Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3](O)=[O:4].C1C=CC=CC=1.[CH3:16][C:17]([NH2:25])([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH3:16][C:17]([NH:25][C:3](=[O:4])[CH:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[Br:1])([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C)(C)C(Br)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(NC(=O)C(Br)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.8 %

Procedure:
Into a 200 ml four-necked flask, there were charged α-bromo-tert-butylacetic acid (9.8 g) and benzene (50 ml), and pyridine (50 ml) and α,α-dimethylbenzylamine (6.9 g) were dropwise added thereto while stirring at room temperature. Dicyclohexylcarbodiimide (10.8 g) was further added thereto, and the reaction was continued at 60°-70° C. for 6 hours, followed by cooling. The solvent was distilled off under reduced pressure, and the residue was extracted with hot benzene. The benzene extract was concentrated by distillation, and the residue was recrystallized from ethanol to give N-(α,α-dimethylbenzyl)-α-bromo-tert-butylacetamide (10.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH2:10]([O:12][C:13](=[O:22])[CH:14]=[CH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:11].C(OCC)C.Cl>ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:4]2[C:3]=1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:22])=[N:5]2
Reactant: CCOC(=O)C=CCC(=O)OCC
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1cc(C(=O)OCC)c2c(Cl)cc(Cl)cc2n1
Yield: 10.4 %

Procedure:
3.5-Dichloraniline (10.95 g) and diethylglutaconate (13.5 g) were dissolved in dry dichloromethane and heated at reflux for 14 h. Diethyl ether, saturated with hydrogen chloride (10 ml) was added and the reaction mixture was heated at reflux for a further 24 h. After this time the solution was filtered and the filtrate was washed with saturated sodium hydrogen carbonate solution, dried (Na2SO4), filtered and concentrated in vacuo to give an oily residue which was purified by silica gel chromatography using 15% ethyl acetate in hexane as the eluent to give as a colourless solid, 5,7-dichloro-2,4-diethoxycarbonylquinoline (2.4 g, m.p. 104°-106° C.); δ (360 MHz, CDCl3), 1.44 (3H, t, J=7.2 Hz, CH3CH2), 1.49 (3H, t, J=7.2 Hz, CH3CH2), 4.51 (2H, q, J=7.2 Hz, CH3CH2), 4.56 (2H, q, J=7.2 Hz, CH3CH2), 7.77 (1H, d, J=1.9 Hz, 6-H or 8-H), 8.17 (1H, s, 3-H) and 8.32 (1H, d, J=1.9 Hz, 6-H or 8-H); m/z 342 (M+1), 269 (100%, M+1 -CO2Et); Found: C, 52.58; H, 3.87; N, 4.04. C15H13Cl2NO4 requires C, 52.65; H, 3.83; N, 4.09% and 5,7-dichloro-4-(3,5-dichloroanilino)-2,4-diethoxycarbonyl-1,2,3,4-tetrahydro-quinoline (0.23 g, m.p. 153°-154° C.; δ (360 MHz, CDCl3) 1.29 (6H, t, J=7.2 Hz, CH3CH2 ×2), 2.34 (1H, dd, J=14.4 and 2.9 Hz, CHAHB -CHC), 2.65 (1H, dd, J=14.4 and 12.3 Hz, CHAHB -CHC), 4.27 (5H, m, CH3CH2 ×2 and HC), 4.91 (1H, br, NH), 5.54 (1H, br, NH), 6.28 (2H, d, J=1.8 Hz, ortho anilino protons), 6.60 (1H, t, J=1.8 Hz, para anilino proton), 6.64 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.68 (1H, d, J=2.1 Hz, 6-H or 8-H); m/z 506 and 504 (M+), 433 (100%, M-CO2Et); Found: C, 49.95; H, 4.07; N, 5.51. C21H20Cl4N2O4 requires C, 49.83; H, 3.98; N, 5.53%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=O)[C:12]([O-:14])=O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[CH2:16]([NH2:19])[CH2:17][NH2:18].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:12](=[O:14])[NH:18][CH2:17][CH2:16][N:19]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: NCCN
Reactant: Cn1ncc2cc(C(=O)C(=O)[O-])ccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1ncc2cc(C3=NCCNC3=O)ccc21

