Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:26][C:27]1[CH:28]=[C:29](/[CH:34]=[CH:35]/[C:36](O)=[O:37])[CH:30]=[C:31]([Cl:33])[CH:32]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.CCOC(C)=O>[C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:18][CH:19]2[CH2:20][CH2:21][N:22]([C:36](=[O:37])/[CH:35]=[CH:34]/[C:29]3[CH:28]=[C:27]([Cl:26])[CH:32]=[C:31]([Cl:33])[CH:30]=3)[CH2:23][CH2:24]2)=[O:25])[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(O)/C=C/c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCNCC2)nn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCN(C(=O)/C=C/c3cc(Cl)cc(Cl)c3)CC2)nn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred suspension of (4-(4-oxo-4-(piperidin-4-ylamino)butyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (Example 37, step 5)(200 mg, 0.516 mmol) and (E)-3-(3,5-dichlorophenyl)acrylic acid (Example 30, step 2) (112 mg, 0.516 mmol) in DMF (2 mL) at RT was added Huenig's base (0.450 mL, 2.58 mmol) followed by T3P® 50% in DMF (0.602 mL, 1.031 mmol) after a few minutes. The reaction mixture was stirred at RT for 20 hours. The reaction mixture was diluted with EtOAc and washed with a saturated solution of brine, organics dried over MgSO4, filtered, and concentrated under reduced pressure to afford the title crude product;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[CH2:10]([O:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)cc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(Br)cc(OCc2ccccc2)c1

Procedure:
A mixture of 3-bromo-5-methylphenol [(40.7 g, 218 mmol) J. Amer. Chem. Soc., 2003, 125, 7792)], benzyl bromide (28.6 mL, 239 mmol) and potassium carbonate (90.2 g, 653 mmol) in acetone (1 L) was heated under reflux for 2 hours. The cooled reaction mixture was then acidified with 2M hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The organic solution was washed with brine (×3), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a red oil in quantitative yield.
Reaction SMILES: C([Cu])#N.[C:4]([Mg]Br)([CH3:7])([CH3:6])[CH3:5].Br[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:16]=1>C1COCC1>[C:4]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:16]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)[Si](OCc1cncc(Br)c1)(C(C)C)C(C)C
Reactant: CC(C)(C)[Mg]Br
Agent: N#C[Cu]
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1cncc(C(C)(C)C)c1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 22.9 %

Procedure:
A mixture of anhydrous CuCN (3.41 g, 38.03 mmol) in 150 mL of anhydrous THF, and ethereal tert-butylmagnesium bromide (38 mL, 76.1 mmol) was stirred under N2 at −78° C. for 20 min. 3-bromo-5-((triisopropylsilyloxy)methyl)pyridine (3.274 g, 9.51 mmol) in THF was added, and the reaction mixture was stirred for 2-3 h at −78° C. and then overnight at room temperature. The reaction mixture was quenched by dropwise addition of saturated aqueous NH4OH and the pH was adjusted to 10 by using 1 M aqueous NaOH, and the resulting solution was extracted with extracted with EtOAc (3×75 mL). The combined organic extracts were dried (Na2SO4,), and concentrated under vacuum to get a residue which was purified by flash column chromatography to give 3-tert-butyl-5-((triisopropylsilyloxy)methyl)pyridine (0.7 g). 1H NMR shows the products contain the desired product and bromine-removed product. 1H NMR (CDCl3): d: 1.124 (m, 22H), 1.369 (s, 5H), 4.878 (s, 2H), 7.298 (m, 0.5H), 7.738 (m, 1H), 8.414 (s, 0.6H), 8.607 (m, 1.5H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:11](=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])=[CH:19][CH:20]=2)[C:11](=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O)cc1
Reactant: CN(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Yield: 66.6 %

