Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:10]([CH3:31])[CH:9]=2)=[N:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][C@@H:34]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:33]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([N:32]4[CH2:37][CH2:36][CH2:35][C@@H:34]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:33]4)=[O:27])=[CH:29][CH:30]=3)[CH2:15][CH2:16][C:17]([F:19])([F:18])[F:20])=[C:10]([CH3:31])[CH:9]=2)=[N:4][CH:3]=1
Reactant: Cc1cc(-c2ncc(Cl)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-c4ncc(Cl)cn4)cc3C)cc2)C1

Procedure:
A solution of 4-((1-(4-(5-chloropyrimidin-2-yl)-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoic acid, ethyl (3R)-piperidine-3-carboxylate (6.40 mL), 1-hydroxybenzotriazole (5.61 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.96 g) and diisopropylethylamine (7.25 mL) in dimethylformamide (60 mL) was stirred at room temperature overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (8.88 g).
Reaction SMILES: CO.O.[CH3:4][O:5][C:6]1[CH:22]=[CH:21][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)=[CH:8][CH:7]=1>CO.O.[Fe]>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[NH2:18])=[CH:21][CH:22]=1
Reactant: COc1ccc(COc2cccc([N+](=O)[O-])c2)cc1
Agent: [Fe]
Solvent: O
Solvent: CO
Product: COc1ccc(COc2cccc(N)c2)cc1
Yield: 99.2 %

Procedure:
Fe (5.6 g, 100.28 mmol) was mixed with methanol:H2O (15 ml:3 ml) and refluxed for 30 minutes. After the temperature is dropped to room temperature, 1-(4-methoxybenzyloxy)-3-nitrobenzene (1.3 g, 5.01 mmol) dissolved in 6 ml of methanol:H2O (5:1) was added and then refluxed for 15 hours. Fe was removed using cellite, then the reaction mixture was washed using methanol and concentrated under vacuum to remove the solvent. After extraction with 100 ml of saturated ammonium chloride+150 ml of dichloromethane, the organic layer was washed with water. The organic solvent was concentrated under vacuum to obtain the title compound (1.14 g, 99%).
Reaction SMILES: [C:1]([C:3]([S:6][N:7]([CH3:11])[C:8](F)=[O:9])([CH3:5])[CH3:4])#[N:2].[OH:12][C:13]1[CH:14]=[N:15][N:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:3]([S:6][N:7]([CH3:11])[C:8](=[O:9])[O:12][C:13]1[CH:14]=[N:15][N:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: CN(SC(C)(C)C#N)C(=O)F
Reactant: CC(C)n1cc(O)cn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)n1cc(OC(=O)N(C)SC(C)(C)C#N)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
12 g (0.075 mole) of N-(2-cyanoprop-2-ylsulphenyl)-N-methyl-carbamoyl fluoride are added dropwise to a mixture of 9.45 g (0.075 mole) of 4-hydroxy-1-isopropylpyrazole, 8.5 g (0.085 mole) of triethylamine and 100 ml of toluene at 25° C. When the addition has ended, the mixture is stirred at room temperature for 18 hours. For working up, the reaction mixture is washed twice with water, dried over sodium sulphate and freed from the solvent in vacuo. 18 g (85% of theory) of O-(1-isopropylpyrazol-4-yl) N-(2-cyanoprop-2-ylsulphenyl)-N-methyl-carbamate are obtained in the form of a yellow oil of refractive index nD21 1.5070.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:4]=1[C:5]([O:7]C)=O.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C@H:27]([NH2:33])[CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH3:17].C(=O)([O-])O.[Na+]>CN(C)C=O>[N+:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:3]2[C:4]=1[C:5](=[O:7])[N:33]([C@@H:27]([C:21]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([O:18][CH2:16][CH3:17])[CH:20]=1)[CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:2]2)([O-:15])=[O:14]
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Temperature: 72.5 °C
Reaction time: 2 h

