Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[C:25](O)(=[O:29])/[CH:26]=[CH:27]/[CH3:28].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:25]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)(=[O:29])/[CH:26]=[CH:27]/[CH3:28]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: C/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C=C/C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Yield: 97.9 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (2.6 mL), crotonic acid (1.6 g), WSC.HCl (3.6 g), and methylene chloride (110 mL), to give the captioned compound (4.4 g, 98%) as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([NH2:17])[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([NH:17][C:31](=[O:33])[CH3:32])[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1
Reactant: COc1ccc(Oc2ncc(-c3cc(C(C)N)on3)s2)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Oc2ncc(-c3cc(C(C)NC(C)=O)on3)s2)c(Cl)c1
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
To a solution of Example 37A (358 mg, 1.02 mmol) and triethylamine (426 μL, 3.06 mmol) in dichloromethane (5 mL) was added acetic anhydride (116 μl, 1.22 mmol) at ambient temperature. The reaction was stirred for 10 minutes and was then concentrated on a rotary evaporator. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 30% to 80% ethyl acetate in hexanes to give 338 mg (94%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.42 (d, J=7.35 Hz, 3H) 1.87 (s, 3H) 3.82 (s, 3H) 4.98-5.18 (m, 1H) 6.89 (s, 1H) 7.05 (dd, J=9.19, 2.94 Hz, 1H) 7.27 (d, J=2.94 Hz, 1H) 7.56 (d, J=9.19 Hz, 1H) 7.94 (s, 1H) 8.51 (d, J=7.72 Hz, 1H); MS (ESI) m/z 394.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:37])[C@H:15]([N:23]=[C:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][CH:39]([CH3:46])[CH2:40][CH2:41][CH2:42][C:43](O)=[O:44].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:43](=[O:44])[CH2:42][CH2:41][CH2:40][CH:39]([CH3:46])[CH3:38])[CH2:10][C@@H:9]1[C@@H:14]([OH:37])[C@H:15]([N:23]=[C:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1[C@@H](O)[C@@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCCC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](Cc2ccccc2)N=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
Dissolve (2-(R)-[2-(R)-(benzhydrylidene-amino)-1-(S)-hydroxy-3-phenylpropyl]-piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.22 mmol) in 2.2 ml of dichloromethane and react with 5-methylhexanoic acid (28.6 mg, 0.22 mmol), EDCI (50.6 mg, 0.26 mmol), HOBT (35.6 mg, 0.26 mmol), triethylamine (0.09 ml, 0.66 mmol) and dimethylaminopyridine (2.6 mg, 0.02 mmol). Stir at room temperature overnight. Dilute with CH2Cl2, and wash with 5%NaHCO3 and saturated aqueous sodium chloride. Dry organic layers with MgSO4 and remove the solvent under reduced pressure. Subject residue to silica gel chromatography, eluting with hexanes/ethyl acetate/triethylamine 67:32:1 to obtain 103 mg (76% yield) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[NH2:34][C:35]1[S:36][CH:37]=[CH:38][N:39]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:11]1([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:33]=[CH:32][C:7]=3[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:28])[NH:34][C:35]4[S:36][CH:37]=[CH:38][N:39]=4)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9]2=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)Nc2nccs2)cc1OC
Yield: 7.7 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 100 starting from 1 g of the compound obtained in EXAMPLE 13, 0.3 g of 2-aminothiazole, 1.2 g of BOP, 1 ml of DIPEA and 20 ml of DCM. It is chromatographed on silica using a DCM/MeOH mixture (99.5/0.5; v/v) as the eluent to give 0.09 g of the expected product after crystallization from EtOH. M.p.=213° C.
