Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([O:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(F)(F)F.CCOCC>C(OCC)C.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH2:5]([O:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]1([NH2:16])[CH2:2][CH2:1]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#Cc1cccc(F)c1OCc1ccccc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2cccc(F)c2OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of ethylmagnesium bromide, 3M in diethyl ether (28.2 mL) was added as a slow stream to a mechanically stirred mixture of tetraisopropyl orthotitanate (13.09 mL), and 2-(benzyloxy)-3-fluorobenzonitrile (Example 283a, 9.6 g) in diethyl ether (400 mL) cooled to −78° C. The resulting solution was stirred at −78° C. for 15 min and then warmed to room temperature over 1 h 30 min. An ice bath was placed around the reaction and boron trifluoride etherate (10.71 mL) was added as a slow stream (caution exothermic) and the mixture was stirred for 30 min. The reaction was cooled (ice bath) and quenched with 1 M aqueous HCl (400 mL added portionwise). The aqueous layer was separated and the diethyl ether layer further extracted into 1M HCl (2×200 mL) (ethyl acetate added to the diethyl ether to aid solubility). The aqueous layer was cooled in an ice bath and basified with stirring with a 10M aqueous NaOH solution. The resulting precipitate was filtered through Celite, washing the pad with water (200 mL) then DCM (4×200 mL) then DCM/MeOH (90:10, 300 mL). The combined filtrates were separated and the aqueous layer further extracted with DCM (2×200 mL). The combined organics were dried (MgSO4) and evaporated, the residue was purified on SCX resin (50 g) eluting with DCM, methanol (discarded) and flushing with 20% ammonia in methanol to give the subtitle compound as an oil (2.54 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:12])[CH:9](Br)[CH3:10])[CH:5]=[CH:6][CH:7]=1.[NH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16]>C(#N)C.C(OCC)(=O)C>[OH:12][C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[NH:13][CH:9]1[CH3:10]
Reactant: CC(C)(N)CO
Reactant: CC(Br)C(=O)c1cccc(Cl)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1NC(C)(C)COC1(O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 3′-chloro-2-bromo-propiophenone (61.2 g, 247 mmol) in acetonitrile (752 mL) was added 2-amino-2-methyl-1-propanol (56.5 g, 630 mmol). The reaction mixture was allowed to reflux for 8 hours, then slowly cooled to room temperature. The solution was concentrated in vacuo to provide a yellow solid. The crude material was dissolved in 600 mL of ethyl acetate and washed with water (300 mL×2). The ethyl acetate layer was dried (MgSO4), filtered, and concentrated in vacuo to give the product in 90% yield. 1H NMR (CDCl3) δ0.82 (d, J=6.6 Hz, 3H), 1.07 (s, 3H), 1.39 (s, 3H), 3.19 (q, J=6.5 Hz, 1H), 3.42 (d, J=11.2 Hz, 1H), 3.83 (d, J=11.2 Hz, 2H), 7.2-7.65 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25]C)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1
Yield: 45 %

Procedure:
A solution of the 9-[(3-fluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (130.8 mg, 0.37 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 5 h at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 57.4 mg (45%) of the 9-[(3-fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.5 (m, 2H), 7.3 (m, 2H), 7.15-7.0 (m, 2H), 6.95 (d, 1H, J=8 Hz), 6.85 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H). IR (CHCl3, cm−1) 3431, 3200 (br), 1628, 1614, 1600, 1580, 1546, 1488, 1448, 1329, 1261, and 776. MS (ES) m/e 333, 335.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>ClCCl.C(N(CC)CC)C>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[S:1][CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13]
Reactant: OCc1ccccc1S
Reactant: C=CC(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCSc1ccccc1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a stirring solution of 2-mercaptobenzyl alcohol (1.00 g, 7.10 mmol) in dichloromethane (20 mL) at 0° C. was added methyl acrylate (0.70 mL, 7.70 mmol) followed by triethylamine (50 μL, 0.35 mmol). The mixture was allowed to warm to room temperature and stir for 4 h, at which point the solvent was removed with a rotary evaporator. The residue was subjected to column chromatography on silica gel (0-10% ethyl acetate in dichloromethane), affording 1.40 g (86%) of methyl 3-(2-hydroxymethylphenylthio)propionate. 1H NMR (CDCl3) δ2.63 (t, 2, J=7), 3.18 (t, 2, J=7), 3.68 (s, 3), 4.79 (s, 2), 7.27 (m, 2), 7.43 (m, 2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=2)=[C:4]([Cl:23])[CH:3]=1.C(=O)([O-])[O-].[Ca+2].[C:29](Cl)(Cl)=[S:30].Cl>ClCCl.O>[Cl:23][C:4]1[CH:3]=[C:2]([N:1]=[C:29]=[S:30])[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=1
Reactant: CS(=O)(=O)Nc1cccc(-c2c(Cl)cc(N)cc2C(F)(F)F)c1
Reactant: S=C(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(-c2c(Cl)cc(N=C=S)cc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a cold (0° C.) suspension of N-(4′-amino-2′-chloro-6′-(trifluoromethyl)biphenyl-3-yl)methanesulfonamide (570 mg, 1.56 mmol, Eq: 1.00) and calcium carbonate (313 mg, 3.13 mmol, Eq: 2) in dichloromethane (3.38 ml) and water (3.38 ml) was added thiophosgene (198 mg, 131 μl, 1.72 mmol, Eq: 1.1). The reaction mixture was allowed to warm up to room temperature and was vigorously stirred for 16 h. 1N HCl was added to adjust the pH to ca. 2. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and washed with water then brine and purified on silica gel (column 24 g, dichloromethane/ethyl acetate 1:0 to 85:15) to give 565 mg (89%) of the desired product as a colorless oil.