Procedure:
The mixture of 2-(1-methyl-1H-indazol-5-yl)-2-oxoacetate (520 mg, 2.2 mmol), ethylenediamine (0.15 mL, 2.2 mmol), and sodium sulfate in toluene (9 mL) was heated at reflux for 12 hours. The reaction was cooled, and diluted with ethyl acetate. The mixture was filtered through a pad of celite and was washed with ethyl acetate. Concentration and purification with flash column chromatography (EtOAc) gave 3-(1-methyl-1H-indazol-5-yl)-5,6-dihydropyrazin-2(1H)-one. LCMS-ESI+: calc'd for C12H13N4O: 229.3 (M+H+); Found: 229.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](NCCN2CCCCC2)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][OH:25]>>[Cl:8][C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([O:25][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)[N:5]=1
Reactant: Clc1nc(Cl)nc(NCCN2CCCCC2)n1
Reactant: OCc1ccccn1
Product: Clc1nc(Cl)nc(OCc2ccccn2)n1

Procedure:
Following the general procedure A-2, 4,6-dichloro-N-(2-(piperidin-1-yl)ethyl)-1,3,5-triazin-2-amine was coupled with 2-pyridinemethanol with reaction time of 3 h. Purification by column chromatography gave the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C1(C)C=CC=CC=1.[C:26]([NH:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[C:26]([NH:29][C:30]1[CH:35]=[C:34]([C:16]2[C:6]3[N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:8]=[N:9][C:5]=3[CH:4]=[C:3]([C:1]#[N:2])[CH:17]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)Nc1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Yield: 36.3 %

Procedure:
5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 3-acetamidophenylboronic acid (90 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) were combined and the mixture was stirred at reflux overnight. The solvent was removed under reduced pressure and the crude product was purified on a 2 g silica Isolute® SPE column, eluting with dichloromethane/methanol (98:2). The eluent from this column was evaporated under reduced pressure and the crude product was purified further by prep LCMS, then recrystallised from dichloromethane/diethyl ether to give the product as a white solid (64 mg, 36%) m/z, 353.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[C:4]([NH2:18])[N:3]=1.C1C(=O)N([I:26])C(=O)C1>C(Cl)Cl.CO>[I:26][C:7]1[C:2]([CH3:1])=[N:3][C:4]([NH2:18])=[N:5][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(N)n1
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(N)nc(-c2cccc(C(F)(F)F)c2)c1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 5.0 g (14 mmol) 4-methyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-2-ylamine and 3.3 g (15 mmol) NIS. Yield after chromatography on silica gel with DCM/MeOH: 3.8 g (73%).
Reaction SMILES: [CH3:1][CH:2]1[C:7]2=[CH:8][C:9]([NH2:11])=[N:10][N:6]2[CH2:5][CH2:4][O:3]1.[C:12]([O:15][CH2:16][C:17]1[C:18]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=3)[C:33]2=[O:47])=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[C:27](Br)[C:26](=[O:30])[N:25]([CH3:31])[CH:24]=1)(=[O:14])[CH3:13].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:12]([O:15][CH2:16][C:17]1[C:18]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:44])([CH3:43])[CH3:45])[CH:38]=3)[C:33]2=[O:47])=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[C:27]([NH:11][C:9]2[CH:8]=[C:7]3[CH:2]([CH3:1])[O:3][CH2:4][CH2:5][N:6]3[N:10]=2)[C:26](=[O:30])[N:25]([CH3:31])[CH:24]=1)(=[O:14])[CH3:13]
Reactant: CC1OCCn2nc(N)cc21
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCOC4C)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 150h (25 mg, 1.0 eq., 0.16 mmol), (4-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-3-yl)methyl acetate 142c (181 mg, 2.0 eq., 0.32 mmol), Pd2(dba)3 (15 mg, 0.1 eq., 0.016 mmol), Xantphos (19 mg, 0.2 eq., 0.032 mmol), Cs2CO3 (105 mg, 2.0 eq., 0.32 mmol), and dioxane (10 mL). The mixture was subjected to three cycles of vacuum/argon flush and stirred at 100° C. for 2 hr. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 150i as a brown solid (48 mg, 48%).
Reaction SMILES: C1(C)C(C)=CC=CC=1.Cl.[NH2:10][C:11]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[C:13]([F:19])[C:12]=1[SH:20].[CH2:21]([O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]#N)[CH3:22]>C(O)C>[CH2:21]([O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[S:20][C:12]2[C:13]([F:19])=[CH:14][C:15]([F:18])=[C:16]([F:17])[C:11]=2[N:10]=1)[CH3:22]
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: CCOC(=O)CCCCCC#N
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCO
Product: CCOC(=O)CCCCCc1nc2c(F)c(F)cc(F)c2s1
Yield: 39.7 %

