Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])=[CH:4][C:3]=1[S:17](Cl)(=[O:19])=[O:18].[CH2:21]([NH2:24])[C:22]#[CH:23]>O1CCCC1>[CH2:21]([NH:24][S:17]([C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])(=[O:19])=[O:18])[C:22]#[CH:23]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1NS(=O)(=O)C(F)(F)F
Reactant: C#CCN
Solvent: C1CCOC1
Product: C#CCNS(=O)(=O)c1cc(NS(=O)(=O)C(F)(F)F)c(C)cc1C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
2,4-Dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) was added to tetrahydrofuran (20 ml) containing propargylamine (0.5 g), and the resultant mixture was allowed to stand overnight at room temperature. Upon completion of the reaction, the mixture was concentrated. A 5% aqueous solution of hydrochloric acid was added to the residue, whereby an oily substance was deposited. The oily substance was extracted with chloroform and washed with a 5% aqueous solution of hydrochloric acid and water in order. The extract was concentrated and recrystallized from toluene to give 1.05 g of N-propargyl-2,4-dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonamide. M.P., 130.5°-132° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][CH2:22][CH2:23]Cl)[CH3:20]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:20][CH2:19][O:21][CH2:22][CH3:23])=[CH:4][C:3]=1[CH3:10]
Reactant: CCOCCCl
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCOc1cc(C)c(Br)c(C)c1
Yield: 97.5 %

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (12 g, 59.7 mmol), potassium iodide (1.5 g, 9.0 mmol) and potassium carbonate (9.9 g, 71.6 mmol) in N,N-dimethylformamide (80 mL) was added 2-chloroethyl ethyl ether (9.7 g, 89.3 mmol) at room temperature with stirring and the mixture was stirred at 70° C. for 2 days. The reaction mixture was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=19/1) to give the title compound (15.9 g, yield 98%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][C@H:20]([O:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[F:33])[C:19]3=[O:34])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:22][CH2:21][C@H:20]([O:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[O:29])=[CH:26][C:25]=4[F:33])[C:19]3=[O:34])[CH2:16][CH2:17]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(C(F)(F)F)cc4Cl)CC3)C2=O)c(F)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(O[C@H]2CCN(C3CCN(c4ncc(C(F)(F)F)cc4Cl)CC3)C2=O)c(F)c1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.3 %

Procedure:
To a solution of (S)-4-(1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoic acid (0.040 g, 0.080 mmol) and pyrrolidine (0.028 g, 0.40 mmol) in DMF (1 mL) was added HTBU (0.060 g, 0.16 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc (20 mL) and washed with 1 N HCl (5 mL), 1 N NaOH (5 mL), and brine (5 mL), and the combined organic phases were dried over MgSO4, and concentrated under vacuum. The material was purified on silica, using EtOAc as eluent to yield (S)-1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(pyrrolidine-1-carbonyl)phenoxy)pyrrolidin-2-one (0.0026 g, 0.005 mmol, 6% yield). Mass spectrum (apci) m/z=555.0 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:12][N:13]1[C:21]2[N:20]=[C:19]([CH:22]([CH3:24])[CH3:23])[NH:18][C:17]=2[C:16](=[O:25])[NH:15][C:14]1=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)CC.[Ni]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:12][N:13]1[C:21]2[N:20]=[C:19]([CH:22]([CH3:24])[CH3:23])[NH:18][C:17]=2[C:16](=[O:25])[N:15]=[CH:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2c(=S)[nH]c(=O)c3[nH]c(C(C)C)nc32)cc1OCc1ccccc1
Agent: [Ni]
Solvent: CCCO
Product: COc1ccc(Cn2cnc(=O)c3[nH]c(C(C)C)nc32)cc1OCc1ccccc1
Yield: 75.5 %

