Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[C:14]([O:18][C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)([CH3:17])([CH3:16])[CH3:15].N1C=CC=CC=1>C(Cl)Cl.CCOCC.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:14]([O:18][C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)=[CH:25][CH:24]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reaction time: 0.17 h
Yield: 29.5 %

Procedure:
4 Å molecular sieves were added to a stirred solution of 3-(trifluoromethyl)phenylboronic acid (2.4 g, 12.643 mmol, 2 eq) and [2-(4-Hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.5 g, 6.321 mmol, 1 eq) in dry DCM (68.7 ml) at ambient temperature in a dark flask flushed with dry air. The reaction mixture was stirred for 10 min with a drying tube attached. Copper (II) acetate (1.16 g, 6.385 mmol, 1.01 eq), TEA (4.4 ml, 31.609 mmol, 5 eq) and pyridine (2.55 ml, 31.609 mmol, 5 eq) were added and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with 50 ml of Et2O, filtered through celite and washed with 0.5 M HCl. Organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give a crude product. Crude product was purified via Biotage SP-1 Snap Si 50 g; 40 mil/min; in the gradient of EtOAc in Cy: 3% for 1.5 CV, 3-25% for 12 CV; 25-40% for 8 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product {2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (710 mg, yield=22.4%, purity=76%). [M+H]+=382.40 1H NMR (300 MHz; CDCl3) δ/ppm 1.43 (s, 9H), 2.77 (t, J=7.0 Hz, 2H), 3.37 (q, J=6.5 Hz, 2H), 4.58 (br. s., 1H), 6.92-6.97 (m, 1H), 7.06-7.22 (m, 5H), 7.28-7.33 (m, 1H), 7.34-7.45 (m, 1H)
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: OB(O)c1ccccc1Cl
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1ccccc1-c1cccc2[nH]ccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
To a mixture of 4-bromoindole (5.5 g, 28 mmol), and 2-chlorophenylboronic acid (4.4 g, 28 mmol) in THF (96 mL) were added Palladium catalyst Pd(PPh3)4 (0.975 g, 0.8 mmol) and the freshly prepared sodium hydroxide solution (3.4 g, 84 mmol in 40 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 2.41 g (38%) of 4-(2-chloro-phenyl)-1H-indole.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C@@H:29]2[CH2:33][O:32]C(C)(C)[O:30]2)[C:24]=1[F:36])=[O:22])[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])=[O:12]>C(O)(=O)C.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C@@H:29]([OH:30])[CH2:33][OH:32])[C:24]=1[F:36])=[O:22])[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])=[O:12]
Reactant: CC1(C)OC[C@@H](c2cccc(C(=O)C(C(=O)c3cccc(C#N)c3)=C3Nc4ccccc4N3)c2F)O1
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cccc(C(=O)C(C(=O)c2cccc([C@@H](O)CO)c2F)=C2Nc3ccccc3N2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A 140 mg portion of 3-(2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-{3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluorophenyl}-3-oxopropanoyl)benzonitrile was dissolved in 5 ml of acetic acid-water (4:1) and stirred at 50° C. for 3 hours. The solvent was evaporated to carry out an azeotropic treatment using Tol. The thus formed residue was purified by a silica gel column chromatography, and the foamy substance obtained from a chloroform-methanol (10:0-9:1) eluate was recrystallized from ethyl acetate hexane to obtain 105 mg (82%) of 3-(2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-{3-[(1R)-1,2-dihydroxyethyl]-2-fluorophenyl}-3-oxopropanoyl)benzonitrile (Example 4-11).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[C:5]([Br:7])[N:6]=1.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>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.[Cu]I>[Br:7][C:5]1[N:6]=[C:2]([C:23]#[C:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:3][C:4]=1[C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: O=C(c1sc(Br)nc1Br)N1CCCCC1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=C(c1sc(C#Cc2ccccc2)nc1Br)N1CCCCC1
Temperature: 90 °C
Yield: 17.4 %

