Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:7]=1[CH2:8][NH:9][C:10]([C:12]1([CH:18]([OH:20])[CH3:19])[CH2:16][CH2:15][C:14](=[O:17])[CH2:13]1)=[O:11])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:7]=1[CH2:8][NH:9][C:10]([C:12]1([CH:18]([OH:20])[CH3:19])[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]1)=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(O)C1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)CCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)C1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)CCC(O)C1
Reaction time: 0.33 h

Procedure:
A cooled (0° C.) solution of N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-1-(1-hydroxyethyl)-3-oxocyclopentanecarboxamide (6.27 g, 15.6 mmol) in methanol was treated with sodium borohydride (591 mg, 15.6 mmol) and stirred for 20 min. The reaction mixture was concentrated and the residue was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-3-hydroxy-1-(1-hydroxyethyl)cyclopentanecarboxamide as a mixture of 8 isomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12](C3CCCCO3)[N:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[ClH:19].CCOC(C)=O>CO>[ClH:19].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][NH:11][N:12]=2)=[N:6][CH:7]=1
Reactant: Fc1ccc(-c2ccnn2C2CCCCO2)nc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2cc[nH]n2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-fluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]pyridine obtained in Reference Example 9 (81.2 g, 0.33 mol) in methanol (250 mL), a 4M solution of HCl-EtOAc (0.25 L, 0.96 mol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, then EtOAc (500 mL) was added to the residue, and the resulting mixture was heated to reflux for 1 hour. The reaction mixture was allowed to cool to room temperature, then ice-cooled, and then the precipitate was filtered out and dried to obtain a hydrochloride (colorless solid) of the title compound. Water (700 mL) and EtOAc (350 mL) were added to the obtained hydrochloride, and the resulting mixture was stirred for 30 minutes and then separated. The obtained organic layer was extracted with 1.2M hydrochloric acid (100 mL) three times. The aqueous layers were combined and the pH was adjusted to 12 with an 8M aqueous solution of NaOH, and then the organic layer was extracted with CHCl3. The extracted organic layer was passed through an ISOLUTE Phase Separator, and the solvent was distilled off under reduced pressure. Diisopropyl ether (300 mL) was added to the obtained residue, and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was allowed to cool at room temperature, then ice-cooled, and then the precipitate was filtered out and dried to obtain the title compound (44.9 g) (pale pink solid).
Reaction SMILES: O.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([OH:8])=[O:7].ClC1C=[C:16](C=CC=1O)[C:17](O)=[O:18].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[C:17]([O:12][C:11]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:2])(=[O:18])[CH3:16]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C(=O)O)cc1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
3-Chloro-4-hydroxybenzoic acid hemihydrate (10.16 g, 56 mmol) was dissolved in 20 ml of acetic anhydride, followed by the addition of 0.5 ml of concentrated sulfuric acid. The resulting mixture was stirred at 100° C. for 3 hours and was then allowed to stand overnight at room temperature. The precipitate was collected by filtration and then washed with benzene, whereby 8.95 g of 4-acetoxy-3-chlorobenzoic acid were obtained (yield: 75%, melting point: 149-151° C.). A mixture of 8.95 g (41.7 mmol) of 4-acetoxy-3-chlorobenzoic acid and 22.23 g (167 mmol) of aluminum chloride was then heated at 180° C. for 3 hours. Subsequent to the addition of ice and 1N hydrochloric acid, the resultant mixture was extracted with ethyl acetate. The organic layer was washed with water and was then dried over MgSO4. The solvent was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate, whereby 2.97 g of the title compound were obtained as yellow powder (yield: 33%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1)(=O)=O>CN(C)C=O.O>[N:1]([CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)OCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Temperature: 105 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
Sodium azide (350 mg, 5.38 mmol) was added to a solution of methanesulfonic acid, 2-(2-benzotriazol-1-ylmethyl-benzimidazol-1-yl)-ethyl ester (200 mg, 0.54 mmol) in 5 mL of anhydrous N,N-dimethylformamide. The reaction temperature was raised to 105° C. and stirred for 4 hours. The mixture was cooled, diluted with water and extracted with diethyl ether (3×100 mL). The combined ether extracts were dried over magnesium sulfate, filtered, and evaporated under vacuum. This gave the title compound as a white solid (160 mg, 94% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH3:13])[NH:8][S:7]1(=[O:15])=[O:14].Cl.[Cl:17][C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[N:20][CH:19]=1>CN(C)C=O.C(N(CC)CC)C>[Cl:17][C:18]1[N:23]=[C:22]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[CH2:10][CH:9]([CH3:13])[NH:8][S:7]3(=[O:15])=[O:14])[CH2:28][CH2:29]2)[CH:21]=[N:20][CH:19]=1
Reactant: CC1CC(=O)N(CCCCBr)S(=O)(=O)N1
Reactant: Clc1cncc(N2CCNCC2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1CC(=O)N(CCCCN2CCN(c3cncc(Cl)n3)CC2)S(=O)(=O)N1