Procedure:
4-Benzyloxy-1-(4-hydroxyphenyl)-1H-pyridin-2-one (150 mg, 0.511 mmol), 2-(dimethylamino)ethanol (0.057 mL, 0.562 mmol), triphenylphosphine (269 mg, 1.02 mmols) and diethyl azodicarboxylate (0.163 mL, 1.02 mmols) were stirred overnight in THF (4 mL). Concentrating the reaction liquid under reduced pressure, the resulting residue was purified on silica gel column chromatography (C-300, methanol: chloroform=1:20-1:10) to provide the title compound (124 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[CH2:20]([O:22][C:23]([C:25]([C:30](OCC)=O)=[CH:26][O:27]CC)=[O:24])[CH3:21]>C(O)(=O)C>[CH2:20]([O:22][C:23]([C:25]1[C:26](=[O:27])[N:6]2[N:5]=[C:4]([C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)[C:3]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:2]2[NH:1][CH:30]=1)=[O:24])[CH3:21]
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2c1=O
Yield: 81.4 %

Procedure:
A mixture of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (1.02 g) and 1,1-bis(ethoxycarbonyl)-2-ethoxyethylene (864 mg) in acetic acid (10 ml) was refluxed for 3 hours. After cooling, the crude crystalline was obtained and washed with ethanol to give 4,7-dihydro-6-ethoxycarbonyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-7-oxopyrazolo[1,5-a]pyrimidine (1.23 g).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:19]5[N:20]([CH:45]=[CH:46][N:47]=5)[CH:21]=[C:22]([C:24]5[N:29]=[C:28]([N:30](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH:27]=[N:26][CH:25]=5)[N:23]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:2]1.S(=O)(=O)(O)O.CC(C)=[O:55].[C:57](=[O:60])([O-:59])[O-].[Na+].[Na+]>O>[C:4]([OH:1])(=[O:55])[CH2:3][CH2:2][C:57]([OH:59])=[O:60].[NH2:30][C:28]1[N:29]=[C:24]([C:22]2[N:23]=[C:18]([NH:17][C:14]3[CH:13]=[CH:12][C:11]([N:8]4[CH2:9][CH2:10][N:5]([CH:3]5[CH2:4][O:1][CH2:2]5)[CH2:6][CH2:7]4)=[CH:16][CH:15]=3)[C:19]3[N:20]([CH:45]=[CH:46][N:47]=3)[CH:21]=2)[CH:25]=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cncc(-c2cn3ccnc3c(Nc3ccc(N4CCN(C5COC5)CC4)cc3)n2)n1
Reactant: O=C([O-])[O-]
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Nc1cncc(-c2cn3ccnc3c(Nc3ccc(N4CCN(C5COC5)CC4)cc3)n2)n1
Product: O=C(O)CCC(=O)O
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a slurry of di-tert-butyl {6-[8-({4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl}amino)imidazo[1,2-a]pyrazin-6-yl]pyrazin-2-yl}imidodicarbonate (225 g, 0.35 mol, 1 mol eq.) in water (12 parts) was added a solution of sulfuric acid (3.1 parts, 6.99 mol, 20 mol eq.) in water (5 parts). The reaction was heated to ca. 40° C. and stirred at this temperature for ca. 4 h at which point the reaction is deemed complete. The reaction mixture was cooled to ca. 22° C., acetone (3 parts) was charged and a solution of sodium carbonate (4.1 parts, 8.75 mol, 25.0 mol eq.) in water (15 parts) was added. The resulting slurry was filtered and the wet cake was washed with water in portions (4×1 parts), then with tert-butyl methyl ether (4 parts). The wet cake (Example 2 free base) was dried at ca. 60° C. To the slurry of dry Example 2 free base in 2-propanol (2.3 parts) was added a solution of succinic acid (Based on the isolated Example 2 free base: 0.43 parts, 1.6 mol eq.) in 2-propanol (15 parts). The resulting slurry was heated to ca. 40° C. and stirred at this temperature for ca. 2 h and then cooled to ca. 22° C., followed by a stir period of ca. 16 h. The slurry was filtered at ca. 22° C. and the wet cake was washed with 2-propanol (5 parts) and dried at ca. 60° C. to afford the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([C@:12]2([CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=O)=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C@:12]3([CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH2:16][CH2:15][CH2:14][N:13]3[CH3:17])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C)[Si](OC[C@@]1(C(=O)NNc2ccc(F)cn2)CCCN1C)(C(C)C)C(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)[Si](OC[C@@]1(c2nnc3ccc(F)cn23)CCCN1C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.4 %

