Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[CH3:13].[H-].[Na+].I[CH3:17].N>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([N:7]([CH3:17])[C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[CH3:13]
Reactant: CI
Reactant: COc1ccc(NC(C)=O)cc1C
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(N(C)C(C)=O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4'-methoxy-3'-methylacetanilide (71g) in dry tetrahydrofuran (350 ml) was added over 45 minutes to a stirred suspension of sodium hydride (19 g of a 50% dispersion in mineral oil) in dry tetrahydrofuran (250 ml) under nitrogen. The stirred mixture was heated under reflux for 10 minutes, then cooled to 0 to 5° and iodomethane (25 ml) added dropwise over 10 minutes. After the mixture was stirred and heated under reflux for a further 2 hours, the mixture was cooled to ambient temperature and industrial methylated spirit (50 ml) followed by aqueous ammonia (specific gravity 0.88, 50 ml) were added. After 30 minutes, solvent was removed by evaporation, water (500 ml) added to the residue and the mixture extracted with ethyl acetate (3×300 ml). The combined extracts were washed with aqueous sodium metabisulphite (10% w/w, 2×300 ml), dried over magnesium sulphate, and the solvent removed by evaporation. The residue was triturated with petroleum ether (b.p. 40°-60° ) and the solid collected by filtration to give the novel compound 4'-methoxy-3'-methyl-N-methylacetanilide, m.p. 65°-66°.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:15]CCC.IC>C1COCC1>[CH3:15][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: CI
Solvent: C1CCOC1
Product: CC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 92.5 %

Procedure:
To a solution of fluorene (10.0 g, 60.0 mmol) in 100 mL of THF was added n-BuLi (66.6 mmol) at -78° C. This solution was then added to a chilled solution of iodomethane (15.04 g, 90.6 mmol) in 60 mL of THF. The temperature was kept at about -20° C. to maintain a clear solution. The mixture was allowed to warm to room temperature and then quenched with saturated aqueous NH4Cl and evaporated to a residue which was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with MgSO4, filtered and evaporated to a solid. This solid was dissolved with hot pentane, stirred with decolorizing charcoal, filtered through a celite pad, and evaporated to get 10.0 g(92%) of 9-methyl fluorene was a white solid, mp 42°-43° C. FT-IR (KBr): 3065, 3039, 3016, 2962, 2926, 2864, 1478, 1445, 1309, 1023, 792 cm-1. NMR (300 MHz, CHCl3) δ 1.60-1.62(d, 3H, J=7.5 Hz), 3.93-3.97 (q, 1H, J=7.5 Hz), 7.32-7.38 (m, 4H) , 7.35-7.36 (d, 2H, J=8.0 Hz), 7.81-7.83(d, 2H, J=8.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][N+:6]([O-:8])=[O:7].[CH3:13][N:14]([CH3:18])[C:15](=[S:17])[S-:16].C[NH2+]C>C(=S)=S>[CH3:13][N:14]([CH3:18])[C:15](=[S:16])[S:17][CH:4]([CH2:5][N+:6]([O-:8])=[O:7])[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: CN(C)C(=S)[S-]
Reactant: O=[N+]([O-])C=Cc1ccccc1Cl
Agent: C[NH2+]C
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccccc1Cl

Procedure:
As in Example 17, reaction of o-chloro-β-nitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave o-chloro-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 102° C.-103.5° C. when recrystallized without heating from acetone-methanol solution.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[N:11]=[CH:10][C:9](B(O)O)=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[CH:7]=1)[CH3:2].[CH2:25]([N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34](I)[CH:35]=2)[C:30](=[O:38])[C:29]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:28]1)[CH3:26].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.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>[CH2:25]([N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:9]3[CH:10]=[N:11][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:24])=[CH:7][C:8]=3[C:15]3[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH:35]=2)[C:30](=[O:38])[C:29]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:28]1)[CH3:26]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Reactant: CCOC(=O)c1cn(CC)c2cc(I)ccc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(=O)c(C(=O)OCC)cn(CC)c3c2)cn1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 46.5 %

