O:13][CH3:35])=[O:12])=[CH:8][CH:7]=1)([CH3:30])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)O
Reactant: CN1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)cc1

Procedure:
A slurry of mono-methyl terephthalic acid (32-1, Aldrich) (0.25 g, 1.4 mmol) and 19-2a (0.5 g, 1.4 mmol) in acetonitrile (7 mL) was treated with N-methyl morpholine (0.31 mL, 2.8 mmol) and BOP reagent (0.62 g, 1.4 mmol) for 24 h. The solution was diluted with EtOAc, washed with H2O, 10% KHSO4, saturated NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and evaporated to give a tan solid. Column chromatography (40% EtOAc/Hexanes) gave 32-2 as a white solid.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:19]([C:23]1[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([C:23]1[NH:27][N:26]=[C:25]([NH:28][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: CC(C)(C)c1cc(N)n[nH]1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC=C2C(=O)Nc3ccccc32)n[nH]1

Procedure:
The named compound is prepared by substituting 5-tert-butyl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.1920 gms. of 5-tert-butyl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][O:13][CH3:14])=[C:7]([CH:10]=1)[CH:8]=O.[NH2:15][C:16]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][O:13][CH3:14])=[C:7]([CH:10]=1)[CH:8]=[N:15][C:16]1[C:17]([CH3:23])=[CH:18][CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: COCOc1ccc(OC)cc1C=O
Reactant: Cc1cccc(O)c1N
Solvent: c1ccccc1
Product: COCOc1ccc(OC)cc1C=Nc1c(C)cccc1O
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of 5-methoxy-2-methoxymethoxybenzaldehyde (F1) (2.77 g, 16.5 mmol) and 2-amino-m-cresol (2.03 g, 16.5 mmol) in benzene (70 mL) was refluxed for 15 h using an additional funnel to remove water. After the reaction mixture was cooled to room temperature, the solvent was removed in vacuo and the resulting residue was washed with ethanol to afford the objective compound as a orange solid (84%), which was used for next reaction without further purification: 1H-NMR 400 MHz, DMSO-d6) δ2.31 (s, 3H), 3.45 (s, 3H), 3.85 (s, 3H), 5.18 (s, 2H), 6.59 (s, 1H), 6.77 (d, 1H, J=8.0 Hz), 6.83 (d, 1H, J=8.0 Hz), 6.99 (t, 1H, J=8.0 Hz), 7.03 (dd, 1H, J=9.0, 2.5 Hz), 7.14 (d, 1H, J=9.0 Hz), 7.68 (s, 1H), 8.95 (s, 1H).
Reaction SMILES: CON(C)[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1O[Si](C)(C)C.[Mg].Br[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24].[OH:26]S([O-])(=O)=O.[K+]>>[OH:26][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:16])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[CH:10][CH:9]=1
Reactant: O=S(=O)([O-])O
Reactant: CON(C)C(=O)c1ccccc1O[Si](C)(C)C
Reactant: CC(C)=CCCBr
Agent: [K+]
Agent: [Mg]
Product: CC(C)=CCCC(=O)c1ccc(O)cc1
Reaction time: 8 h

Procedure:
A solution of 6.3 g of N-methoxy-N-methyl-trimethylsilanyioxybenzamide is added dropwise at 0° C. to a Grignard reagent prepared from 1 g of magnesium and 5.7 g of 1-bromo-4-methyl-3-pentene. The reaction mixture is left to stand at room temperature overnight while stirring. The mixture is treated with 10% aqueous KHSO4 solution and then extracted with ethyl acetate. The organic phase is washed neutral with 10% aqueous NaCl solution, then dried and concentrated. The silyl group is cleaved in 10% aqueous THF with 1N hydrochloric acid. Then, the product is taken up in methylene chloride, dried and evaporated. After chromatography over silica gel while eluting with methylene chloride/5% methanol, there are obtained 2.1 g of 1-(4-hydroxy-phenyl)-5-methyl-hex-4-en-l-one. MS: m/e 204 (M+).