Procedure:
To a solution of Intermediate 85h (1.37 g, 2.08 mmol), Ph3P (1.09 g, 4.16 mmol) and Et3N (840 mg, 8.32 mmol) in THF (60 mL) was added hexachloroethane (980 mg, 4.16 mmol) and the mixture stirred at RT for 20 h. The mixture was diluted with DCM, washed with 10% aq. K2CO3 solution, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, to give the title compound as a clear oil (350 mg, 41%). LCMS (Method 4): Rt 3.07 min, m/z 407 [MH+].
Reaction SMILES: Cl[C:2]1[S:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.[I-].[Na+]>C(Cl)(Cl)Cl>[N:16]1([C:2]2[S:6][N:5]([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4](=[O:15])[CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=c1cc(Cl)sn1CCc1ccccc1
Reactant: C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1cc(N2CCCCC2)sn1CCc1ccccc1
Yield: 20.8 %

Procedure:
A mixture of 2.4 g. (0.01 mole) of 5-chloro-2-phenethyl-4-isothiazolin-3-one, 0.85 g. (0.01 mole) of piperidine, 1.0 g. (0.01 mole) triethylamine and 0.1 g. sodium iodide in 10 ml of CHCl3 was heated under reflux for 18 hours. The mixture was washed with water, dried (MgSO4) and concentrated to dryness to give 2.7 g. of a liquid residue. This was purified by a dry column chromatography (11/2×20", silica gel, diisopropyl ether) to give 1.0 g. of a solid product, which was recrystallized from 100 ml of diisopropyl ether to give 0.6 g of the named product, mp 106°-108°.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([O:17]C)=[O:16])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO.C1COCC1>[C:1]1([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([OH:17])=[O:16])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccn1S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate (Intermediate 1) (500 mg, 1.885 mmol) in MeOH (7 ml) and THF (7 ml) cooled to 0° C., aqueous 1N KOH (2.827 ml, 2.83 mmol) was added drop-wise and the resulting mixture was stirred at RT for 24 hours. UPLC-MS analysis showed the presence of desired compound in admixture with methyl 1H-pyrrole-2-carboxylate as the main product. The mixture was poured into ice-water and washed with DCM. The aqueous phase was acidified with 37% HCl (pH=2) and extracted with DCM. The organic layer was dried over sodium sulfate, filtered and evaporated to afford a mixture of 1-(phenylsulfonyl)-1H-pyrrole-2-carboxylic acid (Intermediate 2) (MS/ESI+252.0 [MH]+) and methyl 1H-pyrrole-2-carboxylate (MS/ESI+126.0 [MH]+) (234 mg, ratio about 3/7). This mixture was used as such in the next step.
Reaction SMILES: [CH2:1]([CH2:7][OH:8])[CH2:2][NH:3][CH2:4][CH2:5][NH2:6].CS[C:11](=[C:14]([C:17]#[N:18])[C:15]#[N:16])SC.C(OC(C)C)(C)C>C(Cl)Cl>[CH2:5]1[NH:6][C:11](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[N:3]([CH2:2][CH2:1][CH2:7][OH:8])[CH2:4]1
Reactant: CSC(SC)=C(C#N)C#N
Reactant: NCCNCCCO
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: N#CC(C#N)=C1NCCN1CCCO
Reaction time: 1 h
Yield: 88.7 %

