Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)=[CH:10][C:9]([NH2:21])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:25]=1[CH2:26][N:27]1[C:32](=[O:33])[CH:31]2[C:29]([C:34](O)=[O:35])([CH2:30]2)[CH2:28]1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)=[CH:10][C:9]([NH:21][C:34]([C:29]34[CH2:30][CH:31]3[C:32](=[O:33])[N:27]([CH2:26][C:25]3[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:24]=3[O:23][CH3:22])[CH2:28]4)=[O:35])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(CN2CC3(C(=O)O)CC3C2=O)c(OC)c1
Reactant: CCCc1cccc(-c2cc(N)nn2-c2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cccc(-c2cc(NC(=O)C34CC3C(=O)N(Cc3ccc(OC)cc3OC)C4)nn2-c2ccccc2)c1
Reaction time: 14 h
Yield: 90.7 %

Procedure:
To a solution of 1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (3.5 mg) prepared according to the same procedures as Preparation 2-2 in N,N-dimethylformamide (0.5 ml) were sequentially added 3-(2,4-dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (3.7 mg) and WSC.HCl (3.6 mg) at room temperature, and the mixture was stirred for 14 hours. To this reaction mixture were added diisopropylethylamine (3.3 μl) and HATU (7.3 mg), and the mixture was stirred at room temperature for additional 72 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give the titled compound (6.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]3[CH:11]([CH2:12]3)[N:10](C(OCC3C=CC=CC=3)=O)[C:9]2=[O:24])[CH:5]=[CH:4][N:3]=1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:9](=[O:24])[NH:10][CH:11]3[CH:13]2[CH2:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(OCc1ccccc1)N1C(=O)N(c2ccnc(Cl)c2)C2CC21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1NC2CC2N1c1ccnc(Cl)c1
Yield: 82.2 %

Procedure:
A solution of benzyl 4-(2-chloropyridin-4-yl)-3-oxo-2,4-diazabicyclo-[3.1.0]hexane-2-carboxylate (I-30b: 20.0 mg, 0.058 mmol) in 3.0 mL of 6N HCl was heated to 100° C. for 1 hour. The resulting mixture was basified with 1N NaOH. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was concentrated and washed with hexane to afford 10 mg of the product (83% yield).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH2:8])=[N:5][N:4]=1)[CH3:2].N1C=CC=CC=1.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:15]1([O:21][C:22](=[O:23])[NH:8][C:6]2[S:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1nnc(N)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1nnc(NC(=O)Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5-Ethyl-[1,3,4]thiadiazol-2-ylamine (2.5 g, 19.4 mmol) and pyridine (1.72 ml, 21.3 mmol) in dichloromethane (70 ml) is cooled to −70° C. and treated with a solution of phenylchloroformate (2.45 ml, 19.6 mmol) in dichloromethane (10 ml) dropwise. The reaction mixture is allowed to warm to ambient temperature and stirred for 3 hours during which a precipitate forms. The precipitate is collected by filtration, and dried under vacuum to afford (5-Ethyl-[1,3,4]thiadiazol-2-yl)-carbamic acid phenyl ester as white solid. [M+H] 250.15
Reaction SMILES: [CH3:1][C:2](=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][CH:4]=1>[Pd].C(O)C>[CH3:1][CH:2]([NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][CH:4]=1
Reactant: CCCCCCCCCc1ccc(C(C)=Nc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCc1ccc(C(C)Nc2ccccc2)cc1

Procedure:
N-alpha-methyl-p-nonyl benzylidene) aniline (XXX) (40 g) prepared by the procedure described in Example XVI A was hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent. N-(alpha-methyl-p-nonyl benzyl) aniline (XXXI) was obtained by fractional distillation. XXXI had a boiling point of 183° C. at 0.15 millimeter.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH3:18][NH:19][CH3:20]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:19]([CH3:20])[CH3:18])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Reactant: CNC
Solvent: CCO
Product: CN(C)CC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), N-methylmethanamine (2.0 M in MeOH, 0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 289 (M+, 0.2), 141 (2), 95 (4), 75 (5), 59 (4), 58 (bp).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH3:16].Cl.[CH2:19]([O:21][C:22](=[O:25])[CH2:23][NH2:24])[CH3:20].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:14]([C:13]1[N:24]([CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25])[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=1)[CH2:15][CH3:16]
Reactant: CCCC(=O)Nc1cnc2ccccc2c1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1nc2cnc3ccccc3c2n1CC(=O)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.8 %