Procedure:
(1S)-7-nitro-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one was prepared by the following procedure. A mixture of methyl 2-bromomethyl-6-nitrobenzoate (100.0 g, 365 mmol, prepared previously in Example 6.5.2.), (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (104.7 g, 383 mmol, prepared previously in Example 6.5.3.), sodium hydrogen carbonate (67.5 g, 8.03 moles, from Aldrich Chemicals) and dimethyl formamide (500 mL) was charged into a 1-L 3-necked flask at room temperature under nitrogen. The reaction mixture was gradually heated to an internal temperature of 70-75° C. for two hours until there was less than <2% of unreacted methyl 2-bromomethyl-6-nitrobenzoate. The reaction mixture was gradually heated to an internal temperature of 95-100° C. for 18 hours. The reaction mixture was cooled to 20-25° C. and transferred to an 1-L addition funnel. After purified water (1500 mL) was charged into a 5-L 3-necked flask, the reaction mixture in the addition funnel was added into water in the 5-L 3-necked flask at room temperature over 1-2 hours maintaining an internal temperature below 30° C. The reaction mixture was stirred for 2 hours at room temperature. The solid was filtered out under vacuum, washed with water (3×300 mL) and methanol (2×400 mL), and then charged into a 2-L 3-necked flask followed by methanol (1000 mL). The mixture was refluxed for 1 hour. The mixture was cooled to room temperature. The solid was collected by filtration under vacuum, washed with 200 mL methanol (2 vol), and dried to a constant weight at 40-45° C. under a vacuum at 100-120 torr. The yield of (1S)-7-nitro-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one was 123.0 g (78%), based on 100.0 g input of methyl 2-bromomethyl-6-nitrobenzoate. The product was found to have a purity of >99% measured by HPLC based on area percentage, and a water content of <0.1% measured by Karl Fisher titration.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[CH3:39][N:40]1[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][CH:42]=[N:41]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:39][N:40]1[C:44]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]2[N:22]=[C:21]([O:23][C@H:24]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]43[CH2:27][CH2:26]4)[CH:20]=[N:19][CH:18]=2)=[CH:43][CH:42]=[N:41]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Temperature: 150 °C
Yield: 100 %

Procedure:
(4R)-tert-Butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (158 mg, 0.270 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Aldrich, St. Louis, Mo.; 84 mg, 0.405 mmol), PdCl2(Amphos) (Aldrich, St. Louis, Mo.; 19.14 mg, 0.027 mmol), and potassium phosphate (172 mg, 0.811 mmol) in a mixture of dioxane (2.5 mL) and water (0.250 mL) was heated by microwave at 150° C. for 5 min. The resulting mixture was heated at 100° C. for 3 h. The mixture was subsequently concentrated onto silica gel and chromatographically purified (ISCO, 12 g silica gel column, 0-80% EtOAc/hexanes, 15 min, 254 nm) to provide (4R)-tert-butyl 4-(6-(5-(1-methyl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (158 mg, 0.270 mmol, 100% yield) as a light-yellow oil: 1H NMR (400 MHz, CDCl3) δ ppm 9.06 (1 H, s), 8.43 (1 H, s), 8.21 (1H, br. s.), 7.76 (1 H, d, J=8.6 Hz), 7.58 (1 H, s), 7.49 (1 H, d, J=8.4 Hz), 6.33 (1H, s), 5.86 (1 H, d, J=7.6 Hz), 4.57 (1 H, br. s.), 4.31-4.40 (1 H, m), 4.19-4.29 (1 H, m), 4.06 (1 H, d, J=11.0 Hz), 3.93 (3 H, s), 3.75-3.87 (1 H, m), 3.15 (1 H, d, J=14.1 Hz), 2.92 (1 H, br. s.), 2.60-2.74 (1 H, m), 2.43 (1 H, br. s.), 2.25 (1 H, m, J=9.0, 4.1 Hz), 2.17 (1 H, d, J=14.9 Hz), 1.76-1.91 (2 H, m), 1.74 (2 H, br. s.), 1.13 (9 H, br. s.), 0.78-0.88 (2 H, m), 0.62-0.73 (2 H, m). MS (ESI, pos. ion) m/z: 586.4 (M+1).
Reaction SMILES: [CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][O:17][CH2:18][CH2:19]O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(C(C(C(O)=O)O)O)(O)=O.[NH:42]1[CH2:47][CH2:46][CH2:45][C@@H:44]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43]1.C(O)(=O)C(C(C(O)=O)O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.C(N(CC)CC)C>[CH2:51]([O:50][C:48]([C@@H:44]1[CH2:45][CH2:46][CH2:47][N:42]([CH2:19][CH2:18][O:17][CH2:16][CH2:15][N:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[S:6][C:5]3[C:14]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:43]1)=[O:49])[CH3:52]
Reactant: OCCOCCN1c2ccccc2Sc2ccccc21
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CS(=O)(=O)Cl
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(CCOCCN2c3ccccc3Sc3ccccc32)C1
Reaction time: 0.75 h
Yield: 36.1 %