Procedure:
To xylene (6 ml) was added 2-amino-3,4,6-trifluorothiophenol hydrochloride (647 mg, 3 mmol), 6-cyanohexanoic acid ethyl ester (507 mg, 3 mmol) and ethanol (0.5 ml) and the mixture was heated to reflux for 60 hours under a nitrogen stream. The resultant reaction mixture was washed with water, dried and then evaporated to yield a residue, which was purified on a silica gel column to give 6-(4,5,7-trifluorobenzothiazol-2-yl)hexanoic acid ethyl ester (395 mg, 40%) as an oil.
Reaction SMILES: [F:1][C:2]1([F:24])[C:10]2([C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])[CH2:9][C:8]2[C:3]1=[CH:4][C:5]([C:20]([O:22]C)=[O:21])=[CH:6][CH:7]=2.[OH-].[Na+].Cl>CO>[F:24][C:2]1([F:1])[C:10]2([C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])[CH2:9][C:8]2[C:3]1=[CH:4][C:5]([C:20]([OH:22])=[O:21])=[CH:6][CH:7]=2
Reactant: COC(=O)c1ccc2c(c1)C(F)(F)C1(C2)C(=O)Nc2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(c1)C(F)(F)C1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C

Procedure:
A mixture of methyl 1,1-difluoro-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-6-carboxylate (100 mg, 0.30 mmol) and aqueous 6 N sodium hydroxide solution (0.15 mL, 0.91 mmol) in MeOH (5 mL) is heated at reflux for 1 h. The mixture is allowed to cool to ambient temperature before it is acidified to pH ˜6 with aqueous 1 N hydrochloric acid solution. The resulting mixture is filtered, and the filtrate is concentrated. The residue is partitioned between water (10 mL) and 2-methyltetrahydrofuran (2-MeTHF, 10 mL). The aqueous layer is extracted with 2-MeTHF (5×10 mL), and the combined organic layers are dried over sodium sulfate and concentrated in vacuo to provide the title compound.
Reaction SMILES: [CH3:1][C:2]([O:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[H][H].[OH-].[Na+]>FC(F)(F)C(O)=O.O.[Pt](=O)=O>[CH3:18][C:2]([O:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH3:1])[CH2:3][N:4]1[C:16]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1
Reactant: [H][H]
Reactant: CC(C)(Cn1cnc2c(N)nc3ccccc3c21)OCCS(C)(=O)=O
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(Cn1cnc2c(N)nc3c(c21)CCCC3)OCCS(C)(=O)=O
Yield: 108.8 %

