Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12]([C:14]1[C:23]([OH:24])=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)=[O:13].C([C@H](C(N)CC1C=CC=C(Cl)C=1)C(O)=O)(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12]([C:14]1[C:23]([OH:24])=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)=[O:13]
Reactant: O=C(c1nc2ccccc2nc1O)N1CCCC[C@@H]1Cc1cccc(Cl)c1
Agent: CC(C)(C)OC(=O)[C@@H](C(=O)O)C(N)Cc1cccc(Cl)c1
Product: O=C(c1nc2ccccc2nc1O)N1CCCC[C@H]1Cc1cccc(Cl)c1

Procedure:
Compound 7-8 (S isomer) was prepared analogous to the preparation of Compound 7-7 beginning from Boc-(R)-3-amino-4-(3-chlorophenyl)butyric acid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C)C=O.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>O>[N+:8]([C:7]1[C:2]([NH:29][CH:26]2[CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncccc2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 79.3 %

Procedure:
2-Chloro-3-nitro-pyridine (5 g, 33.3 mmol), anhydrous N,N-dimethylformamide (50 mL), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (6.7 g, 33.3 mmol) and anhydrous sodium carbonate (7.1 g, 66.6 mmol) were combined with stirring under nitrogen. The reaction mixture was heated at 90° C. overnight. Then it was poured into water and the resulting yellow solid was filtered off and found to be tert-butyl 4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (8.5 g, 26.4 mmol, 79.4% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C@@H:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:29]=2[CH3:35])[C@H:23]([OH:36])[CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O>[CH3:35][C:29]1[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:28]=1[O:27][CH:24]1[CH2:25][CH2:26][N:21]([C:19]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20])[CH2:22][C:23]1=[O:36]
Reactant: Cc1cccc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)c1C
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cccc(OC2CCN(C(=O)OCc3ccccc3)CC2=O)c1C
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
A solution of oxalyl chloride (3.5 ml, 40 mmol, 1.1 eq.) in dichloromethane (350 ml) was cooled to −60° C. (internal temp.) and treated drop-wise with dimethyl sulfoxide (5.18 ml, 73.0 mmol, 2 eq.). On completion of addition the reaction mixture was stirred at −60° C. for 5 min. before drop-wise addition of a solution of trans-benzyl-4-(2,3-dimethylphenoxy)-3-hydroxypiperidine-1-carboxylate (13.0 g, 36.5 mmol) in dichloromethane (50 ml). After 30 min. triethylamine (15.5 ml, 110 mmol, 3.0 eq.) was added drop-wise and the solution stirred at −60° C. for 10 min, before allowing the mixture to warm slowly to room temperature. After 18 h. the reaction mixture was diluted with water (400 ml) and the resultant biphasic system separated. The aqueous layer was extracted with dichloromethane (400 ml). Combined organics were washed with aqueous hydrochloric acid (200 ml, 0.1N), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to furnish benzyl 4-(2,3-dimethylphenoxy)-3-oxopiperidine-1-carboxylate as a pale yellow amorphous solid (12.8 g, 99%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8](Cl)(=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>CCOCC>[C:8]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: NCC(=O)O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCCCCCCCCC(=O)NCC(=O)O
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of glycine in a 1 N-sodium hydroxide, an ether solution of n-dodecanoyl chloride and a 1 N-aqueous solution of sodium hydroxide were dropped simultaneously and the mixture was stirred for 1 hour. The reaction mixture was then neutralized with hydrochloric acid and ether was removed from the solution. N-n-dodecanoylglycine was obtained from the remaining reactant after the purification by column chromatography with the yield of 84.7%. The melting point of the product was 115.5° to 116.7° C.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:22])[CH2:16][C:17]1[CH:21]=[CH:20][S:19][CH:18]=1.CI>C1COCC1>[CH3:13][O:14][C:15](=[O:22])[CH:16]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)[CH3:1]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)Cc1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccsc1
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Anhydrous diisopropylamine (24.3 g) was added to Anhydrous THF (100 ml) which was then cooled by a dry ice-acetone bath. To this solution was first added dropwise n-butyllithium (15% w/o % in Hexane, 147 ml), then in a second step a THF solution (50 ml) of 3-thiophene acetic acid methyl ester (31.2 g). Thereafter, this solution was kept at the same temperature under cooling, while stirring was continued for 30 minutes. Then, methyl iodide (36.9 g) was added in one portion to the reaction mixture which after 30 minutes, was removed from the cooling bath to be allowed to reach to room temperature. After the reaction, THF was distilled off under reduced pressure and the formed residue was dissolved in water which was extracted by two portions of 200 ml ether. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by distillation to obtain 26.6 g 2-(3-thienyl)propionic acid methyl ester with bp 90°-92° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C:2]([C:5]([NH:7][C@@H:8]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6])([CH3:4])[CH3:3].[CH2:36]([N-:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH:37]([CH3:39])[CH3:38].CSC.C(S)CS.N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]([C:5]([NH:7][C@@H:8]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6])([CH3:3])[CH3:4].[CH2:36]([N-:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@@H]1C(=O)O
Agent: CC(C)C[N-]CC(C)C
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: SCCS
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(N)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@@H]1C(=O)O
Yield: 86.2 %

