Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](I)[C:3]=1[OH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.O>CN(C=O)C.C(NCC)C>[F:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]2[O:10][C:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[CH:20][C:4]=2[CH:5]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Oc1c(F)cc(F)cc1I
Solvent: O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(F)cc(F)c3o2)cc1
Reaction time: 1 h

Procedure:
A solution of 2,4-Difluoro-6-iodo-phenol (1.0 g, 3.9 mmol), 4-Methoxyphenylacetylene(0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and Cul (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a solid which was triturated with MeOH and filtered to give 86 as a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:10])=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.N1C=CN=C1.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[O:22][C:23]1[CH:24]=[C:25]([C:32](O)=[O:33])[C:26](=[CH:30][CH:31]=1)[C:27](O)=[O:28].O>CN(C=O)C.C(OCC)(=O)C>[NH2:9][C:5]1[C:4]([F:10])=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:1]1[C:32](=[O:33])[C:25]2[C:26](=[CH:30][CH:31]=[C:23]([O:22][C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:16]=3)[CH:24]=2)[C:27]1=[O:28]
Reactant: O=C(O)c1ccc(Oc2ncccn2)cc1C(=O)O
Reactant: NCc1cccc(N)c1F
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cccc(CN2C(=O)c3ccc(Oc4ncccn4)cc3C2=O)c1F
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 10.2 %

Procedure:
3-Aminomethyl-2-fluoro-phenylamine (50.8 mg, 0.362 mmol) and imidazole (26.0 mg, 0.382 mmol) were added to a solution of 4-(pyrimidin-2-yloxy)phthalic acid (94.1 mg, 0.362 mmol) in DMF (2.0 mL), and the mixture was stirred in a Microwave at 300 W, 150° C. for 5 minutes. Water was then added to the reaction mixture, extraction was performed with ethyl acetate, and the organic extract was washed with saturated saline. After drying over magnesium sulfate, it was concentrated under reduced pressure to yield a crude product, which was then purified by column chromatography to yield the title compound (13.4 mg, 10%) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl[Si:10]([CH3:13])([CH3:12])[CH3:11]>C[Si](C)(C)N[Si](C)(C)C>[I:1][C:2]1[CH:3]=[N:4][C:5]([O:8][Si:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1
Reactant: O=c1ncc(I)c[nH]1
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)Oc1ncc(I)cn1

Procedure:
A suspension of 15.06 g (67.83 mmol) of 5-iodo-2(1H)-pyrimidinone was refluxed in 40 ml of hexamethyldisilazane and 2 ml of chlorotrimethylsilane for 1 hour. The excess reagent was removed in vacuo to yield a yellow oil 5-iodo-2-trimethylsilyloxypyrimidine, which was dissolved with 30 ml of dry degassed triethylamine. To this solution was added 11.5 ml (81.37 mmol) of trimethylsilylacetylene, 0.32 g (2.5 mol%) of CuI and 0.48 g (1 mol %) of (O3P)2PdCl2. The reaction mixture was stirred under nitrogen, at room temperature, for 3 days and diluted with 100 ml of dry THF. The mixture was filtered under dry nitrogen; the precipitate washed several times with dry THF and the filtrate was concentrated to a residue. The latter was treated with methanol to give a white crystalline, chromatographically homogeneous material 5-(2-Trimethylsilyl)ethynyl-2(1H)-pyrimidinone (9.99 g, 76.6%). Analytically pure material could be obtained by recrystallization from methanol; mp 203°-206° C.
Reaction SMILES: C([O:8][C:9](=[O:30])[CH2:10][NH:11][CH:12](C(OC(C)(C)C)=O)[C:13]([O:15]CC1C=CC=CC=1)=[O:14])C1C=CC=CC=1.Cl.CCOCC>O1CCOCC1>[NH:11]([CH2:12][C:13]([OH:15])=[O:14])[CH2:10][C:9]([OH:30])=[O:8]
Reactant: CC(C)(C)OC(=O)C(NCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(O)CNCC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 247.2 %

