Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([N:23]2[C:27](=[O:28])[CH:26]=[CH:25][C:24]2=[O:29])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(N(CC)CC)C>[CH:17]1([N:23]2[C:27](=[O:28])[CH2:26][CH:25]([S:11][C:9]3[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=3)[C:24]2=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C1C=CC(=O)N1C1CCCCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SC2CC(=O)N(C3CCCCC3)C2=O)cc(C(C)(C)C)c1O
Yield: 50.3 %

Procedure:
The procedure of Example 1 is repeated using 11.95 grams of 2,6-di-tert-butyl-4-mercaptophenol, 8.96 grams of N-cyclohexylmaleimide, and 0.5 grams of triethylamine. The residue is recrystallized from a heptane-toluene mixture to give 10.5 grams of a white solid, m.p. 94°-98° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:19]S(C(C)(C)C)=O)([CH3:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO>[NH2:19][C:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][CH:10]=1)([CH3:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: CCCCOc1ccc(C(C)(CC(=O)OC)NS(=O)C(C)(C)C)cc1
Agent: Cl
Solvent: CO
Product: CCCCOc1ccc(C(C)(N)CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
To a stirred solution of Intermediate 107B (1 g, 2.71 mmol) in MeOH (6 mL) was added 4 N HCl (3.38 mL, 13.53 mmol). The reaction was stirred at rt for 4 h. The reaction mixture was concentrated in vacuo and diluted with EtOAc. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated to yield the desired product (700 mg, 97%) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.38 (d, J=8.80 Hz, 2H), 6.86 (d, J=8.80 Hz, 2H), 3.95 (t, J=6.46 Hz, 2H), 3.59 (s, 3H), 1.73-1.80 (m, 2H), 1.53 (s, 2H), 1.45-1.52 (m, 2H), 1.19 (s, 3H), 0.98 (t, J=7.29 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[NH:15][C:14]1=[S:26])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].O.[CH2:29](O)C.[OH-].[NH4+].IC>O>[CH3:1][C:2]([CH3:27])([CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[C:14]1[S:26][CH3:29])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CCO
Reactant: CC(C)(CNC(=O)OC(C)(C)C)Cn1c(=S)[nH]c2cnc3ccccc3c21
Agent: [NH4+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1nc2cnc3ccccc3c2n1CC(C)(C)CNC(=O)OC(C)(C)C

Procedure:
A suspension of tert-butyl 2,2-dimethyl-3-(2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (7.78 g, 20.1 mmol) and 100 mL of 1:1 water/ethanol was treated with 20 mL of concentrated ammonium hydroxide and iodomethane (1.50 mL, 24.2 mmol). Two hours later an additional 50 mL of H2O was added, and the precipitate was filtered and rinsed with ether. When the ether was added, the funnel became clogged, so the precipitate was transferred into a flask with the aid of methanol and CH2Cl2. The solvents were removed under reduced pressure to give a light yellow solid. The filtrate was then concentrated under reduced pressure to ˜150 mL of mostly water. Organic material was extracted from this solution using CH2Cl2 (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, combined with the precipitated material, and concentrated under reduced pressure to give tert-butyl 2,2-dimethyl-3-[2-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (7.81 g) as a light yellow solid.
