Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([OH:14])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([O-:13])=[O:12])[OH:10])O)[OH:6])[OH:4].[K+].[CH3:16][O-].[Na+]>>[CH3:16][O:13][C:11]([C@@H:9]([OH:10])[C@H:7]1[O:14][C:2](=[O:1])[C@H:3]([OH:4])[C@H:5]1[OH:6])=[O:12]
Reactant: C[O-]
Reactant: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)O
Agent: [K+]
Agent: [Na+]
Product: COC(=O)[C@@H](O)[C@H]1OC(=O)[C@H](O)[C@H]1O

Procedure:
Monopotassium D-glucarate and sodium methoxide solution (NaOMe) (0.5 M in methanol) were commercial products. Methyl D-glucarate 1,4-lactone was prepared as previously described (Kiely, 1994). Some carbohydrate diacids and diamines or polyamines were prepared as needed. Other commercial chemicals and solvents were used without further purification. Solutions were concentrated in vacuo (15-20 mbar) using a rotary evaporator and water bath at 30° C. pH was estimated using pHydrion paper produced by Micro Essential Laboratory (Brooklyn, N.Y., USA).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[F:10][C:11]1[C:16]([O:17][C:18](=O)[O:19]C2C(F)=C(F)C(F)=C(F)C=2F)=[C:15]([F:32])[C:14]([F:33])=[C:13]([F:34])[C:12]=1[F:35]>C1COCC1>[F:10][C:11]1[C:16]([O:17][C:18](=[O:19])[NH:8][C:6]2[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([CH3:1])[CH:7]=2)=[C:15]([F:32])[C:14]([F:33])=[C:13]([F:34])[C:12]=1[F:35]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: Cc1cc(N)cc(C)n1
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc(C)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2,6-dimethyl-pyridin-4-ylamine (Example C1.2., 1.23 g, 10 mmol) in THF (30 mL) is slowly added to a cooled (−10° C.) solution of bis(pentafluorophenyl)carbonate (3.94 g, 10 mmol) in THF (10 mL). The mixture is stirred at r.t. for 48 h and the solution of title compound is used as stock solution for subsequent coupling reactions.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([Cl:8])=[N:6][CH:7]=1.F[C:18]1[C:23]([C:24]2[N:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH2:31])[N:25]=2)=[CH:22][C:21]([O:32][CH3:33])=[CH:20][N:19]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[NH4+].[Cl-]>CN(C=O)C>[NH2:31][C:26]1[N:27]=[C:28]([CH3:30])[N:29]=[C:24]([C:23]2[C:18]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:19][CH:20]=[C:21]([O:32][CH3:33])[CH:22]=2)[N:25]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N)cnc1Cl
Reactant: COc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cnc(Nc2cnc(Cl)c(NC(=O)OC(C)(C)C)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
To a 15 mL RB flask was added tert-butyl 5-amino-2-chloropyridin-3-ylcarbamate (0.130 g, 0.533 mmol), 4-(2-fluoro-5-methoxypyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (Example 330 step 5)(0.151 g, 0.640 mmol), and DMF (2.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (Aldrich) (2.134 mL, 2.134 mmol) was then added to the solution in one portion. The now burgundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 30 min. The reaction mixture was poured into the beaker which had filled with 15 mL sat. NH4Cl. The resulting mixture was stirred at rt for 5 h. The ppt in the solution mixture was collected by filtration. The solid was rinsed with water and dried opened to the air for 4 h. This crude product was purified by column chromatography (40 g, 3% MeOH in DCM) to afford the desired product as a yellow solid (210 mg). MS (ESI pos. ion) m/z: 459.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.47 (s, 9H) 2.45 (s, 3H) 3.85 (s, 3H) 7.80 (br. s., 1H) 7.94 (br. s., 1H) 8.20 (d, J=3.07 Hz, 1H) 8.42 (d, J=3.07 Hz, 1H) 8.58 (d, J=2.34 Hz, 1H) 8.63 (d, J=2.34 Hz, 1H) 8.75 (s, 1H) 11.91 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:4]([C:9]([OH:11])=O)=[N:5][CH:6]=[CH:7][N:8]=1.[CH2:14]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[CH:25]([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])[NH2:21])[CH:15]([CH3:17])[CH3:16].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[CH2:14]([C:18]1[CH:19]=[C:20]([NH:21][C:9]([C:4]2[C:3]([C:2]([F:1])([F:13])[F:12])=[N:8][CH:7]=[CH:6][N:5]=2)=[O:11])[CH:22]=[CH:23][C:24]=1[CH:25]([C:30]([F:31])([F:32])[F:33])[C:26]([F:27])([F:28])[F:29])[CH:15]([CH3:17])[CH3:16]
Reactant: O=C(O)c1nccnc1C(F)(F)F
Reactant: CC(C)Cc1cc(N)ccc1C(C(F)(F)F)C(F)(F)F
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)Cc1cc(NC(=O)c2nccnc2C(F)(F)F)ccc1C(C(F)(F)F)C(F)(F)F
Yield: 61.9 %