Procedure:
A neat mixture of N-(4-chloroquinolin-3-yl)butanamide (5.0 g, 20 mmol) and glycine ethyl ester hydrochloride (10.0 g, 72 mmol) was heated gently with a heat gun until the solids melted. The reaction was followed by LC/MS, and heat was applied briefly twice more until no starting material remained. Dichloromethane (100 mL) and saturated aqueous sodium bicarbonate (50 mL) were added, and the resulting mixture was stirred until all solids were dissolved. The aqueous layer was separated and extracted with dichloromethane (2×50 mL), and the combined organic fractions were washed sequentially with saturated aqueous sodium bicarbonate (50 mL) and water, dried over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was (3.6 g) was dissolved in hot toluene (150 mL), and pyridinium tosylate (100 mg) was added. The reaction was heated at reflux under a Dean-Stark trap for one hour, allowed to stand at ambient temperature for three days, heated at reflux for two hours, cooled to ambient temperature, and diluted with dichloromethane (150 mL). The resulting solution was washed with saturated aqueous sodium bicarbonate (2×35 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 3.2 g of ethyl (2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)acetate as a light brown solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][N:26]=2)[CH2:20][CH:21]2[CH2:24][O:23][CH2:22]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[H-].[Na+]>CS(C)=O>[CH:31]([C:28]1[CH:29]=[CH:30][C:25]([N:19]([CH2:20][CH:21]2[CH2:22][O:23][CH2:24]2)[S:16]([C:13]2[CH:14]=[CH:15][C:10]([O:8][CH2:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[N:26][CH:27]=1)([CH3:33])[CH3:32]
Reactant: OCC1CCOCC1
Reactant: CC(C)c1ccc(N(CC2COC2)S(=O)(=O)c2ccc(F)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)c1ccc(N(CC2COC2)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2)nc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of (tetrahydro-2H-pyran-4-yl)methanol (20.08 mg, 0.173 mmol) and 4-fluoro-N-(5-isopropylpyridin-2-yl)-N-(oxetan-3-ylmethyl)benzenesulfonamide (63 mg, 0.173 mmol) in dimethyl sulfoxide (DMSO) (1 mL) stirred in air at room temperature was added sodium hydride (6.91 mg, 0.173 mmol, 60% wt in mineral oil). The reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was carefully quenched with methanol (2 mL) and water (2 mL), then solvents evaporated in vacuo. The crude product was purified by flash silica (Si) (25% ethyl acetate-cyclohexane gradient) to give the title product (63.2 mg). LCMS (2 min, High pH) Rt 1.23 min, m/z (ES+) 461 (M+H).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[NH:28]1[CH2:33][CH2:32][S:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: C1CSCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(Nc1ncc(CN2CCSCC2)s1)N(C1CCCCC1)C1CCCCC1
Yield: 9.2 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (60 mg, 0.18 mmol), acetic acid (11 μL, 0.18 mmol), thiomorpholine (21 μL, 0.22 mmol) and sodium triacetoxyborohydride (38 mg, 0.20 mmol) to afford 7 mg (9%) of the desired product after purification.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[CH3:7][NH:8][C:9](=[O:19])[O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([CH3:18])[CH:12]=1.N1C=CC=CC=1>O>[CH3:7][NH:8][C:9](=[O:19])[O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[C:13]([CH3:18])[CH:12]=1
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(OC(=O)NC)cc1C
Reaction time: 1 h

Procedure:
Ethanesulfonyl chloride (2.2g., 0.0171 mole) was added dropwise to a stirred solution of 3-methyl-4-aminophenyl N-methylcarbamate (3.0g., 0.0166 mole) in 20 ml. of pyridine. The temperature rose to a maximum of 38° C. and then subsided. Stirring was continued at ambient temperature for one hour, and the reaction mixture poured into excess water to give an insoluble precipitate. Recrystallization from ethanol-water gave the product as a beige powder, m.p. 146.5°-48.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[N:3]=1.Cl.C(OCC)C>C(O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cc1ccc2c(OCCN3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc2c(OCCN3CCNCC3)cccc2n1
Temperature: 40 °C
Reaction time: 17 h
Yield: 90.8 %