Reaction SMILES: P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)O>C1C=CC=CC=1>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Reactant: c1c[nH]cn1
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccccc1
Product: Clc1ccccc1C(c1ccccc1)(c1ccccc1)n1ccnc1
Yield: 78.9 %

Procedure:
A mixture of benzene (20 ml), diphenyl phosphite (5.62 g, 24 mmole), imidazole (2.45 g, 36 mmole) and o-chlorophenyldiphenylmethanol (2.95 g, 10 mmole) obtained in Example 1 (B) was refluxed for 8 hours. The reaction mixture was treated in the same manner as in Example 2 to give 2.72 g of 1-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 79%. M.P., 143°-144° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:16][C:17](=[O:26])[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])(=O)C.[OH-].[Na+].O>O1CCOCC1.CN(C)C=O>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[C:17]([NH:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][C:6]([CH2:5][OH:4])=[CH:15]2)=[O:26]
Reactant: CC(=O)OCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1cccc2cc(CO)cnc12)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A mixture of 3-acetoxymethyl-8-(2,6-dichlorobenzoylamino)quinoline (25.9 mg), 1N sodium hydroxide solution (0.24 ml) in dioxane and dimethylformamide (4 drops) was stirred for 2 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethyl acetate-n-hexane to give 8-(2,6-dichlorobenzoylamino)-3-hydroxymethylquinoline (20 mg).
Reaction SMILES: ClC1C=C(C=CC=1[N+]([O-])=O)C(Cl)=O.N1C=CN=N1.C([O-])([O-])=O.[K+].[K+].[Cl:25][C:26]1[CH:27]=[C:28]([N+:37]([O-])=O)[CH:29]=[CH:30][C:31]=1[C:32]1[O:33][CH:34]=[CH:35][N:36]=1.NC1C=CC=CC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>S1(CCCC1)(=O)=O.C1COCC1.O>[O:33]1[CH:34]=[CH:35][N:36]=[C:32]1[C:31]1[CH:30]=[CH:29][C:28]([NH2:37])=[CH:27][C:26]=1[Cl:25]
Reactant: O=[N+]([O-])c1ccc(-c2ncco2)c(Cl)c1
Agent: O=C(Cl)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Solvent: Nc1ccccc1
Solvent: O=S1(=O)CCCC1
Product: Nc1ccc(-c2ncco2)c(Cl)c1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with 3-chloro-4-(2-oxazolyl)aniline to generate the title compound. The 4-(2-oxazolyl)-3-chloroaniline was prepared by treating commercial 3-chloro-4-nitrobenzoyl chloride sequentially with 1,2,3-triazole at 140° C. in sulfolane containing K2CO3 to generate 3-chloro-4-(2-oxazolyl)nitrobenzene which was reduced to the desired aniline with Na2S2O4 in THF/H2O at 90° C.
Reaction SMILES: CC([Si]([CH:18]([CH2:23][CH2:24][P:25]([CH:29]=[CH:30][C:31]1[C:32]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[N:33][C:34]2[C:39]([C:40]=1[CH:41]([CH3:43])[CH3:42])=[CH:38][CH:37]=[CH:36][CH:35]=2)([O:27][CH3:28])=[O:26])[C:19]([O:21][CH3:22])=[O:20])(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.CC(O)=[O:53].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1>[F:50][C:47]1[CH:46]=[CH:45][C:44]([C:32]2[C:31](/[CH:30]=[CH:29]/[P:25]([O:27][CH3:28])([CH2:24][C@@H:23]([OH:53])[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:26])=[C:40]([CH:41]([CH3:42])[CH3:43])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=2)=[CH:49][CH:48]=1
Reactant: CC(=O)O
Reactant: COC(=O)C(CCP(=O)(C=Cc1c(-c2ccc(F)cc2)nc2ccccc2c1C(C)C)OC)[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C[C@H](O)CP(=O)(/C=C/c1c(-c2ccc(F)cc2)nc2ccccc2c1C(C)C)OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 72.9 %

Procedure:
A solution of (S,E)-3-[[(1,1-Dimethylethyl)-diphenylsilyl]-4-[[2-[2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethenyl]methoxyphosphinyl]butanoic acid, methyl ester (542 mg, 0.749 mmol) in THF (10 ml) was treated with HOAc (215 ul, 226 mg, 3.76 mmol) and tetra-n-butylammonium fluoride (1.0M in THF, 2.25 ml, 2.25 mmol). After stirring at room temperature for 22 hours, the solution was poured into saturated NaHCO3 and extracted with EtOAc. The EtOAc extract was washed with brine, dried (Na2SO4), filtered and stripped to give an oil which was subsequently chromatographed (flash, Merck, SiO2, 1:1 acetone:hexane followed by 20% hexane in acetone). (S,E)-4-[[2-[2-(4-Fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]-ethenyl]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester (265 mg, 73%) was obtained as a white foam.