Procedure:
A well-stirred mixture of the above alcohol (1.5 g, 5.2 mmol), triethylamine (1.8 ml) and toluene (20 ml) placed under an atmosphere of nitrogen was cooled on an ice-bath. A solution of methanesulfonyl chloride (1.5 g, 10.4 mmol) in toluene (5 ml) was added within 15 minutes. Stirring was continued for 45 minutes on an ice-bath and then for 30 minutes at room temperature. Water (15 ml) was added and the mixture was stirred at room temperature for 15 minutes. The phases were separated and the aqueous phase was extracted with toluene (20 ml). The combined organic extracts were washed with a 5% sodium bicarbonate solution, brine and then dried over sodium sulphate. The solvent was evaporated in vacuo to give an oil, which was dissolved in toluene (30 ml). To this solution was added potassium carbonate (2.5 g, 18.3 mmol) and ethyl (R)-3-piperidinecarboxylate tartrate (3.2 g, 10.4 mmol) and the suspension was heated at reflux temperature for 3 days. The cooled reaction mixture was filtered and the solid washed with a small portion of toluene. The solvent was evaporated from the filtrate in vacuo to give a residue, which was dissolved in a mixture of ethyl acetate (30 ml) and water (30 ml). A 34% aqueous solution of tartaric acid was added until pH 4. The phases were separated and the aqueous phase was extracted with ethyl acetate (15 ml). To the combined organic phases were added water (10 ml) and a 34% aqueous solution of tartaric acid (3.5 ml). The phases were separated and the organic phase was extracted with a mixture of water (10 ml) and a 34% aqueous solution of tartaric acid (2 ml). The acidic aqueous phases are combined and washed with ethyl acetate (15 ml). All the organic phases were discarded and to the acidic aqueous phase was added ethyl acetate (50 ml) and water (50 ml). A 4 N sodium hydroxide solution was added until pH 8.5 and the phases were separated. The aqueous phase was extracted with ethyl acetate (15 ml) and the combined organic phases were washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo to give 0.8 g of (R)-N-(2-(2-(10H-phenothiazin-10-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.20 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1 ).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[C:11]=2[CH3:19])=[N:6]1)[CH3:4].[C:20]([C:23]1[O:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[O:24][CH:25]=[C:26]([C:28]([NH:1][CH2:2][C@@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[C:11]=3[CH3:19])=[N:6]2)[CH3:4])=[O:29])[N:27]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1nc(C(=O)O)co1
Reactant: Cc1c(-c2ccn([C@@H](C)CN)n2)ccc(C#N)c1Cl
Product: CC(=O)c1nc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3C)n2)co1
Yield: 33.4 %

Procedure:
(S)-2-acetyl-N-(2-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propyl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from ((S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (549 mg, 2.00 mmol) and 2-acetyloxazole-4-carboxylic acid (372 mg, 2.40 mmol). The product was purified by Flash-chromatography. Yield 33.4%. 1H-NMR (400 MHz; CDCl3): δ 1.63 (d, 3H), 2.58 (d, 3H), 2.60 (s, 3H), 3.78-3.98 (m, 2H), 4.60-4.71 (m, 1H), 6.44 (d, 1H), 7.44-7.62 (m, 4H), 8.31 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[C:12](O)(=[O:14])[CH3:13]>C1(C)C=CC=CC=1>[C:12]([O:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4])(=[O:14])[CH3:13]
Reactant: CC(O)C(=O)O
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC(=O)OC(C)C(=O)O
Yield: 92 %

