Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[N:4][CH:3]=1.[C:16]([O:20][C:21](=[O:29])[NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:26]2[CH2:25][CH2:24][CH:23]([NH:22][C:21](=[O:29])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:28][CH2:27]2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCn1c(=O)ccc2ncc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 18.8 %

Procedure:
To a solution of 1.66 g of (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde in 42 mL of chloroform, 1.61 g of tert-butyl(piperidin-4-yl)carbamate and 0.48 g of acetic acid were added, and the mixture was stirred at room temperature for 7.5 hours. To the reaction mixture, 2.56 g of sodium triacetoxyborohydride was added, and the mixture was stirred for 10 hours. Thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol was added to the resultant residue, and the solid was filtered off to obtain 0.59 g of tert-butyl (1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][O-].[Na+].Br[C:13]1[CH:14]=[C:15]([O:19]C)[CH:16]=[CH:17][CH:18]=1>N1C=CC=CC=1.CO.Cl[Cu]>[CH3:9][O:2][C:1]1[CH:3]=[C:4]([O:5][C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C[O-]
Reactant: COc1cccc(Br)c1
Reactant: Oc1cccc(O)c1
Agent: Cl[Cu]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: COc1cccc(Oc2cccc(O)c2)c1

Procedure:
In a round-bottomed flask fitted with a Vigreux column, a reflux divider and a condenser, 77.08 g (0.70 mol.) of resorcinol are dissolved, under argon, in 250 ml of dry pyridine. 84.3 g of sodium methoxide solution in methanol (30% solution) are added dropwise to the reaction mixture, with stirring. Methanol is then removed from the reaction mixture by distillation. The reflux divider is then closed and 261.9 g (1.40 mol.) of 3-bromoanisole are added dropwise. 3.5 g (0.04 mol.) of CuCl are also added. The mixture is allowed to boil under reflux for 6 hours. Pyridine is then distilled off via the opened reflux divider, during which the sump temperature rises to 150° C. The mixture is then allowed to cool and the residue is stirred into 250 ml of semi-concentrated hydrochloric acid. The mixture is extracted with 300 ml of toluene. The organic phase is washed first with semi-concentrated hydrochloric acid and then a further two times with NaOH solution (10%). The combined alkaline phases are acidified with dilute HCl and extracted with a diethyl ether/toluene mixture (1:1). After removal of the solvent, 65.5 g of a brown oil are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:12]=1)[C:7](O)=[O:8])([O-])=O.O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[NH2:1][C:4]1[CH:12]=[C:11]([CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(N)cc(CO)c1
Yield: 93.6 %

Procedure:
85 g of 3-nitro-5-methoxycarbonylbenzoic acid was dissolved in 200 ml of THF under a flow of nitrogen, and 43.4 ml of borane dimethylsulfide complex was added with stirring under ice-cooling. After stirring for 18 hours, 200 ml of water was added, and then 96 g of potassium carbonate was added. It was extracted with ethyl acetate, and theorganic layer was washed with salt solution. After drying with magnesium sulfate, the resulting solid was dissolved in 800 ml of ethyl acetate, 750 mg of 10% Pd/C was added, and stirring was continued under the flow of hydrogen. After the reaction was completed, it was subjected to the filtration, and then the filtrate was concentrated to produce 64 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([O:17][CH2:18]C)=[O:16])[C:13](=[O:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]3[CH2:31][CH2:32][C:33](=[O:34])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].O=C1N(C2C=CC=C(C(F)(F)F)C=2)C2CCC(=O)C=2[C@@H](C2C=CC(C#N)=C[C:57]=2[S:64](C)(=[O:66])=[O:65])N1.ClC(OC)=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[N:14]([C:15]([O:17][CH3:18])=[O:16])[C:13](=[O:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]3[CH2:31][CH2:32][C:33](=[O:34])[C:10]2=3)=[C:5]([S:64]([CH3:57])(=[O:66])=[O:65])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Agent: COC(=O)Cl
Product: COC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)[C@H]1c1ccc(C#N)cc1S(C)(=O)=O