Procedure:
3-(3-Benzyloxy-4-methoxy-benzyl)-8-isopropyl-2-thioxanthine (21.83 g, 50 mmole) was heated under reflux in 1-propanol (700 ml) with Raney-nickel (30 g) (pre-treated with 0.1% of aqueous acetic acid). After 4 hours the nickel was filtered off and washed with hot propanol and chloroform. The solution was evaporated to dryness in vacuo. The residue was dissolved in chloroform, extracted with IM sodium carbonate solution, dried (Na2SO4), treated twice with charcoal (0.8 g), filtered and evaporated to dryness in vacuo. The residue was suspended in hot acetone (250 ml), concentrated and the solid collected at 0-5° C. to give 3-(3-benzyloxy-4-methoxy-benzyl)-8-isopropyl-hypoxanthine (15.27 g, 75.5%), mp 233-235° C.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([OH:16])=O)[CH:10]=2)[C:5]1=[O:17])[CH:2]=[CH2:3].Cl.[F:19][C:20]([F:40])([F:39])[C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][N:30]=2)[NH2:28])=[CH:23][CH:22]=1>>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([NH:28][C@@H:27]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:40])([F:19])[F:39])=[CH:22][CH:23]=3)[C:29]3[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][N:30]=3)=[O:16])[CH:10]=2)[C:5]1=[O:17])[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)c2ccc(C(=O)O)cc2C1=O
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Agent: Cl
Product: C=CCN1C(=O)c2ccc(C(=O)N[C@@H](c3ccc(C(F)(F)F)cc3)c3ncccc3C(F)(F)F)cc2C1=O

Procedure:
2-Allyl-1,3-dioxoisoindoline-5-carboxylic acid was then coupled with Intermediate 1 using the general methods described above for the amide coupling reaction (Table 2) to provide the title compound, (S)-2-allyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.93 (d, J=3.9 Hz, 1H), 8.44 (d, J=7.6 Hz, 1H), 8.30-8.21 (m, 2H), 8.11-8.02 (m, 1H), 7.98-7.89 (m, 1H), 7.64-7.46 (m, 5H), 6.88 (d, J=7.6 Hz, 1H), 5.99-5.75 (m, 1H), 5.34-5.15 (m, 2H), 4.31 (d, J=5.7 Hz, 2H). MS (ESI pos. ion) m/z: 534.1 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][C:6]=1[CH2:14][OH:15]>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][C:6]=1[CH:14]=[O:15]
Reactant: CCCc1ccc(OCOC)c(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: CCCc1ccc(OCOC)c(C=O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
A mixture of (2-methoxymethoxy-5-propylphenyl)methanol (4.98 g), activated manganese dioxide (15.0 g) and ethyl acetate (300 ml) was stirred at room temperature for 15 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-methoxymethoxy-5-propylbenzaldehyde as an oil (4.19 g, 85%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23].[CH:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[C:27](O)[CH:26]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(#N)C>[N+:31]([C:30]1[CH:25]=[CH:26][C:27]([O:23][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:3]2[C:4]([CH3:12])=[CH:5][C:6]([O:10][CH3:11])=[C:7]([O:8][CH3:9])[C:2]=2[OH:1])=[CH:28][CH:29]=1)([O-:33])=[O:32]
Reactant: COc1cc(C)c(CCCCCCCCCC(=O)O)c(O)c1OC
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: COc1cc(C)c(CCCCCCCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)c(O)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10-(2-Hydroxy-3,4-dimethoxy-6-methylphenyl)decanoic acid (236.9 mg, 0.7 mmol) and p-nitrophenol (107.1 mg, 0.77 mmol) were dissolved in acetonitrile (2 ml). To this solution was added DCC (158.9 mg, 0.77 mmol) under ice-cooling. The solution was stirred at room temperature for 16 hours. The insoluble material was removed by filtration and the solvent was evaporated under reduced pressure. The residue was chromatographed on a silica gel column with chloroform as eluent to obtain about 5 m mol of 10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decanoic acid p-nitrophenyl ester. The ester was dissolved in DMF (1.5 ml). To this solution was added methyl 1-α-O-benzyl-N-acetylmuramyl-L-valyl-D-isoglutaminate (0.15 g, 0.25 mmol), HoBt(0.14 g, 1 mmol) and NEM (128 μl, 1 mmol) and the reaction mixture was stirred at room temperature for four days. After evaporation, the residue was purified by the chromatography on a silica gel column with chloroform/acetone/methanol (10:3:1, v/v) as eluent and precipitated as a gel from ethanol/ether to obtain methyl 1-α-O-benzyl-6-O-{10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decanoyl}-N-acetylmuramyl-L-valyl-D-isoglutaminate (0.13 g). [α]D22 +71.8° (C 0.5, DMF). Rf4 =0.70.
Reaction SMILES: [F-].[F-].[F-].B.C(Cl)Cl.C(Cl)Cl.[NH2:11][C:12]1[C:17]([O:18]C)=[C:16]([F:20])[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:14]([CH3:27])[C:13]=1[C:28]#[N:29]>O>[NH2:11][C:12]1[C:17]([OH:18])=[C:16]([F:20])[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:14]([CH3:27])[C:13]=1[C:28]#[N:29]
Reactant: COc1c(N)c(C#N)c(C)c(-c2ccccc2)c1F
Agent: B
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
Under nitrogen atmosphere, at −78° C., 1 M borane trifluoride/methylene chloride solution (3.0 ml, 3.0 mmol) was dropwise added to a methylene chloride (10 ml) solution of 4-amino-3-cyano-6-fluoro-5-methoxy-2-methylbiphenyl (I-39) (250 mg, 1.0 mmol), taking 10 minutes, followed by stirring for 4 hours and a half with gradually heating up to 0° C. Water with ice was added to the reaction liquid, followed by neutralization at pH of 7 with aqueous 10% sodium carbonate solution and extraction three times with chloroform, the organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue gave the entitled compound (225 mg, 93%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Na+].[I-].Br[CH:35]([CH2:41][CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37].C([N+](CCCC)(CCCC)CCCC)CCC.[NH4+].[Cl-]>CC(C)=O.O>[CH2:39]([O:38][C:36](=[O:37])[CH2:35][CH2:41][CH2:42][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:20]=[CH:21][C:22]([CH2:24][CH3:25])=[CH:23][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([F:19])[CH:14]=1)[CH3:40]
Reactant: CCOC(=O)C(Br)CC
Reactant: CCc1ccc(Oc2ccc(O)cc2F)c(OCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc(Oc2ccc(CC)cc2OCc2ccccc2)c(F)c1
Temperature: 60 °C
Reaction time: 14 h
Yield: 73.3 %