Procedure:
The title compound is prepared by adding to a stirred solution of 2 g (0.006 mol) of 2-(4-bromobutyl)-5,6-dihydro-5-methyl-2H-1,2,6-thiadiazin-3(4H)-one 1,1-dioxide in 50 mL of dimethylformamide, 4 mL of triethylamine and 1.41 g (0.006 mol) of 1-(6-chloro-2-pyrazinyl)piperazine hydrochloride.
Reaction SMILES: [CH2:1]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][N:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:25][CH:24]=2)[CH3:22])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+:36]>>[Na+:36].[CH2:1]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][N:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:27][CH:28]=2)[CH3:22])=[CH:12][CH:11]=1)[C:6]([O-:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)C(=O)[O-]

Procedure:
0.69 g of 2-butyl-3-[4-[2-[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionic acid obtained in Example 24 was treated with 1.50 ml of 1N sodium hydroxide according to Example 20 to obtain 0.65 g of the desired compound as a powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2-c2cccs2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccc2-c2cccs2)cc1
Yield: 97.5 %

Procedure:
A solution of 123 mg (0.492 mmol) of 4-methyl-2'-(2-thienyl)-1,1'-biphenyl, 18.5 mg of AIBN and 110 mg (0.62 mmol) of N-bromosuccinimide in 50 mL of carbon tetrachloride was heated at reflux until a negative starch iodide reaction was obtained (2 hr). The reaction mixture was evaporated under vacuum and the residue triturated with hexane. The hexane washes were filtered and the filtrate evaporated under vacuum to give 158 mg of product. 1H NMR (300 MHz, CDCl3): 4.48 (s, 2H), 6.68 (dd, 1H), 6.88 (dd, 1H), 7.11 (m, 5H), 7.36 (m, 3H), 7.50 (dd, 1H).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[O:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:20][CH:19]([O:21][CH3:22])[CH2:18]3)=[O:16])[N:14]=2)[CH2:7]1)(=O)=O.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CN(C)C=O>[C:23]([S:25][CH:6]1[CH2:7][N:8]([C:10]2[O:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:18][CH:19]([O:21][CH3:22])[CH2:20]3)=[O:16])[N:14]=2)[CH2:9]1)(=[O:26])[CH3:24]
Reactant: CC([O-])=S
Reactant: COC1CN(C(=O)c2coc(N3CC(OS(C)(=O)=O)C3)n2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC1CN(C(=O)c2coc(N3CC(SC(C)=O)C3)n2)C1
Temperature: 80 °C
Reaction time: 6 h
Yield: 61.7 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidine (580 mg, 1.75 mmol) (obtained as described in Reference Example 73(3)) in dimethylformamide (30 ml) was added potassium thioacetate (1.20 g, 10.5 mmol) at room temperature and the mixture was stirred in an oil bath (80° C.) for 6 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (97:3) as the eluant to afford 3-acetylthio-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidine (336 mg, yield 62%) as a pale brown solid.
Reaction SMILES: C([O-])(=O)C.C([O:9][C:10]1[C:11]([CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:24]#[N:25])[CH2:19][CH2:18]2)=[N:12][CH:13]=[CH:14][N:15]=1)(C)(C)C.[OH-].[Na+]>C(OCC)(=O)C>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][CH:23]([CH:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:11]2[C:10](=[O:9])[NH:15][CH:14]=[CH:13][N:12]=2)[CH2:22][CH2:21]1)[C:24]#[N:25]
Reactant: CC(C)(C)Oc1nccnc1CN1CCC(C(C#N)Cc2ccccc2F)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#CC(Cc1ccccc1F)C1CCN(Cc2ncc[nH]c2=O)CC1
Reaction time: 1 h
Yield: 79.9 %

