Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=1.[C:16]([O-])(O)=O.[Na+]>CO>[NH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccc(C(=O)O)n1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(N)n1

Procedure:
H2SO4 (3.0 eq.) was added to a suspension of 6-aminopyridine-2-carboxylic acid in MeOH (0.3 M). The reaction mixture was heated to reflux for 20 h. After cooling down, the solvent was reduced in vacuo and the residue was added to cooled sat. aq. NaHCO3. The aqueous phase was extracted with DCM (2×) and the combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent yielded the title compound as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6, 300K) δ 7.50 (1H, t, J=7.8 Hz), 7.18 (1H, d, J=7.3 Hz), 6.65 (1H, d, J=8.3 Hz), 6.28 (2H, bs), 3.79 (3H, s). MS (ES+) C7H8N2O2 requires: 152, found: 153 (M+H)+.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:6]=1[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])(=[O:4])=[O:3].[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH2:18]([NH:22][C:23]([NH:1][S:2]([C:5]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:6]=1[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])(=[O:4])=[O:3])=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN=C=O
Reactant: CC(C)OC(=O)c1ccc(Cl)cc1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1cc(Cl)ccc1C(=O)OC(C)C
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A mixture of 1063.4 g of isopropyl 2-(aminosulfonyl)-4-chlorobenzoate, 590.4 g of n-butyl isocyanate and 590.4 g of K2CO3 in 10.8 liters of 2-butanone are heated under reflux overnight. After cooling to room temperature, the reaction mixture is in each case poured into 10 liters of ice-water. The aqueous phase is extracted with 9 liters of methylene chloride. The aqueous phase is acidified to pH 1.0 using concentrated HCl, and the resulting precipitate is filtered off. After drying, 714.6 g of isopropyl 2-[N-(N-butylaminocarbonyl)aminosulfonyl]-4-chlorobenzoate (44% of theory) of melting point 129-132° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:17].[H-].[Na+].[CH2:21](Cl)[O:22][CH3:23]>C1COCC1>[CH3:21][O:22][CH2:23][O:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:7]1([CH2:8][CH2:9][CH2:10]1)[CH2:6][C:5]2=[O:17]
Reactant: COCCl
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC1(CCC1)O2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1c(C)c(C)c2c(c1C)C(=O)CC1(CCC1)O2
Reaction time: 0.08 h

