Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[S:16][C:17]=2[CH3:18])=[CH:6][CH:5]=1.[NH2:30][NH2:31]>CO.O>[CH3:18][C:17]1[S:16][C:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[N:14][C:13]=1[CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:30][NH2:31])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)sc2C)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1ccc(C(=O)NN)cc1
Temperature: 60 °C
Reaction time: 66 h
Yield: 66.2 %

Procedure:
To a suspension of 4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylethoxy]-benzoic acid methyl ester (Example 4, 410 mg, 1 mmol) in methanol (3 mL) add anhydrous hydrazine (0.32 ml, 10 mmol). Warm the resulting mixture to 60° C. and stir at this temperature for 66 hrs. Cool the resulting solution to room temperature, and add 3 drops of water. Filter the precipitate wash with ether to give the title compound (279 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:24][C:25]([C:27]1([CH2:42]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31][CH2:30][N:29]([C:32](=[O:41])[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[CH2:28]1)=[O:26])[CH3:23]>CS(C)=O>[CH2:22]([O:24][C:25]([C:27]1([CH2:42][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:31][CH2:30][N:29]([C:32](=[O:41])[C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[CH2:28]1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C1(COS(=O)(=O)c2ccc(C)cc2)CCN(C(=O)c2ccc(OC)cc2)C1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cc3)cc2)CCN(C(=O)c2ccc(OC)cc2)C1
Temperature: 80 °C
Yield: 93.6 %

Procedure:
4′-hydroxy-4-biphenyl carbonitrile (107.0 g, 549 mmol) and potassium carbonate (94.9 g, 687 mmol) were added to a stirred solution of 1-(4-methoxy-benzoyl)-3-(toluene-4-sulfonyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (211.3 g, 457.8 mmol) (see Preparation 11) in dimethylsulphoxide (422 mL). The reaction mixture was heated at 80° C. for 18 hours then partitioned between ethyl acetate (2000 mL) and water (2000 mL). The organic layer was washed with water (2000 mL) then separated and concentrated under reduced pressure to afford the title compound as an orange oil (207.7 g, 93%). (>99.5% e.e.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[O:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:25]3[C:26]([NH2:30])=[N:27][CH:28]=[CH:29][C:24]=3[NH:23][CH:22]=2)=[CH:17][CH:16]=1.[ClH:31].O1CCOCC1>C(Cl)Cl.CC#N>[ClH:31].[NH2:30][C:26]1[C:25]2[C:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[O:13])=[CH:16][CH:17]=3)=[CH:22][NH:23][C:24]=2[CH:29]=[CH:28][N:27]=1
Reactant: Nc1ccc(-c2c[nH]c3ccnc(N)c23)cc1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1nccc2[nH]cc(-c3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3)c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
2-(4-Fluorophenyl)acetyl isocyanate (Compound C of Example 3, 0.29 M, 0.062 mL, 0.018 mmol, 2.0 eq) was added to a solution of 3-(4-aminophenyl)-1H-pyrrolo[3,2-c]pyridin-4-amine (0.002 g, 0.009 mmol, 1.0 eq) in 1/1 DCM/CH3CN (1 mL) and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (SiO2, eluting 0-5% MeOH in CHCl3). The appropriate fractions were isolated and concentrated in vacuo. The residue was dissolved in THF (1 mL), cooled to 0° C. and treated with anhydrous 4 N HCl in dioxane (1 mL, 4.0 mmol, 168 eq). The reaction mixture was stirred at 0° C. for 1 h and the resulting heterogeneous solution was concentrated in vacuo. The residue was triturated with Et2O, discarding the filtrate and the solid dried in vacuo to afford the title compound (0.002 g, 50%) as a pale yellow solid. MS(ESI+) m/z 404 (M+H)+.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][NH2:11].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27]([NH:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([C:3]3[O:2][CH:6]=[CH:5][CH:4]=3)[CH:8]=2)=[O:28])=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: NCc1cccc(-c2ccco2)c1
Agent: Cl
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)NCc1cccc(-c2ccco2)c1

