Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.O.C([O:16][C:17](=O)[CH2:18][CH3:19])C>>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH2:11][C:17](=[O:16])[CH2:18][CH3:19])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC
Reactant: CC(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCC(=O)CC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a suspension of NaH (60%, 106 mg, 4.44 mmol) in 2 mL propionic acid ethyl ester was added 1-(4-methylphenyl)ethanone (500 mg, 3.7 mmol) at 0-5° C. The reaction mixture was stirred overnight at rt. Water was added, and the mixture was extracted with EtOAc (3×50 mL). The organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by flash column chromatography (PE/EtOAc=10/1) to give the title compound (370 mg, 52%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.22 (3H, m), 2.45 (5H, m), 6.17 (2H, s), 7.27 (2H, d, J=10 Hz), 7.81 (2H, d, J=11.2 Hz). [M+H] Calc'd for C12H14O2, 191. Found, 191.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH:12]1[CH2:16][CH2:15][N:14]=[C:13]1[NH2:17].[Na].[NH2:19][C:20]1[C:21]([C:28](OC(C)=CC(=O)NC(C)(C)C)=[O:29])=[N:22][C:23]([Cl:27])=[C:24]([NH2:26])[N:25]=1>CC(O)C>[NH2:19][C:20]1[C:21]([C:28]([NH:17][C:13]2[NH:14][CH2:15][CH2:16][N:12]=2)=[O:29])=[N:22][C:23]([Cl:27])=[C:24]([NH2:26])[N:25]=1
Reactant: NC1=NCCN1
Reactant: CC(=CC(=O)NC(C)(C)C)OC(=O)c1nc(Cl)c(N)nc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)NC2=NCCN2)nc1Cl

Procedure:
A mixture of 4,5-dihydro-1H-imidazol-2-ylamine tosylate (1.69 g; 6.57 mmol) and sodium (119 mg; 5.19 mmol) in 2-propanol (20 ml) is refluxed for 30 min. 1-(tert-Butylcarbamoyl)prop-1-en-2-yl 3,5-diamino-6-chloropyrazine-2-carboxylate (example 2) (0.900 g; 2.75 mmol) is added and the mixture is refluxed for further 60 min. The precipitate formed is filtered off with suction, suspended in water, filtered off again and dried at 50° C. to yield the title compound (C8H10ClN7O).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])=[O:14].C([O-])([O-])=O.[K+].[K+].CC#N>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.O>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: COC(=O)Cc1ccsc1Br
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
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: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)Cc1ccsc1-c1ccc(S(C)(=O)=O)cc1

Procedure:
Intermediate B (2.30 g, 9.78 mmol), 4-methylsulfonylphenylboronic acid (1.96 g, 9.78 mmol), K2CO3 (4.15 g, 30.0 mmol), tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.130 mmol), MeCN (30 ml) and water (10 ml) were heated at 70° C. for 1 hour. The organic phase was removed in vacuo and the crude material was dissolved in DCM. The mixture was purified by flash chromatography using 30% and 50% EtOAc in iso-hexane as eluent. Yield: 2.25 g (74%); white solid. 1H NMR (400 MHz, CDCl3): δ 3.11 (s, 3H), 3.67 (s, 2H), 3.74 (s, 3H), 7.13 (d, J 5.0 Hz, 1H), 7.39 (d, J 5.0 Hz, 1H), 7.67-7.72 (m, 2H), 7.98-8.04 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[C:11]1(=O)O[C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)(O)[O-].[Na+].O(O)O>C1(C)C=CC=CC=1.C1COCC1.C(Cl)Cl.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10]
Reactant: COc1c(C)cccc1C
Reactant: O=C1CCC(=O)O1
Agent: O=C([O-])O
Agent: OOO
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1c(C)cc(CCCCO)cc1C
Reaction time: 2.7 h

Procedure:
A mixture of 2,6-dimethylanisole (4.45 g), succinic anhydride (4.80 g) and aluminum chloride (4.70 g) in toluene (60 ml) is stirred for 2.7 hr at 20°-25°. A 100 ml aliquot of methylene chloride is added for solubility. The reaction is run for 6 hr. The reaction is poured onto ice and extracted with methylene chloride-isopropanol. The organic phase is washed with saline, dried over sodium sulfate, concentrated and dried under reduced pressure overnight to give a solid. This material is stirred with borane-methyl sulfide complex (1.0M, 38 ml) in THF at 20°-25° for 24 hr. Aqueous sodium bicarbonate, methylene chloride and water are added. The ketoalcohol product is combined with other partly reduced materials and treated with borane-methyl sulfide complex in excess in methylene chloride for 72 hr. It is important that the ketoacid Friedel Crafts adduct should be reduced exhaustively with excess borane-methyl sulfide complex.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]([NH2:13])=[S:12])([CH2:4]3)[CH2:2]2.Br[CH2:15][C:16](OCC)=[O:17]>>[CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]1[S:12][CH2:15][C:16](=[O:17])[N:13]=1)([CH2:4]3)[CH2:2]2
Reactant: CCOC(=O)CBr
Reactant: NC(=S)NC12CC3CC(CC1C3)C2
Product: O=C1CSC(NC23CC4CC(CC2C4)C3)=N1