Procedure:
Reflux a mixture of 2-hydroxy-propionic acid (480 ml, 85% in water) and sulfuric acid (2 mL) in acetic acid (2500 mL) and toluene (300 mL) for overnight. After removal of solvent under vacuum, purify the residue by distillation to give 2-acetoxy-propionic acid (550 g, 92%) as colorless oil. 1H NMR (CDCl3, 400 MHz): δ 9.27 (brs, 1H), 5.10 (m, 1H), 2.13 (s, 3H), 1.53 (d, J=7.2, 3H).
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]([O:15][C:16]([NH:18][CH:19]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:20][CH2:21][C:22](O)=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12].C1C=CC2N(O)N=NC=2C=1.CNC(N=C=NCC)CCNC>C(Cl)Cl.CCOC(C)=O>[C:11]([O:15][C:16](=[O:17])[NH:18][CH:19]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:20][CH2:21][C:22](=[O:23])[N:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:8][CH2:9][OH:10])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC(CCC(=O)O)C1CCCCC1
Reactant: OCCNC1CCCCC1
Agent: CCN=C=NC(CCNC)NC
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCC(=O)N(CCO)C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of N-cyclohexylethanolamine (0.55 g, 3.9 mmol) and 4-tert-butoxycarbonylamino-4-cyclohexyl-butyric acid (1.0 g, 3.5 mol), in DCM (200 mL), HOBT (0.62 g, 4.5 mmol) and TEA (1.0 mL) were added followed by addition of 1,3-dimethylamino propyl-3-ethylcarbodiimide (EDC, 0.87 g, 4.5 mmol). The reaction mixture was allowed to warm to room temperature and then stirred overnight. EtOAc (300 mL) was added to the reaction mixture. The reaction mixture was then washed with aqueous citric acid solution, saturated NaHCO3 solution, and NaCl solution. The organic layer was collected, dried with MgSO4, and then evaporated to yield {1-cyclohexyl-3-[cyclohexyl-(2-hydroxy-ethyl)-carbamoyl]-propyl}-carbamic acid tert-butyl ester as an oil, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16](=O)[CH3:17])=[CH:11][C:10]=1[CH3:19])([CH3:7])[CH3:6])[CH3:2].[F:21][C:22]([F:41])([F:40])[O:23][C:24]1[CH:25]=[C:26]([C:30]#[C:31][CH2:32]CCOS(C)(=O)=O)[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][CH2:17][CH2:32][C:31]#[C:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:22]([F:21])([F:40])[F:41])[CH:25]=2)=[CH:11][C:10]=1[CH3:19])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SC(C)=O)cc1C
Reactant: CS(=O)(=O)OCCCC#Cc1cccc(OC(F)(F)F)c1
Product: CCOC(=O)C(C)(C)Oc1ccc(SCCCC#Cc2cccc(OC(F)(F)F)c2)cc1C

Procedure:
In analogy to the procedure described in example 1D], 2-(4-acetylsulfanyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 1C]) was reacted with methanesulfonic acid 5-(3-trifluoromethoxy-phenyl)-pent-4-ynyl ester (example 3D]) to give 2-methyl-2-{2-methyl-4-[5-(3-trifluoromethoxy-phenyl)-pent-4-ynylsulfanyl]-phenoxy}-propionic acid ethyl ester as light brown oil.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH:14]([C:23](=[O:48])[NH:24][CH:25]([C:41](=[O:47])[NH:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)[NH:15]C(OC(C)(C)C)=O)[N:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:15][CH:14]([CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)[C:23]([NH:24][CH:25]([C:41](=[O:47])[NH:42][C:43]([CH3:45])([CH3:46])[CH3:44])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:32]=1)=[O:48]
Reactant: CC(C)(C)NC(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)C(Cc1cn(C(=O)OC(C)(C)C)cn1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)C(N)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
A solution of [S—(R*,R*)]-4-{2-[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylcarbamoyl]-2-tert-butoxycarbonylamino-ethyl}-imidazole-1-carboxylic acid tert-butyl ester (1.92 g, 2.87 mmol) in 70 mL dichloromethane was cooled to 3° C., then TFA (14 mL) was added. The resulting solution was warmed to 25° C. and stirred 2 hours. The mixture was concentrated at reduced pressure to a viscous amber oil which was dissolved in 100 mL ethyl acetate and washed twice with 100 mL saturated aqueous sodium bicarbonate solution and twice with 100 mL brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure affording 1.18 g (85%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]([CH3:13])[C:9](=[O:12])OC)=[CH:6][C:5]([F:14])=[CH:4][N:3]=1.[C:15]([O:19][C:20](=[O:27])[NH:21][C@H:22]1[CH2:25][C@H:24]([NH2:26])[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1.O>[C:15]([O:19][C:20](=[O:27])[NH:21][C@H:22]1[CH2:25][C@H:24]([N:26]2[C:2]3=[N:3][CH:4]=[C:5]([F:14])[CH:6]=[C:7]3[N:8]([CH3:13])[C:9]2=[O:12])[CH2:23]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)N(C)c1cc(F)cnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(=O)n([C@H]2C[C@H](NC(=O)OC(C)(C)C)C2)c2ncc(F)cc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Methyl (2-chloro-5-fluoropyridin-3-yl)(methyl)carbamate (intermediate 37, 0.343 g, 1.569 mmol), tert-butyl(trans-3-aminocyclobutyl)carbamate (0.292 g, 1.569 mmol), BrettPhos Precatalyst (0.125 g, 0.157 mmol), and sodium tert-butoxide (0.377 g, 3.92 mmol) were mixed in 1,4-dioxane (2 mL) under an argon atmosphere. The reaction mixture was heated to 50° C. and stirred for 30 min. The reaction mixture was diluted with water and extracted once with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography eluting with EtOAc in hexanes to yield tert-butyl(trans-3-(6-fluoro-1-methyl-2-oxo-1 h-imidazo[4,5-b]pyridin-3(2h)-yl)cyclobutyl)carbamate (0.250 g, 0.743 mmol, 47.4% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[CH:24]=[N:25][C:26](S(C)(=O)=O)=[N:27][CH:28]=3)[CH2:13][CH2:12]2)=[O:10])[N:3]=1.CN.C[CH2:36][N:37](C(C)C)C(C)C>C(O)(C)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[CH:24]=[N:25][C:26]([NH:37][CH3:36])=[N:27][CH:28]=3)[CH2:13][CH2:12]2)=[O:10])[N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3-c3cnc(S(C)(=O)=O)nc3)CC2)n1
Agent: CN
Solvent: CC(C)O
Product: CNc1ncc(-c2ccccc2N2CCN(C(=O)Cn3nc(C)cc3C)CC2)cn1
Reaction time: 0.25 h
Yield: 42 %