Procedure:
Using the same method as in Example 1 (ii), 3-(furan-2-yl)benzylamine hydrochloride was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(furan-2-yl)benzyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 84%). Note that 3-(furan-2-yl)benzylamine.hydrochloride was neutralized in DMA by adding an equivalent amount of triethylamine, and then used in the reaction.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:12](S(C3C=NC=CC=3)(=O)=O)[CH:11]=[C:10]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
tert-Butyl {[5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (4.78 g) was dissolved in tetrahydrofuran (20 mL) and methanol (10 mL), 8 mol/L aqueous sodium hydroxide solution (4 mL) was added under ice-cooling. After stirring at room temperature for 4 hr, about half of the solvent was evaporated under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→ethyl acetate) to give the title compound as a pale-yellow oil (yield 2.84 g, 87%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[O:27][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:24]=3)[CH:18]=2)[C:13]([F:34])=[CH:12][N:11]=1>>[F:34][C:13]1[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[O:27][C:26]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:25][N:24]=3)[CH:18]=2)=[N:15][C:10]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=2)=[N:11][CH:12]=1
Reactant: Fc1cnc(Cl)nc1Nc1cccc(-c2nnc(-c3ccccc3)o2)c1
Reactant: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(F)c(Nc3cccc(-c4nnc(-c5ccccc5)o4)c3)n2)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-5-fluoro-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-4-pyrimidineamine gave 5-fluoro-N2-(3-hydroxyphenyl)-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.72 (bs, 1H), 7.96 (bd, 3H), 7.85 (m, 2H), 7.56 (m, 4H), 7.14 (d, 1H, J=2.1 Hz), 6.91 (m, 2H), 6.28 (dd, 1H, J=1.8 and 6.9 Hz); LCMS: purity: 80%; MS (m/e): 441 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][C@H:8]1[C:13]([O:15]CC)=[O:14])=[O:6])[CH:2]=[CH2:3].Cl>C(O)C.[OH-].[Na+]>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][C@H:8]1[C:13]([OH:15])=[O:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCOC[C@H]1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCOC(=O)N1CCOC[C@H]1C(=O)O
Reaction time: 1 h
Yield: 100.4 %

Procedure:
A solution of ethyl (3S)-4-allyloxycarbonylmorpholine-3-carboxylate (5.90 g) in a mixture of ethanol (15 ml) and 4N aqueous sodium hydroxide (15 ml) was stirred at 30°-40° C. for one hour. Ethanol was evaporated to give an aqueous solution. The aqueous solution was adjusted to pH 2 with concentrated hydrochloric acid, extracted with ethyl acetate (100 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give (3S)-4-allyloxycarbonylmorpholine-3-carboxylic acid (5.24 g) as a syrup.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH:15]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16]#[C:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[O:23][CH:24]=1>S(=O)(=O)(O)O.CC(C)=O>[O:14]=[C:15]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16]#[C:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[O:23][CH:24]=1
Reactant: CCCCCCCCCCCC(O)C#CCCc1coc([Si](CC)(CC)CC)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)C#CCCc1coc([Si](CC)(CC)CC)c1
Reaction time: 0.33 h

Procedure:
Jones reagent (a 2.6M solution in sulfuric acid; 0.13 ml, 0.36 mmol) was added dropwise to a solution of 4-(5-hydroxy-3-hexadecynyl)-2-triethylsilylfuran (136.4 mg, 0.33 mmol) in acetone (5 ml) at 0 degrees. After 20 minutes, the excess Jones reagent was destroyed with ethanol (ca 1 ml) and the mixture was diluted with water. The organic phase was separated, dried (magnesium sulfate) and evaporated down to give an oil, which was purified by preparative silica plates to give the titled ketone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([C@H:12]3[CH2:15][CH2:14][C@H:13]3[C:16](O)=[O:17])=O)=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:19].O.[NH2:21][NH2:22]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:12]4[CH:13]([C:16](=[O:17])[NH:21][N:22]=3)[CH2:14][CH2:15]4)=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:19]
Reactant: NN
Reactant: O=C1Cc2cc(C(=O)[C@H]3CC[C@H]3C(=O)O)ccc2N1
Solvent: O
Solvent: CCO
Product: O=C1Cc2cc(C3=NNC(=O)C4CCC34)ccc2N1
Yield: 92.1 %