Reaction SMILES: [CH:1]12[CH2:8][N:7]([C:9](OC(C)(C)C)=O)[CH2:6][CH:5]1[CH2:4][CH2:3][NH:2]2.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH2:19]Cl.CCN(CC)CC.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38]1[N:51]=[C:41]2[N:42]=C(S(C)(=O)=O)[N:44]=[C:45]([NH2:46])[N:40]2[N:39]=1>CC#N.CCOC(C)=O>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH2:19][N:2]1[CH2:3][CH2:4][CH:5]2[CH2:6][N:7]([C:9]3[N:44]=[C:45]([NH2:46])[N:40]4[N:39]=[C:38]([C:34]5[O:33][CH:37]=[CH:36][CH:35]=5)[N:51]=[C:41]4[N:42]=3)[CH2:8][CH:1]12
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC2CCNC2C1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1nc(N2CC3CCN(Cc4c(Cl)cccc4Cl)C3C2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Tert-butyl 2,7-diazabicyclo[3.3.0]octane-7-carboxylate (0.3 mmol; see U.S. Pat. No. 5,071,999) dissolved in 2 mL of CH3CN along with 0.3 mmol of 2,6-dichlorobenzyl chloride and 0.5 mmol of Et3N. The reaction mixture was stirred at room temperature for 18 hours. It was then diluted with EtOAc, washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The resulting residue was dissolved in 2 mL of 25% TFA in CH2Cl2 and allowed to stand at room temperature for 3 hours. It was then concentrated to dryness. The resulting residue was dissolved in 3 mL of CH3CN along with 0.3 mmol of 2-furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (see J. Chem. Soc. Perkin Trans. 1, 801 (1995)) and 0.8 mmol of Et3N. The reaction mixture was stirred at reflux for 3 hours. It was then concentrated and purified by preparative HPLC to afford the title compound. 1H NMR (400 Hz, DMSO-d6) δ 8.20 (brs, 1H), 7.8 (d, J=1.0 Hz, 1H), 7.30 (d, J=3.6 Hz, 1H), 7.1-7.30 (m, 3H) 6.60 (dd, J=3.6, 1.0 Hz, 1H), 4.80 (brs, 2H), 2.30-3.8 (m, 10H). MS m/z: 472 [M+H]+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][O:12][C:13](=[O:46])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH:25]([C:32](=[O:41])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=3)[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:23]3[CH:42]=[CH:43][CH:44]=[CH:45][C:22]=3[N:21]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:11][O:12][C:13](=[O:46])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH:25]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[C:32](=[O:41])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH:1]=[O:3])[CH:35]=3)[C:23]3[CH:42]=[CH:43][CH:44]=[CH:45][C:22]=3[N:21]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2nc3ccccc3n2C(C(=O)Nc2cccc(N)c2)C2CCCCC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc3ccccc3n2C(C(=O)Nc2cccc(NC=O)c2)C2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
A mixture of acetic anhydride (162 mg, 1.58 mmol, 2.2 equiv.) and formic acid (73 mg, 1.58 mmol, 2.2 equiv.) was heated to 60° C. for 15 minutes. The reaction was cooled to room temperature and a solution of 4-{1-[(3-amino-phenylcarbamoyl)-cyclohexyl-methyl]-1H-benzoimidazol-2-yl}-benzoic acid methyl ester (35 mg, 0.72 mmol, 1.0 equiv.) in dichloromethane (2 mL) was added and the reaction mixture stirred at room temperature for 16 hours. The reaction mixture was washed with 1 N HCl (2 mL) and the organic layer dried over magnesium sulphate. The reaction mixture was concentrated in vacuo to afford 4-{1-[cyclohexyl-(3-formylamino-phenylcarbamoyl)-methyl]-1H-benzoimidazol-2-yl}-benzoic acid methyl ester, 23 mg (62% yield) as a yellow solid, MS (ES+): 511 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][NH:7][C:6]1=[S:15].Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1>CN(C)C=O>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[NH:5][C:6](=[S:15])[NH:7][CH2:8]3)=[O:24])[CH:18]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: S=C1NCc2ccccc2N1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(c1cccnc1)c1ccc2c(c1)CNC(=S)N2