Procedure:
To a slurry of 6-(3-ethylureido)-4-(4-trifluoromethylthiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 17, 330 mg, 0.91 mmol), ethyl 1-ethyl7-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 9, 281 mg, 0.75 mmol) and trans-dichlorobis(triphenylphosphine)palladium (II) (53 mg, 0.075 mmol) in 1,4-dioxane (8 ml) was added a solution of potassium carbonate (210 mg, 1.52 mmol) in water (3 ml). The reaction was stirred for 1.5 hours at 70° C. The reaction was cooled to room temperature, and ethyl acetate (8 mL) was added to help separate the layers. The water was removed, and the organic phase was washed with water (3 mL). The reaction was then concentrated and ethanol (5 mL) was added. The suspension was filtered, and the solid washed with methyl tert-butyl ether (2×, 5 ml). The solid was dried in a vacuum oven at 50° C. for 4 hours to give 195 mg (60%) of ethyl 1-ethyl7-(6-(3-ethylureido)-4-(4-trifluoromethylthiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1.[Cl:41][C:42]1[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44][N:45]([CH2:48][C:49](O)=[O:50])[C:46]=1[CH3:47]>>[CH3:25][O:26][C:27](=[O:40])[C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][N:37]([C:49](=[O:50])[CH2:48][N:45]3[C:46]([CH3:47])=[C:42]([Cl:41])[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44]3)[CH2:36][CH2:35]2)=[CH:32][CH:33]=1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COC(=O)c1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1ccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)cc1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 4-Piperazin-1-yl-benzoic acid methyl ester and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.78 (d, 2H), 6.98 (d, 2H), 5.38 (s, 2H), 3.71 (s, 3H), 3.60 (m, 4H), 3.46 (m, 2H), 3.37 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) expect M+H=445.1, found 445.0.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[BH4-]>C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([Br:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1cc(Cl)c(Br)cc1C(=O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: Nc1cc(Cl)c(Br)cc1CO
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 2-amino-5-bromo-4-chlorobenzoic acid (9.0 g, 36.0 mmol) in THF (150 mL) was added borohydride in THF (144 mL, 1 M) at room temperature, and the reaction mixture was stirred overnight. The reaction mixture was quenched with methanol (50 mL), and concentrated to a volume of 50 mL. The residue was diluted with water (100 mL) and extracted with ethyl acetate (150 mL×3). The organic layers were separated, combined, washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (crude, 6 g, 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[CH:5]=[N:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.CS(O[CH2:35][CH2:36][CH:37]1[CH2:39][C:38]1([F:41])[F:40])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:40][C:38]1([F:41])[CH2:39][CH:37]1[CH2:36][CH2:35][O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:7]3[N:6]=[CH:5][C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])=[CH:3][C:2]=3[F:1])[O:9][C:10]=2[CH:16]=1
Reactant: CS(=O)(=O)OCCC1CC1(F)F
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(O)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1cnc(-c2nc3ccc(OCCC4CC4(F)F)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Triethylamine (14.1 mL) was added to a solution of hexachloroethane (7.46 g) and triphenylphosphine (9.91 g) in acetonitrile (50 mL) at room temperature, and the mixture was stirred at room temperature for 10 min. Then a mixture of tert-butyl [(1S)-2-({6-[(2,4-dihydroxyphenyl)carbamoyl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate (5.31 g) and acetonitrile (50 mL) was added, and the mixture was stirred at room temperature for 2 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (10.7 g) as a mixture with impurities. A mixture of tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (4.28 g, a mixture with impurities), 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (0.531 g), potassium carbonate (0.367 g), and DMF (30 mL) was stirred at 60° C. for 1 hr. Then additional 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (0.531 g) and potassium carbonate (0.367 g) were added, and the mixture was stirred at 60° C. for 1 hr. Then additional 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (1.06 g) and potassium carbonate (0.733 g) were added, and the mixture was stirred at 60° C. for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.83 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:35]#[N:36])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:35]#[N:36])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
42 mg (0.08 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) (Example 21.1E) were hydrolysed with TFA according to General Method 2. Yield: 24 mg (64% of theory)
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[S:10][N:9]=[C:8]([CH3:11])[CH:7]=1>O1CCCC1>[CH3:11][C:8]1[CH:7]=[C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])[S:10][N:9]=1
Reactant: Cc1cc(N)sn1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1cc(C)ns1
Yield: 54.5 %