Procedure:
5.22 g (0.02 mole) of cis-2-(indolin-2-on-5-oyl)cyclobutanecarboxylic acid are refluxed with 1.1 g (0.022 mole) of hydrazine hydrate and 50 ml of ethanol for 11 hours. The solid is filtered off with suction at room temperature and recrystallized from dimethylformamide/water to give 4.7 g (92%) of 2-(indolin-2-on-5-yl)-3,4-diazabicyclo[4.2.0]oct-2-en-5-one of melting point 309°-312° C.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13]([C:15]1[C:39]([OH:40])=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:37]=[CH:36][C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[C:27]([Cl:35])[CH:26]=2)=[CH:21][CH:20]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1(CO)C=CC=CC=1>[Cl:35][C:27]1[CH:26]=[C:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]3[C:15]([C:13]([O:12][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:14])=[C:39]([OH:40])[C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][CH:36]=3)=[CH:24][CH:23]=2)[CH:30]=[CH:29][C:28]=1[CH2:31][C:32]([O:34][CH3:1])=[O:33]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)c(Cl)c3)cc2)ccc(C(F)(F)F)c1O
Solvent: OCc1ccccc1
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)cc1Cl
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A trimethylsilyldiazomethane-0.6M hexane solution (0.20 ml, 0.12 mmol) was added to a solution of (4′-{[2-(tert-butoxycarbonyl)-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-3-chloro-1,1′-biphenyl-4-yl)acetic acid (60 mg, 0.11 mmol) obtained in Example (18-4) in a mixture of benzene-methanol (4:1, 2.5 ml), and the mixture was stirred for 1 hour. The residue obtained by removing the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: hexane/methylene chloride/ethyl acetate=9/1/1) to give the title compound (45 mg, yield: 73%).
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8](/[CH:9]=[C:10]2/[C:11](=[O:16])[NH:12][C:13](=[O:15])[S:14]/2)=[CH:7][CH:6]=1.N1C=CC=CC=1C1C=CC=CN=1.[BH4-].[Na+].[BH4-]>C1COCC1.[Co](Cl)Cl.CC(O)=O.O>[OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1
Reactant: COc1ccccc1C(O)COc1ccc(/C=C2\SC(=O)NC2=O)cc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 0 °C
Yield: 62.7 %

Procedure:
(5Z)-5-{4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzylidene}-1,3-thiazolidine-2,4-dione (1.00 g, 2.69 mmol) was dissolved in THF (20 ml). Water (20 ml) was added and then sufficient additional THF was added to give a clear solution. A small crystal of cobalt chloride was added followed by 2,2′-bipyridine (95 mg, 0.61 mmol). The reaction mixture was cooled to 0° C. NaBH4 was added in portions until the blue color persisted. The color gradually faded and was regenerated repeatedly by small additions of borohydride and HOAc. When HPLC indicated that the reaction was complete the reaction mixture was partitioned between EtOAc and H2O. HOAc was added until the pH of the aqueous phase was ca. 6, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 20% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 0.63 g (63%) of the title compound as a white solid. MS (ESI−) for C19H19NO5S m/z 372.1 (M−H)−.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:13].[F:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23](O)=[O:24])[CH:18]=[C:19]([F:21])[CH:20]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23]([NH:1][N:2]2[N:11]=[C:10]([CH3:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:13])=[O:24])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Cc1nn(N)c(=O)c2ccccc12
Product: Cc1nn(NC(=O)Cc2cc(F)cc(F)c2)c(=O)c2ccccc12