Procedure:
After adding 3 ml of 4N hydrogen chloride/ethyl is acetate to 188 mg of 2-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-3-(2-fluorophenyl)propionitrile while cooling on ice, the mixture was stirred 1 hour. A 2N sodium hydroxide solution was added to the reaction solution for neutralization, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (129 mg, 80% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1(O)[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1(O)c1cc(F)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(F)c(C2=NCCCC2)c1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a stifled solution of tert-butyl 2-(2,5-difluorophenyl)-2-hydroxypiperidine-1-carboxylate (9.4 g, 30 mmol) in DCM was added TFA (34.2 g, 300 mmol) and stifled at room temperature for 2 h. After completion of reaction, solvent was removed under vacuum and residue was quenched with sat.NaHCO3 and extracted with DCM. Organic layer was washed with water, brine and dried over anhydrous Na2SO4 and concentration to afford crude product as brown liquid (5.5 g), this crude was directly used for next step without any purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]([CH2:16][CH2:17][O:18][C:19]([F:22])([F:21])[F:20])[C:5]2=[N:6][CH:7]=1.[CH3:23][CH:24]([SH:26])[CH3:25]>>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:9]1[N:8]([CH2:16][CH2:17][O:18][C:19]([F:22])([F:21])[F:20])[C:5]2=[N:6][CH:7]=[C:2]([S:26][CH:24]([CH3:25])[CH3:23])[CH:3]=[C:4]2[N:10]=1
Reactant: CC(C)(C)Cc1nc2cc(Br)cnc2n1CCOC(F)(F)F
Reactant: CC(C)S
Product: CC(C)Sc1cnc2c(c1)nc(CC(C)(C)C)n2CCOC(F)(F)F

Procedure:
The title compound was prepared according to the procedure described in Step E of Example 32 from 6-bromo-2-(2,2-dimethylpropyl)-3-[2-(trifluoromethoxy)ethyl]-3H-imidazo[4,5-b]pyridine (Step D of Example 49) and 2-propanethiol (TCI Tokyo Kasei Kogyo Co., Ltd.).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=1[O:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([C:13]1[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=1[O:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([Cl:1])[N:17]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1Oc1nc(Cl)ccc1N
Temperature: 40 °C
Yield: 67.4 %

Procedure:
A solution of N-chlorosuccinimide (556 mg, 4.2 mmol) in DMF (10 ml) was added to a solution of 1b (960 mg, 4.0 mmol) in DMF (15 ml) at rt. The reaction was heated at 40° C. for 30 min. The reaction mixture was cooled to rt and the reaction was quenched with saturated aqueous sodium thiosulfate (Na2S2O3) solution (100 mL). The mixture was extracted with ethyl acetate (3×20 ml) and the organic layers were washed with aqueous sodium thiosulfate solution, brine and were dried over sodium sulfate. The solvents were removed under reduced pressure and the dark red oil was purified by chromatography on silica (continuous gradient 0 to 40% Hexane/EtOAc) to give 125a as an off-white solid (746 mg, 68% yield). [M+H]+=277.11. 1H NMR (500 MHz, CDCl3): 7.41 (d, 1H, J=7.4 Hz), 7.20 (t 1H, J=7.4 Hz), 7.11 (t, 1H, J=7.4 Hz), 7.01 (d, 1H, J=8.1 Hz), 6.93 (d, 1H, J=8.1 Hz), 6.85 (d, 1H, J=8.1 Hz), 3.91 (s, 1H), 1.39 (s, 9H).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](OCC)(=[O:18])[CH:15]([CH3:17])[OH:16]>>[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:18])[CH:15]([CH3:17])[OH:16]
Reactant: CCOC(=O)C(C)O
Reactant: CCCCCCCCCCCCO
Product: CCCCCCCCCCCCOC(=O)C(C)O
Temperature: 60 °C
Reaction time: 28 h
Yield: 80 %

