Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[N:23]([CH3:31])[N:22]=3)[N:19]=2)[N:14](COCC[Si](C)(C)C)[CH:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@@H:4]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[N:23]([CH3:31])[N:22]=3)[N:19]=2)[NH:14][CH:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC[C@H](CC(C)C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: COC[C@H](CC(C)C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.8 %

Procedure:
In a 10 mL round-bottom flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-methoxymethyl-3-methyl-butyl)-amide (35 mg, 0.063 mmol) and TFA (0.6 ml, 7.8 mmol) were combined with dichloromethane (2 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (1 mL) and ethylenediamine (0.32 ml, 4.7 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (hot dichloromethane/heptane) to afford 16 mg (60%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-methoxymethyl-3-methyl-butyl)-amide as a white solid. MS: [M+H]+=425, 1H NMR (300 MHz, DMSO-d6) δ: 12.87 (s, 1H), 9.13 (s, 1H), 8.53 (dd, J=8.7, 5.3 Hz, 1H), 8.44 (s, 1H), 8.17 (d, J=9.4 Hz, 1H), 7.71 (dd, J=9.8, 2.3 Hz, 1H), 7.11 (td, J=9.1, 2.3 Hz, 1H), 4.41 (td, J=9.1, 4.9 Hz, 1H), 4.16 (s, 3H), 3.52 (dd, J=9.4, 4.2 Hz, 1H), 3.46 (dd, J=9.4, 4.2 Hz, 1H), 3.27 (s, 3H), 1.48-1.75 (m, 3H), 0.91 (d, J=6.4 Hz, 3H), 0.86 (d, J=6.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:14])=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:15]([O-])([O-])=O.[Cs+].[Cs+].IC.O>CO>[CH3:15][O:6][C:5](=[O:7])[C:4]1[C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1C(=O)O
Agent: [Cs+]
Solvent: CO
Solvent: CI
Solvent: O
Product: COC(=O)c1c([N+](=O)[O-])ccc(F)c1C
Temperature: 25 °C

Procedure:
To a solution of 3-fluoro-2-methyl-6-nitro-benzoic acid in 200 mL of methanol, Cs2CO3 (4.34 g, 13.3 mmol) is added and stirred at the room temperature. The solution is concentrated under reduced pressure then the resulting yellow solids are suspended in 26 ml of DMF. Iodomethane (1.7 ml 26.6 mol) is added at 0° C. and stirred at the room temperature for 30 min. Water is added to the solution and extracted with ethyl acetate. The organic layer is washed with H2O followed by brine, dried over Na2SO4, filtered and evaporated in vacuo to afford 3-fluoro-2-methyl-6-nitro-benzoic acid methyl ester (5.70 g) as yellow oil in quantitative yield. 1H-NMR (400 MHz, δ, ppm) CDCl3: 2.30 (d, 3H), 3.99 (s, 3H), 7.22 (dd, 1H), 8.07 (dd, 1H).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[C:5]([C:9]1[C:10](=[O:26])[CH2:11][CH:12]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([NH2:24])[C:17]=2[CH3:25])[CH2:13][C:14]=1[OH:15])(=[O:8])[CH2:6][CH3:7].C(OCC)(=O)C>O.C(O)(=O)C>[C:5]([C:9]1[C:10](=[O:26])[CH2:11][CH:12]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([NH:24][C:2]([NH2:3])=[O:1])[C:17]=2[CH3:25])[CH2:13][C:14]=1[OH:15])(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(N)c2C)CC1=O
Reactant: N#C[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(NC(N)=O)c2C)CC1=O
Reaction time: 1 h