Procedure:
To a stirred solution of a mixture of intermediate 49 (2,4-Dibromo-thiazol-5-yl)-piperidin-1-yl-methanone (325 mg, 0.918 mmol), bis(triphenylphosphine)palladium(II) chloride (12.9 mg, 0.0184 mmol), copper(I) iodide (8.74 mg, 0.0459 mmol) and phenylacetylene (0.101 mL, 0.918 mmol) was added triethylamine (3.0 mL, 22 mmol) and the reaction was heated at 90° C. for 30 minutes in a microwave (150 watts). The solvent triethylamine was removed and the crude product was extracted with dichloromethane and washed the organic portion with aqueous citric acid solution, water and brine. Purification of the crude product afford the titled compound (4-Bromo-2-phenylethynyl-thiazol-5-yl)-piperidin-1-yl-methanone (60 mg, 20%) as a pale brown color solid
Reaction SMILES: N[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([CH2:10][CH2:11][CH2:12][CH3:13])[N:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([O:30]C(C)(C)C)=[O:29])=[CH:18][CH:17]=1.[NH+]1C=CC=NC=1.[OH-].[Na+].FC(F)(F)C(O)=[O:46]>CN(C=O)C.CO>[CH2:10]([CH:4]1[NH:3][C:2](=[O:46])[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([OH:30])=[O:29])=[CH:18][CH:17]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1nc(C)c(C)c(N)n1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Agent: c1cnc[nH+]c1
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCC1NC(=O)C(C)=C(C)N1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Heating 4-amino-2-n-butyl-5,6-dimethylpyrimidine (from Example 23) with 4-bromomethyl-2'-t-butoxycarbonylbiphenyl in an appropriate solvent such as methanol or DMF, followed by treatment of the intermediate pyrimidinium species with aqueous base such as 0.1N sodium hydroxide as described by Brown, Hoerger, and Mason (J. Chem. Soc., 1955, 4035), followed by treatment with neat trifluoroacetic acid to achieve final deprotection for the carboxyl group, would provide the title compound.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[C:4]([CH3:14])[CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].CO.CCOC(C)=O>C(N(CC)CC)C.[Cu]I.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>[CH3:14][C:4]1[CH:3]=[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:13]=[CH:12][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: Cc1cc(Br)ccc1Cn1ccnc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C#C[Si](C)(C)C)ccc1Cn1ccnc1
Temperature: 70 °C
Yield: 81.5 %

Procedure:
Using General Procedure D; 1-(4-bromo-2-methyl-benzyl)-1H-imidazole (Intermediate 139, 160.0 mg, 0.64 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (12.0 mg, 0.07 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 0.71 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (45.0 mg, 0.07 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (140.0 mg, 82%) was isolated by chromatography (5% MeOH-EtOAc) as an orange oil.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:11])[CH2:4][CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][NH:6]1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:20]=[C:19]([S:21](Cl)(=[O:23])=[O:22])[S:18][C:17]=2[CH:25]=1.C(N(CC)CC)C>O.C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:20]=[C:19]([S:21]([N:9]3[CH2:8][CH2:7][NH:6][CH:5]([CH2:4][CH:3]([CH3:11])[CH3:2])[CH2:10]3)(=[O:23])=[O:22])[S:18][C:17]=2[CH:25]=1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: CC(C)CC1CNCCN1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a methylene chloride solution (30 ml) of 2-(2-methylpropyl)piperazine hydrochloride (353 mg) were added 6-chlorobenzo[b]thiophene-2-sulfonyl chloride (438 mg) and triethylamine (498 mg). The resulting mixture was stirred at room temperature for 3 hours. Distilled water and methylene chloride were added. The water layer thus obtained was extracted three times with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column (methanol methylene chloride=1:100), whereby the title compound (363 mg) was obtained as a pale yellow oil.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].Cl[S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8].[Cl:13][C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][C:32]=1[Cl:33])[O:17][CH:18]1[CH2:23][CH2:22][N:21]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:20][CH2:19]1.C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][C:32]=1[Cl:33])[O:17][CH:18]1[CH2:19][CH2:20][N:21]([CH:24]2[CH2:25][CH2:26][N:27]([S:7]([NH:10][C:11](=[O:12])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:9])=[O:8])[CH2:28][CH2:29]2)[CH2:22][CH2:23]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Reactant: Clc1ccc(OC2CCN(C3CCNCC3)CC2)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NS(=O)(=O)N1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Temperature: 0 °C

Procedure:
tert-Butanol (0.48 ml) in dichloromethane (2 ml) was added to a solution of chlorosulfonylisocyanate (0.43 ml) in dichloromethane (5 ml) stirring at 0° C. The resulting solution was then added to a solution of 4-(3,4-dichlorophenoxy)-1,4′-bipiperidine (1.6 g) and triethylamine (0.77 ml) in dichloromethane (20 ml) at 0° C. After stirring at 0° C. for 2 h, the reaction mixture was washed with 0.1M hydrochloric acid (30 ml), dried (MgSO4) and evaporated. The residue was triturated with diethylether (20 ml) to give the title compound as a white solid. (1.9 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[NH:11][C:10](=[S:20])[NH:9]1.[CH3:21][I:22]>CCO>[IH:22].[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C@H:12]1[C@@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[NH:9][C:10]([S:20][CH3:21])=[N:11]1
Reactant: CI
Reactant: S=C1N[C@H](c2ccccc2Cl)[C@H](c2ccccc2Cl)N1
Solvent: CCO
Product: CSC1=N[C@@H](c2ccccc2Cl)[C@@H](c2ccccc2Cl)N1
Product: I
Temperature: 25 °C
Yield: 75.8 %

