Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[CH3:3]C(C)=O.[NH:7]1[CH2:12][CH2:11][O:10][C@H:9]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@:16]3([C:34]4[C:25](=[CH:26][C:27]5[O:32][CH2:31][CH2:30][O:29][C:28]=5[CH:33]=4)[O:24][CH2:23]3)[C:15]2=[O:35])[CH2:8]1.N1CCC(CN2C3C(=CC=CC=3)C3(C4C(=CC5OCCOC=5C=4)OC3)C2=O)CC1>ClCCCl.O1CCCC1>[CH3:3][N:7]1[CH2:12][CH2:11][O:10][C@H:9]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@:16]3([C:34]4[C:25](=[CH:26][C:27]5[O:32][CH2:31][CH2:30][O:29][C:28]=5[CH:33]=4)[O:24][CH2:23]3)[C:15]2=[O:35])[CH2:8]1
Reactant: O=C1N(C[C@@H]2CNCCO2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: CC(C)=O
Agent: C=O
Agent: O=C1N(CC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN1CCO[C@H](CN2C(=O)[C@@]3(COc4cc5c(cc43)OCCO5)c3ccccc32)C1

Procedure:
Following the procedure described in EXAMPLE 11.100 and making non-critical variations using 37% w/w aqueous formaldehyde to replace acetone, tetrahydrofuran to replace 1,2-dichloroethane and (8S)-1′-[(2S)-morpholin-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 1′-(piperidin-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrocholride, (8S)-1′-{[(2S)-4-methylmorpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (68%) as a colorless solid: mp 85-90° C.; 1H NMR (300 MHz, CDCl3) δ 7.27 (d, J=7.5 Hz, 1H), 7.15-6.98 (m, 3H), 6.47 (s, 1H), 6.20 (s, 1H), 4.86 (d, J=9.0 Hz, 1H), 4.61 (d, J=9.0 Hz, 1H), 4.19-4.05 (m, 4H), 3.92-3.56 (m, 5H), 2.76 (d, J=11.4 Hz, 1H), 2.60 (d, J=11.4 Hz, 1H), 2.26 (s, 3H), 2.17-2.05 (m, 1H), 1.97-1.87 (m, 1H); 13C NMR (300 MHz, CDCl3) δ177.6, 155.1, 144.5, 142.6, 138.2, 132.0, 128.7, 123.6, 123.2, 121.0, 111.4, 109.4, 99.2, 80.0, 73.5, 66.7, 64.4, 63.8, 58.1, 57.8, 54.6, 46.3, 43.1; MS (ES+) m/z 409.2 (M+1).
Reaction SMILES: O=[C:2]1[C@@H:7]2[CH2:8][C@@H:4]([CH2:5][N:6]2[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:3]1.[NH2:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].[O-]S([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.C(Cl)Cl>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([N:6]2[CH2:5][C@H:4]3[CH2:8][C@@H:7]2[C@@H:2]([NH:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:3]3)=[CH:10][CH:11]=1)#[N:14]
Reactant: N#Cc1ccc(N2C[C@H]3CC(=O)[C@@H]2C3)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N[C@H]1C[C@@H]2C[C@H]1N(c1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a round bottom flask under argon was added 4-((1S,4R)-6-oxo-2-azabicyclo[2.2.1]heptan-2-yl)benzonitrile (272 mg, 1.282 mmol), tert-butyl (1R,2R)-2-aminocyclohexylcarbamate (330 mg, 1.538 mmol), CH2Cl2 (6.4 ml), solid anhydrous Na2SO4 (1 gm) and HOAc (1 drop). Argon was bubbled through the reaction mixture for 1 min and then the reaction was stirred under argon at rt for 1 hr. After this time, sodium triacetoxy borohydride (815 mg, 3.84 mmol) was added to the reaction which was then stirred at rt overnight. The reaction mixture was then diluted with CH2Cl2. The resulting solution was wash with saturated aqueous NaHCO3, water and saturated aqueous NaCl. The organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex. The fractions containing the desired product were concentrated to give tert-butyl (1R,2R)-2-((1R,4R,6S)-2-(4-cyanophenyl)-2-azabicyclo[2.2.1]heptan-6-ylamino)cyclohexylcarbamate (466 mg, 1.135 mmol, 89% yield). Anal. Calcd. for C24H34N4O2 m/z 410.5, found: 411.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.45 (2 H, d, J=8.8 Hz), 6.55 (2 H, d, J=8.8 Hz), 4.26 (1 H, s), 3.65 (1 H, br. s.), 3.47-3.41 (1 H, m), 3.30 (1 H, dt, J=8.8, 3.0 Hz), 3.15 (1 H, d, J=8.8 Hz), 2.98 (1 H, d, J=8.2 Hz), 2.64 (1 H, s), 2.29-2.19 (2 H, m), 2.10-2.02 (1 H, m), 2.01-1.93 (1 H, m), 1.74-1.59 (4 H, m), 1.45-1.37 (1 H, m), 1.35 (9 H, s), 1.30-1.18 (2 H, m), 1.09- -0.93 (2 H, m), 0.90 (1 H, ddd, J=12.9, 3.8, 3.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([C:14](OCC)=[O:15])[CH:10]=1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Mg+2]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([CH2:14][OH:15])[CH:10]=1