Procedure:
A solution of potassium cyanate (0.54 g, 6.66 mmol) in water (3 ml) was added cautiously to a solu tion of 2-propionyl-3-hydroxy-5-(3-amino-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.0 g, 3.32 mmol) in acetic acid (9 ml) and water (3.2 ml). Stirring was continued for 1 hr then allowed to stand for 15 hr. Water and ethyl acetate were added. The organic layer was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield 2-propionyl-3-hydroxy-5-(3-ureido-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as a brown semi solid (0.96 g, 84%). The compound was characterized by proton magnetic resonance spectroscopy (CDCl3, δ in ppm): 1.11 (3H,t); 2.20 (3H,s); 2.32 (6H,s); 2.4-4.1 (7H,m); 5.12 (2H,brs); 6.82 (1H,s); 7.25 (1H,brs).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1.C(O)(=O)/C=C\C(O)=O.ClC1[N:38]=[N:37]C2CCNCC=2C=1.C1C2C(=CC=CC=2)C=CC=1C(Cl)=O>C(O)C>[NH:37]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1)[NH2:38]
Reactant: Clc1cc2c(nn1)CCNC2
Reactant: O=C(c1ccc2ccccc2c1)N1CCc2nnc(Cl)cc2C1
Agent: O=C(Cl)c1ccc2ccccc2c1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccc3ccccc3c1)C2

Procedure:
The 3-chloro-6-(2-naphthoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, is produced in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 2-naphthoyl chloride. Reaction time 22 hours at room temperature. M.P. 167°-170°(decomp., from 95% ethanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[NH:4][C@H:5]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[C:18]3[C:23]([CH:24]=[CH:25][C:15]=2[N:14]=1)=[CH:22][C:21]1[C:26]2[C:31]([CH2:32][O:33][C:20]=1[CH:19]=3)=[CH:30][C:29]([C:34]1[NH:38][C:37]([C@@H:39]3[CH2:43][C@H:42]([CH2:44][O:45][CH3:46])[CH2:41][NH:40]3)=[N:36][CH:35]=1)=[CH:28][CH:27]=2)=[O:7].[CH3:54][O:55][C@H:56]([CH3:66])[C@H:57]([NH:61][C:62]([O:64][CH3:65])=[O:63])[C:58](O)=[O:59].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:53])[NH:4][C@H:5]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[C:18]3[C:23]([CH:24]=[CH:25][C:15]=2[N:14]=1)=[CH:22][C:21]1[C:26]2[C:31]([CH2:32][O:33][C:20]=1[CH:19]=3)=[CH:30][C:29]([C:34]1[NH:38][C:37]([C@@H:39]3[CH2:43][C@H:42]([CH2:44][O:45][CH3:46])[CH2:41][N:40]3[C:58](=[O:59])[C@H:57]([C@@H:56]([CH3:66])[O:55][CH3:54])[NH:61][C:62]([O:64][CH3:65])=[O:63])=[N:36][CH:35]=1)=[CH:28][CH:27]=2)=[O:7]
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl{(1R)-2-[(2S)-2-(9-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (51 mg, 0.072 mmol), (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (14 mg, 0.072 mmol), HATU (30 mg, 0.079 mmol) and 0.4 mL 10% DIPEA in DMF was stirred at room temperature for 1 hour. The product was purified by reverse phase HPLC. The product was converted to the free base by dissolution in 2 mL 1:1 acetonitrile:methanol and passage through a prepacked cartridge of polymer supported carbonate. The eluent was concentrated, the taken up in 1% TFA in 1:1 acetonitrile:water, frozen, and lyophilized to give the product as a trifluoroacetate salt. (24 mg)
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]#[N:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:11]([C:15]1[CH:16]=[C:17]([OH:25])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:21]([C:19]1[CH:18]=[C:17]([CH:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:20]=1)[O:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]#[N:10])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Reactant: N#Cc1ccccc1CBr
Product: CC(C)(C)c1cc(OCc2ccccc2C#N)cc(C(C)(C)C)c1