Procedure:
To a solution of 6-Hydroxy-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one (2.2 g) in 20 mL of THF at 0° C. was added sodium hydride (370 mg, 60% in mineral oil). After 5 min, MOM-Cl (0.96 mL) was added slowly to the reaction. After the reaction was complete, the mixture was extracted with ethyl acetate and was washed with water. The organic layer was separated and dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with 20% ethyl acetate in hexane to give 2.0 g of 6-(methoxymethoxy)--5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one as a yellow paste.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[C:8]([NH:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])=[N:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[N:11][CH:12]=1.[C:27]([N:34]([CH3:40])[C@H:35]([C:37](O)=[O:38])[CH3:36])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C.O>[F:20][C:16]1[CH:15]=[C:14]([NH:13][C:10]2[N:9]=[C:8]([NH:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[C:7]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][NH:1][C:37](=[O:38])[C@@H:35]([N:34]([CH3:40])[C:27](=[O:28])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH3:36])=[CH:12][N:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COCCCNc1nc(Nc2cccc(F)c2)ncc1C#CCCCN
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COCCCNc1nc(Nc2cccc(F)c2)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of 5-(5-amino-1-pentyn-1-yl)-N2-(3-fluorophenyl)-N4-(3-methoxypropyl)pyrimidine-2,4-diamine (J7, 55 mg), N-Boc-N-methyl-L-alanine (63 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (59 mg) and 1-hydroxybenzotriazole monohydrate (42 mg) in N,N-dimethylformamide (700 μL), N,N-diisopropylethylamine (108 μL) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain (S)-tert-butyl (1-((5-(2-((3-fluorophenyl)amino)-4-((3-methoxypropyl)amino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (J8, 84 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([F:1])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)cc1F
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc(C)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
A solution of 3-fluoro-4-methyl-benzoic acid (2.5 g, 16.2 mmol) in acetone (27.0 mL) was treated with potassium carbonate (5.83 g, 42.2 mmol) and dimethyl sulfate (6.14 g, 4.6 mL, 48.7 mmol). The reaction was stirred at 25° C. for 24 h and then was heated to 90° C. for 8 h. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. for 6 days. At this time, the reaction was filtered through a sintered glass funnel. The potassium carbonate cake was washed thoroughly with acetone. The filtrate was concentrated in vacuo. The residue was then taken up in ethyl acetate (30 mL) and triethylamine (7 mL) and stirred at 25° C. for 30 min. The solution was then transferred to a separatory funnel and washed with water (1×75 mL), a 2N aqueous hydrochloric acid solution (1×75 mL), and a saturated aqueous sodium chloride solution (1×75 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 3-fluoro-4-methyl-benzoic acid methyl ester (2.26 g, 82.9%) as a light yellow oil. ES+-HRMS m/e calcd for C9H9O2F [M+H+] 169.0660. Found 169.0659. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.70 (dd, J=7.8, 1.5 Hz, 1H) 7.62 (dd, J=10.3, 1.5 Hz, 1H) 7.46 (t, J=7.8 Hz, 1H) 3.85 (s, 3H) 2.31 (d, J=1.5 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C1COCC1.[OH-].[Na+]>CO>[O:25]1[CH2:24][CH2:23][CH:22]([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([S:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=3)(=[O:12])=[O:11])[CH:14]=2)[CH2:27][CH2:26]1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCOCC3)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCOCC3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Add to a suspension of 4-[3-(tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzoic acid methyl ester (16.7 g, 41.83 mmol) in methanol (200 mL) with stirring THF (600 mL). Treat the solution with 5N NaOH (23.5 ml, 2.8 eq.) and stir for 2 h at room temperature. Concentrate the solution to near dryness and treat with 1N HCl (125 mL), a solid separates. Dilute to 500 mL total volume with water, filter, back-wash with water, and dry (20 mm Hg, 60° C.) to give a resulting solid found to be pure title compound (15.8 g, 98%); 1H NMR(DMSO-d6) 13.57 (s, 1H), 8.08 (m, 4H), 7.93 (d, J=8.2 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.57 (s, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.27 (t, J=7.1 Hz, 1H), 3.95 (m, 2H), 3.47 (t, J=12.0 Hz, 2H), 3.03 (m, 1H), 1.85 (m, 2H), 1.70 (m, 2H); MS(ESI) m/z 384 (m−H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:35])C(=O)C1.[NH4+].[Cl-].CCOCC>C(#N)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:25])([F:23])[F:24])=[CH:14][CH:15]=2)[C:10]([Cl:35])=[C:9]1[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOCC
Product: Cc1c(Cl)c2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of 100 mg (0.26 mmol) of 2-(1-benzyl-2-methyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 80) in 1 mL of acetonitrile were added 25 mg (0.185 mmol) of NCS. After stirring at RT for 2 hrs, the mixture was poured into a mixture of a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/CH2Cl2 1:3 yielded 70 mg (65%) of 2-(1-benzyl-3-chloro-2-methyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, white solid, MS: 420 ((M−H−), 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:31][CH2:30][N:29]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:28]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
4-Chlorobenzyl chloride (4.15 g, 25.8 mmol) and i-Pr2NEt (6.67 g, 51.6 mmol) were added to the DMF solution (50 mL of 3-{(tert-butoxycarbonyl)amino}pyrrolidine (4.81 g, 25.8 mmol) in DMF (50 ml). The reaction mixture was stirred at 70° C. for 15 hours, and the solvent was then removed under reduced pressure. The residue was recrystallized (CH3CN, 50 mL) to obtain the objective 3-{(tert-butoxycarbonyl)amino}-1-(4-chlorobenzyl)pyrrolidine (6.43 g, 80%) as the yellowish white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][N:20]=1)=[O:18]>C(OCC)(=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][N:20]=1)=[O:18]
Reactant: CCOC(=O)n1c(C(=O)c2cc(OC)ccn2)c(N)c2ccc(Cl)cc21
Solvent: CCOC(C)=O
Product: COc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-amino-6-chloro-1-(ethoxycarbonyl)-2-(4-methoxypyridine-2-carbonyl)indole (step 1). m.p.: 195-196° C. (ethyl acetate)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][CH2:12][C:13]#[N:14])=[O:9])=[C:5]([CH3:7])[N:6]=1.NC1SC(C(NCC)=O)=C(C)N=1.[CH2:27]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([C:34]1[CH:35]=[CH:36][C:37]([C:38]([NH:1][C:2]2[S:3][C:4]([C:8]([NH:10][CH2:11][CH2:12][C:13]#[N:14])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[O:39])=[CH:41][CH:42]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1nc(N)sc1C(=O)NCCC#N
Reactant: O=C(Cl)c1ccc(Cc2ccccc2)cc1
Agent: CCNC(=O)c1sc(N)nc1C
Product: Cc1nc(NC(=O)c2ccc(Cc3ccccc3)cc2)sc1C(=O)NCCC#N