Procedure:
tert-Butyl 4-[2-(2-methylquinolin-5-yloxy)ethyl]piperazine-1-carboxylate (1.04 g, 2.8 mmol) was dissolved in ethanol (60 mL) and treated with 1 M hydrochloric acid in diethyl ether (16 mL, 16 mmol) and stirred at 40° C. for 17 h. The reaction mixture was filtered and the white solid was collected and dried in vacuo. The hydrochloride salt precipitate was dissolved in water (25 mL) and potassium carbonate was added until the pH reached 10. The aqueous layer was washed with 5% methanol in dichloromethane (4×100 mL) then 10% methanol in dichloromethane (4×100 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo, affording the title compound as a brown oil (0.69 g, 91%).
Reaction SMILES: C(CC1C=CC(C[CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=CC=1)(O)=O.[CH3:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[CH2:11]([N:12]([CH2:27][C:28]1[CH:29]=[CH:30][C:21]([CH2:14][CH2:13][N:44]2[CH2:45][CH2:46][CH:41]([CH3:40])[CH2:42][CH2:43]2)=[CH:22][CH:23]=1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[C@@H:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=2[CH2:22]1)[CH3:10]
Reactant: CC1CCNCC1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Product: CCN(Cc1ccc(CCN2CCC(C)CC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 33.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 4-methylpiperidine (17 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (3.1 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=2[F:28])=[N:16]1.[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)#[CH:30].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:30]#[C:29][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=3)=[CH:23][C:22]=2[F:28])=[N:16]1
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3F)[nH]c2=O)c1)C1CC1
Reactant: C#Cc1cccc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#Cc4cccc(C(F)(F)F)c4)cc3F)[nH]c2=O)c1)C1CC1
Yield: 37.2 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 by using N-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide (Intermediate-48, 0.050 g, 0.097 mmol), 1-ethynyl-3-(trifluoromethyl)benzene (Intermediate-50, 0.025 g, 0.14 mmol), TBAF (0.061 g, 0.19 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (1.0 mL) at 80° C. to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.65-0.70 (m, 4H), 1.60 (m, 1H), 4.31 (d, J=6.0 Hz, 2H), 7.28-7.41 (m, 2H), 7.51-7.61 (m, 4H), 7.67-7.97 (m, 4H), 8.68 (m, 1H), 12.0 (br s, 1H); MS (m/z): 555.05 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C@@H:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>[Pt]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[NH:12][C@H:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CCC(c2ccc(Br)cc2)=N1
Agent: [Pt]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CC[C@H](c2ccc(Br)cc2)N1
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A solution of methyl (2S)-5-(4-bromophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (D76, 799 mg, 2.83 mmol) and Pt/C (50 mg) was stirred under hydrogen (1 atm) overnight. Then TFA (0.25 ml) was added and hydrogenation was continued for another 2 h. Then more Pt/C (100 mg) was added and the mixture was stirred for additional 9 h under hydrogen (1 atm). After that additional catalyst (100 mg) and TFA (0.25 ml) was added and stirring was continued for another 5 h under hydrogen atmosphere. Then additional catalyst was added (100 mg). After additional 4 h the reaction was finished and the solution was filtered over celite, evaporated and purified using a SCX cartridge to afford the title compound (641 mg, 79%). UPLC: Rt 0.47 min; MS: (ES/+) m/z: 284, 286 [MH+], C12H14BrNO2 requires 284.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.Cl.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:27]1([NH:33][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[N:15][C:7]=2[O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([S:2][CH3:1])[CH:4]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CSc1cccc(Oc2ncccc2C(=O)O)c1
Reactant: NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncccc2C(=O)NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.8 %

Procedure:
2-[3-(Methylsulfanyl)phenoxy]nicotinic acid (200 mg, 0.77 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (427 ul, 3.07 mmol) was added followed by cyclohexylamine hydrochloride (88 ug, 0.77 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg, 1.53 mmol) and 1-hydroxybenzotriazole (114 mg, 0.84 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between water (50 ml) and diethyl diethyl ether (50 ml). The organic phase was washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (20:80 to 35:65) as eluant to give a white solid which was recrystallised from diethyl diethyl ether/pentane to give N-cyclohexyl-2-[3-(methylsulfanyl)phenoxy]nicotinamide (134 mg) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]3[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[O:21])=[C:15]([Cl:30])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[Cl:29][C:26]1[N:25]=[CH:24][C:23]([NH:22][C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[CH:14][C:15]=2[Cl:30])=[O:21])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)Nc3ccc(Cl)nc3)c(Cl)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)nc1)Nc1ccc(C2CCNC2)cc1Cl
Temperature: 25 °C
Reaction time: 34 h
Yield: 17 %

