Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:12]Cl.O>O1CCCC1.CCCCC>[CH3:20][O:19][C:15]1[CH:14]=[C:11]([CH2:12][CH:2]2[S:3][CH2:4][CH2:5][CH2:6][S:1]2)[CH:10]=[C:9]([O:8][CH3:7])[C:16]=1[O:17][CH3:18]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: C1CSCSC1
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: O
Product: COc1cc(CC2SCCCS2)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 26.7 g of 1,3-dithiane in 222 ml of tetrahydrofuran which has been cooled to -78° C. was added over a period of 15 minutes, 137 ml of 1.7M solution of tetra-butyl lithium in pentane. The resultant mixture was then stirred for 45 minutes, while maintaining the temperature at -78° C., after which time it was warmed to 0° C. The mixture was then added to an ice-cold solution of 48.0 g of 3,4,5-trimethoxybenzyl chloride in 222 ml of tetrahydrofuran over a period of 20 minutes, after which time it was stirred for an additional 90 minutes at 0° C. 50 ml of water was then carefully added and the tetrahydrofuran was removed by evaporation at a temperature below 40° C. The resultant white slurry was then extracted with a mixture of methylene chloride and water. The organic layer was then evaporated and the crude product was washed with petroleum ether to yield a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:18]3[S:17][C:16]([NH:19][C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:21])=[N:15][C:14]=3[C:13]([O:28][CH3:29])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[S:17][C:16]([NH:19][C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:21])=[N:15][C:14]=3[C:13]([O:28][CH3:29])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C2=CCN(C(C)=O)CC2)c2sc(NC(=O)N3CCOCC3)nc12
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C2CCN(C(C)=O)CC2)c2sc(NC(=O)N3CCOCC3)nc12
Reaction time: 6 h
Yield: 8 %

Procedure:
To a solution of 0.03 g (0.72 mmol) of morpholine-4-carboxylic acid [7-(1-acetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-4-methoxy-benzothiazol-2-yl]-amide in 2.0 ml of methanol 10.0 mg of Pd/C (10%) were added. The reaction mixture was hydrogenated at 60° C. for 6 h, then filtered and evaporated to dryness in vacuo to yield 0.024 g (80%) morpholine-4-carboxylic acid [7-(1-acetyl-piperidin-4-yl)-4-methoxy-benzothiazol-2-yl]-amide as a white solid. F.p.: 196° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[N:6]=[C:5]2[CH3:22].N1C=CC=CC=1.[C:29](Cl)(Cl)=[O:30]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N:11]=[C:29]=[O:30])[N:7]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[N:6]=[C:5]2[CH3:22]
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3cc(Br)c(N)cc32)cc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2nc(C)c3cc(Br)c(N=C=O)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-3-methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-ylamine (138 mg, 0.36 mmol) was dissolved in 5 ml of toluene at room temperature. DMAP (1 eq, 44 mg), pyridine (1.3 eq, 0.04 ml) were added followed by phosgene (1.33 eq, 0.24 ml of a 20% solution in toluene). The mixture was allowed to stir at room temperature for 2 hours, forming a fine white precipitate. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated in vacuo again to give 5-bromo-6-isocyanato-3-methyl-1-(toluene-4-sulfonyl)-1H-indazole (150 mg, quantitative) as a white crystalline solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[OH:7][C:8]1[N:12]=[C:11]([O:13][CH2:14][CH3:15])[S:10][N:9]=1>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:9]1[C:8](=[O:7])[N:12]=[C:11]([O:13][CH2:14][CH3:15])[S:10]1)=[O:6]