Procedure:
3-Trifluoromethyl-2-pyrazine carboxylic acid (192 mg, 1 mmol), 3-isobutyl-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]aniline (199 mg, 1 mmol), 2-chloro-1-methylpyridinium iodide (255 mg, 1 mmol) and triethylamine (303 mg, 3 mmol) were dissolved in THF (10 ml) and refluxed under heating for 2 hours. The reaction solution was diluted with ethyl acetate, followed by washing with water. The organic layer was dried over magnesium sulfate anhydride, and concentrated under reduced pressure, and then the solution was purified by using silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 293 mg of the desired compound as paste state.
Reaction SMILES: [C:1]([CH2:3][N:4]([C:16]1[CH:21]=[CH:20][N:19]=[C:18](F)[N:17]=1)[C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])#[N:2].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:18]1[N:17]=[C:16]([N:4]([CH2:3][C:1]#[N:2])[C:5](=[O:15])[C@H:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:7])[CH:21]=[CH:20][N:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: N#CCN(C(=O)[C@@H](N)Cc1ccccc1)c1ccnc(F)n1
Product: N#CCN(C(=O)[C@@H](N)Cc1ccccc1)c1ccnc(NCc2ccccc2)n1

Procedure:
The title compound was prepared from the product from step (ii) (0.2 g) and benzylamine (0.37 ml) by the method of example 1 step (iv). Yield 0.11 g.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.CCCCCC.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH3:21].Br[CH2:32][CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35].Cl>C1COCC1.O>[CH2:20]([O:22][C:23]([C:25]1([CH2:32][CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CCC(CC)CBr
Reactant: CCOC(=O)C1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)C1(CC(CC)CC)CCCCC1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 78.7 %

Procedure:
To a solution of dicyclohexylamine (15.55 g, 85.77 mmol) in THF (90 mL) 1.6 M n-BuLi in hexane (48.0 mL, 76.8 mmol) was added with stirring over 50 min at temperature between −20° C. and −15° C. The orange suspension was stirred 10 min at −20° C. and then warmed up to 0° C. To this suspension a solution of cyclohexanecarboxylic acid ethyl ester (10.0 g, 64.0 mmol) in THF (30 mL) was added over 15 min at 0° C. The resulting solution was stirred 30 min at 0° C. then 1-bromo-2-ethylbutane (14.79 g, 89.6 mmol) in THF (37.5 mL) was added at the same temperature over 15 min. Stirring was continued 5 h at 0° C. and overnight at room temperature. At 5° C. cold water (25 mL) was added, followed by 2N HCl (60 mL). The white suspension was filtered and the filter cake was washed with water and ethyl acetate. The organic phase of the filtrate was washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (16.0 g) was distilled at 60° C. (0.05 mbar) to give 12.1 g (79%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid ethyl ester as colorless oil, purity 97% (GC area) (cyclohexanecarboxylic acid dicyclohexylamide as impurity: not detectable in distilled product and 0.7% in crude product).
Reaction SMILES: [NH2:1][C:2](=[O:35])/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:8]2[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1>CO.O1CCCC1.[C].[Pd]>[NH2:1][C:2](=[O:35])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:9]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[C:8]2[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(/C=C/C(N)=O)cc23)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(CCC(N)=O)cc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.9 %

