Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a solution of 12-hydroxydodecanoic acid (10.0 g, 0.046 mol) in 150 mL THF, p-toluenesulfonic acid (0.087 g, 0.01 eq) was added followed by 3,4-dihydro-2H-pyran (5.95 g, 0.070 mol). After stirring this homogeneous reaction mixture for 16 hours at room temperature under a nitrogen atmosphere, NaHCO3 saturated solution was added to the mixture. The mixture was then extracted with methylene chloride, dried (MgSO4), and concentrated in vacuo (30° C.) to yield 13.0 g (0.043 mol, 94%) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To 4′-bromo-2,2,2-trifluoroacetophenone (5.0 g, 19.76 mmol) in THF (50 mls) at 0° C. was added NaBH4 (1.5 g, 39.52 mmol). The mixture was warmed to room temperature and stirred for 1 hour. The reaction was complete by TLC (CH2Cl2). The mixture was quenched with H2O, rotary evaporated to remove most of the THF, and extracted 2 times with CH2Cl2. The organics were combined, washed with brine, concentrated to a small volume and filtered through a plug of silica gel. The silica was washed with CH2Cl2 to elute the product, and the resulting solution was concentrated to give 4.65 g of 1-(4-bromophenyl)-2,2,2-trifluoroethanol. Yield 92%.
Reaction SMILES: [BH4-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][C:9]=1[OH:17]>C(O)C.O1CCCC1>[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[OH:16])=[CH:10][C:9]=1[OH:17]
Reactant: CC(=O)c1ccc(OCCCCl)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)c1ccc(OCCCCl)c(O)c1
Temperature: 10 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
To a flask charged with sodium borohydride (1.5 g, 39.4 mmol) under nitrogen and chilled to 10° C. was added, slowly, a solution of 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone (6.0 g, 26.2 mmol) dissolved in ethanol-tetrahydrofuran (120 ml, 2:1). After total addition, the ice bath was removed and the reaction was stirred at ambient temperature for 3 hours. An additional amount of sodium borohydride (0.2 g, 5.3 mmol) was carefully added. After stirring at ambient temperature for one hour, the solvent was removed in vacuo. The resultant solid residue was diluted with water (100 ml) and left overnight. The product was isolated by vacuum filtration yielding 3.8 g. Two consecutive recrystallizations from toluene provided 3.3 g (55%) of 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzene methanol as a light brown solid, m.p.=107°-109° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[O-:14].[K+].Br[CH2:17][CH2:18][OH:19].Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[O:14][CH2:17][CH2:18][OH:19]
Reactant: OCCBr
Reactant: COc1cc([N+](=O)[O-])cc(OC)c1[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])cc(OC)c1OCCO

Procedure:
A slurry of potassium 2,6-dimethoxy-4-nitrophenolate [Collins, R. P. and Davis, M. J. Chem. Soc. (1961), 1986] (38 g, 160 mmol) in DMF (600 ml) was treated with 2-bromoethanol (25 ml, 353 mmol) and hexamethyl-phosphorus triamide (31 ml, 176 mmol) and the reaction heated at 115° for 6 h. After cooling, the reaction was poured onto 1M hydrochloric acid (1.5 l) and extracted with ethyl acetate (5×500 ml). The organics were washed with 1M sodium hydroxide (4×700 ml), brine (200 ml) and defined (MgSO4). Concentration in vacuo gave 3,5-dimethoxy-4-(2-hydroxyethoxy)nitro-benzene as an off white solid (31 g) δH (CDCl3) 7.52 (2H, s), 4.21 (2H, t, J 2.9 Hz), 3.94 (3H, s), 3.76 (2H, m) and 2.94 (1H, br s). MS (ES+) 266 (MNa+, 50%), 244 (MH+, 100%). A mixture of this nitrobenzene (750 mg, 3.16 mmol) and 10% palladium on carbon (75 mg) in ethanol (50 ml) was degassed and then subjected to an atmosphere of hydrogen (balloon) for 16 h. at 20°. Dichloromethane was added and the solution filtered and solvent removed in vacuo to give 3,5-dimethoxy-4-(2-hydroxyethoxy)-aniline as a grey solid (620 mg) after trituration with diethyl ether. δH (CDCl3 +DMSO) 5.84 (2H, s), 3.87-3.84 (2H, m), 3.64 (6H, s) and 3.52-3.49 (2H, m). MS (ES+) 214 (MH+, 100%.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>CCCCCC.C1COCC1>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([B:15]([OH:20])[OH:16])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
n-Butyllithium in n-hexane (925.0 mL, 1.59 M) was added dropwise to a mixture of THF (1,000 mL) and 1-bromo-3-methoxybenzene (T-1) (250.0 g, 1.34 mol) at −70° C. under an atmosphere of nitrogen. After the addition had been completed, the reaction mixture was stirred at the same temperature for 1 hour. Triisopropyl borate (300.9 g, 1.60 mol) was added dropwise, and then the mixture was warmed slowly to room temperature. The stirring was continued at room temperature for 18 hours, and the reaction mixture was poured into 6M-hydrochloric acid. The mixture was extracted with ethyl acetate (500 mL) four times, and the organic layer was washed with water. After the organic layer had been dried over anhydrous magnesium sulfate, the organic solvent was distilled off under reduced pressure. The residue was sufficiently washed with heptane to leave colorless solids (156.1 g) of 3-methoxyphenylboronic acid (T-2).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>O>[Br:7][C:5]1[N:6]=[C:2]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:3][CH:4]=1
Reactant: C1COCCN1
Reactant: Brc1csc(Br)n1
Solvent: O
Product: Brc1csc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
A solution of 2,4-dibromothiazole (500 mg, 2.06 mmol) in morpholine (4.0 mL, 22.3 mmol) was warmed at 50° C. in a sealed tube. After 16 hours, the mixture was cooled to room temperature, diluted with 20 mL of water and extracted with three 30 mL portions of diethyl ether. The combined organic layers was washed with five 30 mL portions of water, 30 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed over SiO2 using ethyl acetate in hexanes (0-30% gradient) to afford 458 mg (89%) of 4-(4-bromothiazol-2-yl)morpholine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([Cl:18])[CH:10]=2)=[C:4]([Cl:19])[CH:3]=1.C1C(=O)N([Cl:27])C(=O)C1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([Cl:18])[C:10]=2[Cl:27])=[C:4]([Cl:19])[CH:3]=1
Reactant: O=C(O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.9 %

