Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[N:12]1([C:2]2[N:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Clc1ncc2ccccc2n1
Solvent: Cc1ccccc1
Product: c1ccc2nc(N3CCNCC3)ncc2c1
Temperature: 0 °C

Procedure:
A solution of 2-chloroquinazoline (5 g) in 20 mL of toluene is added dropwise to a refluxing solution of piperazine (20 g) in 150 mL of toluene and the resultant solution refluxed for an additional 24 h. After cooling to 0° C. for 0.5 h, the solution is filtered and the filtrate extracted with 10% acetic acid. The aqueous extracts are washed with ether, basified and extracted with toluene. The toluene layer is then washed with water, dried and concentrated. Finally, the material is placed under vacuum overnight (6.8 g, m.p. 188-121° C.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:16]2[CH2:17][O:18][CH2:19][CH:9]1[C:10]1[CH:11]=[N:12][O:13][C:14]=1[CH:15]2O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:27])CC>C(Cl)Cl.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH:16]2[CH2:17][O:18][CH2:19][CH:9]1[C:10]1[CH:11]=[N:12][O:13][C:14]=1[CH:15]2[F:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2COCC1C(O)c1oncc12
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2COCC1C(F)c1oncc12
Reaction time: 6 h

Procedure:
To a solution of 7-Hydroxy-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene-12-carboxylic acid tert-butyl ester 106d (141 mg, 0.5 mmol, 1.0 eq) in DCM (5 mL) was added DAST (166 mg, 1 mmol, 2.0 eq) at −78° C. Then mixture was stirred for 6 h from −78° C. to room temperature. The reaction was diluted with EA (20 mL), and washed with aqueous NaHCO3 (5%, 20 mL). The organic layer was dried and concentrated to give 7-Fluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene-12-carboxylic acid tert-butyl ester as an oil, 150 mg, crude yield: 100%. MS: calc'd (MH+) 285, measured (MH+) 285.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4]=[N:5][OH:6].[Cl:12]N1C(=O)CCC1=O>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[N:5][OH:6])[Cl:12]
Reactant: ON=Cc1c(F)cccc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1c(F)cccc1F
Yield: 64.9 %

Procedure:
In a fashion similar to that for preparation 14, 2,6-difluorobenzaldehyde oxime (2.00 g, 12.7 mmol), N-chlorosuccinimide (1.75 g, 13.2 mmol), and DMF (20 ml) gave 2,6-difluorobenzoylchloride oxime (1.58 g, 65%) after column chromatography (silica gel, hexanes/diethyl ether gradient).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22](OC)=[O:23])=[CH:4][N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[C:3]([CH:22]=[O:23])=[CH:4][N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]=1[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: COC(=O)c1cn(-c2ccccc2)c(S(=O)(=O)c2ccccc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C=O)cn(-c2ccccc2)c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
A solution of methyl 4-methyl-1-phenyl-5-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (410 mg) in tetrahydrofuran (10 mL) was cooled to −78° C., and 1.5 mol/L toluene solution of diisobutylaluminum hydride (2.3 mL) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 30 min. Saturated brine was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was filtered through celite, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A solution of the residue in acetonitrile (10 mL) was cooled to 0° C., tetra-n-propylammonium perruthenate (40 mg), N-methylmorpholine N-oxide (269 mg) and molecular sieves 4 A powder (1.0 g) were added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→2:1) to give the title compound as a pale-yellow oil (yield 170 mg, 45%).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][C:18](OC)=[O:19])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.CO.Cl>C1(C)C=CC=CC=1.O>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH:18]=[O:19])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cn1cc(Cc2ccccc2)c2ccccc21
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: O=CCn1cc(Cc2ccccc2)c2ccccc21
Temperature: -65 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Step 1 (470 mg, 1.68 mmol) in toluene (15 mL) at -65° C. there was slowly added 1.0M DIBAL in toluene (2.24 mL, 2.24 mmol) and the mixture was stirred at -65° C. for 1 hour. There was slowly added MeOH (5 mL) and the mixture was then allowed to warm up to r.t. There was added H2O (20 mL) and 1N aqueous HCl (10 mL) and after shaking the organic phase was washed with H2O, dried over MgSO4 and evaporated down to an oily residue which was taken as such to the next step.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1O
Solvent: CCO
Product: Oc1ccccc1C=Nc1ccccc1
Reaction time: 0.25 h

