Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[N:29]=[CH:30][N:31]([CH3:33])[CH:32]=4)[N:26]=3)[N:21](COCC[Si](C)(C)C)[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C1(C2N=C3C(C(N[C@H](C(C)(C)C)C(=O)N4CCCC4)=O)=CN(COCC[Si](C)(C)C)C3=NC=2)CC1>>[C:1]([CH:3]1[CH2:4][CH2:5][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[N:29]=[CH:30][N:31]([CH3:33])[CH:32]=4)[N:26]=3)[NH:21][CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: Cn1cnc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C(C)(C)C)cn3COCC[Si](C)(C)C)c1
Agent: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C(=O)N1CCCC1
Product: Cn1cnc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(C#N)CC4)C(C)(C)C)c3n2)c1

Procedure:
Prepared according to the procedure outlined in Example 1, Step 4 substituting 2-(1-methyl-1H-imidazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide for (R)-2-cyclopropyl-N-(3,3-dimethyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide. MS: (M+H)+=449.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:23])[CH3:22].[N:24]1C=CC=C[CH:25]=1.Cl.CN>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([S:18]([NH:24][CH3:25])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:23])[CH3:22]
Reactant: c1ccncc1
Reactant: CC1(C)CC(c2cccc(S(=O)(=O)Cl)c2)Nc2ccc(Cl)cc21
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNS(=O)(=O)c1cccc(C2CC(C)(C)c3cc(Cl)ccc3N2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-benzenesulfonyl chloride (234 mg, 0.63 mmol) was dissolved in dichloromethane (5 ml). Pyridine (5 ml) was added to the mixture. The resulting solution was cooled to 0° C., and methylamine hydrochloride (64 mg, 0.95 mmol) was added. The mixture was stirred at room temperature for 2 h. Solvent was removed and the residue was purified on Thin layer chromatography using petroleum ether/ethyl acetate=3:1 as eluent to afford 3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-N-methyl-benzenesulfonamide as white solid (100 mg, yield: 40%). MS (ESI+APCI) M+1=395.1.
Reaction SMILES: C([O:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:18]=2[C:19]([NH:21][CH2:22][C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH2:28][O:29][C:25]=3[CH:24]=2)=[O:20])[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.CO.[OH-].[Na+]>O1CCCC1>[OH:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:18]=2[C:19]([NH:21][CH2:22][C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH2:28][O:29][C:25]=3[CH:24]=2)=[O:20])[CH2:12][CH2:11]1
Reactant: O=C(O[C@H]1CC[C@@H](Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc3c(c2)OCO3)CC1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@@H](O)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(cis4-benzoyloxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (64.0 mg), methanol (5 mL), tetrahydrofuran (5 mL) and 1N-sodium hydroxide solution (1 mL) was stirred for 2 hours at 60° C. After evaporation of the organic solvent, the aqueous layer was diluted with water and extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (50.5 mg).
Reaction SMILES: [OH:1][CH:2]([CH:28]1[CH2:32][O:31]C(C)(C)[O:29]1)[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:26])(=[O:25])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[CH:8][CH:7]=1>CO.O>[OH:1][CH:2]([CH:28]([OH:29])[CH2:32][OH:31])[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:25])(=[O:26])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:24])([F:22])[F:23])[CH:15]=2)=[CH:8][CH:7]=1
Reactant: CC1(C)OCC(C(O)CNC(=O)c2ccc(S(=O)(=O)Nc3ccc(F)c(C(F)(F)F)c3)cc2)O1
Solvent: CO
Solvent: O
Product: O=C(NCC(O)C(O)CO)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1

Procedure:
Analogously to Example 1l(b), 3.8 g (7.5 mmol) of 4-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]-benzoic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] in methanol/water with cation exchanger is converted into the title compound. 1.74 g=83% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH:5]([NH2:11])[CH2:6][C:7]([F:10])([F:9])[F:8].C(N(CC)CC)C.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH2:28][S:29][C:30]#[N:31])=[CH:23][CH:22]=1>C(O)C>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]=[C:30]([NH:11][CH:5]([CH2:6][C:7]([F:9])([F:8])[F:10])[C:4]([O:3][CH3:2])=[O:12])[S:29][CH:28]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)C(N)CC(F)(F)F
Reactant: N#CSCC(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)C(CC(F)(F)F)Nc1nc(-c2ccc(Br)cc2)cs1
Temperature: 55 °C
Yield: 56 %