Procedure:
To a solution of tert-butyl {[6-[(1E)-3-amino-3-oxoprop-1-en-1-yl]-2-isobutyl-4-(4-methylphenyl)-quinolin-3-yl]methyl}carbamate (250 mg, 0.53 mmol) in methanol (5 ml) and tetrahydrofuran (5 ml) was added 5% palladium-carbon (0.10 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 12 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give tert-butyl {[6-(3-amino-3-oxopropyl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (204 mg, yield 81%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[N:18]=2)[CH:14]=[CH:13][S:12]3)[CH:6]=[CH:7][CH:8]=1.[ClH:37]>O1CCOCC1.CCOCC>[ClH:37].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)[N:18]=2)[CH:14]=[CH:13][S:12]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)n2)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
The tert-butyl (3R)-3-({4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate (21 g, 41.5 mmol) is dissolved in 250 ml of dioxane and treated with 75 ml of anhydrous a four molar HCl in dioxane at room temperature (RT). The reaction mixture is stirred at room temperature for three hours. The mixture is then diluted with 350 ml of ether and stirred until product separates as a solid. Solid product is filtered and washed with ether. The solid is dissolved in MeOH (200 ml) and concentrated to dryness twice. The product is dried at high vacuum to yield 20.275 g of yellow solid (tris HCl salt) (90%). M.p.=220-225° C.; 300 MHz 1H NMR (DMSO-d6 at 80° C.) δ: 9.6-9.3 (br. s, 2H), 8.9-8.4 (br. s, 2H), 8.82 (s, 1H), 8.11 (d, J=5.8 Hz, 1H), 7.50 (d, J=4.7 Hz, 1H), 7.39 (t, J=7.98 Hz, 1H), 7.2-7.1 (m, 2H), 7.08-7.0 (m, 1H), 6.49 (d, J=5.8 Hz, 1H), 4.4-4.3 (m, 1H), 3.79 (s, 3H), 3.39 (d, J=10.2 Hz, 1H), 3.16 (br. s, 1H), 3.05-2.7 (m, 2H), 2.2-1.6 (m, 3H), 1.55-1.2 (m, 1H). LCMS: 407 [M+H]; calc. for C21H22N6OS 3.3 HCl 0.05 dioxane 0.3 methanol: C, 47.75; H, 5.01; N, 15.54; found. C, 47.73; H, 5.26; N, 15.55.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][CH2:4][NH:5][C:6](=[O:28])[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([F:27])([F:26])[F:25])[CH2:19]1.C1COCC1>[Pd].CO>[F:30][C:2]([F:1])([F:29])[CH2:3][CH2:4][NH:5][C:6](=[O:28])[C:7]1[CH:12]=[C:11]([NH2:13])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([F:27])([F:26])[F:25])[CH2:19]1
Reactant: CNc1cc(N2CCCC(C(F)(F)F)C2)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(N2CCCC(C(F)(F)F)C2)c(C(=O)NCCC(F)(F)F)cc1N
Reaction time: 8 h