Procedure:
Methylisocyanate (1.96 milliliters, 0.04 mole) was added dropwise to a thirty (30) milliliter solution of the distilled tetrahydrofuran containing the above mentioned 5-amino-3-methylisothiazole (5.0 grams, 0.04 mole), and then the resulting yellow solution was refluxed for 3 hours, during which time a white precipitate formed. The solution was cooled and filtered, giving 3.73 grams of N-(3-methyl-5-isothiazolyl)-N'-methylurea, also referred to as 3-methyl-5-N-methylureiodisothiazole.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C@H:10]2[C@@H:14]3[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@@H:13]3[C@H:12]([CH2:20][N:21]([CH3:36])[CH2:22][CH2:23][CH2:24][N:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])[CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[CH:37]([O-])([O-])OCC>C(O)(=O)C>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]2[C:2]=1[N:1]=[CH:37][N:9]2[C@H:10]1[C@@H:14]2[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@@H:13]2[C@H:12]([CH2:20][N:21]([CH3:36])[CH2:22][CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]2=[O:34])[CH2:11]1
Reactant: CCOC([O-])[O-]
Reactant: CN(CCCN1C(=O)c2ccccc2C1=O)C[C@@H]1C[C@@H](Nc2ncnc(Cl)c2N)[C@@H]2OC(C)(C)O[C@H]12
Solvent: CC(=O)O
Product: CN(CCCN1C(=O)c2ccccc2C1=O)C[C@@H]1C[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Temperature: 130 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A solution of 2-(3-((((3aR,4S,6R,6aS)-6-((5-amino-6-chloropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)propyl)isoindoline-1,3-dione (180 mg, 0.35 mmol) in ethyl orthoformate (5.8 mL, 35 mmol) was treated with acetic acid (4 drops) and heated at 130° C. for 7 hours. The reaction was cooled to room temperature and stirring was continued overnight. The reaction was concentrated and purified by flash chromatography (7N NH3 in MeOH/DMC 4:96) to yield 2-(3-((((3aR,4S,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)propyl)isoindoline-1,3-dione (165 mg, 90%) as a thick light brown syrup. MS (ESI+) for C26H29ClN6O4 m/z 525.4 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)=[O:8])[CH3:2].[NH:18]([C:25]1[C:30]([Br:31])=[CH:29][N:28]=[C:27](Cl)[N:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH:18]([C:25]1[C:30]([Br:31])=[CH:29][N:28]=[C:27]([NH:13][C:12]2[CH:11]=[CH:10][C:9]([C:7](=[O:8])[NH:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:16][CH3:17])=[CH:15][CH:14]=2)[N:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCN(CC)CCNC(=O)c1ccc(N)cc1
Reactant: Clc1ncc(Br)c(Nc2ccccc2)n1
Product: CCN(CC)CCNC(=O)c1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1

Procedure:
Using an analogous method to that described in Example 103, but starting from 4-{N-[2-(diethylamino)ethyl]carbamoyl}aniline and 4-anilino-5-bromo-2-chloropyrimidine (Method 15), the product was obtained. NMR: 1.0 (t, 6H), 2.4 (m, 4H), 3.3 (m, 4H) 7.2 (t, 1H), 7.4 (t, 2H), 7.6 (t, 6H), 8.1 (bs, 1H), 8.2 (s, 1H), 8.7 (s, 1H), 9.6 (s, 1H); MS (MH+): 483, 485.
Reaction SMILES: [Cl:1][C:2]1[C:12](I)=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[CH:18]([Sn](CCCC)(CCCC)CCCC)=[CH2:19]>C1(C)C=CC=CC=1.CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[Cl:1][C:2]1[C:12]([CH:18]=[CH2:19])=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(I)c1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=Cc1ccc([Si](C)(C)C)c(C(=O)NCC)c1Cl
Reaction time: 24 h
Yield: 21.3 %

Procedure:
To a solution of the compound of Example 239 (0.382 g, 1.0 mmol), tetrakis(triphenylphosphine)-palladium(0) (23 mg, 0.02 mmol) and 2.6-di-t-butyl-4-methylphenol (1.5 mg) in toluene (10 mL) was added vinyltributyltin (0.349 g, 1.1 mmol). The light yellow solution was heated at reflux for 24 h, additional tetrakis(triphenylphosphine)palladium(0) (15 mg) was added, and reflux was continued for 24 h. The cool mixture was diluted with ether, filtered through Celite, concentrated and purified by RC (ethyl acetate/hexanes). The product was further purified by recrystallization from pentane to afford the title compound as white needles (0.060 g, 21%). m.p. 127-128° C.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([C:7]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)([CH2:11][CH:12]=[CH2:13])[C:8](O)=[O:9])=[CH:3][CH:2]=1.S(Cl)(Cl)=O>CN(C)C=O.C(Cl)Cl>[C:17]1([CH3:20])[CH:18]=[CH:19][C:14]([C:7]2([C:4]3[CH:5]=[CH:6][C:1]([CH3:21])=[CH:2][CH:3]=3)[C:8](=[O:9])[CH:13]=[CH:12][CH2:11]2)=[CH:15][CH:16]=1
Reactant: C=CCC(C(=O)O)(c1ccc(C)cc1)c1ccc(C)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C2(c3ccc(C)cc3)CC=CC2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.1 %