Procedure:
In 10 ml of methylene chloride was dissolved 10.4 g of N-(2-aminoethyl)propanolamine, and the solution was added to 15.0 g of [bis(methylthio)methylene]propanedinitrile. The mixture was allowed to stand at room temperature for 1 hour under reduced pressure. Diisopropyl ether was added to the mixture, and the solid was collected by filtration. The crystals were purified by silica gel column chromatography (chloroform:methanol=5:1) to give 15.0 g (87%) of Compound (VIa) as pale yellow crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[CH3:17].[C:18](Cl)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CC(C)=O.O>[C:18]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[CH3:17])(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C(=O)O)ccc1NC(=O)C=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
8.2 g of potassium carbonate was added to a suspension of 3.0 g of 4-amino-3-methylbenzoic acid in 60 ml of acetone and 60 ml of water. Thereto was dropwise added, with ice-cooling, a solution of 4.0 g of cinnamoyl chloride in 30 ml of acetone. The mixture was stirred at the same temperature for 30 minutes to give rise to a reaction. The reaction mixture was poured into ice water, and the mixture was made acidic with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and recrystallized from methanol to obtain 2.9 g of 4-cinnamoylamino-3-methylbenzoic acid as a white powder.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:28][C:21]3=[N:22][CH:23]=[C:24]([CH2:26]O)[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:31])=O>ClCCl>[Cl:31][CH2:26][C:24]1[CH:25]=[C:20]2[CH:19]=[C:18]([CH:7]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=3)[CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[NH:28][C:21]2=[N:22][CH:23]=1
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CO)cnc3[nH]2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CCl)cnc3[nH]2)cc1
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a stirred solution of {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-methanol (prepared as in Example 8, 800 mg, 1.92 mmol) in dichloromethane (20 mL) at 0° C. was added a solution of thionyl chloride (0.36 mL, 4.89 mmol) in dichloromethane (2 mL) and the mixture was stirred for 2 h. The resulting mixture was concentrated in vacuo and the residue was extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 5-chloromethyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (798 mg, quant.) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C22H25ClN2O2S [M+H]+ 417.97, observed 417.0.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(O)[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:9]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:8]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Br:42])(=O)C.CO>C1(C)C=CC=CC=1>[Br:42][C:11]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:9]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Br
Reactant: COc1ccc(C2(O)C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(C2(Br)C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1

Procedure:
54.19 g (0.11 mol) of 1,2,3,4-tetraphenyl-5-p-methoxyphenylcyclopenta-1,3-dien-5-ol were suspended in 300 ml of toluene. 74 g (0.6 mol) of acetyl bromide were added dropwise in the course of 20 minutes at room temperature and the reaction batch was then refluxed for 2 hours. Toward the end of the reaction, 2 ml of methanol were also added dropwise. Excess acetyl bromide and toluene were distilled off in vacuo. The remaining oil crystallized after addition of 100 ml of petroleum ether. The orange precipitate was filtered off with suction, rinsed with petroleum ether and dried. The product was used for the further syntheses. Analytically pure orange product was obtained by recrystallization from toluene. (Yield: 54. 32 g (89%); elemental analysis for C36H27OBr: found: C, 77.06%, H, 4.90%. calculated: C, 77.84%, H, 4.90%).
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN.[CH2:11]([N:13](CC)CC)C.[N:18]1[O:19][N:20]=[C:21]2[CH:26]=[C:25]([C:27](Cl)=[O:28])[CH:24]=[CH:23][C:22]=12>C(O)C.ClCCl.[Pd].CCOCC>[CH:1]1([N:13]([CH3:11])[C:27]([C:25]2[CH:24]=[CH:23][C:22]3=[N:18][O:19][N:20]=[C:21]3[CH:26]=2)=[O:28])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=C1CCCCCC1
Reactant: O=C(Cl)c1ccc2nonc2c1
Agent: [Pd]
Agent: CN
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCO
Product: CN(C(=O)c1ccc2nonc2c1)C1CCCCCC1
Reaction time: 2 h