Procedure:
A mixture of N-(3,3,3-trifluoro-propyl)-2-[3-trifluoromethyl-piperidinyl]-4-methylamino-5-nitro-benzoic acid amide (100 mg, 0.22 mmol), Pd/C (10 mg), THF (5 mL) and MeOH (15 mL) is stirred under 3 bar H2-atmosphere overnight. The mixture is filtered, and the filtrate is concentrated.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19]C(=O)C)[C:8]([N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])=[O:9])(=O)C.N>C(O)C.O>[OH:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[OH:19])[C:8]([N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])=[O:9]
Reactant: CC(=O)Oc1ccc(C(=O)N2CCNC2=O)cc1OC(C)=O
Agent: N
Solvent: CCO
Solvent: O
Product: O=C1NCCN1C(=O)c1ccc(O)c(O)c1
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
1-[3,4-Bis(acetyloxy)benzoyl]-2-imidazolidinone (11 g, 0.035 mol) was suspended in a mixture of 50 ml of ethanol and 50 ml of water, 4.2 ml (0.07 mol) of aqueous ammonia solution was added with stirring. After 15 minutes, a clear solution was formed, which was evaporated to a small volume. 1-(3,4-Dihydroxybenzoyl)-2-imidazolidinone crystallized out yielding 6.1 g of the title compound, melting point 208°-210° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([CH3:17])[C@H:10]([NH:15][CH3:16])/[CH:11]=[CH:12]/[C:13]#[N:14].[C:18]([O:22][C:23]([NH:25][CH:26]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:27]([OH:29])=O)=[O:24])([CH3:21])([CH3:20])[CH3:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>ClCCl.CCCCCC.CCOCC>[C:13](/[CH:12]=[CH:11]/[C@@H:10]([N:15]([CH3:16])[C:27]([C@@H:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:19])([CH3:20])[CH3:21])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29])[CH:9]([CH3:17])[CH3:8])#[N:14]
Reactant: CN[C@H](/C=C/C#N)C(C)C
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)[C@@H](/C=C/C#N)N(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Yield: 33.9 %

Procedure:
To a solution of (E,4S)-5-methyl-4-(methylamino)-2-hexenenitrile trifluoroacetic acid (˜1.68 mmol, from Reference Example 14), 2-tert-Butoxycarbonylamino-3,3-dimethyl-butyric acid (389 mg, 1.68 mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP, 916 mg, 1.76 mmol) in dichloromethane (5 mL) at 0° C. is added Hunig's base (0.877 mL, 5.04 mmol). After 5 min the cooling bath is removed. After 24 h 5% aqueous citric acid is added. The aqueous phase is washed with dichloromethane three times. The combined organic extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo to give an oil. Chromatography (silica gel, hexane/ether) gave the title compound as a yellow foam (200 mg). MS (ES): m/z 352.0 (M+H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N+:9]=2[O-:23])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2cccc(C)n2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2cccc(C)[n+]2[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
A solution of 2-(4-methylphenyl)-6-methylpyridine (4.5 g) in 100 ml of chloroform was cooled to 0° C., and m-chloroperbenzoic acid (7.7 g) in 50 ml of chloroform was added over a period of 15 minutes. The mixture was stirred at room temperature for 3 hours, then at 50° C. for 2 hours, followed by stirring overnight at room temperature. Solvent was evaporated to a small volume under reduced pressure, and the residue passed through an alumina column, eluting with 2% methanol in methylene chloride to remove benzoic acid. The eluate was flash-Chromatographed on silica gel, eluting with 5% methanol in methylene chloride, to yield 2.8 g of 2-(4-methylphenyl)-6-methylpyridine-N-oxide, m.p. 95° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:20][CH2:19]1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47].C([O-])([O-])=O.[Cs+].[Cs+].[ClH:54]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:30].[ClH:54].[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:20][CH2:19]2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1)C1CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1)C1CC1
Temperature: 80 °C