Procedure:
To a solution of 2,2-bis(p-tolyl)-4-pentenoic acid (8.17 g) in N,N-dimethylformamide (1.0 ml) and methylene chloride (45 ml) was added thionyl chloride (3.2 ml), and the solution was stirred at room temperature for 1 day. The solution was evaporated in vacuo and the residue was dissolved in methylene chloride (50 ml). The solution was added dropwise to a suspension of aluminum chloride (4.66 g) in methylene chloride (50 ml) with dry ice-acetone bath cooling under nitrogen atmosphere, and the resulting mixture was stirred at room temperature overnight. The mixture was poured into cooled 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, water, 1N sodium hydroxide, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate (10:1~5:1) as an eluent to give 5,5-bis(p-tolyl)-2-cyclopenten-1-one (2.30 g).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=O)[C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[CH:8][O:9][C:4]=2[C:3]=1[CH3:20].C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.C(O)C.[Pd]>[OH:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[C:3]=1[CH3:20]
Reactant: Cc1ccc(-c2coc3c(C)c(O)ccc3c2=O)cc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc(C2COc3c(ccc(O)c3C)C2)cc1

Procedure:
7-Hydroxy-8-methyl-3-(4-methylphenyl)-4H-1-benzopyran-4-one (400 mg) in a mixture of dioxane and ethanol 1:1 (200 ml) is hydrogenated for 64 h at room temperature over palladium 10% on active charcoal (100 mg) in the presence of p-toluenesulfonic acid monohydrate (120 mg). After filtration of the catalyst, the filtrate is evaporated under reduced pressure to a volume of about 50 ml. Water (150 ml) is added and the solution is extracted with dichloromethane (3×100 ml). The combined organic solutions are washed with water, dried and evaporated. The product is dried in vacuo to constant weight to yield 3,4-dihydro-7-hydroxy-8-methyl-3-(4-methylphenyl)-2H-1-benzopyran, m.p. 136°-137°.
Reaction SMILES: [Zn](CC)[CH2:2]C.C(O)(C(F)(F)F)=O.ICI.[CH3:16][O:17][C:18](=[O:32])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([CH2:29][CH:30]=[CH2:31])[CH:20]=1>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:32])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([CH2:29][CH:30]2[CH2:2][CH2:31]2)[CH:20]=1
Reactant: C=CCc1cc(C(=O)OC)cc(OC)c1OC
Reactant: CC[Zn]CC
Solvent: ClCCl
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(CC2CC2)c(OC)c(OC)c1
Temperature: 23 °C
Reaction time: 0.33 h
Yield: 76.7 %

Procedure:
To stirred dichloromethane (10 mL) at 0° C. was added Et2Zn (1.0 M in hexane, 10.0 mL, 10 mmol, 2 eq.). The resulting solution was then treated with a solution of TFA (0.77 mL, 10 mmol) in CH2Cl2 (5.0 mL) added over the course of 3 min. After stirring for 20 min at 0° C. diiodomethane (0.80 mL, 10.0 mmol) in CH2Cl2 was added. After 20 min at 0° C., a solution of 3-allyl-4,5-dimethoxybenzoic acid methyl ester (Example 30, Step 1, 1.18 g, 5.0 mmol) in CH2Cl2 (5.0 mL) was added and the reaction was warmed to 23° C. After 50 min the reaction was quenched by addition of 0.1 N HCl (25 mL) and then diluted with hexanes (100 mL). The organic layer was separated, washed with saturated NaHCO3 (100 mL), H2O (100 mL), brine (100 mL) dried MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using 20% EtOAc in hexanes as an eluent to furnish 3-cyclopropylmethyl-4,5-dimethoxybenzoic acid methyl ester (0.96 g, 80% yield).
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:34])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[N:14][CH:15]=1.B(Br)(Br)Br.[Cl-].[NH4+]>C(Cl)Cl>[CH3:33][C@@H:30]1[O:29][C:28]([C:25]2[NH:24][C:23]([C:21]3[CH:22]=[C:6]([CH:7]=[C:8]([O:9][C:10]4[CH:15]=[N:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=4)[CH:20]=3)[O:5][C@@H:4]([CH3:34])[CH2:3][OH:2])=[CH:27][CH:26]=2)=[N:32][CH2:31]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C[C@H]1CN=C(c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(O[C@@H](C)CO)c3)[nH]2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulfonyl)pyridine (310 mg, 0.638 mmol) synthesized in Example (76c) was dissolved in methylene chloride (7.0 mL), and boron tribromide (1.0 mol/L dichloromethane solution, 1.00 mL, 1.0 mmol) was added dropwise at −78° C., followed by stirring at room temperature for 1 hour under nitrogen atmosphere. To this reaction solution, a saturated aqueous ammonium chloride solution (20 mL) was added, and extraction was carried out with methylene chloride (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=1%-3%) to afford the desired compound (245 mg, yield 81%) as a white solid.