Procedure:
2-Amino-4,4,4-trifluoro-butyric acid methyl ester hydrochloride (1.1 g, 5.3 mmol) was dissolved in 30 mL of ethanol and 2-(4-bromophenyl)-2-oxoethyl thiocyanate, prepared in step 1 of Example 1, (1.23 g, 4.8 mmol) was added followed by triethylamine (0.73 mL, 5.3 mmol). The mixture was heated to 55° C. for 18 h then cooled and concentrated under reduced pressure. Flash chromatography (5% acetone/hexane) afforded methyl 2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}-4,4,4-trifluorobutanoate (1.21 g, 56%) as a white solid. mp 113-114° C. HRMS: calcd for C14H12BrF3N2O2S+H+, 408.98277; found (ESI, [M+H]+), 408.9831. Analytical HPLC: retention time 11.5 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:25])[CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:25])[CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2ccc(C(F)(F)F)cc2C1=O
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(N)cc1N1C(=O)c2ccc(C(F)(F)F)cc2C1=O

Procedure:
The mixture of 3.55 g of N-(4-nitro-o-tolyl)-4-trifluoromethylphthalimide, 200 ml of 95% aqueous ethanol and 0.18 g of 5% palladium on carbon is hydrogenated at 3.1 atm. and 45° until the hydrogen uptake ceases. It is filtered, evaporated and the residue recrystallized from ethanol, to yield the N-(4-amino-o-tolyl)-4-trifluoromethylphthalimide melting at 161°-163°.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]([F:28])([F:27])[CH2:17][O:18][C:19]1[N:24]=[C:23]([CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:26]([CH2:25][C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([O:18][CH2:17][C:16]([F:28])([F:15])[F:27])[N:24]=3)[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: NCc1cccc(OCC(F)(F)F)n1
Agent: Cl
Product: O=C1c2ccnc(Cl)c2CN1Cc1cccc(OCC(F)(F)F)n1
Yield: 60 %

Procedure:
The title compound is prepared in 60% yield (31 mg, white solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (38 mg, 0.14 mmol) and (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine hydrochloride (35 mg, 0.14 mmol, Amine-19) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])[CH3:2].[H-].[Na+].[Br:29][C:30]1[C:35]([CH2:36]Br)=[C:34]([O:38][CH3:39])[C:33]([O:40][CH3:41])=[C:32]([O:42][CH3:43])[C:31]=1[O:44][CH3:45]>CN(C=O)C.O>[Br:29][C:30]1[C:31]([O:44][CH3:45])=[C:32]([O:42][CH3:43])[C:33]([O:40][CH3:41])=[C:34]([O:38][CH3:39])[C:35]=1[CH2:36][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: COc1c(Br)c(CBr)c(OC)c(OC)c1OC
Reactant: CCOC(=O)c1ccc(OCCCC(C(=O)OCC)C(=O)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCCCC(Cc2c(Br)c(OC)c(OC)c(OC)c2OC)(C(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 2-ethoxycarbonyl-5-(4-ethoxycarbonylphenoxy)pentanoate (25.9 g) in DMF (200 ml) was portionwise added sodium hydride (60% oil dispersion, 3.11 g) with cooling with ice. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. To the reaction mixture was dropwise added a solution of 1-bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene (28.8 g) in DMF (50 ml) with cooling with ice. The reaction mixture was allowed to warm to room temperature and stirred for 6 hr. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=7:1) to yield the entitled compound (42.6 g) as an oil.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:28])[CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:15]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:28])[CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:15]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccnc(NC(=O)OC(C)(C)C)c1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccnc(NC(=O)OC(C)(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
A solution of KOH (0.19 g, 3.43 mmol) in ethanol (5 mL) was added to a solution of 2-(2-tert-butoxycarbonylamino-pyridin4-ylmethyl)-malonic acid diethyl ester (1.20 g, 3.27 mmol) in ethanol (5 mL) and methylene chloride (5 mL) at 0° C. The mixture was stirred for 18 h at room temperature. The mixture was concentrated under reduced pressure and water was added to the residue. The aqueous layer was washed with diethyl ether, acidified to pH 4 by 1M HCl, and extracted with methylene chloride. The organic layer was washed with water, brine and dried. After filtration and evaporation in vacuo, the crude product was purified by flash chromatography (CH3OH/CH2Cl2, 1:20) to yield 2-(2-tert-butoxycarbonylamino-pyridin4-ylmethyl)-malonic acid monoethyl ester (0.90 g, 81%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:3]=[CH:4][C:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=4)[CH2:14][CH2:13]3)=[O:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(C#N)c2)C1=O
Yield: 68.5 %