Procedure:
Boc-Iminodiacetic acid dibenzyl ester (4.5 g, 10.88 mmol) was dissolved in dioxane (15 mL), then 4.6 M HCl in dioxane (20 mL) was added. The mixture was stirred for 90 min at room temperature and Et2O (200 mL) was added. The crystalline product was filtered off, washed twice with Et2O and dried in vacuo to afford the title compound (3.58 g, 94.2%).
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].C([O:11][C:12](=O)[CH:13]([NH:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[Cl:28])[C:14](OCC)=[O:15])C>C(O)C>[Cl:28][C:22]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=1[C:20]([NH:19][C:13]1[C:12]([OH:11])=[N:7][C:5]([CH3:6])=[N:8][C:14]=1[OH:15])=[O:29]
Reactant: CCOC(=O)C(NC(=O)c1cc(F)ccc1Cl)C(=O)OCC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(O)c(NC(=O)c2cc(F)ccc2Cl)c(O)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
1.5 equivalents of sodium methoxide (30% in methanol) were added to a suspension of 13.4 g of acetamidine hydrochloride in 150 ml of ethanol. The precipitate was filtered off and washed with 100 ml of ethanol. Additional 1.5 equivalents of sodium methoxide (30% in methanol) were added to the filtrate. Then a solution of 39.3 g of 2-(2-chloro-5-fluoro-benzoylamino)malonic acid diethyl ester in 100 ml of ethanol was added dropwise. The reaction mixture was stirred at 60° C. for 2 h. After cooling to 0° C. for 30 min, the precipitate was filtered off with suction, washed with 100 ml of a solution of hydrogen chloride in isopropanol and dried to give 35.7 g of the title compound.
Reaction SMILES: FC1C([O:8][C:9]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([C:20]=2[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([Cl:31])[CH:24]=2)=[CH:18][C:17]([C:32]#[N:33])=[CH:16][CH:15]=3)=O)=C(F)C(F)=C(F)C=1F.[BH4-].[Na+]>CN(C=O)C>[Cl:31][C:25]1[CH:24]=[C:23]([CH2:22][NH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:32]#[N:33])[CH:18]=3)[N:13]=[CH:12][C:11]=2[CH2:9][OH:8])[CH:28]=[CH:27][C:26]=1[O:29][CH3:30]
Reactant: COc1ccc(CNc2c(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cnc3ccc(C#N)cc23)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2c(CO)cnc3ccc(C#N)cc23)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.6 %

Procedure:
To 530 mg (1.0 mmol) of 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylic acid pentafluorophenyl ester was added 15 mL of anhydrous DMF, and the resulting mixture was cooled to 0° C. A solution of 75 mg of NaBH4 in 5 mL of anhydrous DMF was added to the reaction mixture, resulting in a clear red solution with gas evolution. After stirring for 1 hour at 0° C., the reaction was quenched with 2% TFA/MeOH, and the solvent was removed under reduced pressure. The oily residue was purified by flash chromatography (silica gel, 3-5% MeOH/CH2Cl2) to afford 87 mg (25% yield) of the title compound. LC: 2.60′; MH+: 354.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[C:5]([CH3:12])[CH:4]=1.[CH3:13][C:14]1([CH3:30])[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:15]1>>[CH3:13][C:14]1([CH3:30])[CH2:19][C:18]([CH3:20])([CH3:21])[CH2:17][C:16]([O:22][S:23]([C:26]([F:29])([F:27])[F:28])(=[O:24])=[O:25])=[CH:15]1.[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[CH2:19][C:14]([CH3:30])([CH3:13])[CH:15]=2)=[C:5]([CH3:12])[CH:4]=1
Reactant: COc1ccc(B(O)O)c(C)c1
Agent: CC1(C)C=C(OS(=O)(=O)C(F)(F)F)CC(C)(C)C1
Product: COc1ccc(C2=CC(C)(C)CC(C)(C)C2)c(C)c1