Procedure:
To a solution of 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenol (0.30 mmol; 100 mg) in dry acetone (2 mL), under argon, were added potassium carbonate (0.35 mmol; 49 mg), NaI (0.06 mmol; 9 mg) and ethyl bromobutyrate (0.35 mmol; 51 μL). The reaction was stirred 14 hours at 60° C. Water (100 μL) and tetrabutylammonium hydroxyde (0.03 mmol; 8 mg) were added and the mixture was stirred 16 hours at 60° C. The reaction was hydrolysed with NH4Cl sat. (5 mL) and extracted with ethyl acetate (3*3 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo. The title compound (100 mg; 0.22 mmol; 75%) was obtained as a yellow oil, after purification by preparative TLC (cyclohexane/ethyl acetate: 7/3).
Reaction SMILES: C([O:4][C:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6])C=C.[OH-].[Na+]>CO.O1CCCC1>[C:16]([O:15][C:13]([C:12]([CH3:21])([O:11][C:10]1[CH:9]=[C:8]([CH2:7][C:5]([OH:6])=[O:4])[CH:24]=[CH:23][CH:22]=1)[CH3:20])=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: C=CCOC(=O)Cc1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-[3-(allyloxycarbonylmethyl)phenoxy]-2-methylpropionate (3.35 g, 10.62 mmol) was dissolved in methanol (40 mL) and tetrahydrofuran (40 mL). Subsequently, an aqueous 2M sodium hydroxide solution (40 mL) was added thereto, and the mixture was stirred for three hours at room temperature. The resultant mixture was concentrated under reduced pressure, and the resultant concentrate was acidified with 3M hydrochloric acid. The mixture was extracted with chloroform, followed by drying over sodium sulfate and concentration under reduced pressure, whereby the target compound was obtained (2.98 g, 10.12 mmol, 95.5%).
Reaction SMILES: C1COCC1.[C:6]1([C:12]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:22](=O)[C:23]5[CH:34]=[C:33]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:26]6=[CH:27][CH:28]=[CH:29][C:30]7[C:31](=O)[C:14](=[C:15]([C:24]=5[C:25]=76)[C:16]=34)[CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[C:6]1([C:12]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[CH:22]=[C:23]5[CH:34]=[C:33]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:26]6=[CH:27][CH:28]=[CH:29][C:30]7[CH:31]=[C:14]([C:15]([C:16]=34)=[C:24]5[C:25]=76)[CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=c1c2cc(-c3ccccc3)c3cccc4c(=O)c5cc(-c6ccccc6)c6cccc1c6c5-c2c34
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(-c2cc3cc4cccc5c(-c6ccccc6)cc6cc7cccc2c7c3c6c45)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a 1 L of three neck flask with nitrogen protected condenser were charged with 500 mL of anhydrous tetrahydrfuran (THF) containing 9.2 g (0.02 mol.) of 4,10-Diphenyl-dibenzo[def,mno]chrysene-6,12-dione. Then 20 mL of 1.0 M of boran etherate was added by syringe slowly to above solution. The reaction mixture was slowly warm to 70° C. while stirring until the reaction mixture change to a completely pale yellow solution and then another 5 mL of 0.1.0 M of boran etherate was added by syringe. The reaction was continued for another 1 hour at 70° C. The reaction mixture was cooled to room temperature and 15 mL of methanol was slowly added to quench the excess boran agent. After the bubbles were ceased, the solvents were removed with a rotary evaporator. The residue was added to 20 mL of ethanol and the precipitates were filtered and dried. The 6.4 g of pure 4,10-Diphenyl-dibenzo[def,mno]chrysene was obtained by nitrogen flow sublimation at 275˜285° C. under 2 torr vacuum. Yield is in 74.8%.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=O)[C:33]=1[O:43][CH:44]([F:46])[F:45]>CCOCC>[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=[CH:2][O:3][CH3:4])[C:33]=1[O:43][CH:44]([F:46])[F:45]
Reactant: O=C(c1nccc(Cl)c1OC(F)F)C1CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: COC=C(c1nccc(Cl)c1OC(F)F)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.6 %