Reactant: CCOC(=O)c1c[nH]c(-c2c(F)cccc2F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OCc1c[nH]c(-c2c(F)cccc2F)c1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution (35 mL) of ethyl 5-(2,6-difluorophenyl)-1H-pyrrole-3-carboxylate (3.35 g) in tetrahydrofuran was cooled to −50° C., and a 1.5 mol/L solution (30 mL) of diisobutylaluminum hydride in toluene was added dropwise by small portions. The mixture was stirred at the same temperature for 1 hr, water was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, celite and anhydrous magnesium sulfate were added and the mixture was further stirred for 15 min. The suspension was filtrated, and the obtained filtrate was concentrated under reduced pressure to give the title compound as pale-red crystals (yield 2.70 g, 97%).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:5]=[N:4][CH:3]=[N:2]1.C(N(C(C)C)CC)(C)C.[C:29]([C:31]1[CH:32]=[CH:33][C:34]([O:41][C:42]2[CH:47]=[C:46]([Cl:48])[CH:45]=[C:44]([Cl:49])[CH:43]=2)=[C:35]([S:37](Cl)(=[O:39])=[O:38])[CH:36]=1)#[N:30]>C1COCC1>[C:29]([C:31]1[CH:32]=[CH:33][C:34]([O:41][C:42]2[CH:47]=[C:46]([Cl:48])[CH:45]=[C:44]([Cl:49])[CH:43]=2)=[C:35]([S:37]([N:12]2[CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH:7]2[CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)(=[O:38])=[O:39])[CH:36]=1)#[N:30]
Reactant: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNC(Cn2cncn2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc(C#N)ccc2Oc2cc(Cl)cc(Cl)c2)C(Cn2cncn2)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of tert-butyl 3-(1H-1,2,4-triazol-1-ylmethyl)-1-piperazinecarboxylate (29.5 mg, 0.11 mmol) and di-isopropyl-ethyl amine (28.5 mg, 0.22 mmol) in THF (2 ml) was added 5-cyano-2-(3,5-dichlorophenoxy)benzenesulfonyl chloride (40.0 mg, 0.11 mmol). The mixture was stirred at 50° C. overnight. The solvent was removed and the residue was diluted with CHCl3, washed with sat. NaHCO3 aq. and brine. The organic layer was dried over MgSO4. The solvent was evaporated in vacuo, and the resulting residue was purified by prep. TLC (MeOH/CHCl3= 1/10) to give tert-butyl 4-{[5-cyano-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-3-(1H-1,2,4-triazol-1-yl methyl)-1-piperazine-carboxylate (42.5 mg, 64.9%): HPLC-MS (ESI): Calcd for C25H26Cl2N6O5S [M+H]+ 593, found: 593.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([OH:10])(=[S:9])[CH3:8].[C:11]([O:15][C:16]([NH:18][C@@H:19]1[CH2:24][CH2:23][C@H:22](OS(C)(=O)=O)[CH2:21][CH2:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(OCC)(=O)C>CN(C=O)C.O>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([S:9][C:7](=[O:10])[CH3:8])[CH2:21][CH2:20]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(O)=S
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of potassium tert-butoxide (0.78 g, 7.00 mmol) and DMF (10 mL), thioacetic acid (0.50 mL, 7.0 mmol) was added at 0° C. The mixture was stirred for ˜5 mins and then a solution of cis methanesulfonic acid 4 tert-butoxycarbonylamino-cyclohexyl ester (1.36 g, 4.70 mmol) in DMF (4.1 mL) was added. The mixture was heated to 80° C. for 3.75 hours and was then poured into a mixture of ethyl acetate (50 mL) and water (50 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (×2). The combined organic extracts were washed with 10% aqueous citric acid solution, saturated sodium hydrogen carbonate solution, and brine, dried with sodium sulfate and concentrated under vacuum. Purification by column chromatography on silica gel (ethyl acetate/cyclohexane, 1:6) gave 325 mg (26%) of trans thioacetic acid S-(4-tert-butoxycarbonylamino-cyclohexyl) ester as an orange solid. 1H NMR (400 MHz, CDCl3) δ: 4.38 (br s, 1H), 3.42 (br s, 1H), 3.33 (m, 1H), 2.29 (s, 3H), 2.02 (m, 5H), 1.44 (s, 9H), 1.26-1.25 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N+:3]=1[O-:10].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N+:3]([O-:10])=[CH:4][C:5]([CH2:8][N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: [O-][n+]1cc(CCl)ccc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(Cc2ccc(Cl)[n+]([O-])c2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 84.2 %