Procedure:
To a thick suspension of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid (13.25 g, 36.8 mmol) in 350 ml DMF was added NCS (4.94 g, 37 mmol) and the suspension was stirred at room temperature for 3 days. Since the reaction did not go to completion (NMR control), an additional 1.987 g NCS was added and the mixture was stirred for 18 h, upon which the reaction went to completion. The mixture was poured into a solution of 20 g sodium metabisulfite in H2O (1 l) and the thick suspension was rest for 30 min. It was filtered, and the precipitate was washed with water, then with hexanes and it was dried in oil pump vacuo at 50° C. for 24 hours to obtain the desired compound as a white solid (13.11 g, 90%). 1H-NMR (500 MHz, DMSO-D6): δ=9.90 (s, br, 1H), 8.63 (s, 1H), 7.74 (s, 1H), 7.43-7.42 (dd, 1H), 6.99-6.97 (dd, 1H).
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[O:3].[CH2:6]([NH:13][C:14]([NH2:16])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([N:13]1[CH:1]([OH:5])[C:2](=[O:3])[NH:16][C:14]1=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: O=CC(=O)O
Product: O=C1NC(=O)N(Cc2ccccc2)C1O
Temperature: 100 °C

Procedure:
75 parts by weight of a 50% strength aqueous glyoxylic acid (0.5 mol glyoxylic acid) and the catalyst are placed in a heatable, stirred apparatus. The mixture is subsequently heated to an internal temperature of 100° C. while stirring. 75 parts by weight of benzylurea (corresponds to 0.5 mol) are then added at a constant rate over a period of 30 minutes. After addition of the benzylurea is complete, the reaction mixture is stirred at 100° C. for another 30 minutes, a sample is taken and analysed by HPLC. Table 1 shows the composition of the organic components of the reaction mixtures examined. The following reaction equation shows the formulae of the compounds which can be formed.
Reaction SMILES: CN1CCOCC1.[CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:9].Cl.[NH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH:8]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:16])=[CH:17][CH:18]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)CN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COC(=O)CNC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Added N-methylmorpholine (2.93 mL, 26.6 mmol) to a solution of 4-formylbenzoic acid (1 g, 6.66 mmol), methyl 2-aminoacetate, hydrochloride (1.045 g, 8.33 mmol), 1-hydroxy-7-azabenzotriazole (1.813 g, 13.32 mmol), and EDC (2.55 g, 13.32 mmol) in Dimethyl Sulfoxide (DMSO) (30 mL). Let stir at RT for 16 hours. Added water and extracted with DCM. Combined DCM extracts and washed with water, brine and dried over MgSO4, filtered and rotovapped off DCM. The residue was purified via Biotage (0% to 75% gradient; EtOAc:Hex; 25 g-HP-silica gel column). Obtained 570 mg 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.83 (s, 3H), 4.28 (d, J=5.05 Hz, 2H), 7.98 (s, 4H), 10.10 (s, 1H); [M+H]+=222.1.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30](O)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.P(Cl)(Cl)(OC1C=CC=CC=1)=O.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>O1CCCC1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of p-nitrobenzyl α-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-α-(1-hydroxyethylidene)acetate (4.69 g.) in tetrahydrofuran (60 ml.) under a nitrogen atmosphere at 0°-5° C. was added triethylamine (1.6 ml.) followed by dropwise addition of phenyl dichlorophosphate (1.72 ml.) over 5 minutes. After stirring for 3 hours at 20° C., the reaction mixture was cooled to 0° C. and morpholine (4.0 ml.) was added dropwise over 10 minutes with the reaction temperature maintained at 0°-5° C. After stirring for 3 hours at this temperature, the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a yellow foam in essentially quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1:1.4) about the enamine double bond and was identical to that produced in example 8.