Procedure:
0.82 g of (methoxymethyl) triphenyl phosphonium chloride was suspended in 8 ml of anhydrous ether, to which was dropped 2.71 ml of 0.88 M phenyllithium and the resulting mixture was stirred at a room temperature for 15 minutes. 6 ml of ether solution of 0.53 g of (4-chloro-3-difluoromethyl-2-pyridyl)cyclopropylketone (X) was dropped thereto and the resulting mixture was stirred at a room temperature for 2 hours. The resulting residue was separated by filtering and washed with ether, and thereafter, the ether filtrate and ether used for washing were collected together and the collected solution was washed with water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 0.11 g of 2-(4-chloro-3-difluoromethyl-2-pyridyl)-2-cydopropyl-1-methoxyethene (XI).
Reaction SMILES: [CH2:1]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21]Cl>>[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]1=[O:16]
Reactant: ClCCCCCl
Reactant: CCCCCCn1c(=O)[nH]c2ccccc21
Product: CCCCCCn1c(=O)n(CCCCCl)c2ccccc21

Procedure:
The compound may be prepared according to the procedure described in J. Het. Chem. 18, 85 (1981) from 3-n-hexyl-2,3-dihydro-1H-benzimidazol-2-one and 1,4-dichlorobutane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]([CH2:16][CH2:17][O:18][C:19]([F:22])([F:21])[F:20])[C:5]2=[N:6][CH:7]=1.[CH2:23]([SH:25])[CH3:24]>>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:9]1[N:8]([CH2:16][CH2:17][O:18][C:19]([F:22])([F:21])[F:20])[C:5]2=[N:6][CH:7]=[C:2]([S:25][CH2:23][CH3:24])[CH:3]=[C:4]2[N:10]=1
Reactant: CC(C)(C)Cc1nc2cc(Br)cnc2n1CCOC(F)(F)F
Reactant: CCS
Product: CCSc1cnc2c(c1)nc(CC(C)(C)C)n2CCOC(F)(F)F

Procedure:
The title compound was prepared according to the procedure described in Step E of Example 32 from 6-bromo-2-(2,2-dimethylpropyl)-3-[2-(trifluoromethoxy)ethyl]-3H-imidazo[4,5-b]pyridine (Step D) and ethanethiol (Wako Pure Chemical Industries, Ltd.).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1>>[C:19]1([CH3:23])[CH:20]=[CH:21][CH:22]=[C:17]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=2)[CH:18]=1
Reactant: Cc1cccc(I)c1
Reactant: C#Cc1ccc(OCC(=O)OCC)cc1
Product: CCOC(=O)COc1ccc(C#Cc2cccc(C)c2)cc1