Procedure:
Under N2 atmosphere, the Boc-Aib-DTrp-DPro-diisobutylamide was dissolved in 30 ml of CH2Cl2, 1 ml of methylsulfide and 0.5 ml of 1,2-ethanedithiol were added as scavengers to suppress the indole alkylation of tryptophan. 10 ml of trifluoracetic acid was added dropwise while being stirred. The reaction mixture was stirred for 30 min. Volatiles were removed under vacuum and the residue was dissolved in 30 ml of CH2Cl2 and washed with 10 ml saturated NaHCO3 aqueous solution. The organic layer was removed and the aqueous layer was extracted with CH2Cl2 (3×10 ml). The organic layer was dried over anhydrous sodium sulfate, and filtered and the solvents were removed in vacuum. The residue was further purified by column chromatography (SiO2, CHCl/MeOH, 85:15) to afford 0.43 mmol (86.2%) of compound (YL-156) which was characterized by TLC and mass spectra M+=497.6.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=[O:19])[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.C(N(C(C)C)CC)(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([CH:18]=[O:19])[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C=O)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 26.2 %

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (1g) (30 mg, 0.08 mmol) was dissolved in methanol (0.5 mL). A 4 N hydrochloric acid/ethyl acetate solution (2.5 mL) was added, and the mixture was stirred at room temperature for 4.5 hours. Following concentration under reduced pressure, the residue was dissolved in DMF (2 mL). Diisopropylethylamine (0.054 mL, 0.31 mmol) was added, and the mixture was stirred at 140° C. using a microwave reactor for one hour. Saline was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by reverse phase high performance liquid chromatography (Develosil, 2 cm diameter×10 cm, 0.1% formic acid-containing acetonitrile/water mixed solvent) to obtain 6.6 mg of the title compound as a pale yellow solid (27%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C@H:23]3[O:32][C@@H:26]4[O:27]C(C)(C)[O:29][C@@H:25]4[C@@H:24]3[CH2:33][CH2:34][N:35]3[C:43](=[O:44])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]3=[O:45])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>C(OCC)(=O)C.O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C@@H:23]3[C@@H:24]([CH2:33][CH2:34][N:35]4[C:36](=[O:45])[C:37]5[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:43]4=[O:44])[C@@H:25]([OH:29])[C@@H:26]([OH:27])[O:32]3)=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CC1(C)O[C@H]2O[C@H](CCc3ccc(-c4ccc(Cl)cc4)cc3)[C@@H](CCN3C(=O)c4ccccc4C3=O)[C@H]2O1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CC[C@H]1[C@@H](O)[C@@H](O)O[C@@H]1CCc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1 mL) and water (0.5 mL) were added to the compound obtained from step k above (0.04 g). The reaction mixture was stirred at room temperature for 2 hours. The solvents were evaporated at reduced pressure. The residue thus obtained was taken in ethyl acetate and water. The organic layer was separated, washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was concentrated under reduced pressure to yield the title compound (0.028 g).
Reaction SMILES: [N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:52]1[CH:57]=[C:56]([O:58][C@@H:59]([C@H:61]2[CH2:65][O:64][C:63]([CH3:67])([CH3:66])[O:62]2)[CH3:60])[N:55]=[C:54]([S:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[C:71]=2[F:77])[N:53]=1.[Cl-].[NH4+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:77][C:71]1[C:72]([F:76])=[CH:73][CH:74]=[CH:75][C:70]=1[CH2:69][S:68][C:54]1[N:53]=[C:52]([NH:10][S:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:9])=[O:8])[CH:57]=[C:56]([O:58][C@@H:59]([C@H:61]2[CH2:65][O:64][C:63]([CH3:66])([CH3:67])[O:62]2)[CH3:60])[N:55]=1
Reactant: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Reactant: NS(=O)(=O)N1CCOCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCOCC2)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Temperature: 100 °C