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[NH:10][N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].F[C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][C:29]=1[C:39]([N:41]1[CH2:50][CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1)=[O:40]>>[Cl:13][C:12]1[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:23][CH2:24][CH2:25][CH3:26])=[N:9][N:10]([C:28]2[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][C:29]=2[C:39]([N:41]2[CH2:50][CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)=[O:40])[C:11]=1[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: CCOC(=O)c1ccc(F)c(C(=O)N2CCc3ccccc3C2)c1
Reactant: CCCCN(CCCC)C(=O)c1n[nH]c(CCOC2CCCCO2)c1Cl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCC)cc2C(=O)N2CCc3ccccc3C2)c(CCOC2CCCCO2)c1Cl
Yield: 29.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, N,N-dibutyl-4-chloro-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole-3-carboxamide (407 mg, 1.06 mmol) and ethyl 4-fluoro-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (380 mg, 1.16 mmol) were converted to the title compound (219 mg, 30%). 1H NMR (CD3OD, mixture of amide rotamers) δ 8.26 (td, J=8.4, 1.8 Hz, 1H), 8.19-8.10 (m, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.29-7.07 (m, 3.5H), 6.94 (d, J=7.5 Hz, 0.5H), 4.71-4.48 (m, 2H), 4.47-4.39 (m, 2H), 4.16-3.86 (m, 1H), 3.80-3.37 (m, 5H), 3.26-2.58 (m, 5H), 1.87-0.74 (m, 22H), 0.72-0.66 (m, 1H); MS(ESI+) m/z 609.3 (M+H-THP)+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[C:16](=[O:18])=[O:17]>CCOCC.CCCCCC>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:16]([OH:18])=[O:17])[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCO2
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(O)c1cccc2c1OCCC2
Temperature: 0 °C

Procedure:
At RT a solution of chroman (17.7 mmol) in ether (15 mL) is added over 10 min to a solution of n-BuLi (19.5 mmol) in a mixture of hexane (12.2 mL) and ether (15 mL). The mixture is stirred at reflux for 150 min, allowed to reach RT and poured into a mixture of dry ice and ether. Ice water is added and the layers are separated. The aq. layer is made acidic and extracted with a mixture of ether and EtOAc. The combined organic layers are washed with water, dried over Na2SO4 and concentrated in vacuo to give a crude product which is purified by CC (heptane/EtOAc 9/1 to EtOAc). LC-MS: tR=0.76 min; [M+CH3CN+H]+=220.1.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:39])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>O1CCCC1.CO>[CH2:3]([NH:10][C:11](=[O:39])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][C:35]([F:37])([F:38])[F:36])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCC(F)(F)F)c1
Yield: 29 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 50 mg (1.25 mmol, 13 eq) of sodium hydroxide and 50 mg (0.096 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(3,3,3-trifluoropropoxy)biphenyl-4-yl]propanoate in 3 ml of a tetrahydrofuran/methanol mixture (8/2) at room temperature for 2 hours, and after crystallization from pentane/isopropyl ether, 14 mg of 3-[3′-(3-heptyl-1-methylureido)-2-(3,3,3-trifluoropropoxy)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=90° C.). Yield=29%
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[C:19](C)[CH:20]=[CH:21][CH:22]=3)[C:3]=12.[F:25][C:26]([F:36])([F:35])C1C=CC(C=O)=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:26]([F:36])([F:35])[F:25])=[CH:21][CH:22]=3)[C:3]=12
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1cccc(-c2nn(C)c3nnc(-c4ccccc4)c(Cl)c23)c1
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 23 was synthesised following similar procedures outlined in Example 24 (Compound 19), using 4-trifluoromethylbenzaldehyde instead of 3-methylbenzaldehyde in Step 1. As a slightly modified procedure, in Step 2, the reaction mixture was filtered and following evaporation of the filtrate, purification of (3,5-dichloro-6-phenylpyridazin-4-yl)(4-(trifluoromethyl)phenyl)methanone was carried out by trituration of the solid residue in diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11]C)=[O:10])=[C:4]([F:14])[CH:3]=1.CO.[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH:17]1([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])=[C:4]([F:14])[CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)C(C)c1ccc(N)cc1F