Procedure:
Synthesis was performed from N-tricyclo[3.3.1.0˜3,7˜]non-3-ylthiourea and ethyl bromoacetate according to Method D1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](Br)=[CH:7][CH:6]=1)=[O:4].[CH2:16]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH2:18]>C1(C)C=CC=CC=1.CCOCC.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>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:18][CH:17]=[CH2:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C(=O)OC)c2ccccc12
Temperature: 120 °C
Yield: 89 %

Procedure:
To a solution of 4-bromo-naphthalene-1-carboxylic acid methyl ester (2.0 g, 7.9 mmol) in toluene (20 mL) was added allyltributyltin (2.7 mL), tetrakis(triphenylphosphine)palladium(0) (183 mg, 0.16 mmol) and 2 crystals of BHT. The system was purged under vacuum and nitrogen and allowed to heat to 120° C. under N2 for 4 h. TLC analysis (silica, 1:1 ethyl acetate-hexanes) showed the reaction to be completed with only one new fluorescent spot present. The mixture was diluted with ether, washed with H2O, 10% HCl, and then saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 9:1 hexanes-ether) to give (1.6 g, 89%) 4-allylnaphthalene-1-carboxylic acid methyl ester as a colorless liquid. MS m/z 227.1 (M+1). 1H NMR (400 mHz) CDCl3 8.95(d 1H), 8.11(d, 1H), 8.08(d, 1H), 7.58(m, 2H), 7.37(d, 1H), 6.09(m, 1H), 5.11(m, 2H), 3.99(s, 3H), 3.88(d, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([F:19])[CH:13]=1>CN(C)C=O>[Br:11][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([F:19])[CH:13]=1)[O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2cc(F)cc(Br)c2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
Combine 1-methyl-piperidin-4-ol (5.97 g, 51.81 mmol) and N,N-dimethylformamide (100 mL) and treat, in portions, the resulting solution with 95% sodium hydride (1.31 g, 51.81 mmol) and stir. After 1 hr., add 1-bromo-3,5-difluoro-benzene (10.0 g, 51.81 mmol), stir and heat to 80° C. After 2 hr., cool to ambient temperature, partition between water (100 mL) and ethyl acetate (100 mL), separate and wash the water layer with ethyl acetate (100 mL). Combine the ethyl acetate layers and wash with water (5×75 mL). Wash the organic layer with aqueous NaCl solution (75 mL), dry over sodium sulfate, filter and concentrate to an oil. Purify the residue by silica gel flash chromatography eluting with 10% (2M NH3/methanol)/methylene dichloride to obtain of the title compound (10.61 g, 71%). Mass spectrum (electrospray): m/z=288 (M+1−1), 290 (M+1+1); 1H NMR (CDCl3): 6.85 (s, 1H), 6.8 (m, 1H), 6.55 (m, 1H), 4.3 (m, 1H), 2.6 (m, 2H), 2.3 (m, 5H), 2.0 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])=[CH:4][CH:3]=1.[CH2:20]([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:20]([O:25][C:26](=[O:31])[C:27]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[C:9]([CH3:19])=[C:8]2[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(O)ccc2n1C
Reactant: CCCCCOC(=O)C(C)(C)Br
Product: CCCCCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc(Cl)cc1)c(C)n2C