Procedure:
A mixture of 2-chloro-5-(chloromethyl)pyridine 1-oxide (0.5 g, 2.8 mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16, 333), 1-methylpiperazine (0.34 g, 3.37 mmol), and potassium carbonate (0.78 g, 5.62 mmol) in acetonitrile (5 mL) was stirred at room temperature for 13 h. The solvent was removed in vacuo and the residue was purified on a silica gel column using a gradient dichloromethane/methanol, (100:1 to 2:1), as the eluent affording 0.57 g (84% yield) of the title compound as a colorless solid: 1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 7.38 (d, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 3.42 (s, 2H), 2.52 (s, 8H), 2.34 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 140.6, 140.6, 136.3, 126.7, 58.9, 55.0, 52.6, 45.8; MS (ESP) m/z 242 (M++1).
Reaction SMILES: [C:1]([O:5][NH:6][C:7](=[O:24])[C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C@H:9]([OH:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([O:5][NH:6][C:7](=[O:24])[C@H:8]([N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:32][C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)[C@H:9]([O:11][CH2:32][C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)[CH3:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1cccnc1
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)NOC(C)(C)C)[C@@H](C)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NOC(C)(C)C)[C@@H](C)OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl]amino]-3(R)-hydroxybutanamide (3.04 g, 8.44 mmol) in dimethylformamide (150 mL) is added 3-picolyl chloride hydrochloride (1.45 g, 8.87 mmol) followed by potassium carbonate (11.65 g, 84.4 mmol). The reaction mixture is stirred at room temperature overnight, then heated to 45° C. for 5 hours. An additional amount of 3-picolyl chloride hydrochloride (692.0 mg, 4.23 mmol) is added at this point. The reaction mixture is stirred at 45° C. for 10 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product is purified by silica gel chromatography (ethyl acetate, then 5% methanol/methylene chloride) to give N-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3(R)-(3-picolyloxy)butanamide.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].C(OCC)(=O)C>CN(C=O)C.O>[Si:35]([O:34][CH2:33][CH2:32][CH2:31][N:10]([CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][S:2](=[O:1])(=[O:23])[CH2:3][CH2:4]1)[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])(=[O:12])=[O:13])([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCN1CCS(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCN(CCN1CCS(=O)(=O)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide (0.400 g, 1.10 mmol) was combined with cesium carbonate (0.538 g, 1.65 mmol) in DMF (5 mL). The slurry was stirred at rt for 30 min, then to it was added (3-bromopropoxy)(tert-butyl)dimethylsilane (0.558 g, 2.20 mmol). The resulting mixture was stirred at rt for 18 h. LCMS indicated incomplete conversion, so additional (3-bromopropoxy)(tert-butyl)dimethylsilane (0.558 g, 2.20 mmol) and cesium carbonate (0.538 g, 1.65 mmol) were added and the mixture was heated to 70° C. for 1 h. Dilution with ethyl acetate (60 mL) and water (40 mL) followed by shaking gave a separation of phases. The organic phase was isolated, washed with water (2×30 mL) and brine (25 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a residue. Purification by silica gel chromatography (gradient 100% DCM to 100:1 DCM:MeOH) gave the title compound as a sticky yellow material, partially crystalline (0.548 g, 93% yield). LCMS: m/z 536 (M+H+), retention time 2.26 min (method 11). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.02 (s, 6H) 0.87 (s, 9H) 1.63-1.75 (m, 2H) 2.72 (t, J=6.40 Hz, 2H) 3.07 (s, 8H) 3.32-3.40 (m, 2H) 3.47 (t, J=6.40 Hz, 2H) 3.56 (t, J=5.90 Hz, 2H) 7.63-7.76 (m, 3H) 8.08 (dd, J=7.53, 1.76 Hz, 1H).