Procedure:
Following the procedure as described in Example 20, making variation only as required to use 2-amino-N-(2-cyanoethyl)-4-methylthiazole-5-carboxamide to replace 2-amino-N-ethyl-4-methylthiazole-5-carboxamide to react with 4-benzylbenzoyl chloride, the title compound was obtained; 1H NMR (CD3OD, 400 MHz) δ 7.90 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.6 Hz, 2H), 7.27-7.10 (m, 5H), 4.03 (s, 2H), 3.54 (t, J=6.6 Hz, 2H), 2.73 (t, J=6.6 Hz, 2H), 2.54 (s, 3H), 2.32 (s, 1H); MS (ES+) m/z 405 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]1[NH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)=[CH:31][N:32]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(COC)OC>C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C.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:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]1[NH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:14]=3)=[CH:35][CH:34]=2)=[CH:31][N:32]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Brc1ccnc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
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: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccnc(OCc4ccccc4)c3)cc2)[nH]1
Temperature: 85 °C
Yield: 96.5 %

Procedure:
A mixture of 2-Benzyloxy-4-bromo-pyridine (0.292 g), 2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.533 g, prepared according to WO2008021927 A2) and Pd(PPh3)4 (0.064 g) in aq. K2CO3 solution/dimethoxyethane (1.82 mL/5.0 mL) was heated at 80-90° C. for 8 hours. Reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexanes) to give 2-{5-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.530 g): LCMS-ESI+: calc'd for C30H33N4O3: 497.6 (M+H+). Found: 497.0 (M+H+).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][N:10]1[C:19]1[CH:24]=[C:23]([NH2:25])[CH:22]=[C:21]([CH3:26])[N:20]=1>C1COCC1.N1C=CC=CC=1>[CH2:6]([O:5][C:3](=[O:4])[C:2]([NH:25][C:23]1[CH:22]=[C:21]([CH3:26])[N:20]=[C:19]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)[CH:24]=1)=[O:8])[CH3:7]
Reactant: Cc1cc(N)cc(N2CCc3ccccc3C2)n1
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)Nc1cc(C)nc(N2CCc3ccccc3C2)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
With ice bath cooling, a solution of ethyl chlorooxoacetate (2.0 g, 14.6 mmol) in THF (25 ml) was dropwise added to a solution of 2-(3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-pyridin-4-yl-amine (example 4) (2.9 g, 12.1 mmol) in pyridine (40 ml). The mixture was stirred at 75° C. for 1 hr, evaporated and partitioned (AcOEt/NaHCO3-solution). The organic phase was dried (Na2SO4), concentrated and crystallized yielding 3.1 g (75%) of the title compound as light brown solid. Mp. 128-129° C. (AcOEt), MS: m/e=340 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([O:8]CC2C=CC=CC=2)[CH:6]([O:16]CC2C=CC=CC=2)[CH:5]([CH2:24][O:25]CC2C=CC=CC=2)[CH2:4][CH:3]1[OH:33]>CO.C(O)(=O)C.[Pd]>[NH2:1][CH:2]1[CH:3]([OH:33])[CH2:4][CH:5]([CH2:24][OH:25])[CH:6]([OH:16])[CH:7]1[OH:8]
Reactant: NC1C(O)CC(COCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: NC1C(O)CC(CO)C(O)C1O
Reaction time: 8 h

Procedure:
To a solution of Intermediate B (86.5 mg, 0.194 mmol) in MeOH (3 mL) and acetic acid (1 mL) was added Pd/C (10%, 102 mg, 0.097 mmol). The mixture was hydrogenated at 50 psi and at room temperature for 8 h. Catalyst was removed by filtration and solvents were evaporated under reduced pressure to give the product rac-(1R,2R,3S,4S,6R)-3-amino-6-(hydroxymethyl)cyclohexane-1,2,4-triol as the acetic acid salt (46 mg, 100%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 4.07 (brs, 1H), 3.66-3.58 (m, 3H), 3.20 (t, J=9.5 Hz, 1H), 2.85 (brs, 1H), 1.93-1.85 (m, 2H), 1.86 (s, 3H), 1.42 (t, J=13.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2.[CH:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([CH3:22])[CH3:21].N1C=CC=CC=1.O>ClCCl.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[CH:20]([C:23]1[CH:28]=[C:27]([N:9]2[C:10]3[C:6](=[CH:5][C:4]([O:3][C:2]([F:1])([F:18])[F:19])=[CH:12][CH:11]=3)[CH:7]=[C:8]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)ccc2[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)ccc2n1-c1cccc(C(C)C)c1
Yield: 35 %