Procedure:
The above sulfone (40 mg, 0.088 mmol) is added to a 0.5-2 mL Biotage microwave tube followed by methylamine (2M in THF, 0.22 mL, 0.44 mmol), Hunig's base (0.045 mL, 0.264 mmol) and isopropanol (1 mL). The reaction is carried out in a microwave oven at 175° C. for 15 min. After cooling, the mixture is filtered and purified via prep-HPLC. Removal of the solvent gives the title compound as colorless foam (15 mg).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C:13]1[CH:30]=[CH:29][C:16]2[C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][CH3:27])[O:22][C:21]3=[O:28])=[CH:18][O:19][C:15]=2[CH:14]=1.C(N(CC)CC)C>ClCCl.O>[CH:12]([C:13]1[CH:30]=[CH:29][C:16]2[C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][CH3:27])[O:22][C:21]3=[O:28])=[CH:18][O:19][C:15]=2[CH:14]=1)=[O:11]
Reactant: COC[C@H]1CN(c2coc3cc(CO)ccc23)C(=O)O1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC[C@H]1CN(c2coc3cc(C=O)ccc23)C(=O)O1
Reaction time: 0.25 h

Procedure:
1 ml (14.4 mmol) of dimethyl sulphoxide in 20 ml of dichloromethane is added to a solution, cooled to -70° C., of 0.75 ml (8.6 mmol) of oxalyl chloride in 20 ml of dichloromethane. The mixture is stirred for 15 min and a solution of 2.0 g (7.2 mmol) of (R)-3-[6-(hydroxymethyl)benzofuran-3-yl]-5-(methoxymethyl)oxazolidin-2-one in 35 ml of dichloromethane is slowly added. The mixture is stirred for three hours at -70° C. and 5.0 ml (36 mmol) of triethylamine are added. After returning to room temperature, the mixture is poured into 50 ml of water, the product is extracted with dichloromethane and the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The product is purified by chromatography on silica gel and an oil is recovered which is crystallized from ethyl ether.
Reaction SMILES: C(N(CC)CC)C.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.[N+:15]([C:18]1[CH:29]=[C:28]2[C:21]([NH:22][CH:23]=[C:24]2[CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=1)([O-])=O>CN(C1C=CN=CC=1)C.ClCCl>[CH3:8][O:13][C:11]([NH:15][C:18]1[CH:29]=[C:28]2[C:21](=[CH:20][CH:19]=1)[NH:22][CH:23]=[C:24]2[CH2:25][CH2:26][NH:27][C:11](=[O:12])[CH2:10][CH2:9][C:8]([OH:13])=[O:14])=[O:12]
Reactant: NCCc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1ccc2[nH]cc(CCNC(=O)CCC(=O)O)c2c1
Reaction time: 4 h

Procedure:
Triethylamine (12 mmol), DMAP (0.6 mmol), and succinic anhydride (9 mmol) are added to a solution of 5-nitrotryptamine (6 mmol) in dichloromethane (25 mL). The mixture is stirred 4 h, the solvent removed in vacuo, and the residue chromatographed on silica gel using 10% methanol-chloroform with 1% acetic acid as eluent. The product is then hydrogenated and transformed to the carbamic acid methyl ester as in the previous examples. Purified product is obtained by reverse-phase HPLC as above.