Reactant: CCOc1nc(O)ns1
Reactant: O=C=NCCCl
Solvent: c1ccccc1
Product: CCOc1nc(=O)n(C(=O)NCCCl)s1
Temperature: 20 °C
Reaction time: 17 h
Yield: 95.1 %

Procedure:
41 g of β-chloroethyl isocyanate were added to a solution of 28.7 g of 3-hydroxy-5-ethoxy-1,2,4-thiadiazole in 500 ml of benzene and after stirring for 17 hours at 20° C, the mixture was filtered. The filtrate was evaporated to dryness and the residue was empasted with isopropyl ether and was dried to obtain 47 g of 2-(N-β-chloroethylcarbamoyl)-5-ethoxy-1,2,4-thiadiazole-3-one melting at 82° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH:9]=[CH2:10]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[N:4]1[CH:3]=[C:2]([C:9](=[CH2:10])[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncnc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC(C)(C)C)c1cncnc1
Temperature: 80 °C

Procedure:
A mixture of 30 g 5-bromopyrimidine, 1.2 g palladium acetate, 25 mL triethylamine and 250 ml t-butyl acrylate was heated at 80° C. for 5 days. The resulting mixture was concentrated to a waxy solid in vacuo. The residue was taken up in ethyl acetate and filtered. The filtrate was kept in the cold (-20° C., hexane added), and 10.5 g of tan needles deposited: 1H NMR (300 MHz) (d6-DMSO) δ 1.45 (s, 9H), 6.1 (d, 1H, J=12.3 Hz), 6.8 (d, H, J=12.3 Hz), 8.85 (s, 1H), 9.15 (s, 1H); MS (FAB) m/e (MH+): 206.2
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:11]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C:12]=4[NH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:4]=1.C([BH3-])#N.[Na+]>C(O)(C(F)(F)F)=O>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C@@H:11]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C@@H:12]4[NH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-c2cccc3c2[C@@H]2CCNCC[C@@H]2N3)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10-(4-Chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride (140 mg) was dissolved in TFA (3 ml), cool to 0° C. and sodium cyanoborohydride was added portionwise (150 mg). The reaction mixture stirred two hours, was quenched with 2N NaOH, extracted with EtOAc, dried over MgSO4, filtered and concentrated. The product was dissolved in EtOAc and 1N HCl in Et2O was added. The solvent was evaporated and solid recrystallized from EtOAc/MeOH to provide the title compound: 1H NMR (DMSO-d6) δ 1.31, 1.66, 2.21, 2.7, 2.91, 3.03, 3.27, 4.1-4.4, 6.88, 7.25, 7.52. HRMS (FAB) calcd for C18H21ClN12 (MH+) 299.1315, found 299.1321.
Reaction SMILES: [C:1]1([C:7]([NH:9][C:10](=[CH2:15])[C:11]([O:13][CH3:14])=[O:12])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O:18][C:19](=[CH2:22])[CH:20]=[CH2:21]>ClCCl.[I-].[Zn+2].[I-]>[O:18]=[C:19]1[CH2:20][CH2:21][C:10]([NH:9][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])([C:11]([O:13][CH3:14])=[O:12])[CH2:15][CH2:22]1
Reactant: C=C(NC(=O)c1ccccc1)C(=O)OC
Reactant: C=CC(=C)O[Si](C)(C)C
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)c2ccccc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the crude product (67.0 g) of methyl 2-[(phenylcarbonyl)amino]prop-2-enoate produced above in dichloromethane (300 mL) was added zinc iodide (104 g). To the mixture was added trimethyl[(1-methylideneprop-2-en-1-yl)oxy]silane (173 mL), and the mixture was heated under reflux for 24 hr. The reaction system was allowed to cool to room temperature, washed with water, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration. To the filtrate were added a mixture (1:4, 40 mL) of 1M hydrochloric acid and tetrahydrofuran, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (56.0 g).