Procedure:
o-Hydroxybenzaldehyde (0.20 mole) was treated with aniline with vigorous stirring in a 1 liter Erlenmeyer Flask. After 15 min., 33 cc of 95% ethanol was added and the reaction mixture was stirred vigorously for an additional 5 min. The reaction mixture was left standing at room temperature for 10 min., then it was placed in an ice-bath for 0.5 hour. The crystals which formed were collected, washed with 95% ethanol, and air dried. Recrystallization from 85% ethanol yielded N-(o-hydroxybenzylidene)aniline. m.p. 47°-49° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1.[C:29](Cl)(=[O:31])[CH3:30]>>[C:29]([NH:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:22])=[CH:15][CH:16]=1)(=[O:31])[CH3:30]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN)cc3)nc12
Reactant: CC(=O)Cl
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CNC(C)=O)cc3)nc12

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-aminomethyl-benzamide and acetyl chloride, the title compound was prepared as white crystals (17% yield). MS: m/e=441(M+H+).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([CH2:9][CH2:10][OH:11])[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.[H][H]>[Pd].CO>[CH3:1][O:2][C@H:3]1[C@@H:8]([CH2:9][CH2:10][OH:11])[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CO[C@@H]1CN(Cc2ccccc2)CC[C@@H]1CCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CNCC[C@@H]1CCO
Yield: 100 %

Procedure:
A mixture of 25.9 parts of cis-3-methoxy-1-(phenylmethyl)-4-piperidineethanol (prepared as in EP-A-0,320,032) and 198 parts of methanol was hydrogenated at normal pressure and 50° C. with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 16.5 parts (100%) of cis-3-methoxy-4-piperidineethanol (interm. 45).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH2:20]CO)[CH3:19])[CH3:14].CO>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:12][CH:13]([CH3:14])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:7])=[CH:10][CH:11]=1
Reactant: CC(C)CCCC(C)CCO
Reactant: COC(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)CCCC(C)CCOC(=O)c1ccc(N)cc1
Yield: 28.8 %

Procedure:
Na metal (200 mg, cat.) was added to a suspension of methyl 4-aminobenzoate (45 g, 300 mmol), tetrahydrogeraniol (48 g, 300 mmol) in PhMe (250 mL). The suspension was heated under reflux for 3 hours with the azeotropic removal of MeOH. The mixture was cooled and filtered through a plug of silica (400 mL) with cyclohexane: EtOAc (9:1) as eluant to give the ester (24 g, 30%) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[CH2:11]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>C(CC(C)(C)C)(C)C>[CH2:11]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)=[CH:23][CH:22]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(CCNCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CC(C)(C)C
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 127.9 %