Procedure:
The title compound is prepared in analogy to ethyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(tri-fluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxylate (example 31, 110 mg, 0.23 mmol), using (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10A) as starting material and substituting ethyl chloroformate with methyl chloroformate. Yield: 76 mg; ESI mass spectrum [M+H]+=534; Retention time HPLC: 1.01 min (Z018_S04).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7](CO)[CH:6]=[CH:5][N:4]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:12].O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[C:7]([Cl:12])[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1cc(CO)ccn1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: N#Cc1cc(Cl)ccn1
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a magnetically stirred solution of 9 grams (66 mm) of 2-cyano-4-hydroxymethylpyridine [Swan, et al. J. Chem. Soc., 3440 (1963)] contained in 300 mls of benzene is added 15.1 grams (72 mm) of phosphorous pentachloride. After stirring for 1/2 hour, ice and water are added followed by sodium bicarbonate. The organic layer is washed with water and evaporated. The residual oil is crystallized from petroleum ether, to yield 8.5 grams (83%) of 2-cyano-4-pyridyl chloride, m.p. -55°-56°.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]1([CH:16]([CH2:19][CH:20]=[CH2:21])[CH2:17][OH:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C.Cl>ClCCl>[CH:11]1([CH:16]([CH2:19][CH:20]=[CH2:21])[CH:17]=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=CCC(CO)C1CCCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CCC(C=O)C1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dimethyl sulfoxide (4.82 mL, 67.9 mmol) was added dropwise over 15 minutes to a dichloromethane (75 mL) solution of oxalic acid chloride (4.47 g, 35.2 mmol) cooled to −78° C., and the mixture was then stirred at −78° C. for 30 minutes. Subsequently, a dichloromethane (20 mL) solution of 2-cyclopentylpent-4-en-1-ol (3.50 g, 22.7 mmol) was added dropwise thereto over 15 minutes, and the mixture was stirred at −78° C. for 45 minutes. Triethylamine (16.11 g, 159.3 mmol) was added dropwise thereto over 5 minutes, and the mixture was then stirred at room temperature for 2 hours. The mixture was neutralized with 1 N hydrochloric acid (160 mL). The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain a yellow oil substance as a mixture containing the compound of interest. This compound was used in the next reaction without being further purified.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:7]1[CH:11]=[C:10]([NH2:12])[O:9][N:8]=1)([CH3:6])[CH3:5].C(C1C=C(N[C:22](=[O:30])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)ON=1)(C)C>>[CH3:1][O:2][CH2:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:22](=[O:30])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:9][N:8]=1)([CH3:6])[CH3:5]
Reactant: COCC(C)(C)c1cc(N)on1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Product: COCC(C)(C)c1cc(NC(=O)Oc2ccccc2)on1

Procedure:
Prepared from 3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-amine (100 mg, 0.59 mmol) according to the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to afford phenyl 3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-ylcarbamate as an oil that was not purified further.
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C[O:22][C:23]([C:25]1([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:29][C:28](=[O:30])[N:27]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:26]1)=O>C1COCC1>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([NH:11][C:23]([C:25]2([CH:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:29][C:28](=[O:30])[N:27]([C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:38])[CH2:26]2)=[O:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: COC(=O)C1(C2CCCC2)CC(=O)N(c2c(C)cccc2C)C1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1CC(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(C2CCCC2)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
n-BuLi (2.5 M solution in hexanes, 456 μL, 1.14 mmol) was added to a solution of 3,5-bis-trifluoromethylaniline (177 μL, 0.1.14 mmol) in THF (3 mL) at room temperature. The resulting dark brown colored solution was stirred for 10 min at room temperature. A solution of 3-cyclopentyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 120 mg, 0.38 mmol) in THF (2 mL) was added and stirred for 2 h at 70° C. The reaction mixture was then purified by automated flash chromatography. Pure fractions were combined and concentrated under reduced pressure. The material was recrystallized from MeOH to obtain the desired product 3-cyclopentyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (60 mg, 31% yield) as white crystals. LC-MS: R, (retention time): 3.32 min, MS: (ES) m/z 513.2 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.4 (s, 1H), 8.05 (s, 2H), 7.6 (s, 1H), 7.08-7.13 (m, 2H), 7.02-7.06 (m, 2H), 4.14 (d, 1H, J=11.5 Hz), 3.56 (d, 1H, J=11.5 Hz) 3.17 (d, 1H, J=16.9 Hz), 2.74 (d, 1H, J=16.9 Hz), 2.42-2.52 (m, 1H), 2.2 (s, 3H), 2.14 (s, 3H), 1.75-1.88 (m, 2H), 1.6-1.68 (m, 4H), 1.25-1.48 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Cl[C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C@@H:21]([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[CH3:23][N:22]1[C:15]2[N:16]([C:17](=[O:19])[N:18]=[C:13]([O:11][CH2:10][C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)[CH:14]=2)[CH2:20][C@@H:21]1[CH3:24]
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1cc(F)c(F)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(F)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,4,5-trifluorophenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:26]([C:27](O)=[O:28])=[C:25]([CH3:30])[O:24][N:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:26]3[C:22]([CH3:21])=[N:23][O:24][C:25]=3[CH3:30])=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1noc(C)c1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 3,5-dimethyl-4-isoxazolecarboxylic acid, as starting materials, MS (LC/MS): 426.2 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)[CH:3]1[CH2:6][O:5][CH2:4]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:13][N:12]1[C:8]([CH2:7][N:2]([CH3:1])[CH:3]2[CH2:4][O:5][CH2:6]2)=[CH:9][C:10]([NH2:14])=[N:11]1
Reactant: CN(Cc1cc([N+](=O)[O-])nn1C)C1COC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(Cc1cc(N)nn1C)C1COC1
Temperature: 70 °C
Yield: 83.2 %

