Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=S)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[N:12][C:13]([CH2:16][CH3:17])([CH2:18][CH3:19])[CH2:14][CH3:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCC(CC)(CC)NC(=S)Nc1cc(Cl)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)(CC)N=C=Nc1cc(Cl)cc(Cl)c1
Yield: 88.5 %

Procedure:
To a solution of 810 mg of N-(3,5-dichlorophenyl)-N'-(1,1-diethylpropyl)thiourea produced in Example A-7 and 800 mg of triphenylphosphine in 10 ml of dichloromethane were added 380 mg of triethylamine and 590 mg of carbon tetrachloride. The mixture was refluxed for 4 hours and evaporated in vacuo. The residue was stirred with n-hexane and filtered to remove solid matter. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography using n-hexane as a solvent to give 640 mg of N-(3,5-dichlorophenyl)-N'-(1,1-diethylpropyl)carbodiimide as an oil. To a solution of this oil in 5 ml of DMF were added 470 mg of cyanamide and 0.05 ml of diisopropylethylamine. The mixture was stirred at 100° C. for 3 hours, cooled to room temperature and poured into water. The resulting crystals were collected and recrystallized from benzene to give 480 mg of the title compound as colorless needles melting at 178.5°-180.5° C.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.CN(C)C=O.[NH2-].[Na+].[CH2:28]([N:31]=[C:32]=[O:33])[CH2:29][CH3:30]>O>[N+:17]([C:13]1[CH:12]=[C:11]([N:10]2[C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3](=[O:20])[N:31]([CH2:28][CH2:29][CH3:30])[C:32]2=[O:33])[CH:16]=[CH:15][CH:14]=1)([O-:19])=[O:18]
Reactant: COC(=O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCCN=C=O
Agent: [NH2-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 2.9 g of 2-(m-nitroanilino)benzoic acid methyl ester and 20ml of dry dimethylformamide was added 0.43 g of sodium amide, and the whole was stirred for 30 minutes. To this was added dropwise under cooling 2.6 g of propyl isocyanate. This mixture was allowed to stand for one hour at room temperature and for additional one hour at 60° C, and then reacted for 4 hours at 120° C. The solvent was distilled off from the mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product. This product was recrystallized from methanol to produce 2.4 g of 1-(m-nitrophenyl)-3-propylquinazoline-2,4(1H, 3H)-dione as colorless needles, melting at 162°-163° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([C:18]([F:21])([F:20])[F:19])[CH:10]=2)=[CH:6][C:7]=1[NH2:8].[CH2:24](OC(OCC)OCC)C>[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.C(#N)C>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[N:4]=[C:3]([C:22]#[N:23])[C:2]3[N:1]=[CH:24][NH:8][C:7]=3[CH:6]=2)=[CH:10][C:11]=1[C:18]([F:21])([F:19])[F:20])[CH3:17]
Reactant: CCOC(OCC)OCC
Reactant: CCOc1ccc(-c2cc(N)c(N)c(C#N)n2)cc1C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CCOc1ccc(-c2cc3[nH]cnc3c(C#N)n2)cc1C(F)(F)F
Yield: 57.1 %

Procedure:
A stirred suspension of 3,4-diamino-6-(4-ethoxy-3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile (4.4 g, 13.7 mmol), ytterbium triflate (173 mg, 2 mol %), triethylorthoformate (6.08 g, 41.1 mmol) and acetonitrile (50 ml) was heated to reflux for 30 minutes. The solid precipitate was collected by filtration and washed sparingly with acetonitrile to afford 6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (2.6 g). 1H NMR (DMSO): δ 8.67 (s, 1H), 8.47 (s, 1H), 8.36 (m, 2H), 7,49 (d, 1H), 4.26 (q, 2H), 1.38 (t, 3H). MS m/z 333.3(M+1).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH2:26].C(N(CC)CC)C>C1COCC1>[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH:26][C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 57.4 %

Procedure:
A solution of 10.75 g (38.56 mmol) of trityl chloride is added, at 0° C., to a solution of 6 g (38.56 mmol) of L-serine methyl ester hydrochloride and 7.8 g (77.12 mmol) of triethylamine in absolute THF and this solution is left to stir at 0° C. for 4 h and then at room temperature for 2 days. The solvent is removed in vacuo and the residue is partitioned between dichloromethane and a 10% aqueous solution of citric acid. The phases are separated and the organic phase is washed with water and dried over sodium sulfate. Following filtration, the solvent is removed in vacuo and the residue is chromatographed through silica gel using heptane/ethyl acetate=6/4. 8 g (58%) of (34.3) are obtained after concentrating the product fractions.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].CC(CC(O)=O)=O>ClCCl>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=[O:39])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCCCCCO)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(=O)CC(=O)O
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCCCCC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100 mL round-bottomed flask was solid supported 2,2,6,6-Tetramethyl Piperidinyloxy, Free Radical (0.5 g, 1.1 mmol/g, 0.553 mmol) and 10-(Cholest-5-en-3β-oxy)decan-1-ol (3.00 g, 5.53 mmol) suspended in dichloromethane (20 ml) to give a colorless suspension. lodobenzene diacetate (1.958 g, 6.08 mmol) was added to the mixture, which was allowed to stir overnight at room temperature. The reaction mixture was filtered and the solid support washed with DCM. The combined filtrate was washed with saturated sodium thiosulfate (2×20 mL) and brine (1×20 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The resultant oil was purified via column chromatography with 100% DCM as mobile phase to give 2.70 g (90%) of a colorless wax. 1H NMR (300 MHz, CDCl3) δ0.69 (3H, s); 0.84-1.74 (47H, m); 1.76-2.09 (5H, m); 2.12-2.26 (1H, m); 2.32-2.40 (1H, m); 2.44 (2H, dt, J=7.4, 1.9 Hz); 3.14 (1H, tt, J=11.2, 4.4 Hz); 3.46 (2H, t, J=6.9 Hz); 5.35 (1H, d, J=5.3 Hz); 9.78 (1H, t, J=1.9 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)[CH:7]=1.[N-:15]=[N+:16]=[N-:17].[Na+].O.CCOC(C)=O>CN(C=O)C>[N:15]([CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)[CH:7]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1cn(-c2ccc(I)cc2)cn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1cn(-c2ccc(I)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
The compound 4-chloromethyl 1-(4-iodophenyl)imidazole 1-3 (0.780 g, 2.45 mmol) was dissolved in DMF (10 mL). To the solution, NaN3 (0.520 g, 8.00 mmol) was added. After being stirred at room temperature overnight, water and EtOAc were added. The organic layer was separated, dried over Na2SO4, concentrated in vacuo to give 4-azidomethyl 1-(4-iodophenyl)imidazole 1-4 as a solid (0.725 g). MS 326.0 (M+H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[I:8].C([Sn](CCCC)(CCCC)[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)CCC.C(OCC)C>O1CCCC1.[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>[I:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: Brc1ccccc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: Ic1ccccc1-c1cnccn1
Temperature: 90 °C
Reaction time: 22 h
Yield: 16.2 %

Procedure:
1-Bromo-2-iodobenzene (0.32 mL, 2.4 mmol), copper(I) iodide (50 mg, 0.26 mmol) and bis(triphenylphosphine)palladium(II) chloride (88 mg, 0.12 mmol) were added to a degassed solution of 2-tributylstannylpyrazine (1.0 g, 2.4 mmol) in tetrahydrofuran (10 mL) and stirred at 90° C. under nitrogen for 22 hours. Diethyl ether was added to the cooled mixture, filtered through ‘Hyflo’ silica and concentrated in vacuo. Purification by flash column chromatography eluting with a 10-100% diethyl ether/isohexane gradient gave a pale yellow oil of 2-(2-iodophenyl)pyrazine (0.11 g, 16%) which contained some 2-(2-bromophenyl)pyrazine. 1H NMR (500 MHz, CDCl3) δ 8.85 (1H, d, J=1.4 Hz), 8.71-8.65 (1H, m), 8.59 (1H, d, J=2.5 Hz), 8.00 (1H, d, J=7.9 Hz), 7.49-7.46 (2H, m), 7.19-7.11 (1H, m); m/z (ES+) 283 [MH+].