Procedure:
A mixture of 1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 29, 1.00 g, 2.76 mmol) and platinum(IV) oxide (0.5 g) in trifluoroacetic acid (14 mL) was hydrogenated on a Parr apparatus at 50 psi (3.5×105 Pa) hydrogen pressure for 20 hours. The mixture was filtered through CELITE filter agent, which was washed afterwards with dichloromethane. The filtrate was concentrated under reduced pressure to afford an oil that was suspended in water (50 mL) and adjusted to pH 13 with 50% aqueous sodium hydroxide. A white solid formed that was isolated by filtration, washed with water, and dried under vacuum at 65° C. to afford 1.10 g of 1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 219-223° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1)=O)(C)(C)C.[ClH:23]>CCOC(C)=O>[ClH:23].[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1cccc(O)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1ccccc1-c1cccc(O)c1
Reaction time: 0.08 h

Procedure:
A solution of 2-{N-(tert-butyloxycarbonyl)aminomethyl}-3′-hydroxybiphenyl from Step G (0.732 g, 2.45 mmol) in EtOAc (30 mL) at 0° C. was saturated with HCl gas. The mixture was aged at 0° C. for 5 min, then concentrated to dryness in vacuo to provide the titled compound as a white solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]1(=[O:16])[O:15][CH:13]([CH3:14])[CH2:12]1.Cl>O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:13]([CH3:14])[CH2:12][C:11]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: CC1CC(=O)O1
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)Oc1ccc(Cl)cc1
Temperature: 23 °C

Procedure:
To a solution of 40 g (1 mol) sodium hydroxide in 400 ml water was added 128.6 g (1 mol) 4-chlorophenol and the reaction was heated at reflux for 15 minutes. To the refluxing solution was added 81.5 g (1 mol) of beta-butyrolactone dropwise over 1 hour. The reaction was cooled to 23° C., acidified with 100 ml concentrated hydrochloric acid and extracted with 2×500 ml diethyl ether. The ether layers were combined and extracted with 5×300 ml saturated aqueous sodium bicarbonate solution. The bicarbonate extracts were combined, acidified by slow dropwise addition of 160 ml concentrated hydrochloric acid and extracted with 250 ml diethyl ether. The latter ether extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the product as a white solid, 24 g (11%).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[S:19]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:20])=[O:21]
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc(C)ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2,5-dimethylbenzenesulfonyl chloride (2.05 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 2% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (2.10 g, 72%). 1H-NMR (300 MHz, CDCl3) δ 7.65 (s, 1H), 7.29 (m, 1H), 7.25 (m, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 6.30 (s, 1H), 5.27 (br s, 1H), 2.30 (s, 3H), 2.18 (s, 3H), 2.03 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[C:8]([C:11]1[CH:33]=[CH:32][C:14]([O:15][CH2:16][CH:17]([O:28][C:29](=[O:31])[CH3:30])[CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([CH3:27])=[CH:25][CH:26]=2)[NH2:23])=[C:13]([CH2:34][CH2:35][C:36]([F:39])([F:38])[F:37])[C:12]=1[OH:40])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[C:8]([C:11]1[CH:33]=[CH:32][C:14]([O:15][CH2:16][CH:17]([O:28][C:29](=[O:31])[CH3:30])[CH2:18][O:19][C:20]2[CH:21]=[C:22]([NH:23][C:1](=[O:6])[C:2]([O:4][CH3:5])=[O:3])[C:24]([CH3:27])=[CH:25][CH:26]=2)=[C:13]([CH2:34][CH2:35][C:36]([F:38])([F:37])[F:39])[C:12]=1[OH:40])(=[O:10])[CH3:9]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(=O)OC(COc1ccc(C)c(N)c1)COc1ccc(C(C)=O)c(O)c1CCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cc(OCC(COc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)OC(C)=O)ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.9 ml of methyl chlorooxalate in 8 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 8.3 g of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-acetoxy-propoxy}-6-methyl-aniline and 2.9 ml of triethylamine in 70 ml of methylene chloride in the course of about 5 minutes and the mixture is then stirred at room temperature for a further 2 hours. The reaction mixture is poured onto ice-water and the organic phase is separated off. The methylene chloride phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. Methyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-acetoxy-propoxy}-6-methyl-phenyl}}-oxamate is thus obtained as an oil with an Rf value=0.13 (silica gel; toluene/ethyl acetate=6:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[F:17][C:18]([F:29])([F:28])[CH2:19]OS(C(Cl)(Cl)Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][N:9]([CH2:19][C:18]([F:29])([F:28])[F:17])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(CC(F)(F)F)CC2
Yield: 46.3 %