Procedure:
A mixture of cis-4,5-bis-(2-chlorophenyl)imidazolidine-2-thione (32) (10.1 g, 0.0312 mol) and methyl iodide (3.89 mL, 0.0624 mol) in abs. EtOH (15 mL) is heated at 90° C. for 6 h. The reaction mixture is cooled to rt, concentrated in vacuo, and the residue suspended in abs EtOH. The insoluble material is filtered to give 11 g of the product 49.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:8][C@H:9]([C:15](O)=[O:16])[CH2:10][CH2:11][C:12]([OH:14])=[O:13].N=C=N>O>[NH2:8][C@H:9]([C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=1)=[O:16])[CH2:10][CH2:11][C:12](=[O:13])[OH:14]
Reactant: Nc1ccncc1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: N=C=N
Solvent: O
Product: Nc1ccnc(C(=O)[C@@H](N)CCC(=O)O)c1
Reaction time: 24 h

Procedure:
A mixture of 4-aminopyridine (5 mmol) and glutamic acid (5 mmol) is added to 0.1M carbodiimide [N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide or EDC] in distilled water adjusted to pH 4.5, such that the final volume is 200 ml. The reaction is performed for 24 hours at 4° C. The resulting glutamyl-4-aminopyridine conjugate is collected as an oil and purified to pharmaceutical purity.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:36])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:16]=3)=[N:10][C:9]=2[N:25]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][CH2:31][CH2:30]3)[CH:26]=1)=O)C.[CH2:37]([NH2:39])C>CO>[CH3:37][NH:39][C:4]([C:6]1[C:7](=[O:36])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:23])[CH3:24])[CH:16]=3)=[N:10][C:9]=2[N:25]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][CH2:31][CH2:30]3)[CH:26]=1)=[O:3]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(CN(C)C)c3)ncc2c1=O
Reactant: CCN
Solvent: CO
Product: CNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(CN(C)C)c3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (15 mg, 0.032 mmol) was dissolved in MeOH (1 mL) and ethylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80° C. After 16 h, the solution was cooled to it and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 2.1 mg of 2-(3-dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide. 1H NMR (TFA salt) (400 MHz, CDCl3) δ (ppm): 9.57 (s, 1H), 9.34 (s, 1H), 8.74 (s, 1H), 6.99-7.37 (m, 7H), 3.89 (br s, 2H), 3.39-3.46 (m, 2H), 2.89-3.02 (m, 4H), 2.60 (s, 6H), 2.13-2.17 (m, 2H), 1.19 (t, 1H, J=7.3 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. for C28H30N6O2: 482.24, Found: 483.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH3:30][S:31]SC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([S:31][CH3:30])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSSC
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)cc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1c(F)ccc2onc(OCCNC(=O)OC(C)(C)C)c12
Temperature: -70 °C
Yield: 92.3 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-5-fluoro-1,2-benzisoxazole (0.30 g) in tetrahydrofuran (20 ml) was added lithium diisopropylamide (1.50 ml, 1.5 M hexane solution) dropwise with stirring at -70° C. under nitrogen atmosphere, then after being stirred at the same temperature for 15 minutes dimethyldisulphide (0.21 g) was added. The reaction mixture was stirred for 15 minutes at -70° C. and then the temperature was raised to 0° C. The reaction mixture was poured into ice water (40 ml), extracted with ethyl acetate (twice each with 40 ml) and the combined extracts were dried over anhydrous magnesium sulphate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (9/1) as an eluent, to give the title compound (0.32 g, 94% yield) as a colorless powder.
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][B-:16]([F:19])([F:18])[F:17].[CH3:20][O+](C)C>ClCCl>[F:15][B-:16]([F:19])([F:18])[F:17].[CH:1](=[N:8][N+:9]1[CH:13]=[CH:12][N:11]([CH3:20])[C:10]=1[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[O+](C)C
Reactant: Cc1nccn1N=Cc1ccccc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1n(C)cc[n+]1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.92 g of 1-(benzylideneamino)-2-methylimidazole is dissolved in 10 ml of absolute dichloromethane and then treated with 0.74 g of trimethyloxonium tetrafluoroborate. The mixture is stirred at room temperature overnight and the resulting precipitate is filtered under suction and washed twice with dichloromethane. After reprecipitation from acetonitrile/diethyl ether, there is obtained colorless 1-(benzylideneamino)-2,3-dimethylimidazolium tetrafluoroborate of m.p. 213°-216°.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:11]1[C:10]([F:9])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:14](=[O:19])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCCC(=O)OC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCC#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 4-pentynoic acid methyl ester (75.7 mg, 0.68 mmol) (see Example 8, supra) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene)]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P)4Pd (31.2 mg) and CuI (5.0 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 7 h to yield (Z)-5-[2,3-Dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 86 mg, 90%).
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.[O:6]=[C:7]1[NH:12][CH2:11][CH2:10][N:9]2[N:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:15]=[C:8]12.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:1]1([CH2:4][N:12]2[CH2:11][CH2:10][N:9]3[N:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:15]=[C:8]3[C:7]2=[O:6])[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1cc2n(n1)CCNC2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc2n(n1)CCN(CC1CC1)C2=O
Temperature: 70 °C