Procedure:
Using the method of Example 1, 20.6 g (0.10 mole) of alpha-bromo-o-tolunitrile was reacted with 3,5-di-t-butylphenol to give 9.9 g of white crystalline 2-(3,5-di-t-butylphenoxymethyl)-1-benzenecarbonitrile.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[C:25](Cl)(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1COCC1>[C:25]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(S)-benzyloxazolidin-2-one (56 mmol) (Aldrich, Milwaukee, Wis.) in THF at −78° C. was added 2.5 M n-BuLi in hexane (22.4 mL, 56 mmol) and the reaction stirred at −78° C. for 2 hr. To this was added via cannula a −78° C. solution of hexanoyl chloride (65 mmol) in THF and the mixture stirred at −78° C. for 2 hr, then allowed to warm to room temperature and stirred overnight. The reaction was then quenched with aqueous saturated NH4Cl, extracted with ethyl acetate, dried, and purified by silica gel chromatography (hexanes/ethyl acetate) to afford N-hexanoyl-4-(S)-benzyloxazolidin-2-one J-1.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[C:10](Br)=[CH:9][S:8][CH:7]=1>C(N)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:4][CH2:1][C:2]#[C:3][C:6]1[C:10]([C:3]#[C:2][CH2:1][OH:4])=[CH:9][S:8][CH:7]=1
Reactant: C#CCO
Reactant: Brc1cscc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCN
Product: OCC#Cc1cscc1C#CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Pd(Ph3P)4 (116 mg, 2%), CuI (28 mg, 3%) and propargyl alcohol (0.9 ml, 15 mmol) are added successively to a solution of 3,4-dibromothiophene (1.18 g, 5.0 mmol) in n-propylamine (15 ml), and the reaction mixture is stirred at RT for 1 h and then under reflux for 7 h. More Pd(Ph3P)4 (58 mg, 1%), CuI (14 mg, 1.5%) and propargyl alcohol (0.45 ml, 7.5 mmol) are then added and the mixture is stirred under reflux for another 8 h. After cooling, the reaction mixture is filtered off through kieselguhr and washed with ethyl acetate (20 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [Tol/Ac (8:2)] over a silica gel column. This gives the title compound (0.84 g) as a colorless solid. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.22.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([CH3:19])=[C:12]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[S:13][C:7]=2[N:6]=[CH:5]1.S(Cl)([Cl:22])=O>ClCCCl>[Cl:22][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([CH3:19])=[C:12]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[S:13][C:7]=2[N:6]=[CH:5]1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)N(C)C)sc2ncn(CCO)c(=O)c12
Solvent: ClCCCl
Product: Cc1c(C(=O)N(C)C)sc2ncn(CCCl)c(=O)c12
Reaction time: 1 h
Yield: 138.8 %

Procedure:
29.9 g (106 mmol) of 3-(2-hydroxyethyl)-5-methyl-6-dimethylcarbamoylthieno[2,3-d]pyrimidin-4-one in 200 ml of 1,2-dichloroethane were heated to reflux (slow dissolution), after which 12.7 ml (175 mmol) of thionyl chloride in 20 ml of 1,2-dichloroethane were added dropwise. After 1 h of reflux boiling, the reaction mixture was evaporated after it had been cooled down. The crude product was partitioned between methylene chloride and water at pH=9. After the organic phase had been dried and evaporated, 44.1 g (83%) of product were isolated as a dark oil, which was purified by column chromatography (silica gel, eluent ethyl acetate). 23.8 g (76%) of product, having a m.p. of 120-122° C., were isolated.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([C:16]2[S:48][C:19]3[N:20]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]5[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=5)=[CH:36][CH:35]=4)[C:21](=[O:32])[N:22]([CH2:25][CH:26]([OH:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:23](=[O:24])[C:18]=3[CH:17]=2)[CH2:15][CH2:14]1>O.C(OCC)(=O)C>[CH:13]1([C:16]2[S:48][C:19]3[N:20]([CH2:33][C:34]4[CH:35]=[CH:36][C:37]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[C:46]5[NH:3][C:4](=[O:7])[O:5][N:47]=5)=[CH:38][CH:39]=4)[C:21](=[O:32])[N:22]([CH2:25][CH:26]([OH:31])[C:27]([CH3:28])([CH3:30])[CH3:29])[C:23](=[O:24])[C:18]=3[CH:17]=2)[CH2:15][CH2:14]1
Reactant: O=C([O-])O
Reactant: CC(C)(C)C(O)Cn1c(=O)c2cc(C3CC3)sc2n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(O)Cn1c(=O)c2cc(C3CC3)sc2n(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.51 g), sodium hydrogencarbonate (0.76 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C. for 30 min, 4′-{[6-cyclopropyl-3-(2-hydroxy-3,3-dimethylbutyl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.46 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.18 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 ml) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.29 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[N:11]([CH3:27])[C:10]2=[O:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:29][CH2:30][O:31][C:32]([CH2:34]Br)=[O:33].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:30]([O:31][C:32](=[O:33])[CH2:34][N:16]1[CH2:17][C@@H:18]([C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[C@:12]2([N:11]([CH3:27])[C:10](=[O:28])[N:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:13]2=[O:14])[CH2:15]1)[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1C[C@@H](c2ccc(C#N)cc2)[C@]2(C1)C(=O)N(c1cc(Cl)cc(Cl)c1)C(=O)N2C
Temperature: 25 °C
Yield: 39.2 %