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])[CH3:2].[C:7]([O:13]C)([CH2:10][CH2:11][CH3:12])([CH3:9])[CH3:8]>>[C:7]([O:13][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH2:10][CH2:11][CH3:12])([CH3:8])[CH3:9]
Reactant: CCCC(C)(C)OC
Reactant: CC(C)(C)OO
Product: CCCC(C)(C)OOC(C)(C)C

Procedure:
In similar manner, although optimal conditions may vary, hydrogen peroxide may be reacted with methyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with methyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with ethyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with ethyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with ethyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with n-propyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with n-propyl t-amyl ether to provide t-amyl hydroperoxide or di t-amyl peroxide; or with n-propyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide. Illustrative of reactions employing hydroperoxide reactants are the reaction of t-butyl hydroperoxide with methyl t-butyl ether to provide di-t-butyl peroxide; the reaction of t-hexyl hydroperoxide with methyl t-hexyl ether to provide di-t-hexyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-amyl ether to provide t-butyl t-amyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-hexyl ether to provide t-butyl t-hexyl peroxide; and the reaction of t-amyl hydroperoxide with ethyl t-hexyl ether to provide t-amyl t-hexyl peroxide.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.S(C1C=CC(C)=CC=1)(O[CH2:15][C:16]1([CH3:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)(=O)=O>CO.[I-].[K+]>[CH3:15][C:16]1([CH2:22][O:10][C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)CCCCC2)cc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(OCC2(C)CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a cooled (0° C.), stirred solution of 8.4 g (0.15 mole) of potassium hydroxide in 100 ml of MeOH was added 13.5 g (0.12 mole) of 4-methylphenol over a 15 minute period. The reaction was stirred at room temperature for 0.5 hour and MeOH was evaporated to afford a solid. A solution of this solid, 28.2 g (0.1 mole) of ((1-methyl)cyclohexyl)methyl tosylate and 1.4 g of potassium iodide were heated at 150° C. for 5 hours. The reaction was cooled to room temperature, poured onto ice-water and extracted with EtOAc. The EtOAc layer was washed with 2N aqueous NaOH, brine, dried over MgSO4, filtered and evaporated. The resulting oil was filtered through a plug of silica gel to give 20 g of product as an oil.
Reaction SMILES: CC1C=CC2CCCCC=2[N:3]=1.C1([Li])C=CC=CC=1.C(=O)=O.C[O:23][C:24]([CH:26]1[C:35]2[N:34]=[C:33]([CH3:36])[CH:32]=[CH:31][C:30]=2[CH2:29][CH2:28][CH2:27]1)=O.N1C2CCCCC=2C=CC=1CC(OC)=O>>[CH3:36][C:33]1[CH:32]=[CH:31][C:30]2[CH2:29][CH2:28][CH2:27][CH:26]([C:24]([NH2:3])=[O:23])[C:35]=2[N:34]=1
Reactant: COC(=O)C1CCCc2ccc(C)nc21
Reactant: Cc1ccc2c(n1)CCCC2
Agent: COC(=O)Cc1ccc2c(n1)CCCC2
Agent: O=C=O
Agent: [Li]c1ccccc1
Product: Cc1ccc2c(n1)C(C(N)=O)CCC2
Yield: 30 %

Procedure:
Reaction of 2-methyl-5,6,7,8-tetrahydroquinoline with phenyl lithium and carbon dioxide followed by esterification according to the general method described in Examples 1B and 6B gave an inseparable mixture of methyl-2-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate and methyl 5,6,7,8-tetrahydroquinoline-2-acetate which was converted without purification to a mixture of 2-methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide and 5,6,7,8-tetrahydroquinoline-2-acetamide by reaction with ammonia using the method described in Example 2. Fractional recrystallisation from diisopropyl ether gave the title compound as colourless needles m.p. 114° (overall yield 30%) (Found: C, 69.31, H, 7.45, N, 14.7, C11H14N2O requires: C, 69.45, H, 7.42; N, 14.72%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([N+:26]([O-:28])=[O:27])[CH:17]=2)=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C1COCC1>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([N+:26]([O-:28])=[O:27])[CH:17]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