Procedure:
To a solution of cyclopropylmethyl bromide (0.101 g, 0.75 mmol) and ethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (31.4 mg, 0.150 mmol) in acetonitrile (2 mL) was added cesium carbonate (147 mg, 0.45 mmol). The reaction mixture was heated overnight at 70° C. Upon cooling to room temperature, the insolubles were removed by filtration and the solvent evaporated to dryness to afford crude Intermediate 33.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])NC1=O.[CH2:8]([O:15][CH:16]1[CH2:21][CH2:20]C(=O)[CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.S(=O)(=O)(O)[OH:24]>[OH-].[Ba+2].[OH-]>[NH2:1][C:7]1([C:5]([OH:6])=[O:24])[CH2:18][CH2:17][CH:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:21][CH2:20]1
Reactant: O=C1CNC(=O)N1
Reactant: O=S(=O)(O)O
Reactant: O=C1CCC(OCc2ccccc2)CC1
Agent: [Ba+2]
Agent: [OH-]
Product: NC1(C(=O)O)CCC(OCc2ccccc2)CC1

Procedure:
The hydantoin 42 is hydrolyzed by refluxing with 10 mL of a barium hydroxide solution (saturated at room temperature) for 16 h (Step 39). The solution is neutralized to pH 6 with 2N sulfuric acid and evaporated to dryness in vacuo. The residue is extracted with 50 mL of hot methanol, filtered, and washed with 50 mL of hot methanol. The methanol solutions are combined and evaporated.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CS([C:17]1[N:22]=[CH:21][C:20]2=[CH:23][CH:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]2[N:18]=1)=O.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[CH3:37][N:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]1[N:19]2[C:20]([CH:21]=[N:22][C:17]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][N:11]=3)=[N:18]2)=[CH:23][CH:24]=1)[S:33]([CH3:36])(=[O:34])=[O:35]
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: Nc1ccc(N2CCOCC2)cn1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccccc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)cn3)nn12)S(C)(=O)=O
Temperature: 120 °C

Procedure:
Into a 8-dram vial, 5-Morpholin-4-yl-pyridin-2-ylamine (0.108 g, 0.604 mmol), N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (0.100 g, 0.274 mmol), Cesium fluoride (0.104 g, 0.686 mmol), N,N-Diisopropylethylamine (0.1051 mL, 0.6036 mmol) and tert-Butyl alcohol (1.50 mL) were added. The reaction was heated at 120° C. overnight. LCMS suggested presence of desired product. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a yellow solid (40 mg, 33%). LCMS (E/I+) 480.14 (M+H). NMR 1H (DMSO-d6)-10.49 (bs, 1H), 9.09 (s, 1H), 7.86-7.92 (m, 1H), 7.84 (bs, 1H), 7.70-7.80 (m, 1H), 7.66-7.73 (m, 1H), 7.50-7.64 (m, 3H), 7.13 (bs, 1H), 7.11 (bs, 1H), 3.75 (bs, 4H), 3.14 (s, 3H), 3.11 (bs, 4H), 2.83 (s, 3H).
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[CH2:15]([O:17][C:18]([C:20]1[CH:25]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:23]([CH:38]([CH3:40])[CH3:39])[NH:22][C:21]=1[CH:41]([CH3:43])[CH3:42])=[O:19])[CH3:16]>C(Cl)Cl>[CH2:15]([O:17][C:18]([C:20]1[C:21]([CH:41]([CH3:43])[CH3:42])=[N:22][C:23]([CH:38]([CH3:40])[CH3:39])=[C:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:25]=1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1=C(C(C)C)NC(C(C)C)=C(C(=O)OCC)C1c1ccc(F)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.8 g (16.4 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone is added to a solution of 6.6 g (16.4 mmol) of 1,4-dihydro-2,6-diisopropyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylic acid diethylester in 200 ml of analysis grade methylene chloride, and the mixture is then stirred for 1 h at room temperature. After this, it is drawn off by suction over diatomaceous earth, and the methylene chloride phase is extracted 3 times with 100 ml of water each time and dried on magnesium sulfate. After concentrating in a vacuum, the residue is chromatographed on a column (100 g of silica gel, 70-230 mesh, diameter 3.5 cm, with ethyl acetate/petroleum ether 1:9).