Procedure:
To a solution of 302b (1.8 g, 7.96 mmol) in ethanol (20 mL) and water (20 mL), NH4Cl (3.3 g, 63.6 mmol) and iron powder (1.80 g, 31.8 mmol) were added. The reaction mixture was heated at 70° C. for 2 h. After that, the mixture was cooled to room temperature and filtered. The filtrate was evaporated and the residue was extracted with methylene chloride (3×30 mL), dried Na2SO4, and concentrated to afford the crude product, which was purified on flash column eluting with 50:1 methylene chloride/methanol containing 0.5% triethylamine to afford 302c as a yellow oil (1.3 g, 83%). LCMS: (M+H)+ 197
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[CH:12]=[C:13]([N:15]1CCCC1)C.O.NN>CO.C1COCC1.[Ni]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:15]2
Reactant: CC(=Cc1c(Br)cc(F)cc1[N+](=O)[O-])N1CCCC1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(Br)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.9 %

Procedure:
To a solution of 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (7.49 g, 31.8 mmol) in dioxane (40 mL) were added DMF-DMA (21.0 mL, 158 mmol) and pyrrolidine (2.6 mL, 31.1 mmol). The reaction mixture was heated at 100° C. for 3 h. The mixture was cooled to RT and concentrated in vacuo to give 1-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-1-methyl vinyl]-pyrrolidine as a dark red residue. To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney®-Nickel (suspension in H2O, 15 mL) in MeOH:THF (1:1, 150 mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0° C. and the mixture stirred at RT for 5 hours. The reaction mixture was then filtered through Celite and the filter cake washed with EtOAc. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (silica gel, pentane:EtOAc 75:25) to provide the title compound as a pale oil (2.57 g, 37%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[S:11][C:12]3[N:13]=[C:14]([NH2:23])[N:15]=[C:16](S(C)(=O)=O)[C:17]=3[N:18]=2)[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:47]=[CH:46][C:35]([O:36][CH2:37][C:38]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:39])=[CH:34][CH:33]=1>O1CCOCC1>[NH2:23][C:14]1[N:15]=[C:16]([N:43]2[CH2:44][CH2:45][N:40]([C:38](=[O:39])[CH2:37][O:36][C:35]3[CH:46]=[CH:47][C:32]([Cl:31])=[CH:33][CH:34]=3)[CH2:41][CH2:42]2)[C:17]2[N:18]=[C:10]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:9])[S:11][C:12]=2[N:13]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Reactant: CC(c1ccc(F)cc1)c1nc2c(S(C)(=O)=O)nc(N)nc2s1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(c1ccc(F)cc1)c1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Temperature: 70 °C
Yield: 67.8 %

Procedure:
To a solution of 2-(1-(4-fluorophenyl)ethyl)-7-(methylsulfonyl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.14 mmol) and triethylamine (30 μl, 0.21 mmol) in dioxane (1 ml) was added 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (51 mg, 0.21 mmol). The reaction mixture was heated at 70° C. for 3 hours. After cooling down to room temperature, the volatiles were removed under reduced pressure. The crude residue was purified by chromatography on silica gel (CH2Cl2/MeOH 70:1) furnishing the title compound as a white solid (50 mg, 67%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[K+].[NH:12]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:13]([C:24](ON1C(=O)CCC1=O)=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.O.CCOCC>[NH:12]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:13]([C:24]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 74 %