Procedure:
A mixture of Novozym® 435 (500 g), 1-dodecanol (2000 mL), and ethyl lactate (2000 mL) in a 5 L reactor was stirred (˜200 rpm) at 60±5° C. for 28 hours. Upon work-up, 2000 g of lauryl lactate (>80% yield) was obtained as a pale yellow liquid. The purity of the product was >95% as assessed by GC-FID.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C(O[CH:16](OCC)[CH2:17][N:18](C(OCC1C=CC=CC=1)=O)[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)C.Cl>O>[OH2:2].[ClH:1].[ClH:1].[N:22]1[CH:21]=[CH:20][C:19]([NH:18][CH2:17][CH:16]2[C:9]3[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=3)[CH2:6][CH2:7][NH:8]2)=[CH:24][CH:23]=1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)c1ccncc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Product: Oc1cc2c(cc1O)C(CNc1ccncc1)NCC2
Yield: 158 %

Procedure:
A solution of 3,4-dihydroxyphenethylamine hydrochloride (0.53 g.), N-benzyloxycarbonyl-N-(4-pyridyl)aminoacetaldehyde diethyl acetal (1.2 g.) and conc. hydrochloric acid (1 ml.) in water (6 ml.) was refluxed for 8 hours at 100° C. The reaction mixture was concentrated under reduced pressure and the crystalline residue was recrystallized from a mixture of methanol and ether to give 1-(4-pyridyl)aminomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride monohydrate (0.8 g.), mp 172° to 176° C (dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)=[CH:3][CH:2]=1.[NH2:17][C@@H:18]([CH3:42])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:20]>>[CH2:36]([O:35][CH:34]([O:38][CH2:39][CH3:40])[C@@H:33]([N:21]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)[C:19](=[O:20])[C@@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:16])[CH3:42])[CH3:41])[CH3:37]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Reactant: O=C(O)CONC(=O)NCc1ccncc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(pyridin-4-ylmethyl)ureidooxy)acetic acid (Compound VI-10) 94 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)-propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:19]([NH:21][CH2:22][CH2:23][OH:24])[CH3:20]>C(Cl)Cl>[CH2:19]([N:21]([CH2:22][CH2:23][OH:24])[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:20]
Reactant: CCNCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Benzylchloroformate (5.91 g, 34.67 mmol) and triethylamine (5.2 ml) were added sequentially to a solution of 2-(ethylamino)ethanol (3.0 g, 33.66 mmol) in DCM (180 ml) at 0° C. The ice bath was removed and the reaction mixture was allowed to stir overnight at ambient temperature. The solution was washed with 10% citric acid (100 ml) and H2O (2×100 ml) and concentrated in vacuo. The organic phase was dried (MgSO4), concentrated under reduced pressure, and the concentrate was purified by column chromatography (ISCO, silica gel column, eluting with 60→100% EtOAc/hexanes for 14 minutes) to give the title compound (7.29 g, yield: 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:28]1[N:32]([CH3:33])[C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[N:29]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[N:32]([CH3:33])[C:31]6[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=6[N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5nc6ccccc6n5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-chloro-1-methyl-1H-benzoimidazole following a procedure analogous to that described for Intermediate 12; K2CO3 and acetonitrile are used as base and solvent, respectively, at 110° C. LC (method 4): tR=0.72 min; Mass spectrum (ESI+): m/z=489 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]([OH:12])[CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:34][C:33]1[CH:35]=[CH:36][C:30]([S:27]([O:12][CH:9]([CH2:10][CH3:11])[C@@H:8]([NH:13][C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(OS(=O)(=O)c1ccc(C)cc1)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (S)-tert-butyl 1-cyclohexyl-3-hydroxypentan-2-ylcarbamate (1.067 g, 3.74 mmol), catalytic amount of DMAP, and pyridine (0.651 g, 8.24 mmol) at 0° C. was added TsCl (0.856 g, 4.49 mmol) in CH2Cl2 (4 mL) over 2 min. The resulting solution was stirred at rt overnight. The reaction mixture was diluted with EtoAc, washed with 1 M HCl, sat. aq. NaHCO3, brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by on silica gel chromatography to give (S)-2-(tert-butoxycarbonylamino)-1-cyclohexylpentan-3-yl 4-methylbenzenesulfonate as a white solid. MS ESI +ve m/z 462 (M+Na).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].[Cu](C#N)[C:11]#[N:12]>CN(C)C=O>[Br:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:7]=1[CH3:8])[C:11]#[N:12]
Reactant: Cc1c(Br)cncc1Br
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: Cc1c(Br)cncc1C#N
Temperature: 150 °C