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(NC2CCCC2)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1.50 g (7.6 mmol) of compound (7) in a solvent mixture of 10 mL of methanol and 0.2 mL of acetic acid, 1.4 mL (15.2 mmol) of cyclopentanone and 0.96 g (15.2 mmol) of sodium cyanoborohydride (NaBH3CN) were added. The obtained solution was stirred at room temperature for 12 hours. Next, the reaction mixture was dried under a vacuum and extracted with dichloromethane, followed by drying over anhydrous sodium sulfate and subsequent filtration. The filtrate was dried under a vacuum, and the residue was purified by silica gel chromatograph (n-hexane/ethyl acetate 3:2) to give a methyl ester of compound (11a). This compound was hydrolyzed with sodium hydroxide to give 1.09 g (yield 54%) of compound (11a) of interest as brown powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH2:18][CH2:19][NH:20][C:21]([C:23]1[C:32]([OH:33])=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)=[O:22].[CH2:34]([O:36][C:37](=[O:40])[CH2:38]Br)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OC(=O)C)C>[CH3:34][O:36][C:37](=[O:40])[CH2:38][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[CH2:18][CH2:19][NH:20][C:21]([C:23]1[C:32]([OH:33])=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)=[O:22]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)c(CCNC(=O)c3cc4ccccc4cc3O)c2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1CCNC(=O)c1cc2ccccc2cc1O
Reaction time: 12 h
Yield: 24 %

Procedure:
To a solution of the 3-Hydroxy-naphthalene-2-carboxylic acid [2-(4-hydroxy-4′-methanesulfonyl-biphenyl-3-yl)-ethyl]-amide (18 mg, 0.039 mmol) was in DMF were added ethylbromoacetate (0.039 mmol) and Cs2CO3 (0.039 mmol, 13 mg). The reaction mixture was for 12 hr and the reaction mixture was diluted with ethylacetate and washed with water. The organic layer was separated, dried and the crude obtained after removal of the solvent was purified on a silicagel column to afford the desired product 5 mg, and 5 mg of bis ester.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=1)[CH3:3].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[NH:1][CH:2]([C:4]2[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([C:15]#[C:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:5]=2)[CH3:3])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: CC(N)c1ccc(NS(C)(=O)=O)c(C#Cc2ccccc2)c1
Solvent: ClCCl
Product: CC(NC(=O)Nc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)c(C#Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
N-[4-(1-Aminoethyl)-2-phenylethynylphenyl]methanesulfonamide (440.1 mg, 1.40 mmol) and TEA (390.3 μl, 2.800 mmol, 2 eq) were added in methylene chloride. The reaction mixture was cooled down to 0° C. 4-tert-Butylphenyl isocyanate (248.8%, 1.540 mmol, 1.3 eq.) was added into the mixture. The reaction mixture was stirred for 1 hr. Methylene chloride was removed in vacuo. The residue was purified with column chromatography (n-Hx:EA=2:1) to yield title compound (241.4 mg, 35%) as a solid.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=[O:7])(C)(C)C.[F:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)C(Cl)=O>>[F:44][C:45]1[CH:53]=[C:52]([C:6]([NH:8][C@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:7])[CH:51]=[CH:47][CH:46]=1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)c1cccc(F)c1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)c3cccc(F)c3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and 3-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](N=O)[CH:8]=[C:7]([C:13](C)([CH3:15])[CH3:14])[C:6]=1[OH:17])(C)([CH3:3])[CH3:2].C(C1C=C(N=[O:28])C=C(C(C)C)C=1O)(C)C>>[CH:1]([C:5]1[C:6](=[O:17])[C:7]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:9](=[O:28])[CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(N=O)cc(C(C)C)c1O
Reactant: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Product: CC(C)C1=CC(=O)C=C(C(C)C)C1=O

Procedure:
If 2,6-ditert.butyl-4-nitrosophenol is replaced in this example by an equivalent quantity of 2,6-diisopropyl-4-nitrosophenol, an otherwise identical procedure gives 2,6-diisopropyl-benzoquinone monoxime p-toluenesulphonate of melting point 93° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:23]=[CH:24][CH2:25][CH3:26]>O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:26][CH2:25][CH:24]=[CH2:23])[C:5]([CH3:9])=[CH:4][C:3]=1[CH3:10]