Procedure:
A mixture of Example 15 (100 mg, 0.24 mmol), ethyl bromo acetate (29 μl, 0.26 mmol) and K2CO3 (36.6 mg, 0.26 mmol) in toluene (2 ml) was heated to 100° C. for 5 h. After cooling to room temperature, the precipitate (unreacted starting material) was removed by filtration. The filtrate was concentrated and purified by chromatography over silica gel (eluent: DCM then acetone) to yield the above-titled compound as an oil (47.2 mg). 1H NMR (CDCl3): 7.63 (2H, d, J=8.3 Hz), 7.25-7.30 (3H, m), 6.68 (2H, d, J=1.5Hz), 4.23 (2H, q, J=7.1 Hz), 3.89 (1H, dd, J1=11.7 Hz, J2=6.3 Hz), 3.55-3.65 (2H, m), 3.3-3.5 (3H, m), 3.26 (3H, s), 3.05 (1H, d, J=10.8 Hz), 1.31 (3H, t, J=7.1 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[CH2:15]([Br:24])[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>C(O)(C)C>[BrH:24].[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:7]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: OCCCNc1nc2ccccc2[nH]1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC(C)O
Product: Br
Product: O=C(Cn1c(NCCCO)nc2ccccc21)c1ccccc1

Procedure:
Heat at reflux for 5 to 6 hours a mixture of 1.91 g (10 mmol) of the compound obtained in Step A and 1.99 g (10 mmol) of phenacyl bromide in 20 ml of isopropanol. Cool. Collect the title compound precipitate by filtration and wash with acetone. Recrystallise from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([CH2:14]Br)[O:10][C:9]=2[C:8]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-:23].[Na+].[Na+]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([CH:14]=[O:23])[O:10][C:9]=2[C:8]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(OC2CCCC2)c2oc(CBr)cc12
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(OC2CCCC2)c2oc(C=O)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34686.7 %

Procedure:
To a well stirred solution of Methyl-7-cyclopentyloxy-2-bromomethylbenzo[b]furan-4-carboxylate (50.0 g, 0.140 moles) in dimethyl sulfoxide (250.0 mL) was added powdered sodium carbonate (22.0 g, 0.21 mmoles) at 105-110° C. and stirred for 2-3 hours. Reaction mixture was cooled to room temperature and diluted with water (2.0 L) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with water (2×500 mL) and dried over anhydrous sodium sulfate. Removal of solvent gave crude product (51 g) as brown viscous oil. Purification by silica gel column using chloroform: ethyl acetate (95:5) as an eluent afforded 21 g of pure product.
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13](I)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][O:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:28]4[CH:27]=[CH:26][C:25]([CH2:24][N:21]5[CH2:20][CH2:19][CH:18]([O:17][CH3:16])[CH2:23][CH2:22]5)=[CH:30][CH:29]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Reactant: COC1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC1CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Temperature: 85 °C
Yield: 28.1 %