Procedure:
To a stirred solution of 3,5-dibromo-4-methylpyridine (2.0 g, 7.97 mmol) in dry N,N-dimethylformamide (10 mL) was added copper cyanide (1.07 g, 11.95 mmol) at room temperature. The reaction mixture was heated at 150° C. for 6 h, cooled it, quenched with water (5 mL) and extracted with 50% ethyl acetate/hexane (2×100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. MS (M+1): 199.1.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4]([CH:9]=O)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>S([O-])([O-])(=O)=O.[Cu+2].C(Cl)Cl>[CH3:13][C:14]([S@@:17](/[N:19]=[CH:9]/[C:4]1[C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ncccc1C(F)(F)F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1ncccc1C(F)(F)F
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
To a solution of 3-(trifluoromethyl)picolinaldehyde (Frontier Scientific, 9.80 g, 56.0 mmol) and DCM (50 mL) was added (S)-2-methylpropane-2-sulfinamide (AK Scientific, 10.3 g, 85.0 mmol) and copper(II) sulfate (35.3 g, 221 mmol). After 1.5 h at rt, the reaction was filtered through a pad of Celite® brand filter agent and the pad of Celite® filter agent was rinsed with DCM. The filtrate was concentrated in vacuo to give a dark green oil. The oil thus obtained was loaded onto a silica gel column and eluted with 30% EtOAc in hexanes to give (S,E)-2-methyl-N-((3-(trifluoromethyl)pyridin-2-yl)methylene)propane-2-sulfinamide (13.2 g, 47.5 mmol, 85.0% yield), as a golden oil. 1H NMR (300 MHz, CDCl3) δ ppm 9.02 (d, J=4.3 Hz, 1H), 8.70 (d, J=1.3 Hz, 1H), 8.38 (d, J=7.7 Hz, 1H), 7.79 (dd, J=7.9, 4.8 Hz, 1H), 1.18 (s, 9H). MS (ESI pos. ion) m/z: 279.1 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[CH2:3][NH2:4].[CH3:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](=O)[CH3:23])=[CH:18][CH:17]=1>>[CH3:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][CH:22]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=2)[CH3:23])=[CH:18][CH:17]=1
Reactant: CC(=O)COc1ccc(C)cc1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Product: Cc1ccc(OCC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared in the manner described in Example 3 using 2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine and (4-methylphenoxy)propan-2-one. The residual oil was chromatographed on Kieselgel 60. Elution with 5% methanol-chloroform gave the title compound m.p. 86-96 (heptane). τ(CDCl3) 8.9 (3H, d, J=6 Hz), 7.7 (3H, s), 6.7-7.6 (5H, m, 2H disappears with D2O) 6.0-6.5 (2H, m), 5.3 (1H, m), 3.25 (2H, d, J=9 Hz), 2.95 (2H, d, J=9 Hz), 2.3-2.65 (4H, m).