Procedure:
A mixture of morpholine-4-sulfonamide (prepared according to patent WO 2004/011443, 0.239 g), tris(dibenzylideneacetone)-dipalladium (0) (33 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (17 mg), cesium carbonate (0.176 g) and 4-chloro-2-[(2,3-difluorobenzyl)thio]-6-{(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy}pyrimidine (the product of example 45 step vi) (0.150 g) in anhydrous dioxane (6 ml) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 20 min. Saturated aqueous ammonium chloride was added and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica using a 1:19 to 2:3 mixture of EtOAc and iso-hexane as eluent to give the subtitle compound as a yellow gum. Yield: 0.165 g
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][CH:11]([N:12]3C(=O)C4C(=CC=CC=4)C3=O)[C:6]2=[N:5][C:4]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:3]1.O.NN>C(O)C>[NH2:12][CH:11]1[C:6]2=[N:5][C:4]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[CH:3][C:2](=[O:1])[N:7]2[CH2:8][CH2:9][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCCn2c1nc(-c1ccncc1)cc2=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NC1CCCn2c1nc(-c1ccncc1)cc2=O
Yield: 65.8 %

Procedure:
To a solution of 3.2 g (8.59 mmol) of (+/−) 2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione dissolved in 24 mL of ethanol was added 2.09 mL (43 mmol) of hydrazine hydrate and the resulting mixture was stirred under reflux for 2 hours. The mixture was filtered and the solid obtained was triturated with dichloromethane for 24 h, filtered, and the resulting filtrates were evaporated to dryness. The resulting residue was purified on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 98/2 to 96/4 to give 1.37 g (66%) of the desired compound as a brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:27])[CH:3]=1.[OH:28]OS([O-])=O.[K+]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:24])=[O:28])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:27])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCSC
Reactant: O=S([O-])OO
Agent: [K+]
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCS(C)=O
Yield: 29.5 %

Procedure:
Using a method analogous to that in Example 25, 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-methylthiopropoxy)quinazoline (250 mg, 0.6 mmol), (prepared as described in Example 21), was treated with OXONE, (trade mark of E.I. du Pont de Nemours & Co., Inc), (84 mg) and the product was pied and isolated to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-methylsulphinylpropoxy)quinazoline (75 mg, 29%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCN(C)CC2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCN(C)CC2)nc1-c1ccc(C)cc1
Yield: 107.1 %

Procedure:
To a solution of methyl 2-(4-methyl-2-(4-methylpiperazin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate (0.042 g; 0.105 mmol) in methanol (2 mL) was added a solution of sodium hydroxide 5N (0.131 mL; 0.656 mmol) and the reaction mixture was heated to reflux for 48 h. The volatiles were removed under reduced pressure, the residue dissolved in water and the pH was adjusted to 5 by addition of a solution of hydrochloric acid 2N. The formed precipitate was collected by filtration and dried under reduced pressure. Purification by preparative HPLC (HPLC method 4) furnished 0.043 g (58%) of the title compound as a solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:38]2[N:47]=[CH:46][C:45]3[C:40](=[C:41]([F:52])[CH:42]=[C:43]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:44]=3)[C:39]2=[O:53])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[N:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[C:48]([C:43]1[CH:44]=[C:45]2[C:40](=[C:41]([F:52])[CH:42]=1)[C:39](=[O:53])[N:38]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH:31]6[CH2:34][O:33][CH2:32]6)[CH2:27][C@@H:26]5[CH3:35])=[CH:21][N:20]=4)[C:15](=[O:36])[N:14]([CH3:37])[N:13]=3)[CH:10]=[CH:9][N:8]=1)[N:47]=[CH:46]2)([CH3:50])([CH3:49])[CH3:51]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)n2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)nn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A mixture of 117d (110 mg, 0.15 mmol) and lithium hydroxide (65 mg, 1.5 mmol) in THF/i-propanol (5/3 mL) and water (2 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 117 (100 mg, 95%) as a yellow solid. MS-ESI: [M+H]+ 682.4. 1H NMR (500 MHz, CDCl3) δ 8.73 (d, J=5.0 Hz, 1H), 8.60 (s, 1H), 8.33 (d, J=2.5 Hz, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.65 (d, J=5.0 Hz, 1H), 7.56-7.51 (m, 2H), 7.34 (s, 1H), 6.96 (d, J=9.0 Hz, 1H), 4.73-4.55 (m, 5H), 3.92 (m, 4H), 3.73-3.74 (m, 1H), 3.55-3.53 (m, 1H), 3.16-3.15 (m, 2H), 2.64-2.39 (m, 4H), 1.44 (s, 9H), 1.09-1.07 (m, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:12]([N:20]=[C:21]=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][C:21]([NH:20][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:22])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NCc1ccc2[nH]ccc2c1
Reactant: O=C=NCCc1ccccc1
Product: O=C(NCCc1ccccc1)NCc1ccc2[nH]ccc2c1
Yield: 76 %