Procedure:
Add 6-chloronicotinamide (7.03 g, 44.90 mmol) to a stirred solution of 4-(2-benzylamino-ethyl)-phenol (10.10 g, 44.43 mmol), potassium carbonate (15.35 g, 111.1 mmol), dimethylacetamide (138 mL), and isooctane (16 mL). Using a Dean-Stark trap, heat the reaction to reflux under nitrogen for 6 h. Cool the reaction mixtures to room temperature, filter off the solids, and concentrate most of the solvent off on a rotary evaporator. Take the residue up in ethyl acetate (200 mL) and add 1N hydrochloric acid (200 mL). Stir for 15 minutes and filter off the precipitate washing with ethyl acetate. Dissolve the solid in 400 mL of boiling 1:1 methanol/water. To this solution add 5N sodium hydroxide (35 mL) and allow the solution to cool to room temperature. Filter and wash with water to yield 19.74 g (83%) of 6-[4-(2-benzylamino-ethyl)-phenoxy]-nicotinamide: mass spectrum (ion spray): m/z=348.1 (M+1); 1H NMR (CDCl3): 8.58 (d, 1H), 8.15 (dd, 1H), 7.34-7.24 (m, 7H), 7.06 (d, 2H), 6.93 (d, 1H), 6.08 (br s, 2H), 3.82 (s, 2H), 2.92 (t, 2H), 2.84 (t, 2H), 1.33 (br s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:3]([NH:5][C@@H:6]([CH2:10][S:11][S:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([OH:9])=[O:8])=[O:4].C(N(C(C)C)C(C)C)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([NH:1][C@@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:3]([NH:5][C@@H:6]([CH2:10][S:11][S:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:7]([OH:9])=[O:8])=[O:4])(=[O:38])[CH3:37]
Reactant: CC(C)(C)SSC[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CSSC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A solution of (R)-2-((S)-2-amino-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (H-Trp-Cys(StBu)-OH) (Compound SP639) (280 mg, 0.708 mmol) in methylene chloride (1.4 mL) was mixed with N-ethyldiisopropylamine (DIPEA) (371 μL, 2.12 mmol) and acetic anhydride (66.8 μL, 0.708 mmol) with stirring at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (R)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (Ac-Trp-Cys(StBu)-OH) (Compound SP640) (270 mg, 0.617 mmol, 87%).
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:11]=[C:10]3[O:12][CH2:13][CH2:14][C:9]3=[CH:8][C:6]=2[N:7]=1.[N:16]1([CH2:22][CH2:23][CH2:24][NH2:25])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>COCCOC>[N:16]1([CH2:22][CH2:23][CH2:24][NH:25][C:2]2[N:3]=[N+:4]([O-:15])[C:5]3[CH:11]=[C:10]4[O:12][CH2:13][CH2:14][C:9]4=[CH:8][C:6]=3[N:7]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: NCCCN1CCOCC1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)OCC3
Solvent: COCCOC
Product: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)OCC3
Yield: 85.8 %

Procedure:
A solution of chloride 196 (850 mg, 3.8 mmol) and 3-(4-morpholinyl)propylamine (1.7 mL, 11.5 mmol) in DME (30 mL) was stirred at reflux temperature for 18 h. The solution was cooled, the solvent evaporated and the residue partitioned between dilute aqueous NH3 solution (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (2×25 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-10%) of MeOH/DCM, to give 1-oxide 199 (1.08 g, 85%) as a yellow solid: mp 142-144° C.; 1H NMR δ 7.52 (s, 1H, H-9), 7.41 (s, 1H, H-5), 5.97 (br s, 1H, NH), 4.67 (t, J=8.3 Hz, 2H, H-7), 3.75 (t, J=4.7 Hz, 4H, 2×CH2O), 3.56 (dt, J=6.4, 5.9 Hz, 2H, CH2N), 3.35 (dt, J=8.3, 1.2 Hz, 2H, H-6), 2.42-2.53 (m, 6H, 2×CH2N, CH2), 1.83 (p, J=6.5 Hz, 2H, CH2); 13C NMR δ 158.3, 151.4, 146.1, 140.5, 128.7, 121.8, 96.7, 71.9, 67.0 (2), 57.3, 53.8 (2), 40.8, 29.7, 25.4; MS (APCI) m/z 332 (MH+, 100%). Anal. calcd for C16H21N5O3: C, 58.0; H, 6.4; N, 21.1. Found: C, 58.0; H, 6.0; N, 21.2%.
Reaction SMILES: C[Si](C)(C)[O:3][C:4](OC)([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:5]([F:8])([F:7])[F:6].Cl.O.[Cl-].[Na+]>O1CCOCC1>[F:6][C:5]([F:7])([F:8])[C:4]([C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)=[O:3]
Reactant: COC(O[Si](C)(C)C)(c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Yield: 120.7 %