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:16][CH2:15]1)([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 2-chloro-5-nitropyridine (2.5 g, 15.7 mmol) in THF (25 mL), are added 1-isopropylpiperazine (2.01 g, 15.7 mmol) and K2CO3 (3.25 g, 23.6 mmol). The reaction mixture is stirred at 50° C. for 4 hours and then at 70° C. overnight. The solvent is removed in vacuo and the resultant orange solid is triturated using 10:1 petroleum ether-diethyl ether. The isolated compound (3.7 g, 94%) is used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[N:15]=[C:14]([CH3:16])[NH:13][N:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:12]2[C:11]([CH3:10])=[N:15][C:14]([CH3:16])=[N:13]2)[N:3]=[C:4]([CH3:9])[N:5]=1
Reactant: Cc1n[nH]c(C)n1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 66 h
Yield: 68.8 %

Procedure:
4,6-dichloro-2-methylpyrimidine (2-1) (137.8 g, 845 mmol), 3,5-dimethyl-1H-1,2,4-triazole (2-2) (82 g, 845 mmol), and Cs2CO3 (275 g, 845 mmol) were suspended in DMF (1 L) and the resulting mixture was stirred at room temperature for 66 h. The mixture was then poured into water (2 L) and stirred for 1 hour. The precipitate was filtered, washed with water (2×) and dried under vacuum to afford Intermediate 2 as an off-white solid (130 g, 69%). MS: m/z=224.2 (M+H).
Reaction SMILES: [CH2:1]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([F:24])[CH:18]=2)=[CH:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:25](Cl)(=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>N1C=CC=CC=1>[CH2:1]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:19]([F:24])[CH:18]=2)=[CH:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ncc(-c2ccc(O)c(F)c2)cn1
Reactant: CCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCc1ncc(-c2ccc(OC(=O)CCCCCC)c(F)c2)cn1
Temperature: 0 °C
Yield: 61.6 %

Procedure:
0.80 g (2.42 mM) of 2-decyl-5-(3-fluoro-4-hydroxyphenyl)pyrimidine was dissolved in 10 ml of pyridine. Under stirring on an ice water bath, 0.62 ml (4.00 mM) of heptanoyl chloride was added dropwise to the above solution, followed by stirring for 15 minutes on the ice water bath and further stirring for 20 minutes at 45°-56° C. on a water bath. After the reaction, the reaction mixture was poured into 150 ml of ice water to precipitate a crystal. The crystal was recovered by filtration and washed with water. The washed crystal was dissolved in toluene and washed with water, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized two times from a mixture solvent of acetone-methanol to obtain 0.66 g of 2-decyl-5-(3-fluoro-4-heptanoyloxyphenyl)pyrimidine (Yield: 61.6%). ##STR26##
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].C(=O)([O-])[O-:9].[K+].[K+].[CH3:14][C@@:15]12[C@H:25]3[C@@H:26]([OH:39])[CH2:27][C@:28]4([CH3:38])[C@@:32]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:31][CH2:30][C@H:29]4[C@@H:24]3[CH2:23][CH2:22][C:21]1=[CH:20][C:18](=[O:19])[CH2:17][CH2:16]2>>[CH3:14][C@@:15]12[C@H:25]3[C@@H:26]([OH:39])[CH2:27][C@:28]4([CH3:38])[C@@:32]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:31][CH2:30][C@H:29]4[C@@H:24]3[CH2:23][CH2:22][C:21]1=[CH:20][C:18](=[O:19])[CH2:17][CH2:16]2.[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O-:6])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)CCCBr
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: [K+]
Product: O=C([O-])CCCBr
Reaction time: 120 h