(4-Boc-piperazin-1-yl)-(3-nitro-5-trifluoromethyl-phenyl)-methanone (403 mg) was dissolved in THF (6 ml) and BH3Me2S (300 μl) was added and the reaction was stirred for 3 h at 60° C. and 2 h at RT. The reaction was quenched with MeOH (5 ml) and NaOH (100 mg) and stirred at RT for 1 h. The mixture was concentrated and dissolved in CH2Cl2, washed with sated NH4Cl/NaHCO3, dried (MgSO4), filtered and evaporated to give the compound as an oil. M+H 390.3.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH3:28])[S:22][C:21]=3[S:29]([NH:32]C(C)(C)C)(=[O:31])=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1.BrC1C=CC(CN2C=CN=C2)=CC=1>C1(OC)C=CC=CC=1>[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH3:28])[S:22][C:21]=3[S:29]([NH2:32])(=[O:31])=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CCCCc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: Brc1ccc(Cn2ccnc2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Reaction time: 30 h
Yield: 49 %

Procedure:
Trifluoroacetic acid was added (10 mL) to the crude 3-(4imidazol-1-ylmethylphenyl)-5-butyl-N-tert-butylthiophene-2-sulfonamide from step (c) above, and one drop (ca. 0.05 mL) of anisol was added to the mixture. The reaction mixture was stirred under N2 atmosphere for 30 hours and then evaporated and co-evaporated with acetonitrile. The crude product was purified by column chromatography (CH2Cl2:MeOH (20:1)) to give sub-title compound (232 mg, 0.62 mmol) in 49% yield (from 1-(4-bromobenzyl)-1H-imidazole).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[CH:3]=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([Sn](CCCC)(CCCC)CCCC)=[N:14][CH:15]=1.[Cl-].[Li+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:13]3[CH:12]=[CH:11][C:10]([CH3:9])=[CH:15][N:14]=3)[CH:3]=2)=[N:14][CH:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Reactant: Brc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cccc(-c3ccc(C)cn3)c2)nc1
Temperature: 25 °C

Procedure:
A mixture of 1,3-dibromobenzene (1.88 g, 8 mmol), 5-methyl-2-tri-n-butylstannylpyridine (7.18 g, 18.8 mmol), lithium chloride (28 g, 0.67 mol), bis(triphenylphosphine)palladium dichloride (360 mg, 0.5 mmol) and toluene (150 cm3) was degassed by bubbling argon through the mixture for 15 minutes. The reaction mixture was heated under reflux for 24 h. The mixture was then allowed to cool to room temperature and was filtered through small pad of silica gel, which was then washed with ethyl acetate. The filtrate was evaporated to dryness and the product was purified by column chromatography (silica gel, hexane/ethyl acetate, 1/1) to give the title product as a colourless solid. Yield 728 mg, 35%. δH (270 MHz; CDCl3): 2.36 (6H, s, 2×CH3), 7.54 (1H, t, J 8.0, 5-H), 7.56 (2H, dd, J 8.2 and 2.1, 2×py 4-H), 7.72 (2H, d, J 8.2, 2×py 3-H), 7.99 (2H, dd, J 8.0 and 1.8, 4-H, 6-H), 8.52 (2H, d, J 2.1, 2×py 6-H), 8.54 (1H, t, J 1.8, 2-H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[O:5][CH:6]=1.C(Cl)Cl.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[O:5][CH:6]=1