Procedure:
A mixture of trimethyl-[2,2,2-trifluoro-1-methoxy-1-(4-nitro-phenyl)-ethoxy]-silane (5.5 g), a solution of hydrogen chloride in dioxane (4 M, 15 ml), and water (5 ml) was stirred for 4 hours. The mixture was treated with saturated aqueous sodium chloride solution (100 ml) and extracted with ethyl acetate (100 ml). The organic extract was concentrated under reduced pressure to afford 2,2,2-trifluoro-1-(4-nitro-phenyl)-ethanone (4.5 g, 85% yield)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[CH3:11][C:12]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([CH:11]=[CH2:12])[CH:7]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=Cc1cnc(C#N)c(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 3,5-dichloropicolinonitrile (1.0 eq.), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 95° C. overnight. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[CH:8]1([N:14]([CH2:33][C:34]2C=N[C:37]([N:40]3[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[N:41]3)=[CH:38][CH:39]=2)[C:15]2[N:32]=[CH:31][CH:30]=[CH:29][C:16]=2[C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl>[CH:8]1([N:14]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH:44]=[C:43]([C:45]([F:48])([F:46])[F:47])[CH:42]=[N:41]3)=[CH:3][CH:2]=2)[C:15]2[N:32]=[CH:31][CH:30]=[CH:29][C:16]=2[C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1cccnc1N(Cc1ccc(-n2cc(C(F)(F)F)cn2)nc1)C1CCCCC1
Solvent: ClCCl
Product: O=C(O)CCNC(=O)c1cccnc1N(Cc1ccc(-n2cc(C(F)(F)F)cn2)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.30 mL) was added to a solution of tert-butyl 3-(2-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-yl)methylamino)nicotinamido)propanoate (30 mg, 0.052 mmol) in dichloromethane (0.4 mL). The mixture was stirred at room temperature for 2 hours. The reaction was concentrated and the residue was co-evaporated with dichloromethane, ethyl acetate and toluene several times, to give (+/−)-3-(2-(cyclohexyl(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinamido)propanoic acid, as a solid. 1H NMR (400 MHz, CDCl3, δ): 9.81 (br. s, 1H), 8.94 (br. s, 1H), 8.31-8.21 (m, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.66 (d, J=8.58 Hz, 2H), 7.61-7.51 (m, 1H), 7.39 (d, J=8.39 Hz, 2H), 6.70-6.58 (m, 1H), 4.29-4.17 (m, 1H), 3.69-3.53 (m, 2H), 2.76-2.65 (m, 2H), 2.00-0.91 (m, 11H). MS (M+1): 516.2.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:7]1[CH:8]=[C:9]([S:17]([NH2:20])(=[O:19])=[O:18])[S:10][C:11]=1[S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[CH3:6])(=O)[CH3:2].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:1]([NH:4][CH:5]([C:7]1[CH:8]=[C:9]([S:17]([NH2:20])(=[O:19])=[O:18])[S:10][C:11]=1[S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[CH3:6])[CH3:2]
Reactant: CCS(=O)(=O)c1sc(S(N)(=O)=O)cc1C(C)NC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(C)c1cc(S(N)(=O)=O)sc1S(=O)(=O)CC