Reaction SMILES: C([O:5][C:6](=[O:50])[CH:7]([NH:12][C:13](=[O:49])[C:14]1[CH:19]=[C:18]([NH:20][CH2:21][CH3:22])[CH:17]=[CH:16][C:15]=1[S:23][S:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH3:33])=[CH:27][C:26]=1[C:34](=[O:48])[NH:35][CH:36]([C:41]([O:43]C(C)(C)C)=[O:42])[CH:37]([CH3:40])[CH2:38][CH3:39])[CH:8]([CH3:11])[CH2:9][CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([S:23][S:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH3:33])=[CH:27][C:26]=2[C:34]([NH:35][C@H:36]([C:41]([OH:43])=[O:42])[C@H:37]([CH2:38][CH3:39])[CH3:40])=[O:48])=[C:14]([C:13]([NH:12][C@H:7]([C:6]([OH:50])=[O:5])[C@H:8]([CH2:9][CH3:10])[CH3:11])=[O:49])[CH:19]=1)[CH3:22]
Reactant: CCNc1ccc(SSc2ccc(NCC)cc2C(=O)NC(C(=O)OC(C)(C)C)C(C)CC)c(C(=O)NC(C(=O)OC(C)(C)C)C(C)CC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1ccc(SSc2ccc(NCC)cc2C(=O)N[C@H](C(=O)O)[C@@H](C)CC)c(C(=O)N[C@H](C(=O)O)[C@@H](C)CC)c1

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)]2-{5-ethylamino-2-[4-ethylamino-2-(1-tert-butoxy carbonyl-2-methyl-butylcarbamoyl)-phenyldisulfanyl]-benzoylamino}-3-methyl-pentanoic acid tert-butyl ester (0.8 g, 1.1 mmol) from Example 45, 10 mL dichloromethane, and 10 mL trifluoroacetic acid. The product was washed with hexane/ether to afford 0.6 of the title compound, mp 97°-100° C.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[Cl:12][C:13]1[C:14](Cl)=[N:15][CH:16]=[C:17]([CH:39]=1)[C:18]([NH:20][C:21]1[S:22][C:23]([CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[C:24]([C:26]2[S:27][CH:28]=[C:29]([Cl:31])[CH:30]=2)[N:25]=1)=[O:19]>C1COCC1>[Cl:12][C:13]1[C:14]([N:1]2[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]2)=[N:15][CH:16]=[C:17]([C:18](=[O:19])[NH:20][C:21]2[S:22][C:23]([CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)=[C:24]([C:26]3[S:27][CH:28]=[C:29]([Cl:31])[CH:30]=3)[N:25]=2)[CH:39]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Nc1nc(-c2cc(Cl)cs2)c(CN2CCCCC2)s1)c1cnc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(CN4CCCCC4)s3)cc2Cl)CC1
Reaction time: 120 h

Procedure:
1.3 ml of ethyl isonipecotate was added to a 5 ml THF solution of 413 mg of 5,6-dichloro-N-[4-(4-chlorothiophen-2-yl)-5-(piperidin-1-ylmethyl)-1,3-thiazol-2-yl]nicotinamide, and the mixture was stirred for 5 days. After the solvent was distilled off under reduced pressure, a saturated sodium hydrogencarbonate aqueous solution was added, and the resulting precipitate was collected by filtration. The precipitate was dissolved in chloroform, and a saturated sodium hydrogencarbonate aqueous solution was added. The mixture was extracted with chloroform, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography using hexane:EtOAc (4:1 to 3:1) as an elution solvent to obtain 468 mg of ethyl 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(piperidinomethyl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylate.