Reaction SMILES: Cl.[CH:2]1([N:7]2[CH:15]=[C:10]3[CH2:11][NH:12][CH2:13][CH2:14][C:9]3=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[CH2:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:26]1([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[CH2:17][N:12]3[CH2:13][CH2:14][C:9]4=[N:8][N:7]([CH:2]5[CH2:6][CH2:5][CH2:4][CH2:3]5)[CH:15]=[C:10]4[CH2:11]3)[CH2:21][CH2:22]2)[CH2:29][CH2:28][CH2:27]1
Reactant: O=C(CCl)N1CCN(C2CCC2)CC1
Reactant: c1c2c(nn1C1CCCC1)CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN1CCc2nn(C3CCCC3)cc2C1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-cyclopentyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine hydrochloride (143 mg, 0.63 mmol), 1-(chloroacetyl)-4-cyclobutylpiperazine (136 mg, 0.63 mmol), K2CO3 (348 mg, 2.52 mmol) and KI (10 mg, 0.06 mmol) in CH3CN (10 ml) is stirred at rt overnight. The solvent is removed in vacuo and the residue is partitioned between water (10 mL) and EtOAc (10 mL). The layers are separated and the aqueous layer is extracted with EtOAc (3×10 mL) and the combined extracts are washed with brine (20 mL), dried and evaporated. The resulting oil is purified by flash column with DCM/MeOH/NH4OH (100:5:0.5) to give the title compound as a light yellow solid. MS (M+1): 372.3; 1H NMR (δ, CDCl3): 7.10 (s, 1H), 4.51-4.60 (m, 1H), 3.64 (q, 4H), 3.54 (s, 2H), 3.36 (s, 2H), 2.77-2.83 (m, 4H), 2.64-2.74 (m, 1H), 2.25-2.32 (m, 4H), 1.62-2.62 (m, 14H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH2:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].COC1C=CC(N)=CC=1.C(=O)(O)[O-].[Na+].[CH3:41][C:42]1[N:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](Cl)=[O:45]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:44]([C:43]3[C:42]([CH3:41])=[N:50][CH:49]=[CH:48][CH:47]=3)=[O:45])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Cc1ncccc1C(=O)Cl
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(N)c3ccccc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COc1ccc(N)cc1
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3cccnc3C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-(4-Amino-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester (0.26 g, 0.71 mmol) (prepared following the general procedure in Scheme 3, substituting 4-amino-piperidine-1-carboxylic acid ethyl ester for p-anisidine) in CH2Cl2 (10 mL) and aqueous saturated sodium bicarbonate solution (4 mL) was added 2-methyl nicotinic chloride (0.16 g, 1.07 mmol) and the resulting mixture was stirred at room temperature overnight. The organic layer was separated, dried over sodium sulfate and concentrated. Purification of the residue by column chromatography (2-5% MeOH/CH2Cl2) provided the B-24 (0.09g, 26%). 1H NMR (300 MHz, CDCl3) δ 8.61-8.66 (m, 2H), 8.34 (s, 1H), 8.19-8.28 (m, 1H), 7.94 (d, 2H), 7.60-7.70 (m, 2H), 7.28-7.31(m, 1H), 4.91(d, 1H), 4.03 (q, 2H), 3.85 (d, 2H), 3.20-3.32 (m, 1H), 2.80 (s, 2H), 2.63-2.74 (m, 2H), 1.67 (br s, 4H), 1.16-1.21 (m, 5H). LC/MS m/z 497 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].Br[CH2:28][C:29]#[C:30][Si:31]([CH3:34])([CH3:33])[CH3:32]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)([CH2:28][C:29]#[C:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:8]2=[O:12])=[CH:4][C:3]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccc(Cl)cc1)C2
Reactant: C[Si](C)(C)C#CCBr
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC#C[Si](C)(C)C)(c1ccc(Cl)cc1)C2

Procedure:
Reaction of ethyl [6,7-dichloro-1-oxo-2-(p-chlorophenyl)-5-indanyloxy]acetate with 1-bromo-3-(trimethylsilyl)-2-propyne according to the procedure of Example 1, STEP (b), affords the title compound, m.p. 103°-103.5°; purified by chromatography (silica-gel column eluted with chloroform-n-hexane) and crystallization from ether-cyclohexane.
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([OH:15])=O)[C:8]([Cl:11])=[CH:9][CH:10]=1.[NH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[N:30][C:31]=1[CH3:32].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>CN(C=O)C>[F:23][C:2]([F:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([NH:24][CH2:25][C:26]2[C:31]([CH3:32])=[N:30][C:29]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])=[CH:28][CH:27]=2)=[O:15])[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1CN
Reactant: O=C(O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NC(=O)OC(C)(C)C)ccc1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a solution of 2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}acetic acid (516 mg, 1.5 mmol), as prepared in step 15 of Example 1, in DMF (8.0 mL) was added N-[5-(aminomethyl)-6-methyl (2-pyridyl)](tert-butoxy) carboxamide (498 mg, 2.1 mmol) (Sanderson, P. E., et al., WO 97/01338 (1997)), BOP (1.06 g, 2.4 mmol), and DIEA (0.78 mL, 4.5 mmol). After stirring for 18 hours, additional amine (107 mg, 450 μmol) was added, and the mixture continued to stir for 18 hours. The solvents were evaporated, and the reaction mixture was partitioned between DCM and saturated NaHCO3. The organic layer was separated, and the aqueous layer extracted with DCM. The organic layers were combined, washed with 10% KHSO4 (2 times), H2O, and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with MeOH/DCM (0, 1.5, and 2.5%) to give the title compound (770 mg, 91% yield) as a pale brown foam. 1H-NMR (400 MHz, CDCl3)δ 7.66 (d, J=8.4 Hz, 1H), 7.51-7.41 (m, 6H), 7.23 (bs, 1H), 7.01 (dd, J=8.8, 1.5 Hz, 1H), 6.57 (t, J=9.0 Hz, 1H), 5.64 (br s, 1H), 4.37 (d, J=5.6 Hz, 2H), 4.26-4.22 (m, 1H), 3.79-3.70 (m, 4H), 2.35 (s, 3H), 1.50 (s, 9H). Mass spectrum (LCMS, ESI) calc'd for C28H31ClF3N4O3 (M+H): 563.2. Found: 562.9.