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
106 Parts of N,N-dimethylformamide were added dropwise to 650 parts of aluminum chloride and the solution was stirred for 15 min at 75° C. There were added portionwise 112 parts of 3,4-dihydro-2(1H)-quinazolinethione and, after stirring for 15 min at 75° C., 136 parts of 3-pyridinylcarbonyl chloride hydrochloride. Stirring at 75° C. was continued overnight and then the mixture was poured into 2500 parts of ice-water. The precipitate was filtered off and stirred for 13 hours in a mixture of ice-water and 1530 parts of a sodium hydroxide solution 50%. The product was filtered off, washed with water and dried, yielding 150 parts (82%) of (3-pyridinyl) (1,2,3,4-tetrahydro-2-thioxo-6-quinazolinyl)methanone; (decomp.) (interm. 54).
Reaction SMILES: N1C(N)=NC(N)=NC=1N.[Mo:10](=O)(=O)=[O:11].S([O-])([O-])(=O)=[O:15].[NH4+].[NH4+]>O>[O-2:11].[O-2:15].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[O-2:11].[Mo:10].[Mo:10].[Mo:10].[Mo:10].[Mo:10].[Mo:10].[Mo:10]
Reactant: O=S(=O)([O-])[O-]
Reactant: O=[Mo](=O)=O
Agent: Nc1nc(N)nc(N)n1
Agent: [NH4+]
Solvent: O
Product: [Mo]
Product: [O-2]
Yield: 93.29 %

Procedure:
Melaminium heptamolybdate was prepared as follows, 10.00 grams of melamine, 11.41 grams of molybdenum trioxide, 7.86 grams of ammonium sulfate and 300 milliliters of water were added to a 500 milliliter round-bottom flask equipped with a water-cooled condenser.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]#[N:11])[NH2:6].[C:14]1(=O)[O:19][C:17](=[O:18])[CH:16]=[CH:15]1>C(O)(=O)C>[O:18]=[C:17]1[CH:16]=[CH:15][C:14](=[O:19])[N:6]1[C:5]1[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: N#Cc1ccc(N2C(=O)C=CC2=O)cc1C(F)(F)F
Temperature: 115 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A mixture of 3-trifluoromethyl-4-cyano-aniline (24.0 g, 129 mmol) and maleic anhydride (14.0 g, 143 mmol) in 50 n-L of acetic acid was heated at 115° C. overnight. A precipitate was obtained during the heating period. The reaction was allowed to stand at rt for an additional overnight period. The solid was removed by filtration, the filter cake was washed with diethyl ether and dried to give 21 g (79 mmol, 61%) of compound 471A as an off white solid. HPLC: 100% at 2.11 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[CH:8][N:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([O-])(=O)C.[K+].[N:23](Cl)=[O:24]>C(O)(=O)C.C(OC(=O)C)(=O)C>[N:23]([N:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[N:7][CH:8]=1)[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[O:24]
Reactant: O=NCl
Reactant: CCCCCc1ccc(NC(=O)C(C)C)cn1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCCCCc1ccc(N(N=O)C(=O)C(C)C)cn1

Procedure:
24.8 g of N-(2-pentyl-5-pyridyl)-isobutyramide (boiling point 167°-171°/0.27 bar; obtainable by reacting 2-chloro-5-nitropyridine with Na-2-butylmalonic acid diethyl ester to give 2-(5-nitro-2-pyridyl)-2-butylmalonic acid diethyl ester, hydrolysis and decarboxylation to give 2-pentyl-5-nitropyridine, hydrogenation on 10% strength Pd-C in methanol at 40°-50° under 1 bar to give 2-pentyl-5-aminopyridine and acylation with isobutyric anhydride) are dissolved in a mixture of 110 ml of acetic acid and 50 ml of acetic anhydride, 49 g of anhydrous potassium acetate are added, and a solution of 6.9 g of nitrosyl chloride in 27 ml of acetic anhydride is then added at 0°. N-nitroso-N-(2-pentyl-5-pyridyl)-isobutyramide is formed as the intermediate and is not isolated. After the mixture has been stirred at 0° for 15 minutes, it is poured onto ice and extracted five times with 140 ml of thiophene each time. The phases are separated, the organic phase is kept at 0° and made into a slurry with 22 g of K2CO3 and 35 g of Na2SO4, and the slurry is decanted. The organic phase is warmed at 50° and, when the evolution of gas has ended, boiled for 2 hours, and evaporated and the residue is separated on silica gel using toluene. 