Procedure:
Into a 1-neck round-bottom flask was added 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.500 g, 2.2 mmol), trichloro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (0.45 mL, 2.9 mmol), and potassium carbonate (0.91 g, 6.61 mmol), in N,N-dimethylformamide (5 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was partitioned between saturated aqueous Na2CO3 and dichloromethane. Extraction with another portion of dichloromethane, drying (MgSO4), concentration and flash chromatography isolation (on SiO2, MeOH/dichloromethane 0-3%) provided 7-methoxy-8-nitro-3-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (310 mg, 46%) as a yellow oil. 1H-NMR (CDCl3) δ 7.65 (s, 1H), 6.83 (s, 1H), 3.74 (s, 3H), 3.19 (q, J=9.6 Hz, 2H), 2.95 (m, 4H), 2.88 (s, 4H); LC/MS (ESI+): 305.05 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11](O)=[O:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:12][CH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: O=C(O)Cc1ccc2c(c1)CCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (2,3-dihydrobenzofuran-5-yl)acetic acid (4.9 g--see EP-A-132130) in anhydrous tetrahydrofuran (50 ml) was added dropwise over 10 minutes to a stirred suspension of lithium aluminium hydride (1.57 g) in anhydrous tetrahydrofuran (50 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 1 hour. Water (1.5 ml) was cautiously added dropwise followed by 10% aqueous sodium hydroxide (1.5 ml) and, finally, water (4.5 ml). The mixture was filtered and the inorganic salts washed with ethyl acetate (2×50 ml). The filtrate and washings were combined and concentrated in vacuo to give the title compound as as oil, (3.3 g).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][C@@:8]1([C:31]([CH2:33][OH:34])=[O:32])[C@@:12]2([CH3:29])[CH2:13][C@H:14]([OH:28])[C@:15]3([F:27])[C@:25]4([CH3:26])[C:19](=[CH:20][C:21]([CH:23]=[CH:24]4)=[O:22])[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][C@@H:9]1[CH3:30])=[O:6].[C:35]([NH:42][C@H:43]([C:47]([OH:49])=[O:48])[CH:44]([CH3:46])[CH3:45])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(OCC)(=O)C.CCCCCC>CN(C)C1C=CN=CC=1.ClCCl.O1CCOCC1>[OH:28][C@H:14]1[CH2:13][C@@:12]2([CH3:29])[C@@H:11]([CH2:10][C@H:9]([CH3:30])[C@:8]2([O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][CH3:1])[C:31](=[O:32])[CH:33]([O:49][C:47](=[O:48])[C@@H:43]([NH:42][C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH:44]([CH3:45])[CH3:46])[OH:34])[C@H:16]2[C@@:15]1([F:27])[C@:25]1([CH3:26])[C:19]([CH2:18][CH2:17]2)=[CH:20][C:21](=[O:22])[CH:23]=[CH:24]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCC(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 69.5 %

Procedure:
21 mmol of betamethasone-17-valerate is reacted with 25 mmol of Boc-valine (Boc-Val-OH), 2.5 mmol of 4-dimethylaminopyridine and 27 mmol of dicyclohexylcarbodiimidazole in dichloromethane/dioxane 1:1 analogously to Example 1. Chromatography (1. ethyl acetate/hexane 2:1 and 2. ethyl acetate/hexane 1:1) yields 10.1 g (73%) of pure (2S)-2-((1,1-dimethylethoxycarbonyl)-amino)-3-methyl-butyric acid [11β,21-dihydroxy-3,20-dioxo-9-fluoro-16β-methyl-17-valeroyloxy-pregna -1,4-dien-21-yl] ester as foam.