Reaction SMILES: C[Si](C)(C)CC[S:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[C:8]([F:18])[CH:7]=1.[F:21]C1C=C(C2C=CC=CC=2)C=C(F)C=1>>[F:18][C:8]1[CH:7]=[C:6]([SH:5])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:21])=[CH:14][CH:13]=2)[CH:9]=1
Reactant: Fc1cc(F)cc(-c2ccccc2)c1
Reactant: C[Si](C)(C)CCSc1cc(F)cc(-c2ccccc2)c1
Product: Fc1ccc(-c2cc(F)cc(S)c2)cc1

Procedure:
Following the procedure described in Thiophenol 1, Step 3, but substituting S-(2-trimethylsilylethyl)-3-fluoro-5-(4-fluorophenyl)thiophenol for S-(2-trimethylsilylethyl)-3-fluoro-5-phenylthiophenol, the title compound was obtained as a liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([CH2:10][C@H:11](S(C)(=O)=O)[CH3:12])[C:3]=1[F:17].[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C=O)C>[N:18]([C@@H:11]([CH3:12])[CH2:10][C:4]1[C:5]([F:9])=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=1[F:17])=[N+:19]=[N-:20]
Reactant: C[C@H](Cc1c(F)c(F)cc(F)c1F)S(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](Cc1c(F)c(F)cc(F)c1F)N=[N+]=[N-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (2R)-1,2,4,5-tetrafluoro-3-(2-(methylsulfonyl)propyl)benzene (2.3 g, 8.03 mmol) in anhydrous DMF (10 mL) was added sodium azide (1.045 g, 16.07 mmol) and the solution was heated to 80° C. and stirred for 2 h. Then, the temperature was cooled to rt and 20 mL of water was added, extracted with EtOAc/hexane (1/1 v/v), dried over anhydrous MgSO4 and evaporated to give crude oil, which was passed through silica gel pad and evaporated under reduced pressure to give the product. This was used as starting material for next reduction without more purification.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8])=[CH:5][CH:4]=1)=O.[CH2:17]([O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20].C(O)(=O)C.C([BH3-])#N.[Na+]>CN(C=O)C.COC(OC)OC.CO>[CH2:17]([O:21][C:22]1[CH:23]=[CH:24][C:25]([NH:26][CH2:1][C:3]2[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8])=[CH:5][CH:4]=2)=[CH:27][CH:28]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOc1ccc(N)cc1
Reactant: O=Cc1ccc(C(=O)NCCC(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CC(=O)O
Solvent: CO
Product: CCCCOc1ccc(NCc2ccc(C(=O)NCCC(=O)O)cc2)cc1
Reaction time: 4 h

Procedure:
The above resin bound 3-(4-formylbenzoylamino)propionic acid (50 mg) was treated with a 0.5 M solution of 4-butoxyaniline (0.25 mmol, 41.25 mg) in a mixture of DMF and trimethylorthoformate (1:1, 0.5 mL) and glacial acetic acid (50 μL) for 1 hour at 25° C. Sodium cyanoborohydride (250 μmol, 16 mg) dissolved in a mixture of DMF and methanol (1:1, 0.25 mL) was added, and the mixture was vortexed at 25° C. for 4 hours followed by filtration and washing with a mixture of DMF and methanol (1:1, 2×1 mL) 3×1 mL DMF and 2×1 mL dichloromethane to afford the desired product.