Procedure:
To a suspension of (6-bromo-4-((trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)amino) quinoline-3-yl)(cyclopropyl)methanone (60 mg, 0.13 mmol), 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (54 mg, 0.20 mmol) and Pd(dppf)Cl2 (11 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2CO3 (1.0 M in H2O, 0.4 mL, 0.4 mmol). The reaction mixture was degassed with nitrogen and heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with a satd. aq. NaHCO3 (20 mL) and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The desired fractions were combined and concentrated and the residue was dissolved in methanol (4 mL) and HCl (1.25 M in methanol, 1.5 mL, 1.9 mmol). The mixture was concentrated to obtain the desired product (42.9 mg, 55%) as an off-white solid. 1H NMR (500 MHz, MeOD) δ 9.35 (br s, 1H), 8.47 (br s, 1H), 8.27 (dd, J=8.8, 1.8 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.60 (br s, 1H), 7.53 (d, J=11.1 Hz, 1H), 4.51 (br s, 1H), 3.74-3.66 (m, 2H), 3.18-3.07 (m, 4H), 2.85 (br s, 1H), 2.44 (br s, 2H), 2.24-1.96 (m, 5H), 1.83-1.71 (m, 2H), 1.36-1.18 (m, 6H). ESI MS m/z 522 [C30H33ClFN3O2+H]+; HPLC 98.9% (AUC), tR=10.35 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][N:12](CC2C=CC(OC)=CC=2OC)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OC(Cl)C)=O.CO>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][NH:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C[C@@H](COCc3ccccc3)O[C@@H](C)C2)c(OC)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1CNC[C@@H](COCc2ccccc2)O1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,6S)-rel-2-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-6-methylmorpholine (Intermediate 495, 0.6 g, 1.6 mmol) in DCM (15 mL) was added 1-chloroethyl chloroformate (0.6 mL, 6.9 mmol) and mixture was heated at 50° C. for 10 hour. To the reaction mixture methanol was added and heating was continued for 1 hour. After cooling, the mixture was concentrated give product as solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(NS(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
1-tert-Butoxycarbonyl-4-(4-aminobenzyl)piperidine (1.2 g, 4.15 mmol) was dissolved in tetrahydrofuran (20 mL). To the solution was added triethylamine (0.64 mL, 4.57 mmol). To the mixture was added dropwise methanesulfonyl chloride (0.39 mL, 4.95 mmol) under ice cooling, and the mixture was stirred under ice cooling for 30 minutes and at room temperature for 30 minutes. The reaction mixture was poured into ice-water (20 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the titled compound (1.43 g) as colorless powdery crystals.
Reaction SMILES: Br[C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[CH:13]>[Cu]I.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>[N+:8]([C:6]1[CH:7]=[C:2]([C:13]#[C:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([NH2:11])=[N:4][CH:5]=1)([O-:10])=[O:9]
Reactant: Nc1ncc([N+](=O)[O-])cc1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: Nc1ncc([N+](=O)[O-])cc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
A solution of 3-bromo-5-nitropyridin-2-amine (655 mg, 3.0 mmol, 1.0 eq.) in 1:1 TEA/DMF (40 mL) was degassed with argon for 10 minutes, and ethynylbenzene (1.5 eq.), CuI (0.04 eq.), and PdCl2(PPh3)2 (0.04 eq.) were sequentially added. The mixture was degassed with argon for 10 minutes, and then stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure, and CH2Cl2 (25 mL) was added. The mixture was sonicated for 15 minutes, cooled to 0° C., and collected by vacuum filtration to afford 5-nitro-3-(phenylethynyl)pyridin-2-amine (356 mg, 50%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1)#[N:2].C([Mg]Br)C.[CH3:16][C:17]1([CH3:25])[C:19]([CH3:21])([CH3:20])[CH:18]1[C:22](Cl)=[O:23]>[Cl-].[Zn+2].[Cl-]>[CH3:16][C:17]1([CH3:25])[C:19]([CH3:21])([CH3:20])[CH:18]1[C:22]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[NH:9][CH:8]=1)=[O:23]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: N#Cc1ccc2cc[nH]c2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Product: CC1(C)C(C(=O)c2c[nH]c3cc(C#N)ccc23)C1(C)C
Yield: 48.6 %

Procedure:
A mixture of 6-cyanoindole (Lancaster, 1.0 g, 7.0 mmol), ethylmagnesium bromide (1.0 M solution in THF, 8.4 mL, 8.4 mmol), zinc chloride (1.0 M solution in Et2O, 8.4 mL, 8.4 mmol) and the product of Example 1A (11 mmol) was processed as described in Example 1B to provide the title compound (0.91 g, 3.4 mmol, 49% yield). MS (DCI/NH3) m/z 267 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc(Br)cc1F
Yield: 43.7 %

Procedure:
According to general procedure C, 4-Bromo-2-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and isopropylamine (0.31 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-2-fluoro-N-isopropylbenzenesulfonamide (189 mg, 44%) was provided after purification. MS (ESI) m/z 296. HPLC purity 100.0% at 210-370 nm, 10.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.