Procedure:
To a stirred, refluxing suspension of 4-(1-acetamidoethyl)-5-ethylsulfonylthiophene-2-sulfonamide (2.61 g, 0.0077 mol) in dry tetrahydrofuran under nitrogen atmosphere was added dropwise over 1/2 hour a solution of dimethylsulfide borane complex (2.3 ml of a 10 M solution, 0.023 mol) in dry THF (10 ml). The cloudy solution which formed was stirred at reflux for 11/2 hours. The mixture was cooled in ice and acidified by the dropwise addition of 6N HCl (10 ml), and concentrated in vacuo at room temperature. The moist solid residue was basified with saturated NaHCO3 and was extracted with ethyl acetate (4×50 ml). The amino product was extracted into 3N HCl (4×25 ml). The combined HCl extracts were neutralized with NaHCO3 and extracted with ethyl acetate (4×50 ml). The ethyl acetate extract was dried over anhydrous Na2SO4, filtered and concentrated in vacuo at room temperature. A colorless oil was obtained which solidified to a white solid upon trituration in ethyl acetate. The crude yield was 1.99 g or 80%. The solid after recrystallization from ethyl acetate had m.p. 135-137.5° C. NMR supported the structure and HPLC confirmed the purity.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1.CI.[NH4+]>O1CCCC1.O>[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13]([CH3:1])([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)[C@H]1CCC[C@@H](OC)C1
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(C)CCCC(OC)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, a 2M-lithium diisopropylamide solution (7.32 ml, 0.0146 mmol) was added dropwise to a solution of methyl cis-3-methoxycyclohexane-carboxylate (1.80 g, 0.0105 mol) in tetrahydrofuran (36 ml) at −78° C. over a period of 15 minutes. After 3 hours, a solution of methyl iodide (4.45 g, 0.0314 mmol) in tetrahydrofuran (9 ml) was added dropwise thereto over a period of 20 minutes, and the resulting mixture was slowly warmed up to 0° C. After 3 hours, a saturated aqueous ammonium solution was added thereto and the resulting mixture was poured into water and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain methyl 3-methoxy-1-methylcyclohexanecarboxylate (1.8985 g, 98%, a 4:1 mixture of isomers).
Reaction SMILES: C(OC([N:8]([CH2:31][C@@H:32]([C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[O:33][Si](CC)(CC)CC)[C@H:9]([CH3:30])[CH2:10][C:11]1[C:19]2[C:14](=[C:15]([O:20][CH:21]([CH2:27][CH2:28][CH3:29])[C:22]([O:24]CC)=[O:23])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=O)(C)(C)C.Cl.O>C(O)C.O1CCOCC1>[OH:33][C@H:32]([C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH2:31][NH:8][C@H:9]([CH3:30])[CH2:10][C:11]1[C:19]2[C:14](=[C:15]([O:20][CH:21]([CH2:27][CH2:28][CH3:29])[C:22]([OH:24])=[O:23])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: CCCC(Oc1cccc2c(C[C@@H](C)N(C[C@H](O[Si](CC)(CC)CC)c3cccnc3)C(=O)OC(C)(C)C)c[nH]c12)C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: CCCC(Oc1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12)C(=O)O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of the obtained ethyl 2-((3-((2R)-2-((tert-butoxy-carbonyl) ((2R)-2-pyridin-3-yl-2-((triethylsilyl)oxy)ethyl)amino)propyl)-1H-indol-7-yl)oxy)pentanoate in ethanol (0.2 ml) is added a solution of 4N-hydrogen chloride in dioxane (0.2 ml), and the mixture is stirred at room temperature for 19 hours. After the reaction is completed, water (0.2 ml) is added to the mixture, and the solvent is evaporated under reduced pressure. To a solution of the obtained residue in ethanol (0.35 ml) is added a 5N aqueous potassium hydroxide solution (0.09 ml), and the mixture is stirred at room temperature for 4 hours. After the reaction is completed, the mixture is neutralized with 1N hydrochloric acid, and the solvent is evaporated under reduced pressure. The residue is purified by preparative high performance liquid chromatography (0.035% trifluoroacetic acid/acetonitrile-0.05% trifluoroacetic acid/water) to give 2-((3-((2R)-2-(((2R)-2-hydroxy-2-pyridin-3-ylethyl)-amino)propyl)-1H-indol-7-yl)oxy)pentanoic acid.2 trifluoroacetate (13.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[N:4]=[C:5]([S:30][CH3:31])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([CH2:28]O)[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.COCCN(S(F)(F)[F:43])CCOC.[Cl-].[NH4+].C(OCC)(=O)C>ClCCl>[CH3:1][O:2][C:3](=[O:32])[N:4]=[C:5]([S:30][CH3:31])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([CH2:28][F:43])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(CO)cc(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(CF)cc(OC)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 100 mg of {2-(3-hydroxymethyl-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 1.5 ml of dichloromethane there was added 0.057 ml of [bis(2-methoxyethyl)amino]sulfur trifluoride at −78° C. After stirring at −78° C. for 5 minutes, the mixture was stirred at room temperature for 1 hour and 25 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried through PRESEP™. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (59 mg) as a yellow oil.