Procedure:
Using 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1.2 g) described in Preparation Example 187 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (919 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:19][CH3:20])=[N:7][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[C:9]=1[CH2:10][CH3:11])=[O:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/B(O)O)=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:19][CH3:20])=[N:7][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](/[CH:29]=[CH:28]/[C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[CH:13]=2)[C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Reactant: CCc1nn(-c2cccc(Br)c2)c(CC)c1C(=O)OC
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)OC
Temperature: 80 °C
Reaction time: 20 h

Procedure:
2.10 g (5.0 mmol) of 1-(3-bromo-phenyl)-3,5-diethyl-1H-pyrazole-4-carboxylic acid methyl ester and 1.82 g (10.0 mmol) of (E)-2-(4-chlorophenyl)vinyl boronic acid were dissolved in 50 ml of DMF. 12.5 ml of anhydrous potassium phosphate (tribasic, 2 M in water) were added drop by drop below 25° C., followed by 0.29 g (0.2 mmol) of tetrakis-(triphenylphosphine)-palladium. The reaction mixture was then stirred at 80° C. for 20 hours, cooled to RT, poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (n-heptane:EtOAc 1:0-8:2) to afford the title compound as light yellow solid. MS: 395.0 (MH+, 1 Cl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15](=[O:17])[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][C:15](=[O:17])[NH2:16])[CH2:23][C:22]2[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NCC(N)=O)C1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(N(CC(N)=O)Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(carbamoylmethyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.49 g, 2.03 mmol) in dichloroethane (5.0 mL) was added 4-chlorobenzaldehyde 0.34 g, 2.44 mmol), sodium triacetoxy borohydride (0.86 g, 4.06 mmol) and catalytic acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with 10% aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using ethyl acetate. 1H-NMR (CDCl3) δ: 1.50 (9H, s), 1.60–1.80 (2H, m), 2.10 (1H, m), 3.10–3.60 (8H, m), 5.65 (1H, br, s), 6.90 (1H, br, s) 7.20–7.40 (4H, m). ESI-MS m/z: 367(M+1), UV retention time: 1.94 min.
Reaction SMILES: C[C@H]1[O:7][C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8COCCCCS([O-])(=O)=O)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO.[Na+].[OH-].[Na+].[OH:88][NH:89][S:90]([C:93]1C=[CH:97][CH:96]=[C:95](S(C)(=O)=O)[CH:94]=1)(=[O:92])=[O:91]>O>[OH:88][NH:89][S:90]([C:93]1[O:7][C:96]([CH3:97])=[CH:95][CH:94]=1)(=[O:92])=[O:91]
Reactant: C[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8COCCCCS(=O)(=O)[O-])O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)NO)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)NO)o1