Procedure:
Trifluoro-methanesulfonic acid 3,3,5,5-tetramethyl-cyclohex-1-enyl ester was prepared in accordance with the procedures of Hanack et. al., J. Heterocyclic Chem. 1988, 25, pp 1237-1241. 4-Methoxy-2-methyl-1-(3,3,5,5-tetramethyl-cyclohex-1-enyl)-benzene was prepared in two steps by a Suzuki coupling of 4-methoxy-2-methyl-phenylboronic acid and trifluoro-methanesulfonic acid 3,3,5,5-tetramethyl-cyclohex-1-enyl ester following the procedures of Carmen et. al., Synlett 2005, No. 10, pp 1601-1605, to obtain 4-methoxy-2-methyl-1-(3,3,5,5-tetramethyl-cyclohex-1-enyl)-benzene, which was subsequently hydrogenated to form 1-cyclohexyl-4-methoxy-2-methyl-benzene.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:67][C:68]1[O:69][C:70]2[C:71]([N:76]=1)=[N:72][CH:73]=[CH:74][CH:75]=2>>[O:69]1[C:70]2[C:71](=[N:72][CH:73]=[CH:74][CH:75]=2)[N:76]=[C:68]1[S:67][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[O:36])[CH2:32][CH2:33]1
Reactant: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCOCC2)n1
Reactant: Sc1nc2ncccc2o1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCSc3nc4ncccc4o3)CC2)c(N2CCOCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptooxazolo[4,5-b]pyridine, to thereby yield the title compound as a colorless foamed substance.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[CH3:19][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>CN(C=O)C>[CH3:19][N:8]([CH:5]1[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]1)[C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)OCc1ccccc1)C1CCC(=O)CC1
Reaction time: 0.5 h

Procedure:
Benzyl (4-oxocyclohexyl)carbamate (500 mg, 2.0 mmol) in DMF was treated with lithium hexamethyldisilazid (2.0 mmol) at room temperature. This solution was stirred for 30 min and was then treated with iodomethane (0.25 mL, 4.0 mmol) and stirred for 18 h. DMF was removed under vacuum and the residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: I.I.[NH2:3][C:4]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][N:24]=[C:23]2[NH2:28])[CH2:8][CH2:7][CH2:6][N:5]=1.[CH3:29][OH:30].[OH2:31]>>[C:29]([OH:31])(=[O:30])[CH3:4].[C:29]([OH:31])(=[O:30])[CH3:4].[NH2:3][C:4]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][N:24]=[C:23]2[NH2:28])[CH2:8][CH2:7][CH2:6][N:5]=1
Reactant: CO
Reactant: O
Agent: I
Agent: NC1=NCCCN1CCCCCCCCCCCCN1CCCN=C1N
Product: CC(=O)O

Procedure:
30.0 g (0.048 mol) of 1,12-bis(2-amino-3,4,5,6-tetrahydropyrimidyl)dodecane dihydroiodide in 300 ml of methanol/water (1:1) were filtered through a column containing 250 g of ion exchanger (OH- form). The free guanidine base obtained after working up was dissolved in methanol and converted into the diacetate with excess glacial acetic acid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]O)=[CH:8][C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=3)=[N:6]2)[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:24].N1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:24][CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=2)[CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(-c2cc(CO)c(=O)n(CC3CC3)n2)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(CBr)c(=O)n(CC3CC3)n2)cc1F
Reaction time: 1 h
Yield: 69.2 %

Procedure:
2-Cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one (185 mg, 0.61 mmol), carbon tetrabromide (404 mg, 1.2 mmol) and pyridine (48 mg, 0.61 mmol) were dissolved in tetrahydrofuran (3 mL), and under ice-cold stirring, a solution of triphenylphosphine (319 mg, 1.2 mmol) in tetrahydrofuran (3 mL) was added. Under ice cooling, the mixture was stirred for 1 hour, and further stirred at room temperature. Insoluble materials were filtered off, the solvent was distilled off under reduced pressure, and the residue was isolated and purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to yield the title compound as a yellow powder (yield: 155 mg, 69.5%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(O[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C.COC1C=CC(B2OC(C)(C)C(C)(C)O2)=CN=1>>[CH3:25][C:20]1([CH3:26])[C:21]([CH3:24])([CH3:23])[O:22][B:18]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[N:6][CH:7]=2)[O:19]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(N2CCOCC2)nc1
Agent: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Yield: 71 %