Procedure:
The above compound was prepared from 3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid amylester using a procedure analogous to that of Example 102.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9](Cl)=[O:10])=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:4]=1.[NH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.N1CCCCC1>C(Cl)Cl.[Cl-].[Na+].O>[N:26]1([NH:25][C:9]([C:8]2[C:3]([O:2][CH3:1])=[N:4][C:5]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[C:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:7]=2)=[O:10])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NN1CCCCC1
Reactant: COc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)cc1C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)cc1C(=O)NN1CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 2-(methoxy)-6-(4-chlorophenyl)-5-(phenyl)pyridine-3-carbonyl chloride (0.08 mmol) from Step B in methylene chloride (1 mL) was added to a solution-of 1-aminopiperidine (containing a few percent of piperidine as an impurity) (0.017 mL, 0.16 mmol) and TEA (0.022 mL, 0.16 mmol) in methylene chloride (0.5 mL). The reaction was stirred at rt for 20 h and was then diluted with brine and extracted twice with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a mixture of the crude products. These were separated by preparative TLC (5% methanol in methylene chloride) to give N-(piperidin-1-yl)-2-(methoxy)-6-(4-chlorophenyl)-5-(phenyl)pyridine-3-carboxamide as the lower eluting product. HPLC/MS: 422 (M+1); Rt=3.8 min;
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:22]#[C:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cn1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccc(C#Cc2ccccc2)cn1
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (31 mg, 44.7 μmol, 0.05 equiv.) was dissolved in 2 ml DMF. (230 mg, 894 μmol) 5-Bromo-pyridine-2-carboxylic acid tert-butylamide (Example 1, step 1) and phenylacetylene (183 mg, 196 μl, 1.79 mmol, 2 equiv.) were added at room temperature. Triethylamine (272 mg, 374 μl, 2.68 mmol, 3 equiv.), triphenylphosphine (7 mg, 26.8 μmol, 0.03 equiv.) and copper(I)iodide (5 mg, 26.8 μmol, 0.03 equiv.) were added and the mixture was stirred for 2 hours at 70° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 5-phenylethynyl-pyridine-2-carboxylic acid tert-butylamide (174 mg, 70% yield) was obtained as a light yellow solid, MS: m/e=279.1 (M+H+).
Reaction SMILES: CC(C)CCCC1C=CC(C#C)=CC=1.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:26][CH:27]([CH3:33])[CH2:28][CH2:29][C:30](O)=[O:31]>>[O:31]=[C:30]([C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=1)[CH2:29][CH2:28][CH:27]([CH3:33])[CH3:26]
Reactant: Brc1ccccc1
Reactant: CC(C)CCC(=O)O
Agent: C#Cc1ccc(CCCC(C)C)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)CCC(=O)c1ccc(Br)cc1

Procedure:
Reaction Scheme 5 discloses a specific synthetic route to 4-(4-methylpentyl)-phenylethyne (Compound 28). In accordance with this scheme, bromobenzene (Compound 29) is reacted under Friedel Crafts conditions (AlCl3) with the acid chloride (Compound 30) prepared in situ from 4-methyl valeric acid, to yield 4-(1-oxo-4-methyl-pentyl) bromobenzene (Compound 31). Compound 31 is reduced under Wolff-Kishner conditions (KOH, NH2NH2) to yield 4-(4-methylpentyl) bromobenzene (Compound 32). The bromobenzene derivative 32 is converted to the ethyne derivative 28 through the intermediate trimethylsilyl ethyne derivative 33 in a manner similar to the conversion described in connection with Reaction Scheme 3. ##STR9##
Reaction SMILES: [CH2:1]([C@H:8]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:9]([O:37][Si](C(C)(C)C)(C)C)[CH2:10][C@@H:11]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([C@H:8]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])[C@@H:9]([OH:37])[CH2:10][C@@H:11]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(C[C@@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)NC(=O)OCc3ccccc3)cc2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(C[C@@H](C[C@H](O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)NC(=O)OCc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
The product from Example 92F (0.374 g, 0.517 mmol) was treated with TBAF solution in THF (2 mL, 1N), stirred at 25° C. for 16 hours, concentrated and partitioned between ethyl acetate and water. The organic phase was washed with brined, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-20% ethyl acetate in chloroform, to give the title compound (0.198 g, 63% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=O)[C:12]([OH:14])=O)=[CH:3]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:42][C:43](=[NH:48])[O:44]C(C)C)=[CH:34]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:42]2[C:43](=[O:44])[NH:48][C:12](=[O:14])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:34]1
Reactant: CC(C)OC(=N)Cc1cn(C)c2ccccc12
Reactant: Cn1cc(C(=O)C(=O)O)c2ccccc21
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
A stirred solution of 406 mg (2 mmol) of 1-methyl-3-indolylglyoxylic acid in 20ml of dichloromethane was treated with 202 mg (2 mmol) of triethylamine and 273 mg (2 mmol) of isobutyl chloroformate. After 0.5 hour, the solution was added dropwise to a stirred solution of 533 mg (2 mmol) of isopropyl 1-methyl-3-indoleacetimidate hydrochloride and 808 mg (8 mmol) of triethylamine in 50 ml of dichloromethane. The solution obtained was heated to reflux under nitrogen for 18 hours, cooled and treated with 1.9 g (10 mmol) of p-toluenesulfonic acid. After 1 hour, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using dichloromethane/ethyl acetate (8:1) for the elution to give 107 mg(30% ) of 3,4-bis-(1 -methyl-3-indolyl)-1H-pyrrole-2,5-dione in the form of an orange colored solid of melting point >310° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][C:10]2=[O:12]
Reactant: Cc1ccccc1CCC(=O)O
Solvent: ClCCl
Product: Cc1cccc2c1CCC2=O
Temperature: 0 °C
Yield: 54.2 %