Reaction SMILES: IC.[Br:3][C:4]1[CH:5]=[C:6]([CH:10]([CH:17]2[CH2:19][CH2:18]2)[NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[CH:7]=[N:8][CH:9]=1.[C:20](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[Br:3][C:4]1[CH:5]=[C:6]([CH:10]([CH:17]2[CH2:19][CH2:18]2)[N:11]([CH3:20])[S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])[CH:7]=[N:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(C)C(c1cncc(Br)c1)C1CC1
Temperature: 60 °C
Yield: 15.3 %

Procedure:
Iodomethane (0.059 mL, 0.940 mmol) was added to a mixture of N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (200 mg, 0.627 mmol) and potassium carbonate (130 mg, 0.940 mmol) in DMF (6 mL) at room temperature. The resulting mixture was heated at 60° C. for 24 h. The reaction mixture was diluted with EtOAc and water, and the mixture was washed with H2O and brine. The organic layer was separated and dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by flash column to give 32 mg of N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)-N-methylethanesulfonamide. ESI-MS: m/z 334.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C[Al](C)C.C([O:18][C:19]([C:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])=[CH:29][C:24]=2[O:23][N:22]=1)=O)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][C:19]([C:21]2[C:25]3[CH:26]=[CH:27][C:28]([O:30][Si:31]([CH:35]([CH3:37])[CH3:36])([CH:38]([CH3:40])[CH3:39])[CH:32]([CH3:33])[CH3:34])=[CH:29][C:24]=3[O:23][N:22]=2)=[O:18])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1noc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc12
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1ccc2c(C(=O)Nc3cccc(C(F)(F)F)c3)noc2c1)(C(C)C)C(C)C
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a dried vessel, 207 μl (1.66 mMol) 3-trifluoromethyl-aniline are dissolved in 28 ml toluene and cooled to 10° C. Then 2.5 ml Me3Al (2 M in toluene; 5.0 mMol) are added via syringe. After 1 h at rt, a solution of 602 mg (1.66 mMol) 6-triisopropylsilanyloxy-benzo[d]isoxazole-3-carboxylic acid ethyl ester in 6 ml THF is added and the reaction mixture stirred for 30 min in an oil bath at 110° C. The solution is cooled in ice and hydrolyzed with 70 ml of a sat. NH4Cl. After 15 min stirring, EtOAc and Celite are added. The mixture is filtered through Celite, the solid washed with EtOAc and water, the aq. phase separated from the filtrate and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated, yielding the title compound as an oil: MS: [M−1]=477; TLC(hexane/EtOAc 19:1): Rf=0.30.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:7]([O:11][C:12]([NH:14][OH:15])=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[CH3:3][CH:2]([CH3:4])[C:1]([O:15][NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])=[O:5]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NO
Product: CC(C)C(=O)ONC(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino 2-methylpropanoate is prepared from isobutyryl chloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1 using the method described by Carpino et al. J. Am. Chem. Soc. 1959, 955-957. (6.36 g, 83%), 1H NMR (250 MHz, DMSO-d6) δ ppm 10.51 (1H, br. s.), 2.65 (1H, sept, 7.0 Hz), 1.40 (9H, s), 1.13 (6H, d, 7.0 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]2[O:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[F:16][C:17]([F:25])([F:24])[C:18]([F:23])([F:22])C([O-])=O.[Na+].CN(C=O)C>[Cu]I.C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]([F:23])([F:22])[C:17]([F:25])([F:24])[F:16])=[CH:3][C:4]=1[CH:10]1[O:15][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: COc1ccc(Br)cc1C1OCCCO1
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(C(F)(F)C(F)(F)F)cc1C1OCCCO1
Temperature: 140 °C
Yield: 93.6 %

Procedure:
A 50 ml round bottom flask equipped with Dean-Stark trap and reflux condenser was charged with Compound 38 (1.0 g, 3.66 mmol), sodium pentafluoropropionate (1.29 g, 6.95 mmol) and copper(I) iodide (1.46 g, 7.69 mmol), DMF (15 ml) -toluene (6 ml). The slurry was heated to 120-140° C. (bath temperature) and toluene (6 ml) was removed by distillation. The reaction mixture was heated at 140° C. (inner temperature) for 15 h. The mixture was diluted with water (40 ml) —toluene (15 ml) —ethyl acetate (60 ml). The mixture was filtered through a pad of celite and the filter cake was washed with ethyl acetate. The filtrate was washed with water, and brine, dried(MgSO4) and concentrated in vacuo to give crude product. The crude product was purified by column chromatography on silica gel with hexane-ethyl acetate(10:1-5:1) to give Compound 39 (1.07 g) as a pale yellow oil
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([S:19]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[C:35]([CH3:36])=[C:34]([Cl:37])[C:33]([C:38]([N:40]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][CH3:44])=[O:39])=[N:32]4)=[C:27]([C:49]([N:51]4[CH2:60][CH2:59][C:58]5[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=5)[CH2:52]4)=[O:50])[CH:26]=3)=[O:24])(=[O:21])=[O:20])=[CH:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:45]([N:40]([CH2:41][CH2:42][CH2:43][CH3:44])[C:38]([C:33]1[C:34]([Cl:37])=[C:35]([CH3:36])[N:31]([C:28]2[CH:29]=[CH:30][C:25]([C:23](=[O:24])[NH:22][S:19]([C:15]3[CH:14]=[CH:13][C:12]4[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=4)[CH:16]=3)(=[O:21])=[O:20])=[CH:26][C:27]=2[C:49]([N:51]2[CH2:60][CH2:59][C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[CH2:52]2)=[O:50])[N:32]=1)=[O:39])[CH2:46][CH2:47][CH3:48]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(OCc5ccccc5)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Agent: [Pd]
Solvent: CO
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(O)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Reaction time: 8 h
Yield: 45.3 %

Procedure:
To a solution of 1-(4-(7-(benzyloxy)naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 18, 30 mg, 0.035 mmol) in MeOH (5.0 mL) was added 10% Pd/C (75 mg, 0.71 mmol). The flask was evacuated and purged with H2 from a balloon (2×), and the reaction mixture was then stirred overnight under an atmosphere of H2. The reaction mixture was diluted with CH2Cl2 and filtered through a pad of CELITE®, washing with CH2Cl2. The filtrate was concentrated in vacuo and purified by preparative HPLC to give the title compound (12 mg, 43%). 1H NMR (1:1 CD3OD:CDCl3, 1:1 mixture of amide rotamers) δ 8.37 (s, 1H), 8.17-8.13 (m, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 7.80-7.76 (m, 2H), 7.70 (d, J=8.9 Hz, 1H), 7.34 (dd, J=8.5, 1.3 Hz, 1H), 7.23 (s, 1H), 7.17-7.05 (m, 4.5H), 6.83 (d, J=7.9 Hz, 0.5H), 4.66 (br s, 2H), 4.41 (s, 1H), 3.88 (br s, 1H), 3.51 (br s, 2H), 3.04-3.00 (m, 1H), 2.81-2.78 (m, 1H), 2.24 (s, 1.5H), 2.20 (s, 1.5H), 1.49-1.42 (m, 1H), 1.40-1.33 (m, 2H), 1.30-1.16 (m, 5H), 1.09-0.96 (m, 2H), 0.90-0.84 (m, 3H), 0.72 (t, J=7.4 Hz, 1.5H), 0.67 (t, J=7.4 Hz, 1.5H); MS (ESI+) m/z 756.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C@H:7]1[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)=[O:5])[CH3:2].[C:28]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.C(O)(=O)C>ClC(Cl)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C@H:7]1[C:21]1[CH:22]=[CH:23][C:24]([NH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:25][CH:26]=1)=[O:5])[CH3:2]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)c2ccccc2C)[C@H]1c1ccc(N)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)[C@H]1CCCN(C(=O)c2ccccc2C)[C@H]1c1ccc(NC2CCCC2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
Na(OAC)3BH (495 mg, 2.33 mmol) was added to a solution of the (2R,3S)-2-(4-aminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester (612 mg, 1.67 mmol), cyclopentanone (140 mg, 1.67 mmol) and acetic acid (100 mg, 1.67 mmol) in dry dichloroethane at r.t and the reaction mixture was heated to 50° C. for 4 h, cooled to r.t and stirred for 48 h. It was then diluted with CH2Cl2 (30 mL), washed with saturated aqueous NaHCO3 solution, dried and concentrated in vacuo. The residue was purified by ISCO flash column using ethyl acete and hexanes as mobile phase (40 g column, 0-40% gradient) to afford (2R,3S)-2-(4-Cyclopentylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester (450 mg).