Procedure:
The product from Example 28A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.58-11.61 (m, 1H), 8.32 (d, J=7.9 Hz, 1H), 8.00-8.02 (m, 2H), 7.90-7.93 (m, 1H), 7.09-7.21 (m, 2H), 7.02-7.05 (m, 1H), 3.74 (s, 2H), 2.55 (s, 3H); MS (ESI) m/z 330 (M+H)+.
Reaction SMILES: C([O:8][C@@H:9]([C:11]1[O:12][C:13]2[C:18]([C:19](=[O:28])[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:10])C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[F:27][C:23]1[CH:22]=[C:21]([C:20]2[C:19](=[O:28])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[C@H:9]([OH:8])[CH3:10])[CH:26]=[CH:25][CH:24]=1
Reactant: C[C@@H](OCc1ccccc1)c1oc2ccccc2c(=O)c1-c1cccc(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@@H](O)c1oc2ccccc2c(=O)c1-c1cccc(F)c1
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To (R)-2-(1-(benzyloxy)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one (5.0 g, 13.35 mmol) in dichloromethane (50 ml) cooled to −78° C., boron tribromide (1M in dichloromethane, 36.5 ml, 0.145 mmol) was added dropwise and stirred for 1 h. The reaction mixture was quenched with 2N HCl solution, extracted with dichloromethane, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford (R)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one as an off-white solid (3.05 g, 80%). 1H-NMR (6 ppm, CDCl3, 400 MHz): 8.24 (dd, J=7.9, 1.5 Hz, 1H), 7.73 (m, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.44 (m, 2H), 7.13-7.01 (m, 3H), 4.71 (q, J=6.6 Hz, 1H), 1.56 (d, J=6.5 Hz, 3H). Mass: 284.9 (M+). Purity: 99.73%. [α]25D −0.605 (c=1, CHCl3). Enantiomeric excess: 95.2%, enriched in the late eluting isomer (retention time: 10.19 min.) as determined by HPLC on a chiralpak AD-H column.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([OH:14])[CH3:13].[OH2:15]>S(=O)(=O)(O)O>[O:14]=[C:12]([CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]#[C:4][CH2:3][C:2]([OH:15])=[O:1]
Reactant: CC(O)CCCCCCC#CCCO
Reactant: O
Agent: O=S(=O)(O)O
Product: CC(=O)CCCCCCC#CCC(=O)O
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a vigorously stirred, ice-cold solution of chromic trioxide (5.4 g, 54 mmol) in 50 mL of 6N sulfuric acid was added dropwise over 3 hr, 1.76 g (8.9 mmol) of 20 in 50 mL of acetone5. The reaction was kept in an ice-bath for 30 min and then warmed to 23° C. before workup. Water (200 mL) was added and the reaction extracted with ether (4×75 mL). The ether extract was washed with brine (3×50 mL). Product isolation yielded crude 11-keto-3-dodecynoic acid (23) which was purified by crystallization from 10% ether in hexane (mp 49°-51° C.) to yield 1.28 g (68% yield).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:34])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)=[O:28])[C:23]([OH:25])=[O:24].[CH2:35]1CCN2C(=NCCC2)CC1.S(OC)(OC)(=O)=O>C(OCC)(=O)C>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:34])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)=[O:28])[C:23]([O:25][CH3:35])=[O:24]
Reactant: C1CCC2=NCCCN2CC1
Reactant: C[C@@H]1CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(OC(=O)c1ccco1)C(=O)O
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@]1(OC(=O)c2ccco2)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Step 1 (6.20 g) is dissolved in ethyl acetate (100 mL). DBU (2.20 g) and dimethyl sulphate (1.83 g) are added sequentially. The reaction mixture is stirred at room temperature for 2 hours, then partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried over magnesium sulphate and evaporated. Crystallisation from methanol affords furan-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected 1H-NMR signals (CDCl3) δ 3.75 (3H, s), 6.30 (1H, dd), 6.45 (1H, d), 6.55 (2H, m), 7.15 (1H, d), 7.60 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].[OH:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].N1C=CC=CC=1>[Cu]Cl.ClCCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:14][N:15]1[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]2[C:19]1=[O:20])=[O:4]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: Cl[Cu]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: COC(=O)c1cccc(ON2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 46 %