Procedure:
To a stirred suspension of (RS)-3-{3-chloro-4-[3-(6-chloro-pyridin-3-yl)-ureido]-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (68 mg) in dichloromethane (6 ml) was added trifluoroacetic acid (92 μl) and the reaction mixture was then stirred at room temperature for 34 h. The reaction mixture was then poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis); gradient: heptane/EtOAc/MeOH) to afford (RS)-1-(6-chloro-pyridin-3-yl)-3-(2-chloro-4-pyrrolidin-3-yl-phenyl)-urea (9 mg, 17%) as an off-white solid. MS (ISP): 355.1 ([{37Cl}M+H]+), 353.1 ([{37Cl35Cl}M+H]+), 351.2 ([{35Cl}M+H]+).
Reaction SMILES: [CH2:1](/[N:8]=[CH:9]/[CH2:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[CH2:1]([N:8](/[CH:9]=[CH:10]/[CH3:11])[C:19](=[O:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC/C=N/Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: C/C=C/N(Cc1ccccc1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To benzyl-prop-(E)-ylidene-amine (6.0 g, 40 mmol) in triethylamine (5.67 mL, 40 mmol) at 0° C. was slowly added acetic anhydride (3.81 mL, 40 mmol), and the reaction was stirred for 30 minutes at 0° C. and then overnight at room temperature. The mixture was concentrated, and the residue was purified by silica gel chromatography (0-25% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11](C(O)=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:26](C=O)C.[N-]=[N+]=[N-].[Na+]>C(Cl)Cl.O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:26])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [N-]=[N+]=[N-]
Solvent: O
Solvent: ClCCl
Product: CC(C)c1c(N)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of 1-(4-chlorophenyl)-5-isopropylpyrazole-4-carboxylic acid (10.0 g, 37.78 mmol) in CH2Cl2 (150 mL) was added oxalyl chloride (9.90 mL, 113.6 mmol) and DMF (0.15 mL). The mixture was stirred for 2 h at room temperature, concentrated in vacuo, and re-dissolved into 100 mL of acetone. The obtained acyl chloride solution was added portionwise to another flask containing NaN3 (12.31 g, 190 mmol) in H2O (100 mL) at 0° C. After 10 min, The reaction mixture was diluted with brine (300 mL) and extracted with EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained acyl azide was diluted in 150 mL of toluene and heated at 95° C. until no more gas evolution occurred (approx. 1.5 h). The reaction mixture was cooled to rt and treated with 100 mL of dioxane and 300 mL of 1 M aqueous HCl. The resulting two-phase solution was heated to 95° C. After approx. 2.5 h, the reaction mixture was cooled to rt, made basic with dilute NH4OH, and extracted with EtOAc (500 ml). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (SiO2, 0-100% EtOAc/CH2Cl2 gradient elution) to yield 1-(4-chlorophenyl)-5-isopropylpyrazol-4-amine (5.7 g, 64%).
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].Cl[Si](C)(C)C.[CH:12]1[C:24]2[CH:23]([CH2:25][O:26][C:27]([NH:29][C@H:30]([C:42](O)=[O:43])[CH:31]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]([OH:34])=[O:33])=[O:28])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[SiH3]OC(=O)[C@@H](C)N.Cl>CN(C)C=O.CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH:12]1[C:24]2[CH:23]([CH2:25][O:26][C:27]([NH:29][C@H:30]([C:42]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:43])[CH:31]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32](=[O:33])[OH:34])=[O:28])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: C[C@@H](N)C(=O)O
Reactant: O=C(N[C@H](C(=O)O)C(Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)COC(=O)Cl
Agent: C[C@@H](N)C(=O)O[SiH3]
Agent: C[Si](C)(C)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(Cc1ccccc1)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
D-Alanine (5 g, 0.056 mole) was dissolved in dimethylformamide (100 ml) and treated with chlorotrimethylsilane (6.7 g, 0.063 mole). The reaction mixture was stirred at room temperature until homogeneous (approx. 1 hour). Meanwhile, Nα -9-fluorenylmethyloxycarbonyl-β-benzyl-L-aspartic acid (22.3 g, 0.050 mole) was dissolved in dimethylformamide/tetrahydrofuran (1:1, v/v, 200 ml), cooled to -15° C. and treated with N-methylmorpholine (5.5 ml, 0.050 mole) and isobutyl chloroformate (6.5 ml, 0.050 mole). After 10 minutes' activation at -15° C., the precooled solution of D-alanine silyl ester from above was added, followed by a second equivalent of N-methylmorpholine (5.5 ml, 0.050 mole). The reaction mixture was allowed to warm to room temperature, stirred for 3 hours and then acidified (pH 1-2) using aqueous hydrochloric acid. The reaction mixture was stirred for 30 minutes and ethyl acetate added and the phases separated. The aqueous phase was re-extracted with ethyl acetate and the combined organic extracts washed with 1N hydrochloric acid (3×) and dried (MgSO4). After evaporation of the solvent under reduced pressure the residue was crystallized from ethyl acetate/hexanes to give Nα -9-fluorenylmethyloxycarbonyl-β-benzyl-L-aspartyl-D-alanine (22.5 g), m.p. 114°-116° C., which was homogeneous by TLC. The nmr spectrum of the product was consistent with the assigned structure.