Procedure:
Solutions of leucine (90.0 mmole.) in dimethylformamide (150 ml.) and potassium hydroxide (90.0 mmole.) in water (25 ml.) were combined and chilled in an ice-salt bath. A chilled mixture of BocDTrpOSu (89.7 mmole.) in dimethylformamide (100 ml.) was then added. The mixture was stirred for one hour at the ice-salt bath temperature, allowed to warm to room temperature overnight, and distributed between aqueous citric acid (5%) and ether. The aqueous layer was extracted twice more with ether. The ethereal extracts were combined and dried over magnesium sulfate. The product precipitated from the ether onto the drying agent. Ether was removed from the mixture. Extraction of the solids with methanol, removal of the methanol and recrystallization of the residue from methanol-water afforded BocDTrp-LeuOH in 74% yield (27.85 g., m.r. 187°-190° C.).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:13](=[O:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23].Cl.[OH-].[Na+]>C1COCC1>[CH:1]1([NH:4][C:13](=[O:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:3][CH2:2]1
Reactant: COC(=O)CCCCCCCCC(=O)Cl
Reactant: NC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCCCCC(=O)NC1CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
All reactions reported in this invention were carried in oven-dried three-necked, round-bottomed flasks equipped with a Teflon-coated magnetic stirring bar. The reaction flask was purged with nitrogen, and during the entire operation, the reaction was under nitrogen. To a stirred solution of cyclopropanamine (0.615 g, 10.78 mmol) in 25 mL of dried THF, triethylamine (1.20 g, 11.90 mmol) was added in one portion. After the reaction had been cooled to about 0° C., methyl 10-chloro-10-oxodecanoate (2.53 g, 10.78 mmol) in 5 mL of THF was added dropwise via an addition funnel. After the addition, the reaction was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was subjected to roto-vap distillation to remove the majority of solvent, and the residue was poured with stirring into a mixture of ice-water containing 10 mL of HCl aqueous 2N solution (20 mmol) leading to the immediate precipitation of a white solid. Stirring was continued for an additional 30 min, and then the precipitation was filtered off with suction through a sintered glass funnel. The collected solid was washed with two 50-mL portions of water. The NMR analysis of a dried sample of the material confirmed the structure of the desired ester. The GC retention time of the ester is 12.79 min. The ester was saponified with 20 mL of NaOH aqueous 2N solution (40 mmol) at room temperature overnight. Ice was added to the reaction and acidification with a 30 mL of HCl aqueous 2N solution (60 mmol) led to the immediate precipitation of a white solid. Stirring was continued for an additional 30 min, and then the precipitation was filtered off with suction through a sintered glass funnel. The collected solid was successively washed with three 50-mL portions of water, and two 25-mL portions of hexane. The collected solid was dried in vacuo for two days at ambient temperature to afford 1.81 g (70%) of 10-(cyclopropylamino)-10-oxodecanoic acid as a white solid. HPLC: Rt: 3.52 min. 1H NMR (400 MHz DMSO-d6) δ: 0.25 (m, 2H), 0.48 (m, 2H), 1.14 (m, 9H), 1.37 (m, 4H), 1.89 (m, 2H), 2.09 (m, 2H), 7.70 (br. s, 1H), 1.850 (s, 1H). 13C NMR (100 MHz DMSO-d6) δ: 5.60(C2 & C3), 22.0(C8), 24.46(C13), 25.18(C1), 28.63(C9, C10, C11 & C12), 33.64(C14), 35.0(C7), 173.2(C5), 174.45(C15). LC/MS m/z: 242 [(M+1)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:30]([OH:31])=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1.C1(O)C=CC=CC=1.C(OCC)C>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=1[O:31][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@@H:10]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:21]1[CH:20]=[CH:19][CH:18]=[CH:23][CH:22]=1
Reactant: Oc1ccccc1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccccc1Cc1ccccc1
Yield: 24.8 %

Procedure:
A solution of (±) N-tert-butoxycarbonyl-1,2-iminoindane (2.33 g, 10 mmol), 2-hydroxy diphenylmethane (1.84 g, 10 mmol) and pyridinium p-toluenesulfonate (50 mg) in chloroform (100 ml) was heated at reflux for 3 h. On cooling, the solution was washed sequentially with aq. NaHCO3, water and then brine. After drying over Na2SO4, solvents were removed in vacuo and the resultant brown oil subjected to column chromatography on silica gel eluting with 10% diethyl ether in hexanes to afford a pale yellow oil which was a mixture of the desired adduct and the starting phenol. This mixture was taken up in 1:1 diethyl ether:pentane (200 ml) and washed three times with a 1:1 mixture of methanol and 10% aq. NaOH. After washing with water then brine, the organics were dried over Na2SO4 and then concentrated in vacuo. The residue was recrystallised to afford the title compound as a white solid (1.03 g) m.p. 113°-114.5° C. (from diethyl ether-pentane).
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([NH2:31])[S:30][C:26]=2[CH:25]=1>>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:31][C:29]2[S:30][C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:33]=[CH:32][C:27]=3[N:28]=2)=[O:17])(=[O:11])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc2nc(N)sc2c1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1
Product: COc1ccc2nc(NC(=O)c3cccc(S(=O)(=O)N4CCc5ccccc54)c3)sc2c1

Procedure:
3-(indolin-1-ylsulfonyl)benzoic acid (3) (100 mg, 0.33 mmol) was treated with 6-methoxybenzo[d]thiazol-2-amine (46 mg, 0.25 mmol) using method C. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 3-(indolin-1-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide as a white solid. Yield: 30 mg (25%). 1H-NMR: 8.58 (s, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.77-7.59 (m, 3H), 7.53 (d, J=8.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.08 (dd, J=9.0, 2.5 Hz, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 4.02 (t, J=8.0 Hz, 2H), 2.93 (t, J=8.0 Hz, 2H).