2-(2-Pentyl-5-pyridyl)-thiophene, boiling point 180°-185°/0.013 bar, c.p. -45° is obtained; a little 3-(2-pentyl-5-pyridyl)-thiophene, boiling point 170°-180°/0.015 bar, c.p. -80°, is also formed.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([O:38][CH3:39])=[C:33](B(O)O)[CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C@H:9]([NH:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:31]2[CH:30]=[C:29]([F:28])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])=[CH:3][CH:4]=1)[CH3:15]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)CCC(=O)OC(C)(C)C
Reactant: COc1ccc(F)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)CCC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-tert-butyl 4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoate, intermediate 9, (100 mg, 0.23 mmol) and 5-fluoro-2-methoxyphenylboronic acid (57.6 mg, 0.34 mmol) in toluene (1 mL) and EtOH (0.1 mL) is added Pd(PPh3)4 (26.1 mg, 0.023 mmol) and Na2CO3 (47.9 mg, 0.45 mmol). After stirring at 95° C. under nitrogen for 18 hours, the solution is cooled to ambient temperature and then quenched with aqueous 1 M HCl. The crude is diluted with ethyl acetate, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 30:70) to give (R)-tert-butyl 4-(4-ethoxy-1-(5′-fluoro-2′-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobutanoate (65 mg). HPLC retention time=1.44 minutes (condition B); MS (m+1)=488.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.1 Hz, 3H) 1.48 (s, 9H) 2.41-2.48 (m, 2H) 2.51-2.63 (m, 4H) 2.90 (dd, J=13.6, 6 Hz, 1H) 3.02 (dd, J=13.6, 6 Hz, 1H) 3.81 (s, 3H) 4.14-4.29 (m, 2H) 4.49-4.63 (m, 1H) 6.44 (d, J=8.6 Hz, 1H) 6.89-6.97 (m, 1H) 6.98-7.05 (m, 1H) 7.05-7.11 (m, 1H) 7.27 (d, J=8.1 Hz, 2H) 7.49 (d, J=8.1 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:50][O:51][C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=1)[CH:55]([OH:57])[CH3:56]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:39](=[O:41])[O:57][CH:55]([C:54]1[CH:58]=[CH:59][CH:60]=[C:52]([O:51][CH3:50])[CH:53]=1)[CH3:56]
Reactant: COc1cccc(C(C)O)c1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(C)OC(=O)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2Cl)c1
Temperature: 25 °C
Yield: 54.7 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (82 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (110 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-methoxy-α-methylbenzyl alcohol (56 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (69 mg, yield 55%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[C:12]([O-:16])(=[O:15])[CH:13]=[CH2:14].[K+]>>[C:12]([O:16][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7])(=[O:15])[CH:13]=[CH2:14]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: C=CC(=O)[O-]
Agent: [K+]
Product: C=CC(=O)OCCC[Si](OC)(OC)OC

Procedure:
Trichlorosilane and allyl chloride were subjected to hydrosilylation reaction in a solvent in the presence of a platinum catalyst, followed by esterification reaction with methanol and urea and further by distillation to obtain γ-chloropropyltrimethoxysilane. The thus obtained γ-chloropropyltrimethoxysilane and potassium acrylate were subjected to desalting in a solvent, followed by removal of potassium chloride. Subsequently, low boiling components including the solvent were distilled off under reduced pressure to obtain crude γ-acryloxypropyltrimethoxysilane having a purity of approximately 90%.