Procedure:
Compound 5A (616 mg, 71%) was prepared from 4-(5-bromo-pyridin-2-yl)-morpholine (727 mg, 2.99 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.915 mL, 4.49 mmol) by a route analogous to that used for the preparation of 2A.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH2:10])[CH:3]=1.[N:11]([O-])=O.[Na+].O.O.Cl[Sn]Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH:10][NH2:11])[CH:3]=1
Reactant: COc1ccc(F)cc1N
Reactant: O=N[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(F)cc1NN
Yield: 31.4 %

Procedure:
The title compound was prepared by the general procedure described above for Preparations 2a-i using 4-fluoro-2-aminoanisole (14.11 g), NaNO2 (7.59 g) and SnCl2.2H2O (49.64 g). Workup gave 4.9 g (31%) of (5-fluoro-2-methoxyphenyl)hydrazine. MS (M−H)+: 157.00; 1H NMR (300 MHz, CDCl3) δ6.71 (1H, dd, J=10.5, 3.0 Hz), 6.32 (1H, dd, J=7.5, 4.9 Hz), 6.38 (1H, dt, J=8.4, 3.0 Hz), 3.78 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:9][CH2:8][C:7]1[CH:16]=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CSc2ccccn2)cc1
Solvent: CC(=O)O
Product: Nc1ccc(CSc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 38.5 %

Procedure:
2-[(4-nitrobenzyl)sulfanyl]pyridine (14.5 g) was dissolved in acetic acid (145 ml), reduced iron (43.5 g) was added to the solution, and then, the mixture was stirred for 20 hours at room temperature. The mixture was filtered by Celite, washed with ethyl acetate, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[(2-pyridinylsulfanyl)methyl]aniline (4.9 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](I)[C:3]=1[C:4]#[N:5].CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]3)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:4]([C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]2)#[N:5]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: N#Cc1c(F)cccc1I
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3cccc(F)c3C#N)ccc21
Temperature: 100 °C
Reaction time: 20 h
Yield: 72.4 %

Procedure:
A mixture of 2-fluoro-6-iodobenzonitrile (2.65 g, 10.73 mmol), 1,1-dimethylethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole-1-carboxylate (3.78 g, 10.95 mmol, 1.02 equiv), tricyclohexylphosphine (301 mg, 1.07 mmol, 0.1 equiv), Pd2(dba)3 (491 mg, 0.54 mmol, 0.05 equiv) and K3PO4 (3.87 g, 18.24 mmol, 1.7 equiv) in 40 mL of dioxane and 10 mL of water in a 150 mL pressure vessel was bubbled under argon for 10 min. The mixture was capped and heated in an oil bath at 100° C. for 18 h. LCMS showed conversion complete. The mixture was filtered through Celite. The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (130 mL) and brine (40 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo. The dark brownish oil was stored in the refrigerator for 20 h, which became a cake. Trituration in DCM/hexane (1:4), breaking up of the cake, filtration, and drying under vacuum at room temperature gave 1,1-dimethylethyl 5-(2-cyano-3-fluorophenyl)-2,3-dihydro-1H-indole-1-carboxylate (2.63 g) as a greyish solid. The filtrate was concentrated in vacuo and absorbed onto a dryload cartridge. Purification was done on an RS-120 g silica gel cartridge using gradient elution of 1% EtOAc in hexane to 40% EtOAc in hexane. The product eluted from 29-34% EtOAc in hexane. Concentration in vacuo and drying under vacuum additional 1,1-dimethylethyl 5-(2-cyano-3-fluorophenyl)-2,3-dihydro-1H-indole-1-carboxylate (0.77 g) as a yellow foam.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].CC(C)C(=O)CC(OC)=O.NC1C=CC=CC=1.C(N)CN.[CH:37](=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.N1CCCCC1.NCCC(O)=O>C1(C)C=CC=CC=1.O.CCCCCC.CCCCCCC.C(O)(=O)C>[CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[C:4](=[CH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CC(C)C(=O)CC(=O)Nc1ccccc1
Reactant: O=Cc1ccccc1
Agent: COC(=O)CC(=O)C(C)C
Agent: NCCC(=O)O
Solvent: Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)C(=O)C(=Cc1ccccc1)C(=O)Nc1ccccc1