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][O:6][C:7]1[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]2[CH2:27][CH3:28])=[CH:13][CH:12]=1)=[O:10].[Cl-].[NH4+]>CCOCC>[CH2:27]([CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]([C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[O:6][CH3:5])([OH:10])[CH2:1][CH3:2])=[CH:16][CH:15]=1)[CH3:28]
Reactant: CC[Mg]Br
Reactant: CCC1CCCCN1CCCOc1ccc(C(=O)c2ccccc2OC)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC1CCCCN1CCCOc1ccc(C(O)(CC)c2ccccc2OC)cc1
Reaction time: 1 h

Procedure:
To 80 ml. of a 2.5 molar ethereal ethyl magnesium bromide solution a solution of 19.1 g. of 2-methoxy-4'-[3-(2-ethyl-piperid-1-yl)-propoxy]-benzophenone in 150 ml. of ether is added dropwise, with stirring at a temperature between 0° C. and 5° C., whereupon the reaction mixture is slightly boiled for one hour. After cooling the mixture is decomposed with a 10% aqueous ammonium chloride solution, and the aqueous phase is extracted with ether. The organic phase is washed to neutral with water, dried over anhydrous magnesium sulfate, and ether is distilled off under reduced pressure. Fractionation of the residue in vacuum yields 14.6 g. of the named compound, boiling at 224° to 226° C./13.3 Pa.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[OH:18].CN1CCCC1=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH:16]1[C:17]2[C:8]3[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[O:18][C:9]=3[CH:10]=[CH:11][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: Oc1ccc2ccccc2c1-c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc2c(c1)ccc1oc3ccccc3c12
Temperature: 150 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
Into a 1 L three-neck flask were placed 15 g (63 mmol) of 1-(2-fluorophenyl)-2-naphthol, 300 mL of N-methyl-2-pyrrolidone (NMP), and 18 g (130 mmol) of potassium carbonate. The mixture in this flask was stirred at 150° C. for 6 hours under a nitrogen stream. After that, this mixture was cooled down to room temperature and added to about 500 mL of water. The aqueous layer of this mixture was subjected to extraction with ethyl acetate, and the obtained solution of the extract and the organic layer were combined and washed with water and saturated brine. The organic layer was dried over magnesium sulfate, and after that, this mixture was gravity-filtered. The obtained filtrate was concentrated to give an oily substance. The obtained oily substance was purified by silica gel column chromatography (developing solvent: hexane) to give an oily substance. The obtained oily substance was dried under reduced pressure, so that 11.8 g of a colorless transparent oily substance of the object of the synthesis was obtained in 86% yield. The above-described synthesis scheme is illustrated in the following scheme (B-2).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][C:6]=1[CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:18])=O>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Cl:18])=[CH:7][C:6]=1[CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(CO)ccc1C(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1cc(CCl)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.2 %

Procedure:
Alcohol 26.4 (77.0 mg, 0.37 mmol) was dissolved in anhydrous DCM (5.0 mL). Thionyl chloride (0.041 mL, 0.56 mmol) was added dropwise to the above solution. The resulting mixture was stirred at room temperature for 24 hours. The organic solvent was then removed under vacuo to give a white solid (80 mg). The crude product (26.5) was used in the next step without further purification.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Na+].CS([CH2-])=O.[H-].[Na+].[CH3:31][O:32][C:33]([CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH:41]1[C:46](=O)[CH2:45][CH2:44][O:43][CH2:42]1)=[O:34]>CS(C)=O.C(OCC)(=O)C.O>[CH3:31][O:32][C:33]([CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH:41]1[C:46](=[CH:2][O:3][CH3:4])[CH2:45][CH2:44][O:43][CH2:42]1)=[O:34]