Procedure:
Additionally, a sample of the compound of formula (1) was prepared in water to determine the approximate solubility of the compound in the absence of excipients (e.g., CAPTISOL®). A concentration of approximately 300 mg/mL was achieved, not accounting for the volume contribution of the compound. The pH of the sample was determined to be 2.8, which was adjusted to the target of 4.0 using 0.1 N NaOH. Upon pH adjustment, precipitation of a small amount of solid was observed. The clear solution was diluted in acetonitrile and analyzed by HPLC, resulting in an observed solution concentration of 268 mg/mL. A similar analysis was performed for the compound of formula (2). The compound of formula (2) has a solubility of approximately 10 mg/mL.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[C:21]1(=[O:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[C:28]([O:32][C:33]([N:35]1[CH2:43][CH2:42][CH:38]([C:39](O)=[O:40])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>O1CCCC1.CO.C(Cl)(Cl)Cl>[C:28]([O:32][C:33]([N:35]1[CH2:43][CH2:42][CH:38]([C:39]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C:21]2=[O:27])=[O:40])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)C2CCCCC2=O)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Lithium diisopropylamide solution prepared from diisopropylamine (2.8 ml) and 1 M n-butyl lithium (11 ml) in tetrahydrofuran (40 ml) was cooled to −78° C. and cyclohexanone (2.0 ml) was added. The mixture was stirred at −78° C. for 1 hour and 1-tert-butoxycarbonyl-4-imidazocarbonylpiperidine (4.8 g) prepared from N-tert-butoxycarbonylisonipecotic acid was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and water was added to the obtained residue. The mixture was extracted with ethyl acetate and the extract was dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to give 3.8 g of an oily substance. The oil was subjected to silica gel column chromatography (eluent; chloroform:methanol=20:1) to give 2-((1-tert-butoxycarbonylpiperidin-4-yl)carbonyl)cyclohexanone, m.p. 71-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](=[O:15])[NH:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=1)[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][O:10][CH2:11][C:12]([NH:18][C@@H:19]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=2)[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:21])=[O:14])=[O:15])=[CH:16][CH:17]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(4-chlorobenzyl)ureidooxy)acetic acid (Compound VI-11) 77 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][CH2:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)=O>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:6][CH2:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: COCC(=O)NCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: COCCNCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1

Procedure:
A suspension of 1.5 g of LiA1H4 in 30 ml of tetrahydrofuran (THF) is refluxed and a solution of 7.5 g of the product obtained in step 1 in 40 ml of THF are added dropwise thereto.
Reaction SMILES: [C:1]([CH:3]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([CH3:21])=[C:15]3[N:14]=[C:13]2[CH2:22][CH2:23][CH3:24])=[CH:7][CH:6]=1)#[N:2].C[Sn]([N:35]=[N+:36]=[N-:37])(C)C>C1(C)C=CC=CC=1>[CH3:21][C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[N:12]([CH2:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH:3]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:1]4[NH:37][N:36]=[N:35][N:2]=4)=[CH:10][CH:9]=3)[C:13]([CH2:22][CH2:23][CH3:24])=[N:14][C:15]=12
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(CC(C#N)c2ccccc2)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(CC(c2ccccc2)c2nnn[nH]2)cc1
Yield: 37.3 %

Procedure:
To a solution of the product of the product of Step E (46 mg, 0.12 mmol) in toluene (2 mL) was added 29 mg (0.14 mmol) of trimethylstannyl azide and the reaction mixture was refluxed for 24 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in THF and treated with 12N HCl (5 drops) for 5 minutes at room temperature. The mixture was concentrated in vacuo and purified on a silica gel flash chromatography column eluted with CHCl3 /MeOH/NH4OH (80:20:2) to afford 19.6 mg (38%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH3:22])=[O:10].Br[CH2:24][C:25]1[S:29][CH:28]=[C:27]([C:30]#[N:31])[CH:26]=1>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH3:22])=[O:10])[O:8][CH2:24][C:25]1[S:29][CH:28]=[C:27]([C:30]#[N:31])[CH:26]=1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(O)cc1F
Reactant: N#Cc1csc(CBr)c1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(OCc2cc(C#N)cs2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C from (2-Fluoro-4-hydroxy-phenyl)-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone and 5-(bromomethyl) 3-thiophenecarbonitrile [CAS 186552-10-3]. MS (ES+) m/e 428.3
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][C:15]([CH3:17])=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=2)=[CH:8][CH:7]=1>O.OS(O)(=O)=O>[OH:2][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][C:15]([CH3:17])=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=2)=[CH:8][CH:7]=1
Reactant: O=N[O-]
Reactant: CCOC(=O)c1cc(-c2ccc(N)cc2)oc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(O)cc2)oc1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 19.7 %

Procedure:
A solution of NaNO2 (111 mg, 1.61 mmol) in water (1 mL) was added over 5 min to an ice-cold suspension of ethyl 5-(4-aminophenyl)-2-methyl-3-furanecarboxylate (395 mg, 1.61 mmol) in aqueous 1 M H2SO4 solution (12 mL). The reaction mixture was stirred at 0° C. for 20 min then was heated to 90° C. for 1 h. The cooled mixture was extracted with EtOAc. The organic layer was washed with water (2×) and brine, dried (MgSO4), filtered and concentrated under reduced pressure to yield the title compound (78 mg, 20% yield) as a white solid.