Procedure:
To a solution of cycloheptanone (1.12 g, 10 mmol) in 40 ml of ethanol was added a methylamine (2.5 ml of a 33% solution in ethanol) and 220 mg of Pd on C (10%) were added, and the mixture hydrogenated at 50 psi over night. The solids were filtered off and the mixture concentrated under vacuum to give a pale yellow oil. This material and 1.2 ml of triethylamine were dissolved in 10 ml of dichloromethane and a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (730 mg, 4 mmol) was added slowly. After stirring the mixture for 2 hours, the organic phase was washed with 1N HCl and conc. NaHCO3 solution, dried over magnesium sulfate, and then concentrated under vacuum to give a white solid, after trituration with ether (405 mg, 37%). Mp: 80-81° C., 1H NMR (300 MHz, CDCl3, rotamers) δ 7.93 (m, 1H); 7.80 (s, 1H); 7.43-7.37 (m, 1H); 4.75-4.60 and 3.70-3.55 (m+m, 1H); 3.01 and 2.87 (s+s, 3H); 2.00-1.20 ppm (m, 12H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:16])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])=[C:21]([N+:30]([O-:32])=[O:31])[CH:20]=1>O1CCOCC1>[F:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:8](=[O:16])[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:21]([N+:30]([O-:32])=[O:31])[CH:20]=1
Reactant: NCCCOc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(NCCCOc1ccc(F)cc1[N+](=O)[O-])Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
Triethylamine (2.90 ml, 21.4 mmol) and phenyl chlorocarbonate (2.52 ml, 20.0 mmol) were added to a dioxane solution (43 ml) of 3-(4-fluoro-2-nitrophenoxy)propylamine (4.03 g, 18.8 mmol), while being cooled with ice, and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (dichloromethane:ethyl acetate=30:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 5.92 g of powdery yellow phenyl [3-(4-fluoro-2-nitrophenoxy)propyl]carbamate (yield: 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]2[CH:32]=[CH:31][S:30][C:24]=2[NH:25][C:26](=O)[CH2:27][N:28]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]2[CH:32]=[CH:31][S:30][C:24]=2[NH:25][C:26](=[S:42])[CH2:27][N:28]=1
Reactant: COc1cc(CCc2ccc(C3=NCC(=O)Nc4sccc43)c(Cl)c2)cc(OC)c1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(CCc2ccc(C3=NCC(=S)Nc4sccc43)c(Cl)c2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a solution of 0.25 g (0.53 mmol) of the compound prepared in (e) above in 5 ml of toluene was added 0.13 g (0.32 mmol) of Lawesson's Reagent, and the resultant mixture was heated to 90° C. and maintained at this temperature for 3 hours. After cooling the reaction mixture to 25° C., the solvent it was diluted with 50 ml methylene chloride, washed successively with 1 ml of water and 10 ml of brine, dried over magnesium sulfate and evaporated. The crude residue was pruified by column chromatography on silica gel employing a mixture of ethyl acetate and hexane in 2:1 ratio as the eluent to yield an orange foam.
Reaction SMILES: [C:1]([C:6]1[C:7](=O)[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]=[CH2:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH:19](Cl)(Cl)[Cl:20]>P(Cl)(Cl)(Cl)=O>[Cl:20][CH3:19].[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:20])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]=[CH2:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: ClC(Cl)Cl
Reactant: C=Cc1cccc2cc(C(=O)CCC)c(=O)[nH]c12
Solvent: O=P(Cl)(Cl)Cl
Product: C=Cc1cccc2c(Cl)c(C(=O)CCC)cnc12
Product: CCl
Yield: 38.5 %

Procedure:
3-Butyryl-8-vinylquinolone (23 g, 95 mmol) was heated under reflux in a mixture of phosphoryl chloride (100 ml) and chloroform (100 ml) for 45 minutes. The solvent was evaporated and the residue was mixed with ice, neutralized with ammonia solution and extracted into dichloromethane. The organic solution was washed successively with sodium hydrogen carbonate solution and brine, dried (anhyd. MgSO4), filtered and evaporated. Chromatography (silica gel, 2% methanol in di.chloromethane) afforded 3-butyryl-4-chloro-8-vinylquinoline as a brown oil (9.5 g, 38.5%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[N:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[C:6]1=[O:26].C([O-])([O-])=O.[Cs+].[Cs+].F[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[O:1][CH2:2][CH2:3][CH2:4][N:5]1[N:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=3)=[CH:10][CH:11]=2)[C:6]1=[O:26]
Reactant: Fc1ccccn1
Reactant: O=c1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2cnn1CCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=c1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2cnn1CCCOc1ccccn1
Temperature: 155 °C

Procedure:
A mixture of 2-(3-hydroxypropyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (25 mg, 0.069 mmol), Cs2CO3 (67 mg, 0.21 mmol) and 2-fluoropyridine (100 μL) was heated to 155° C. overnight. The reaction was concentrated and purified by reverse phase HPLC to afford 2-(3-(pyridin-2-yloxy)propyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one as a white solid. C23H18F3N3O3. 441.9 (M+1).