Reactant: COC(=O)CCC/C=C\CC1COCCC1=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [CH2-]S(C)=O
Agent: [Cl-]
Agent: [H-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC=C1CCOCC1C/C=C\CCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
To a solution of (methoxymethyl)triphenylphosphonium chloride (3.17 g) in dimethylsulfoxide (20 ml) was added dimsyl sodium prepared from sodium hydride (370 mg, 60% in oil) with dimethylsulfoxide (25 ml) at room temperature. After being stirred at room temperature for 30 minutes, to the resulting mixture was added 3-[(Z)-6-methoxycarbonyl-2-hexenyl]-4-oxotetrahydropyran (740 mg) in dimethylsulfoxide (2 ml) and the solution was stirred at room temperature for additional 4 hours. The reaction mixture was poured into a mixture of water (100 ml) and ethyl acetate (100 ml) and the organic layer was separated, washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column (30 g) with a mixture of n-hexane and ethyl acetate (4:1) as an eluent to give 3-[(Z)-6-methoxycarbonyl-2-hexenyl]-4-methoxymethylenetetrahydropyran (279 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:15]3[C:11](=[N:12][N:13]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[C:14]=3[CH:24]([CH3:26])[CH3:25])[C:10]2=[O:35])[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:46](Br)[CH:47]=[CH2:48]>>[CH2:48]([C:16]1([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:15]2[C:11](=[N:12][N:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[C:14]=2[CH:24]([CH3:26])[CH3:25])[C:10](=[O:35])[N:9]1[C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[CH:47]=[CH2:46]
Reactant: C=CCBr
Reactant: COc1ccccc1-n1nc2c(c1C(C)C)C(c1ccc(Cl)cc1)N(c1ccc(F)c(Cl)c1)C2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: C=CCC1(c2ccc(Cl)cc2)c2c(nn(-c3ccccc3OC)c2C(C)C)C(=O)N1c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared in analogy to the procedure described for example 74 but using the compound prepared in example 88, 2 equivalents of KHMDS and 2 equivalents of allyl bromide. The reaction mixture was stirred for 1 h at rt and quenched by addition of a saturated solution of ammonium chloride. The crude material was purified by silica gel column chromatography (hexane/EtOAc, 4:1). tR: 6.90 min (HPLC 2); ESI-MS: 550.1 [M+H]+ (LC-MS 2); Rf=0.55 (hexane/EtOAc, 1:1).
Reaction SMILES: Cl.Cl.[F:3][C@H:4]1[C:8]2[N:9]=[CH:10][N:11]=[C:12]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:7]=2[C@H:6]([CH3:19])[CH2:5]1.C(OC([N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C@H:32]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:33](O)=[O:34])=O)(C)(C)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[ClH:42].[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C@@H:32]([C@@H:28]2[CH2:29][CH2:30][CH2:31][NH:27]2)[C:33]([N:16]2[CH2:15][CH2:14][N:13]([C:12]3[C:7]4[C@H:6]([CH3:19])[CH2:5][C@@H:4]([F:3])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:18][CH2:17]2)=[O:34])=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: C[C@@H]1C[C@@H](F)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](F)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCCN4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 151.7 %

Procedure:
(5R,7R)-7-Fluoro-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine di-hydrochloride (0.050 g, 0.16 mmol) was combined with (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (0.055 g, 0.16 mmol) in dichloromethane (10 mL). Diisopropylethylamine (0.1 mL, 0.57 mmol) and HBTU (0.061 g, 0.16 mmol) were added, and the mixture was stirred at ambient temperature for 1 hour. The solvent was removed by concentration in vacuo and the residue was purified by column chromatography on SiO2, eluting with 2:1 hexanes/ethyl acetate. The product was dissolved in dioxane (1 mL) and treated with a solution of 4M HCl in dioxane (2 mL). After stirring at ambient temperature for 2 hours, the mixture was concentrated in vacuo to yield (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone hydrochloride (0.060 g, 81% yield). MS (APCI+) [M+H] 458.2.