Procedure:
4-Methyl-3-oxo-N-phenylpentanamide (XIX) is obtained by heating a mixture of methyl 4-methyl-3-oxopentanoate (XX), aniline and ethylene diamine in toluene. 4-Methyl-3-oxo-N-phenylpentanamide (XIX) is subsequently reacted with benzaldehyde in the presence of a catalyst such as, for example, piperidine and glacial acetic acid, ethylene diamine and glacial acetic acid, β-alanine and glacial acetic acid, and the like in an inert solvent such as, for example, toluene, heptane, hexane, and the like for about 24 to about 36 hours at about 60° to about 120° C. with the removal of water to afford 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide (XVIII). Preferably the reaction is carried out with β-alanine and glacial acetic acid at reflux for about 24 hours in hexane. The 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide (XVIII) is reacted with 4-fluorobenzaldehyde in the presence of a catalyst such as, for example, 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride, 3,4-dimethyl-5-(2-hydroxyethyl)thiazolium iodide, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, thiamine hydrochloride, and the like, and a base such as, for example, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine (DMAP), N,N,N',N'-tetramethylethylenediamine (TMEDA) and the like, either neat or in the presence of a solvent such as, for example, tetrahydrofuran, tertiary-butyl methyl ether, ethanol, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile, methylisobutyl ketone, ethyl acetate, isopropanol, pyridine and the like for about 20 to about 30 hours under anhydrous conditions at about room temperature to about the reflux temperature of the solvent to afford the compound of Formula XVII. Preferably the reaction is carried out in the presence of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide and triethylamine in ethanol at about 75°-80° C. for about 24 hours. The compound of Formula XVII is reacted with a compound of Formula ##STR45## wherein R10 and R11 are alkyl of one to eight carbon atoms or R10 and R11 together are ##STR46## in the presence of a catalyst of Formula
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[C:5]=1[OH:11]
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
Methyl-5-Chloro-2-hydroxylbenzoate (30 g, 160 mmol) is suspended in sulfuric acid (140 mL) and cooled to 0° C. in an ice bath. Nitric acid (13 mL) in sulfuric acid (30 mL) is added drop wise to the suspension over 30 minutes while maintaining the reaction temperature at 0° C. The reaction is warmed to room temperature and stirred for 4 hours. An additional 6 mL of nitric acid is added drop wise to the reaction over 30 minutes and the reaction is heated to 45° C. for 16 hours. The reaction is poured onto crushed ice, and the resulting yellow precipitate collected and washed with copious amount of water and dried in vacuo to give the title compound (33 g 142 mmol, 89%). LCMS (ESMS): m/z 232.7 (M+H+).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH2:7][CH:6]1[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:4].[Li][C:32]#[N:33].C1OCCOCCOCCOC1.O>C1(C)C=CC=CC=1.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>[C:32]([C:8]1[CH2:7][CH:6]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[N:5]([C:3](=[O:4])[C:2]([F:29])([F:1])[F:30])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=1)#[N:33]
Reactant: [Li]C#N
Reactant: COC(=O)CC1CC(OS(=O)(=O)C(F)(F)F)=Cc2ccccc2N1C(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CC1CC(C#N)=Cc2ccccc2N1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of the compound obtained in Step e (1.35 g; 293 mmol) in 16 ml of anhydrous toluene is added to a mixture of LiCN (0.5 M in DMF) (11.72 ml; 5.86 mmol), (Ph3P)4Pd (237 mg; 0.205 mmol) and 12-crown-4 (36 mg; 0.205 mmol) under an argon. atmosphere. The reaction mixture is stirred at ambient temperature for 6 hours. Water (10 ml) is added to the reaction mixture, and the organic phase is extracted with diethyl ether. After drying and concentration, the residue obtained is purified on silica gel (eluant:heptane/EtOAc) to yield the title product.