Reactant: O=Cc1cc(Br)co1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(Br)co2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a solution of 4-bromofuran-2-carbaldehyde (500 mg, 2.85 mmol) and CH2Cl2 (10 mL) was added tert-butyl piperazine-1-carboxylate (1.06 g, 5.74 mmol) and sodium triacetoxyborohydride (1.2 g, 5.74 mmol). The mixture was stirred at room temperature overnight. The resultant mixture was diluted with EtOAc (100 mL), washed with brine then dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0-5% MeOH in CH2Cl2) to afford the sub-title compound (900 mg, 91%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.[CH3:24][O:25][C:26](=[O:64])[N:27]=[C:28]([S:62][CH3:63])[C:29]([C:43]1[CH:48]=[C:47]([O:49][Si](C(C)C)(C(C)C)C(C)C)[CH:46]=[C:45]([O:60][CH3:61])[CH:44]=1)=[N:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:41]=[C:40]([CH3:42])[O:39][N:38]=2)=[CH:33][CH:32]=1.[Cl-].[NH4+]>C(OCC)(=O)C>[CH3:24][O:25][C:26](=[O:64])[N:27]=[C:28]([S:62][CH3:63])[C:29]([C:43]1[CH:44]=[C:45]([O:60][CH3:61])[CH:46]=[C:47]([OH:49])[CH:48]=1)=[N:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:41]=[C:40]([CH3:42])[O:39][N:38]=2)=[CH:33][CH:32]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(O)cc(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
After adding 3.3 ml of TBAF (1.0 M, THF solution) to a 15 ml THF solution containing 1.8 g of {2-(3-methoxy-5-triisopropylsilanyloxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester, the mixture was stirred at 0° C. for 1 hour and 30 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 dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.06 g) as a yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CN([C:14]([O:18][N:19]1N=NC2C=CC=N[C:20]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>CN(C=O)C.O>[CH3:14][O:18][N:19]([CH3:20])[C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4]1)=[O:10]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CON(C)C(=O)[C@H]1CC[C@H](C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of trans-4-methylcyclohexanecarboxylic acid (100 g, 0.70 mol) in DMF (1.2 L) were added HATU (294 g, 0.77 mol) and DIPEA (273 g, 2.1 mol) at room temperature. After stirring for 0.5 h, TLC showed no starting material left (petroleum ether/ethyl acetate=5:1). Then N,O-dimethylhydroxylamine hydrochloride (75.5 g, 0.77 mol) was added slowly. The mixture was stirred at room temperature for 3 h. TLC (petroleum ether/ethyl acetate=5:1) showed the reaction was complete. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water twice, washed with brine, dried over Na2SO4 and concentrated to give crude trans-N-methoxy-N,4-dimethylcyclohexanecarboxamide, which was used for the next step without further purification.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11]O)=[C:6]([F:13])[CH:5]=1.C(O)(=O)C.C(OCC)C.C(=O)([O-])O.[Na+].[BrH:29]>>[Br:29][CH2:11][C:7]1[C:8]([F:10])=[CH:9][C:4]([O:3][CH:2]([F:14])[F:1])=[CH:5][C:6]=1[F:13]
Reactant: OCc1c(F)cc(OC(F)F)cc1F
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Fc1cc(OC(F)F)cc(F)c1CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.76 g of [4-(difluoromethoxy)-2,6-difluorophenyl]methanol (3.62 mmol, 1 eq.) were dissolved in 1.72 ml of 33% hydrogen bromide in glacial acetic acid (9.97 mmol, 2.75 eq.) and stirred at room temperature for 2 hours. 25 ml of diethyl ether were added and the mixture was stirred at room temperature for 15 min. The reaction mixture was added dropwise to 80 ml of aqueous saturated sodium hydrogen carbonate solution and stirred again at room temperature for 15 min. The separated aqueous layer was extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo to yield 991 mg (3.56 mmol, 98.4%) of the analytically pure target compound.