Reaction SMILES: C([Mg]Cl)C(C)C.[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])#[C:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:19]1[CH2:23]O[CH2:21][CH2:20]1>>[CH2:23](/[C:8](=[CH:7]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: C1CCOC1
Agent: CC(C)C[Mg]Cl
Product: CCCC/C(=C/C(=O)OCC)C(=O)OCC
Temperature: -40 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A mechanically stirred suspension of copper(I) bromide-dimethylsulfide complex (20.4 g, 99.0 mmol) in 500 mL of THF was cooled to −40° C. and treated dropwise with 2.0 M solution of i-butylmagnesium chloride in THF (49.5 mL, 99.0 mmol) under an atmosphere of dry nitrogen. After stirring at −40° C. for 2 h, the reaction mixture was cooled to −78° C. and then treated dropwise with a solution of diethyl acetylenedicarboxylate (13.2 mL, 82.5 mmol) in 160 mL of THF. Upon completion of the addition, the mixture was stirred at −78° C. for 1 h, quenched with saturated NH4Cl aq., then allowed to slowly warm up to room temperature, and stirred at this temperature for additional 30 min. The organic phase was separated and the water phase was thoroughly extracted with ether. The combined organic extracts were washed with saturated NH4Cl aq., then with brine, dried over Na2SO4, and distilled in vacuum to give 14.8 g (79% yield, bp 74–75° C./1 mm Hg) of diethyl 2-1-butylmaleate as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C1CCCCC=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[NH2:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1=CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
A mixture of 5-Nitro-1H-indole-2-carboxylic acid ethyl ester 15 (88.7 mg, 0.38 mmol) and cyclohexene (0.1 mL, 0.98 mmol) in THF/MeOH (3/8 mL) in the presence of Pd(OH)2 on activated carbon (Pearlman's catalyst) (2.74 g) was heated to reflux for 5 h. The reaction mixture was cooled to room temperature. The mixture was filtered through a pad of Celite. The Celite and the palladium were washed with EtOAc. The combined solution was concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 5-45% EtOAc/hexane to afford 66.6 mg of ethyl 5-amino-1H-indole 2-carboxylate 20. 1H-NMR (CDCl3): 8.653 (Br, 1 H, NH), 7.228 (d, J=8.5-9.0 Hz, 1 H, Ar—H), 7.031 (dd, J=1.0 Hz and 2.0 Hz, 1 H, Ar—H), 6.932 (d, J=2.5 Hz, 1 H, Ar—H), 6.803 (dd, J=2.5 Hz, 1 H, Ar—H), 4.379 (q, J=7.0-7.5 Hz, 2 H, CH2), 1.396 (t, J=7.0-7.5 Hz, 3 H, CH3). LC-MS: 205.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:17](OC)=[O:18])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:38][NH2:39])[CH2:28][CH2:27]1.CCCC(C)C>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[NH:39][CH2:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)[CH:21]=[CH:22][C:23]=3[CH3:24])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Reactant: CN1CCN(c2ccccc2CN)CC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Product: Cc1ccc(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1NC(=O)c1cnc2cc(Br)ccn12
Temperature: 100 °C

Procedure:
Methyl 3-(7-bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-methylbenzoate (Intermediate 1B) (400 mg, 1.030 mmol) and TBD (143 mg, 1.030 mmol) in toluene (10 ml) was treated with (2-(4-methylpiperazin-1-yl)phenyl)methanamine (212 mg, 1.030 mmol) and heated at 100° C. under nitrogen overnight. Further TBD (106 mg, 0.82 mmol) was added the mixture was heated at 100° C. for a further 24 hrs. The solvent was removed in vacuo and the residue was partitioned between EtOAc (50 ml) and sodium bicarbonate solution (50 ml). The organic portion was separated and washed with sodium bicarbonate (2×25 ml), dried (MgSO4), filtered and evaporated to dryness to give a yellow solid. Purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/DCM afforded a colourless oil. The oil was dissolved in minimum volume of EtOAc and titurated iso-hexane to afford the title compound as a white solid;