Procedure:
A degassed mixture of 6-bromo-3-iodo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (0.50 g, 1.3 mmol), 4-methoxy-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine (0.80 g, 2.4 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.16 g, 0.2 mmol) in 2-methyl THF (20 mL) and saturated aqueous sodium carbonate (10 mL) was heated at 85° C. for 3 h. The material was partitioned between DCM, water and methanol and the phases were separated. The organic phase was separated, dried over sodium sulfate, filtered and evaporated to afford a residue which was purified by flash chromatography (silica, 50 g column, Biotage, 0-10% methanol in DCM). The resultant material was triturated with methanol to afford the title compound as a tan solid (0.165 g, 28%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.84 (d, J=2.2 Hz, 1H), 8.73 (d, J=2.2 Hz, 1H), 8.69 (d, J=0.9 Hz, 1H), 8.30 (d, J=1.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 3.63 (s, H), 2.89-2.76 (m, 2H), 2.37-2.22 (m, 2H), 2.02-1.89 (m, 2H), 1.73-1.56 (m, 2H). LCMS (Method G): RT=3.30 min, M+H+=451.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9]COC)=[CH:7][C:6]([O:13]COC)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]=1[CH2:23][CH2:24][C:25]1[O:29][CH:28]=[N:27][C:26]=1[CH2:30][OH:31])[CH3:2].O1CCOCC1.Cl.[OH-].[Na+]>CO>[CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:13])=[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:4]=1[CH2:23][CH2:24][C:25]1[O:29][CH:28]=[N:27][C:26]=1[CH2:30][OH:31])[CH3:2]
Reactant: CCc1c(OCOC)cc(OCOC)c(-c2ccccc2)c1CCc1ocnc1CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCc1c(O)cc(O)c(-c2ccccc2)c1CCc1ocnc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
(5-{2-[2-Ethyl-3,5-bis(methoxymethoxy)-6-phenylphenyl]ethyl}-1,3-oxazol-4-yl)methanol (200 mg) was dissolved in methanol (5.0 mL), and 1,4-dioxane solution (1 ml) of 4.0 mol/L hydrochloric acid was added thereto and stirred at room temperature for 3 hours. The reaction liquid was neutralized with aqueous sodium hydroxide solution (1 mol/L), and then extracted with chloroform. The organic layer was washed with aqueous saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through preparative thin-layer column chromatography (chloroform/methanol=9/1) to obtain Compound 210 (53 mg, 39%).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[CH2:5].[F-].[Cs+].[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:34])[CH:23]=[CH:24][CH2:25][C:26]1S[CH:29]=[C:28]2[O:31][CH2:32][O:33][C:27]=12.[CH3:35]S(C)=O>>[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:34])[CH2:23][CH:24]([C:25]1[CH:35]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[CH2:3][C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[O:5]
Reactant: C=C(O[Si](C)(C)C)c1ccsc1
Reactant: O=C(C=CCc1scc2c1OCO2)c1ccccc1O
Reactant: CS(C)=O
Agent: [Cs+]
Agent: [F-]
Product: O=C(CC(CC(=O)c1ccccc1O)c1ccc2c(c1)OCO2)c1ccsc1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(thiophen-3-yl)ethylene (7.0 mmol; prepared according to J. Chem. Soc.,Perkin Trans. I 1989, 1585) and CsF (0.27 g, 1.76 mmol) were added to a suspension 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxythenyl)-2-propen-1-one on Wang resin (2.0 g, 1.76 mmol), in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-5-(thiophen-3-yl)-1,5-pentanedione on Wang resin.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][C@@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C@@H:17]2[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.IC.[CH2:37](OCC)C>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][C@@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C@@H:17]2[N:25]([CH3:37])[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1Cc2ccccc2[C@H]1Oc1ccc(OCc2ccccc2)cc1

Procedure:
The title compound was prepared in a similar manner to Preparation 19 from sodium hydride (80% disp. in oil, 83 mg, 2.76 mmol) in dry N,N-dimethylformamide (5 ml), (±)cis-1-(4-benzyloxy phenoxy)-2-tert-butoxycarbonylaminoindane (1 g, 2.3 mmol) in N,N-dimethylformamide (5 ml) and iodomethane (175 μl, 2.76 mmol). Column chromatography on silica gel eluting with a gradient of 10-15% diethyl ether in hexanes afforded the title compound (968 mg) as a colourless oil.