Procedure:
3-Methoxycarbonylphenylboronic acid was subjected to similar coupling procedures with NHP as outlined above (method 1). A 100 mL round bottom flask was charged with N-hydroxyphthalimide (2.19 g, 13.4 mmol), copper (I) chloride (1.34 g, 13.5 mmol), freshly activated 4 Å molecular sieves (˜5 g), and 3-methoxycarbonylphenylboronic acid (4.79 g, 26.6 mmol). 1,2-Dichloroethane (60 mL) was added followed by pyridine (1.20 mL, 14.8 mmol), and the reaction suspension was stirred in an air atmosphere at room temperature. After 4 days, the mixture was adsorbed onto silica gel and concentrated to a powder. Flash chromatographic purification over silica (33-50% gradient EtOAc in hexanes) afforded 13 as a white solid (1.85 g, 46%). 1H-NMR (500 MHz, CDCl3) δ 3.90 (s, 3H), 7.38-7.41 (ddd, J=1.0, 2.5, 8.3 Hz, 1H), 7.44 (t, J=8.3 Hz, 1H), 7.78 (dd, J=1.0, 2.5 Hz, 1H), 7.82-7.86 (m, 3H), 7.92-7.96 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 52.5, 115.0, 119.3, 124.3, 125.9, 129.0, 130.0, 132.1, 135.2, 159.0, 163.0, 166.2; ESI-MS 298 m/z [MH]+, C16H12NO5 requires 298.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][NH2:16])[O:14][CH2:13][CH2:12][O:11]2)=[CH:6][CH:5]=1.[N:17]([CH2:20][CH:21]([CH3:23])[CH3:22])=[C:18]=[S:19].C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH2:15][NH:16][C:18]([NH:17][CH2:20][CH:21]([CH3:23])[CH3:22])=[S:19])[O:11][CH2:12][CH2:13][O:14]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C2(CN)OCCO2)cc1
Reactant: CC(C)CN=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccc(C2(CNC(=S)NCC(C)C)OCCO2)cc1
Yield: 89.65 %

Procedure:
A mixture of 22 parts of 2-(4-methoxyphenyl)-1,3-dioxolane-2-methanamine hydrochloride, 11.5 parts of 1-isothiocyanato-2-methylpropane, 20.7 parts of potassium carbonate and 200 parts of 2-propanol is stirred and refluxed for 3 hours. The reaction mixture is filtered while hot and the filtrate is evaporated. The solid residue is crystallized from a mixture of benzene and petroleumether. The product is filtered off and dried, yielding 26 parts (89.65%) of N-[2-(4-methoxyphenyl)-1,3-dioxolan-2-ylmethyl]-N'-(2-methylpropyl)thiourea; mp. 96° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([Mg]Br)[CH2:13][CH2:12]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[CH:11]1([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:13][CH2:12]1
Reactant: Br[Mg]C1CC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Product: c1nc(C2CC2)c2cc[nH]c2n1
Temperature: 60 °C
Yield: 99.4 %

Procedure:
4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 0.452 g, 2.94 mmol), cyclopropylmagnesium bromide (43, 31.4 mL, 0.50 M in tetrahydrofuran, 15.7 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.240 g, complex 1:1 with dichloromethane, 0.294 mmol) were mixed with 15.4 mL of toluene. The reaction was heated at 60° C. overnight, then quenched with 1 M aqueous hydrochoric acid to pH 4 and filtered through a bed of celite. The layers of the filtrate were separated and the aqueous layer extracted with ethyl acetate: The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (44, 0.465 g). MS (ESI) [M+H+]+=160.1.