Procedure:
A mixture of 0.2 g (0.73 mmol) of ethyl 5-trifluoromethyloxy-1H-indole-2-carboxylate, of 0.24 g (1.46 mmol) of 3-isopropylphenylboronic acid, of 0.2 g (1.1 mmol) of copper diacetate and of 0.12 ml (1.46 mmol) of pyridine in 5 ml of dichloromethane is stirred in the presence of 4 Å molecular sieve at ambient temperature for 4 days. The mixture is poured onto 100 ml of water and 50 ml of dichloromethane. The organic phase is separated, washed with 1N hydrochloric acid, dried over magnesium sulfate and then concentrated under reduced pressure. The residue is purified by chromatography on a silica column, elution being carried out with a mixture of cyclohexane and of ethyl acetate. 0.1 g of product is obtained, which product is used as is in the following stage.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[Cl:20])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+].C(=O)([O-])O.[Na+]>C1COCC1.O>[Cl:20][C:14]1[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][OH:11]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(Cl)c1Cl
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CO)c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Of the compound from Example 181A, 702 mg (2.19 mmol) were dissolved in 7 ml of THF under argon and cooled to 0° C. Then 306 μl (2.19 mmol) of triethylamine and 313 μl (2.41 mmol) of isobutyl chloroformate were added dropwise. The suspension was stirred at 0° C. for 1 h. It was filtered through a Seitz frit into a cooled flask, with washing with a little THF. The resulting filtrate was added slowly dropwise to a solution, cooled to 0° C., of 249 mg (6.58 mmol) of sodium borohydride in 1.5 ml of water. After 1 h, the batch was cautiously admixed with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase was also washed once with saturated aqueous sodium hydrogen carbonate solution and once with saturated aqueous sodium chloride solution. It was dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. Drying in an HV gave 537 mg (56% of theory) of the title compound in 70% purity.
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:29][CH:28]=2)[C:10]=1[C:41]([O:43][CH2:44][CH3:45])=[O:42])C1C=CC=CC=1>CO.[Pd]>[CH3:25][N:23]([CH3:24])[C:22]([C:12]1[N:11]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:31][CH:32]=2)[C:10]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:9]([OH:8])[C:13]=1[OH:14])=[O:26]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OCCCS(C)(=O)=O)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OCCCS(C)(=O)=O)cc1
Yield: 58.7 %

Procedure:
A solution of ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-(3-(methylsulfonyl)propoxy)phenyl)-1H-pyrrole-2-carboxylate (44) (95 mg, 0.15 mmol) in MeOH (4 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 40° C. under H2 (full H2 mode). The output was concentrated in vacuo, and the compound was purified by preparative HPLC (C-18 column, 21.2 mm i.d.×100 mm, 5 micron particle size, gradient 15-40% MeCN in 0.1% aq. formic acid over 16 min) to afford ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-(3-(methylsulfonyl)propoxy)phenyl)-1H-pyrrole-2-carboxylate (UL1-110) (40 mg, 58%) as a yellow solid: m/z 455 (M+H)+ (ES+); 453 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.58 (s, 1H), 8.45 (s, 1H), 7.07-7.02 (m, 2H), 6.89-6.84 (m, 2H), 4.08 (t, J=7.2 Hz, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.29-3.25 (m, 2H), 3.02 (s, 3H), 2.92-2.71 (br s, 6H), 2.21-2.07 (m, 2H), 0.99 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][O:29][CH3:30])[CH:25]=[C:24]([Br:31])[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])C.[OH-].[Na+]>C(O)C.CCOC(C)=O>[Br:31][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([CH2:28][O:29][CH3:30])[CH:25]=1)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]1[C:10]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:39])=[O:3]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(COC)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCc1cc(Br)cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
To a solution of 4-[3-[6-(3-Bromo-5-methoxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (500 mg, 0.82 mmol) in hot ethanol (20 mL) was added aqueous 2.0 N sodium hydroxide (5 mL). The resulting solution was heated to 60° C. and stirred for 4 h. Then, the reaction mixture was cooled down and diluted with EtOAc, washed with 10% aq. HCl and brine. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford 400 mg (89%) of title compound as a light yellow oil. HR-ES(+) calcd for C27H35O7Br [M+Na]+ 573.1458, observed 573.1459.