Reactant: CCC=CBr
Reactant: Cc1cc(C)c(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCOc1cc(Br)c(C)cc1C
Temperature: 95 °C

Procedure:
A 250-mL round bottomed flask is charged with 5-bromo-2,4-dimethylphenol (3.135 g, 15.6 mmol) and dimethylformamide (DMF) (50 mL). Potassium carbonate (23.7 g, 172 mmol) and bromobutene (15.8 mL, 156 mmol) are added and the reaction mixture is heated to 95° C. for 2 hr. After cooling to room temp, water (200 mL) is added. The product is extracted into ether (2×100 mL), and the combined organic fractions are washed with brine, dried over sodium sulfate and dried in vacuo. Yield=3.63 g (91.3%) of light yellow liquid.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([C:7]([OH:9])=O)[CH:2]=1.CN1CCOCC1.[CH3:17][CH:18]([CH2:20][C@H:21]([NH2:26])[C:22]([O:24][CH3:25])=[O:23])[CH3:19].Cl>C(Cl)Cl>[CH3:25][O:24][C:22](=[O:23])[C:21]([NH2:26])([C:7]([C:3]1[CH:4]=[N:5][CH:6]=[CH:1][CH:2]=1)=[O:9])[CH2:20][CH:18]([CH3:19])[CH3:17]
Reactant: O=C(O)c1cccnc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)C(N)(CC(C)C)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 72.6 %

Procedure:
To a solution of niacin (1.35 g, 11.0 mmol) in DCM (20 mL) were added N-methyl morpholine (3.34 g, 33.00 mmol) EDCI.HCl (4.2 g, 22.02 mmol), and L-leucinemethyl ester hydrochloride (2.0 g, 11.0 mmol). The mixture was allowed to stir at room temperature (25° C.) over 2.5 h under nitrogen atmosphere. The resulting mixture was diluted with DCM (200 mL), washed with water (3×100 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was further purified by silica gel column chromatography to obtain required product as white solid (2.0 g, 72%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]12(O)[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.S(=O)(=O)(O)O>ClCCl>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)[C:5]([O:7][CH3:8])=[O:6]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12.16 g (80 mM) of methyl 3-hydroxybenzoate and 12.16 g (80 mM) of adamantanol in 160 ml of dichloromethane are treated with a dropwise addition of 4.37 ml of concentrated sulphuric acid. The reaction mixture is stirred at room temperature overnight. The solid residue is washed withwater and dried to lead to 18.3 g (79.9%) of the expected derivative, of melting point 244°-246° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][CH:7]=1.[F:24][C:25]([F:32])([F:31])[CH2:26][S:27](Cl)(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>ClCCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:27]([CH2:26][C:25]([F:32])([F:31])[F:24])(=[O:29])=[O:28])=[CH:10][CH:11]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: COc1ccccc1Oc1ccc(NCc2cccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: COc1ccccc1Oc1ccc(N(Cc2cccnc2)S(=O)(=O)CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-(2-methoxyphenoxy)phenyl)pyridin-3-ylmethylamine (1.0 equiv.) in 2:1 DCE/Pyridine (0.15 M) was cooled to 0° C. and treated with 2,2,2-trifluoroethanesulfonyl chloride (1.8 equiv.). The mixture was allowed to warm to ambient temperature and stir overnight. The reaction was treated with anhydrous potassium carbonate, stirred for 40 min, and filtered. The filtrate was purified via preparative HPLC eluting with 98:2 to 96:4 DCM/MeOH to give the title compound. Anal Calcd for C21H19F3N2O4S: C, 55.75; H, 4.23; N, 6.19. Found: C, 55.65; H, 4.27; N, 6.19. MS found 4.53.0 [M+H]+
Reaction SMILES: [CH3:1][N:2]([CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)(=[O:5])=[O:4].[CH3:23][NH2:24]>O>[CH3:1][N:2]([CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:24][CH3:23])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)(=[O:5])=[O:4]
Reactant: CN1CCC(N(C)S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reactant: CN
Solvent: O
Product: CNc1ccc(S(=O)(=O)N(C)C2CCN(C)CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.6 g (4.6 mmol) of 4-chloro-3-nitrobenzenesulfonic acid-N-methyl-N-(1-methylpiperidin-4-yl)amide was mixed with 30 mL of 40% methylamine solution and stirred in a sealed flask for four hours at room temperature. Then the mixture was diluted with about 40 mL of water, the product precipitated was suction filtered, washed with water, and dried. Yield: 1.5 g (95% of theory), C14H22N4O4S (343.4); Rf value: 0.45 (silica gel; dichloromethane/ethanol=4:1).