Procedure:
Five portions of 4-bromobutanoylchloride (0.35 ml×5) and potassium carbonate (0.4 g×5) were added in 24 hours to a solution of hydrocortisone (1 g) in CHCl, dried over P2O5 and stirred for 5 days. The solution was treated with water, the organic phase was separated, dried (Na2SO4) and deprived of the solvent at reduced pressure.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([O:6][C:7]1[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:9]([CH:8]=1)[C:17]([O:19][CH3:20])=[O:18])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(OS(C)(=O)=O)cc(C(=O)OC)c1
Yield: 100.5 %

Procedure:
MsCl (0.16 mL, 0.234 g, 2.06 mmol, 1.1 eq) was added to a stirred solution of dimethyl 5-hydroxyisophthalate (0.40 g, 1.86 mmol, 1 eq) and Et3N (0.78 mL, 0.56 g, 5.6 mmol, 3 eq) in 5 mL anhydrous CH2Cl2 at 0° C. under Ar. The reaction was stirred at 0° C. to room temperature over the weekend. The reaction was quenched with water, and the layers were separated. The organic layer was washed with water (×2), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo yielding 0.54 g (1.87 mmol, 100% yield) of dimethyl 5-(methylsulfonyloxy)isophthalate.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].Cl.C(N=C=NCCCN(C)C)C>>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:28]1[CH2:29][CH2:30][CH2:31][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:26][CH2:27]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CCOC(=O)c1cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc2[nH]1

Procedure:
The title compound was synthesized in analogy to Example 1, from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, [1,4]diazepane-1-carboxylic acid tert-butyl ester and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as a white solid (69%).
Reaction SMILES: O.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7](O)[C:8]([O-])=O)=[CH:5][CH:4]=1.[Na+].[C-]#[N:16].[Na+].C(=O)([O-])[O-].[K+].[K+].C(OC)=O>CO>[OH:2][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][C:8]#[N:16])=[CH:5][CH:4]=1
Reactant: O=C([O-])C(O)c1ccc(O)cc1
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: COC=O
Solvent: O
Product: N#CCc1ccc(O)cc1
Yield: 90.2 %

Procedure:
A mixture of sodium p-hydroxymandelate monohydrate (208 g.), sodium cyanide (49 g.), potassium carbonate (69 g.), methyl formate (80 ml.) and methanol (300 ml.) is heated under reflux for 8 hours, the temperature being maintained below 58° C. as methyl formate is consumed in the early stages of the reaction by the dropwise addition of further methyl formate (120 ml.). The mixture is cooled and acidified to pH 4 with concentrated aqueous hydrochloric acid (90 ml.), and water (300 ml.) is added dropwise whilst the mixture is distilled under reduced pressure, until the final volume of the two-layer mixture is 530 ml. The upper organic layer is collected and the lower aqueous layer is extracted twice with methyl isobutyl ketone (80 ml. each time). The extracts and organic layer are combined and the mixture is washed with saturated sodium chloride solution (100 ml.) and then with water (80 ml.). The methyl isobutyl ketone is removed by evaporation and there is thus obtained as residue p-hydroxybenzyl cyanide (120 g.) which is suitable for conversion to p-hydroxyphenylacetamide without further purification.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:12])[CH3:11].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:8][CH2:9][C:10]([NH:13][C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])([CH3:11])[CH3:12])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
Dichloromethane (50 mL) and triethylamine (9.72 ml, 69.7 mmol) were added to a flask containing tert-butyl (1-hydroxy-2-methylpropan-2-yl)carbamate (3.30 g, 17.4 mmol). The reaction mixture was stirred and then chilled to 0° C. for 10 minutes. Methanesulfonyl chloride (2.72 ml, 34.9 mmol) was dissolved in dichloromethane (15 mL) and slowly added to the reaction mixture, which was then allowed to stir at 0° C. for 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate solution and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-((tert-butoxycarbonyl)amino)-2-methylpropyl methanesulfonate. 1H NMR (500 MHz, DMSO-d6): δ 6.73 (s, 1H), 4.20 (s, 2H), 3.12 (s, 3H), 1.36 (s, 9H), 1.17 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([O:20][CH3:21])(=[O:19])[C:12]([CH2:14][C:15](OC)=[O:16])=[CH2:13]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15](=[O:16])[CH2:14][CH:12]([C:11]([O:20][CH3:21])=[O:19])[CH2:13]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: C=C(CC(=O)OC)C(=O)OC
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1
Temperature: 120 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A mixture of (4-methoxyphenyl)methanamine (6.9 g) and dimethyl itaconate (7.9 g) was stirred at 120° C. for 2 hours. After cooling, ethyl acetate was added to the reaction solution. The organic layer was washed with 1 N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (12.7 g).