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C.C(OC([N:41]1[C:49]2[C:44](=[C:45]([O:53][CH3:54])[CH:46]=[C:47]([C:50]([OH:52])=O)[CH:48]=2)[CH2:43][CH2:42]1)=O)(C)(C)C.[CH2:55]([O:57][C:58](=[O:67])[C:59]1[CH:64]=[CH:63][C:62]([NH2:65])=[CH:61][C:60]=1[F:66])[CH3:56]>O1CCCC1>[CH2:55]([O:57][C:58](=[O:67])[C:59]1[CH:64]=[CH:63][C:62]([NH:65][C:50]([C:47]2[CH:48]=[C:49]3[C:44]([CH2:43][CH2:42][NH:41]3)=[C:45]([O:53][CH3:54])[CH:46]=2)=[O:52])=[CH:61][C:60]=1[F:66])[CH3:56]
Reactant: CCOC(=O)c1ccc(N)cc1F
Reactant: COc1cc(C(=O)O)cc2c1CCN2C(=O)OC(C)(C)C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(NC(=O)c2cc3c(c(OC)c2)CCN3)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27 %

Procedure:
Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (0.874 g, 1.88 mmol, 1.1 equiv.) and diisopropyl ethyl amine (0.46 mL, 3.58 mmol, 2.1 equiv.) were added to a solution of 4-methoxy-2,3-dihydro-indole-1,6-dicarboxylic acid 1-tert-butyl ester (0.500 g, 1.7 mmol, 1 equiv.) in tetrahydrofuran (10 mL) and the mixture was shaken for 5 minutes at room temperature. 4-Amino-2-fluorobenzoic acid ethyl ester (3.433 g 1.88 mmol, 1.1 equiv.) was added and the mixture shaken at room temperature for 16 hours. The solvent was removed under vacuum and the residue dissolved in trifluoroacetic acid (10 mL) and shaken for 1 hour at room temperature. The solvent was removed under vacuum and the residue was purified by column chromatography (SiO2, 1:1 Hept/EtOAc to EtOAc). The fractions were combined to afford crude 2-fluoro-4-[(4-methoxy-2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid ethyl ester, 0.476 g (27% yield), this material was taken onto the next step without further purification. LC @215 nm; Rt 1.17: 46%, m/z (ES+): 359 (M+H+.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[C:17]=1[F:26]>CCOC(C)=O>[CH2:7]([O:14][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[C:17]=1[F:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1c([N+](=O)[O-])ccc(F)c1F
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Temperature: 180 °C

Procedure:
To a suspension of potassium carbonate (19.2 g, 138 mmol) and benzyl alcohol (22 mL) is added 1,2-difluoro-3-methyl-4-nitrobenzene (12 g, 69 mmol, ref. WO2007121416) and the mixture is heated to 180° C. for 2 h. The reaction mixture is then diluted with EtOAc and washed with water. The organic layer is concentrated and the residue is separated with FCC (EtOAc/heptane from 0 to 20%) to give 1-benzyloxy-2-fluoro-3-methyl-4-nitrobenzene. 1H NMR (400 MHz, MeOD) δ ppm 7.87 (dd, J=9.35, 2.02 Hz, 1H), 7.44-7.47 (m, 2H), 7.32-7.41 (m, 3H), 7.17 (t, J=8.72 Hz, 1H), 5.26 (s, 2H), 2.49 (d, J=2.78 Hz, 3H).