Procedure:
The title compound was prepared from ethyl (4-ethynylphenoxy)acetate (42 mg, 0.21 mmol) and iodo-3-methylbenzene (0.04 mL, 0.31 mmol) according to the general procedure ID to give 56 mg (93%) of an orange oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:10). Rf: 0.44 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.61-7.56 (m, 2H), 7.51-7.31 (m, 4H), 7.03-6.88 (m, 2H), 4.75 (s, 2H), 4.43-4.36 (dq, 2H, J=7.2 Hz, 2.1 Hz), 2.47 (s, 3H), 1.44-1.38 (tt, 3H, J=7.2 Hz, 1.5 Hz); 13CNMR (CDCl3) δ 168.6, 157.7, 138.0, 133.1, 132.0, 128.9, 128.5, 128.2, 123.2, 116.2, 114.7, 88.6, 88.6, 65.4, 61.5, 21.2, 14.1; EI-MS m/z 294 (M+).
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:27])[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]=[CH2:19])[CH:13]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:27])[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][CH3:19])[CH:13]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1cc(-c2c(CCCCC(=O)O)c(C)nn3c(CC)ccc23)ccn1
Agent: [Pd]
Solvent: CO
Product: CCc1cc(-c2c(CCCCC(=O)O)c(C)nn3c(CC)ccc23)ccn1
Yield: 92.8 %

Procedure:
A solution of 5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (15 mg) in MeOH was added 10% Pd/C (2 mg). The mixture was stirred under under hydrogen atomosphere (1 atm) for 6 h. The reaction mixture was filtered through Celite and the filtrate was concentrarted in vacuo. The residue was triturated with hexane to give 5-[7-ethyl-4-(2-ethyl-4-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (14 mg) as an yellow solid.
Reaction SMILES: [CH:1]1([C@H:6]2[C:33](=[O:34])[N:32]3[CH2:35][C@@H:29]([CH2:30][C@H:31]3[C:36]([NH:38][C@:39]3([C:44](=[O:52])[NH:45][S:46]([CH:49]4[CH2:51][CH2:50]4)(=[O:48])=[O:47])[CH2:41][C@H:40]3[CH:42]=[CH2:43])=[O:37])[O:28][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([OH:27])=[C:17]3[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][C@@H:11]3[CH2:53][CH2:54][CH2:55][C@H:10]3[O:9][C:8](=[O:56])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:74][CH2:75][N:76]2[CH2:80][CH2:79][O:78][C:77]2=[O:81])(=O)=O)=CC=1>CN(C=O)C>[CH:1]1([C@H:6]2[C:33](=[O:34])[N:32]3[CH2:35][C@@H:29]([CH2:30][C@H:31]3[C:36]([NH:38][C@:39]3([C:44](=[O:52])[NH:45][S:46]([CH:49]4[CH2:50][CH2:51]4)(=[O:47])=[O:48])[CH2:41][C@H:40]3[CH:42]=[CH2:43])=[O:37])[O:28][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([O:27][CH2:74][CH2:75][N:76]4[CH2:80][CH2:79][O:78][C:77]4=[O:81])=[C:17]3[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][C@@H:11]3[CH2:53][CH2:54][CH2:55][C@H:10]3[O:9][C:8](=[O:56])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Reactant: Cc1ccc(S(=O)(=O)OCCN2CCOC2=O)cc1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OCCN1CCOC1=O)O2)C(=O)NS(=O)(=O)C1CC1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OCCN1CCOC1=O)O2)C(=O)NS(=O)(=O)C1CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of (3aR,7S,10S,12R,21E,24aS)-7-cyclopentyl-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-19-hydroxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxamide (Example 17) (40 mg) in DMF (0.75 mL) under nitrogen was added cesium carbonate (495 mg) followed by 2-(2-oxo-1,3-oxazolidin-3-yl)ethyl 4-methylbenzenesulfonate (144 mg). The reaction mixture was stirred at room temperature for 30 minutes and at 50° C. for 3 hours. After cooling back to room temperature, the reaction was quenched with water and extracted with ethyl acetate (3×). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (40%-100% ACN/0.15% TFA-water) afforded the desired product (39 mg) after workup with NaHCO3 and ethyl acetate. HRMS (ES+) m/z 903.3933 (M+H)+.