Procedure:
A solution of 12.0 g (73.2 mmol) of 2-methylbenzenepropanoic acid in 125 ml of methylene chloride was added portion-wise to 500 g of polyphosphoric acid. The mixture was heated for six hours on the steam bath and the resulting orange solution was diluted with 1.5 l of ice. The solid was collected, washed with water, and air dried to give 7.2 g crude material. Recrystallization from ethanol/water gave 5.8 g of the desired product; mp 94°-97°. Extraction of the original diluted reaction mixture with methylene chloride gave an additional lot. Total recovery was 7.7 g (72%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:66]=[CH:65][C:53]2[N:54]=[C:55]([CH:57]([NH2:64])[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[NH:56][C:52]=2[CH:51]=1>O1CCCC1.C(Cl)Cl.C(O)C>[Cl:49][C:50]1[CH:66]=[CH:65][C:53]2[NH:54][C:55]([CH:57]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[NH:64][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: NC(c1ccccc1)c1nc2ccc(Cl)cc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C(=O)NC(c2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and C-(5-chlorobenzimidazol-2-yl)-C-phenylmethylamine in tetrahydrofuran. Yield: quantitative; Rf value: 0.59 (silica gel; methylene chloride/ethanol=9:1); C27H25ClN4O2 (472.97); mass spectrum: (M+H)+=473 and (M−H)−=471.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH:23]1([C:28]#[C:29][C:30]#[N:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>>[CH:23]1(/[C:28](/[N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)=[CH:29]/[C:30]#[N:31])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC#CC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(/C(=C\C#N)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a stirred solution of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (17, 7.260 g, 23.01 mmol) and 3-cyclopentylprop-2-ynenitrile (8, 6.140 g, 34.52 mmol, 1.5 equiv) in N,N-Dimethylformamide (DMF, 40.0 mL, 516 mmol) at room temperature was added solid potassium carbonate (K2CO3, 318 mg, 2.30 mmol, 0.1 equiv). The resulting reaction mixture was stirred at room temperature for 30 min. When LCMS showed the reaction was deemed complete, the reaction mixture was quenched with water (80 mL), extracted with EtOAc (2×150 mL). The combined organic layers were washed with water (80 mL) and brine (50 mL), dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-30% EtOAc/hexane gradient elution) to give (Z)-3-cyclopentyl-3-(4-(7((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylonitrile (19, 8.256 g, 10.0 g theoretical, 82.6% yield) as a colorless syrup. For 19: 1H NMR (CDCl3, 300 MHz) δ ppm 9.15 (bs, 1H), 8.96 (s, 1H), 8.56 (s, 1H), 7.51 (d, 1H, J=3.5 Hz), 6.93 (d, 1H, J=3.5 Hz), 5.75 (s, 2H), 5.29 (s, 1H), 3.62 (m, 1H), 3.60 (t, 2H, J=8.2 Hz), 2.16 (m, 2H), 1.81 (m, 4H), 1.59 (m, 2H), 0.98 (t, 2H, J=8.2 Hz), 0.00 (s, 9H); C23H30N6OSi (MW, 434.61), LCMS (EI) m/e 435.2 (M++H).
Reaction SMILES: CN1C(C)=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=N1.Br[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[C:30]([F:32])[C:29]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[C:28]([F:39])[CH:27]=2)[N:25]=1)=[O:19].[H-].[Na+]>CN(C=O)C>[F:39][C:28]1[CH:27]=[C:26]([C:24]2[N:25]=[C:21]([NH:20][C:18](=[O:19])[CH2:17][N:25]3[C:9]4[C:8](=[O:12])[N:7]([CH3:13])[C:6](=[O:14])[N:5]([CH3:15])[C:4]=4[CH:23]=[C:24]3[CH3:26])[S:22][CH:23]=2)[CH:31]=[C:30]([F:32])[C:29]=1[O:33][CH2:34][C:35]([F:38])([F:37])[F:36]
Reactant: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCC(F)(F)F)c(F)c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c(=O)n(C)c(=O)n2C)n1CC(=O)Nc1nc(-c2cc(F)c(OCC(F)(F)F)c(F)c2)cs1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 2 (50 mg, 0.258 mmol) with 2-bromo-N-{4-(3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl)-1,3-thiazol-2-yl}acetamide (133 mg, 0.308 mmol) in the presence of NaH (16 mg, 0.375 mmol) in dry DMF (5.0 mL) to give 60 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 2.26 (s, 3H), 3.16 (s, 3H), 3.34 (s, 3H), 4.80-4.90 (m, 2H), 5.33 (s, 2H), 6.07 (s, 1H), 7.71 (d, J=9.3 Hz, 2H), 7.83 (s, 1H), 12.75 (br s, 1H); ESI-MS (m/z) 544.55 (M+H)+.