Procedure:
(1H-indol-5-yl)methylamine (12.5 mg) was reacted with phenethylisocyanate (30 μl) according to the similar procedure as described in step 2 of Example 1, to give 1-(1H-indol-5-ylmethyl)-3-phenethylurea (1-6) (19 mg, 76%).
Reaction SMILES: C[O:2][C:3](=[O:52])[C@@H:4]([NH:21][C:22]([C@@H:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH:46]5[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][NH:25]1)=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH3:20])=[CH:8][CH:7]=1.[N:53]([C:56]([CH3:59])([CH3:58])[CH3:57])=[C:54]=[O:55]>C(Cl)Cl>[C:56]([NH:53][C:54]([N:25]1[C@H:24]([C:22]([NH:21][C@@H:4]([CH2:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=3[CH3:20])=[CH:10][CH:11]=2)[C:3]([OH:2])=[O:52])=[O:23])[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH:46]5[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26]1)=[O:55])([CH3:59])([CH3:58])[CH3:57]
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Product: Cc1nccc(Oc2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)NC(C)(C)C)O[C@@H](c3ccc(OCC4CCCCC4)cc3)CO5)C(=O)O)cc2)c1C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-{[(3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (25 mg) in DCM was added 2-isocyanato-2-methyl-propane (5 eq.) and the reaction stirred was at room temperature for 1 hour. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 792.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].Br.[NH2:8][C:9]1[N:10]=[C:11]([Br:14])[S:12][CH:13]=1.C([O-])(=O)C.[Na+]>N1C=CC=CC=1>[Br:14][C:11]1[S:12][CH:13]=[C:9]([NH:8][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[N:10]=1
Reactant: Nc1csc(Br)n1
Reactant: CC(C)C(=O)Cl
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1csc(Br)n1
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of isobutyryl chloride (4.15 ml., 40 mM) in pyridine (50 ml.) was cooled to 0° C. and treated portionwise with 4-amino-2-bromothiazole hydrobromide (7.8 g, 30 mM). After stirring for 1 h. the reaction mixture was poured onto 20% aqueous sodium acetate solution (500 ml) and extracted with chloroform (3×200 ml.). The combined organic layers were dried and the solvents removed under reduced pressure to yield an oil which eventually crystallised. Recrystallisation from 60°-80° petroleum ether gave the title compound (2 g, 20%). mp: 95° (Found: C, 34.1; H, 3.8; N, 11.3. C7H9BrN2OS requires C, 33.7; H, 3.6; N, 11.2%).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.[N-:22]=[N+:23]=[N-:24].[Na+].O.C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:3]([N:22]=[N+:23]=[N-:24])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2c(ccc(Cl)c2F)OC1C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2c(ccc(Cl)c2N=[N+]=[N-])OC1C(F)(F)F
Temperature: 85 °C
Yield: 74.2 %

Procedure:
To the solution of ethyl 6-chloro-5-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (1.0 g, 3.1 mmol) in 20 mL of DMSO was added a solution of sodium azide (1.0 g, 5 mmol) in minimum amount of water. The reaction was then heated to 85° C. for 15 hrs. After cooling to room temperature, to the reaction was added 200 mL of ethyl acetate. The resulting suspension was then washed with brine, and dried over anhydrous magnesium sulfate. After removing the solvents, the residue was purified on silica gel column with ethyl acetate/hexane, it gave 0.8 g of a yellow oil. Part of the product was purified on reverse phase HPLC for further analytical characterization. It gave a pink solid. LC-MS(ES+) 348.3(M+1, 70), 320.2(M−27, 100). 1H NMR(CDCl3/400 MHz) 7.99(s, 1H), 7.24(d, J=8.8 Hz, 1H), 6.75(d, J=8.8 Hz, 1H), 5.67(q, J=6.8 Hz, 1H), 4.32(m, 2H), 1.35(t, J=7.2 Hz, 3H). 19F NMR(CDCl3/400 Hz) −78.71(d, J=6.8 Hz). 13C NMR(CDCl3/400 Hz) 163.7, 152.7, 134.4, 133.9, 131.9,123.3(q, J=287.3 Hz), 122.6, 117.7, 114.6, 114.2, 70.6(q, J=33.3 Hz), 61.9, 14.4. HRSM(EI+) m/e calc. for (C13H9ClF3N3O3) 347.0285(M+), found: 347.0294(M+).