Reaction SMILES: [Na].CO.[C:4]([O:8][CH3:9])(=[O:7])[CH2:5][SH:6].Cl[C:11]1[C:16]([C:17](OCC)=[O:18])=[CH:15][CH:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[N:12]=1>CN(C)C=O.O>[CH3:9][O:8][C:4]([C:5]1[S:6][C:11]2=[N:12][C:13]([CH:22]([CH3:23])[CH3:24])=[CH:14][CH:15]=[C:16]2[C:17]=1[OH:18])=[O:7]
Reactant: CCOC(=O)c1ccc(C(C)C)nc1Cl
Reactant: COC(=O)CS
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COC(=O)c1sc2nc(C(C)C)ccc2c1O
Yield: 45.1 %

Procedure:
Under ice-cooling, metal sodium (6.9 g) was added to methanol (70 ml)-and methyl thioglycolate (32 g) was added with stirring. Ethyl 2-chloro-6-isopropylpyridine-3-carboxylate (42 g) synthesized according to U.S. Pat. No. 5,001,137 (Mar. 19, 1991) was dissolved in dimethylformamide (170 ml) and the mixture was stirred at room temperature for 2 hr. The reaction mixture was treated with water, and the organic layer was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from water-containing methanol to give the title compound (20.9 g). melting point: 80-81° C.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCCCCn1cnc(-c2cc(C)c3nc(CCC)n(Cc4ccc(-c5ccccc5C(=O)OC(C)(C)C)cc4)c3c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCn1cnc(-c2cc(C)c3nc(CCC)n(Cc4ccc(-c5ccccc5C(=O)O)cc4)c3c2)c1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:13]2=[O:25])[C:3]([OH:26])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)O)C2)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-(2-oxo-4-m-tolyloxy-2,5-dihydro-pyrrol-1-yl)-propionic acid methyl ester (0.570 g, 0.002 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (0.201 g, 0.008 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-(2-oxo-4-m-tolyloxy-2,5-dihydro-pyrrol-1-yl)-propionic acid (430 mg, 79%) as a light brown solid.
Reaction SMILES: C(=O)=O.CO.S(Cl)(Cl)=O.[NH2:10][C@H:11]([C:15]([OH:17])=[O:16])[CH:12]([CH3:14])[CH3:13].N.[CH:19]1[CH:20]=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2[CH:24]=1>O.CCOCC.C(O)(C)C>[CH:19]([O:16][C:15](=[O:17])[C@H:11]([CH:12]([CH3:14])[CH3:13])[NH2:10])([CH3:20])[CH3:24]
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Reactant: CC(C)[C@H](N)C(=O)O
Agent: N
Agent: O=C=O
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CC(C)OC(=O)[C@@H](N)C(C)C
Temperature: 25 °C

Procedure:
One hundred and twenty-five ml (1.64 mole) of isopropanol was cooled to -10° C with a freezing mixture of dry ice-methanol, and 30 ml (0.42 mole) of thionyl chloride was added dropwise thereto while stirring. Thereafter, 25 g (0.21 mole) of l-valine was added little by little while maintaining this temperature. The reaction mixture was first raised to room temperature gradually and then finally it was reacted at 100° C for 40 hours while stirring. After completion of the reaction, unreacted thionyl chloride and isopropanol were evaporated in vacuo. The residue obtained was dissolved in 10 to 20 ml of water. The solution was covered with 400 ml of ether and an aqueous ammonia was added thereto until the phenolphthalein indicator turned red. After extracting the solution with ether three to four times, the ether extract was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a colorless and clear l-valine isopropyl ester (B.P. 40° - 41° C/3 - 4 mmHg).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3](O)[CH2:2]1.S(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.CN1C=CN=C1>CN(C)C(=O)C>[CH3:16][C:15]1[C:13](=[O:14])[N:12]=[C:10]2[N:9]([C@@H:1]3[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([O:11]2)[CH2:2]3)[CH:17]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: Cn1ccnc1
Agent: O=S(Oc1ccccc1)Oc1ccccc1
Solvent: CC(=O)N(C)C
Product: Cc1cn2c(nc1=O)O[C@H]1C[C@H]2O[C@@H]1CO
Yield: 65 %

Procedure:
For example, when thymidine is heated at ca 156° C. for 45 minutes with a four fold excess of diphenyl sulphite (see, for example, Gerrard, W., J. Chem. Soc., 218, (1940)) in the presence of a catalytic amount of N-methylimidazole in N,N-dimethylacetamide solution, and is then worked-up under basic conditions. 2,3'-anhydrothymidine may easily be isolated in almost 65% yield.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:50][C:51]([NH:53][CH2:54][C:55]([F:61])([F:60])[C:56]([F:59])([F:58])[F:57])=[O:52].[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:50][C:51]([NH:53][CH2:54][C:55]([F:60])([F:61])[C:56]([F:59])([F:57])[F:58])=[O:52])[CH3:22])[CH2:12][C@@H:11]([OH:31])[CH2:10]1
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(CBr)NCC(F)(F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@H](OCC(=O)NCC(F)(F)C(F)(F)F)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
Under a nitrogen atmosphere, (1S,3R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-20-hydroxypregna-5,7,16-triene (30.0 g) was dissolved in tetrahydrofuran (630 mL), and 0.55 mol/L potassium bis(trimethylsilyl)amide solution in toluene (244 mL) was added thereto dropwise at −10° C. After stirring the resulting mixture for 30 minutes, a solution of 2-bromo-N-(2,2,3,3,3-pentafluoropropyl)acetamide (15.9 g) obtained in Example 3 in tetrahydrofuran was added thereto dropwise over 20 minutes at −15° C., and the resulting mixture was continued to be stirred at the same temperature for 30 minutes. Aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution to carry out extraction, and the organic layer was sequentially washed with water and brine, followed by concentration under reduced pressure. Further, ethyl acetate was removed by azeotropic distillation with methanol under reduced pressure. The obtained concentrated residue was then dissolved in N,N-dimethylacetamide (300 mL), and the resulting mixture was added to a solution of 75% aqueous tetra n-butylammonium fluoride solution (51 mL) and acetic acid (6.1 mL) in N,N-dimethylacetamide (60 mL), followed by stirring the resulting mixture at 100° C. to 105° C. for 7 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was sequentially washed with water and brine, followed by concentration of the organic layer under reduced pressure. The obtained residue was recrystallized from 2-propanol and water to obtain [{(1S,3R,20S)-1,3-dihydroxypregna-5,7,16-triene-20-yl}oxy]-N-(2,2,3,3,3-pentafluoropropyl)acetamide as a gray powder (13.1 g; yield: 46.7%).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>CCOCC.O1CCCC1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
A 1.0 M solution of 4-tolylmagnesium bromide in ether (20.5 ml) is added dropwise to a solution of diethyl oxalate (6.5 g) in anhydrous tetrahydrofuran (41 ml) under a nitrogen atmosphere and ice cooling. Five minutes after completing the addition, the mixture is stirred at room temperature for 1.5 hours. To the reaction mixture is added 1 N hydrochloric acid, and the whole is extracted with ether. The organic layer is washed with water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 2.99 g (76%) of ethyl 4-tolylglyoxylate.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][N:5]=1.[CH2:15](Br)[CH:16]=[CH2:17]>CN(C=O)C.C(OCC)(=O)C>[CH2:17]([O:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([Cl:3])=[N:5][CH:6]=1)[CH:16]=[CH2:15]
Reactant: Oc1cnc(Cl)c2ccccc12
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1cnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a stirring solution of NaH (0.334 g, 8.35 mmol) in DMF (10 mL) at 0° C. was added 1-chloroisoquinolin-4-ol (1 g, 5.57 mmol). The mixture was stirred at 0° C. for 10 min. before the addition of allyl bromide (0.808 g, 6.68 mmol) dropwise. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and then quenched with 1N HCl solution. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to get the crude material. The material was purified by flash chromatography with 20% of EtOAc/hexane to afford 4-(allyloxy)-1-chloroisoquinoline (1.0 g, 4.55 mmol, 83% yield) as a white solid. MS: MS m/z 220.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:20])=[C:4]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:17]C)[CH:14]=3)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:20])=[C:4]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=3)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)CN(c1cccc(Br)c1C)C2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(Br)cccc1N1Cc2cc(O)ccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A mixture of 2-(3-bromo-2-methylphenyl)-5-methoxyisoindolin-1-one (Intermediate 1-4, 100 mg, 0.30 mmol) and 1.0 M boron tribromide in DCM (900 μL, 0.90 mmol) was stirred at rt for 4 h. The reaction mixture was diluted with DCM, washed with NaHCO3 (aq) and dried and concentrated. The residue was purified by column chromatography (eluting with EtOAc-hexane) to provide 2-(3-bromo-2-methylphenyl)-5-hydroxyisoindolin-1-one as an off-white solid (62 mg, 65%). 1H NMR (400 MHz, chloroform-d) δ 10.27 (1H, br. s.), 7.64 (1H, dd, J=7.9, 0.9 Hz), 7.59 (1H, d, J=8.4 Hz), 7.44 (1H, d, J=7.3 Hz), 7.25 (1H, t, J=7.9 Hz), 6.98 (1H, d, J=1.5 Hz), 6.93 (1H, dd, J=8.3, 2.1 Hz), 4.77 (2H, s), 2.20 (3H, s). Mass spectrum m/z 318, 320 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[N:9]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18](Br)=[N:19][CH:20]=2)[CH:13]=[CH:12][N:11]=[CH:10]1>>[O:1]1[CH:5]=[CH:4][C:3]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][N:9]3[CH:13]=[CH:12][N:11]=[CH:10]3)=[CH:20][N:19]=2)=[CH:2]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1ccoc1
Product: c1cn(Cc2ccc(-c3ccoc3)nc2)cn1

Procedure:
Synthesized using 3-furanylboronic acid (188 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Brown solid. Yield: 144 mg, 0.61 mmol, 73%. 1H NMR (CDCl3, 500 MHz): OH (ppm): 5.13 (s, 2H), 6.87 (dd, J=1.9, 0.9 Hz, 1H), 6.90 (t, J=1.3 Hz, 1H), 7.10 (s, 1H), 7.41 (dd, J=8.2, 2.2 Hz, 1H), 7.43 (dd, J=8.2, 1.3 Hz, 1H), 7.49 (t, J=1.6 Hz, 1H), 7.56 (brs, 1H), 8.02 (dd, J=0.7 Hz, J=1.4 Hz, 1H); 13C NMR (CDCl3, 125 MHz): 00 (ppm)=48.1, 108.5, 118.9, 120.1, 126.5, 129.5, 130.3, 135.6, 137.3, 141.5, 144.0, 148.6, 152.1; MS (ESI): m/z=226.15 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:46])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:45])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:29]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:27]4[C:22](=[CH:23][C:24]([C:36]5[O:40][C:39]([C:41]([O:43]C)=[O:42])=[CH:38][CH:37]=5)=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>CO.C1COCC1.O>[CH3:1][N:2]([CH3:46])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:45])[NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:29]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:27]4[C:22](=[CH:23][C:24]([C:36]5[O:40][C:39]([C:41]([OH:43])=[O:42])=[CH:38][CH:37]=5)=[CH:25][CH:26]=4)[N:21]=3)=[CH:18][CH:19]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2ccc3c(N4CCOCC4)nc(-c4ccc(NC(=O)Nc5ccc(C(=O)N(C)C)cc5)cc4)nc3c2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ccc(-c5ccc(C(=O)O)o5)cc4n3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.8 %

Procedure:
To a 100 mL round bottom flask, methyl 5-(2-(4-(3-(4-(dimethylcarbamoyl)phenyl)ureido)phenyl)-4-morpholino-quinazolin-7-yl)furan-2-carboxylate (0.1 g, 0.00016 mol) in MeOH (2 mL), THF (2 mL) and water (2 mL) was added. Subsequently, lithium hydroxide monohydrate (0.034 g, 0.0008 mol) was added and stirred at 25° C. for 12 h. The volatiles were evaporated under reduced pressure, the residue redissolved in water and acidified with 2 N HCl to obtain a pH of 5.0. The volatiles were evaporated under reduced pressure and the residue was stirred with water and filtered. The obtained solid was washed with MeOH to yield the title compound [0.06 g, 61%]. 1H NMR (300 MHz, DMSO-d6): δ 12.12 (s, 1H), 8.57 (s, 1H), 8.54 (s, 1H), 8.25 (s, 1H), 8.05 (d, J=9.0 Hz, 2H), 7.97 (d, J=7.5 Hz, 2H), 7.87 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.28 (s, 2H), 7.04 (s, 1H), 3.85 (s, 8H), 2.98 (s, 6H). LC-MS (ESI): Calculated mass: 606.2; Observed mass: 607.2 (RT: 0.63 min).