Reaction SMILES: [Cl:1][C:2](Cl)(Cl)[C:3]1[CH:8]=[CH:7][C:6]([S:9]([F:14])([F:13])([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[OH2:17].Cl>>[F:10][S:9]([F:14])([F:13])([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([C:2]([Cl:1])=[O:17])=[CH:4][CH:5]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C(Cl)(Cl)Cl)cc1
Reactant: O
Agent: Cl
Product: O=C(Cl)c1ccc(S(F)(F)(F)(F)F)cc1
Reaction time: 1 h
Yield: 41.9 %

Procedure:
Into a 50 mL flask equipped with a stirrer were placed 16.08 g (50 mmol) of 4-trichloromethyl(pentafluorosulfanylbenzene) prepared in Example 1 and 406 mg (5 mol %) of FeCl3. The bath was heated to 70° C. to 75° C., and 900 mg (50 mmol) of water was added dropwise over at least 2 hours. HCl gas was generated during the addition. After the addition was complete, the mixture was heated with stirring for 1 hour. This mixture was distilled under reduced pressure to yield 5.59 g of 4-pentafluorosulfanylbenzoic chloride (product yield: 42%).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:23]=[CH:24][CH:25]=[CH:26][C:4]1=2.[CH3:27][S:28]([NH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:30])=[O:29]>>[N:17]1([CH2:16][CH2:15][O:14][C:12]2[CH:11]=[CH:10][C:9]3[C:3](=[CH:2][C:34]4[CH:33]=[C:32]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH:37]=[CH:36][CH:35]=4)[C:4]4[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=4[CH2:6][CH2:7][C:8]=3[CH:13]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: BrC=C1c2ccccc2CCc2cc(OCCN3CCOCC3)ccc21
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3cc(OCCN4CCOCC4)ccc32)c1

Procedure:
Following procedures essentially as described in Example 219, below, and using 4-[2-(5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-2-yloxy)-ethyl]-morpholine (220 mg, 0.53 mmol) and 3-methanesulfonamidophenylboronic acid (125 mg, 0.58 mmol). Purification on silica gel eluting with EtOAc then EtOAc/1% MeOH/NH3, gave 57 mg of pure E-isomer. MS (ES)505 (M+1), 503(M−1). HPLC shows 92% purity at t=1.79 min.
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([OH:3])[OH:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2[N:25]=[CH:26][CH:27]=[CH:28]C=2N=N1.C(N(CC)C(C)C)(C)C.N1CCC1>CC#N>[N:25]1([C:8]([C:7]2[CH:6]=[CH:5][C:4]([B:1]([OH:2])[OH:3])=[CH:12][CH:11]=2)=[O:10])[CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C1CNC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(B(O)O)cc1)N1CCC1
Reaction time: 72 h
Yield: 55.4 %

Procedure:
A solution of 4-boronobenzoic acid (527.4 mg, 3.18 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.61 g, 4.23 mmol) and N,N-diisopropylethylamine (1.665 mL, 9.53 mmol) in CH3CN (40 mL) was stirred at room temperature for 30 min. Azetidine (0.321 mL, 4.76 mmol) was added. After stirring for 3 days, the mixture was concentrated and purified by reverse phase HPLC (Sunfire S10 30×250 mm column, 10-40% solvent B gradient) to give the expected product as white solid (361 mg, 55% yield). 1H NMR (500 MHz, methanol-d4) δ ppm 7.68 (2H, d, J=7.70 Hz), 7.60 (2H, d, J=7.97 Hz), 4.37 (2H, t, J=7.56 Hz), 4.19 (2H, t, J=7.84 Hz), 2.36 (2H, quin); MS (ES+) m/z: 206 (M+H); LC retention time: 2.01 min (analytical HPLC Method A).
Reaction SMILES: P([O-])(O)(O)=O.[Na+].CC(=CC)C.[Cl:12][C:13]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:14]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][C:24]([CH2:28][CH3:29])=[C:23]2[CH:30]=[O:31])=[O:16].Cl([O-])=[O:38].[Na+]>C(O)(C)(C)C.O>[C:30]([C:23]1[C:22]2[C:27](=[C:18]([NH:17][C:15](=[O:16])[C:14]3[C:32]([Cl:36])=[CH:33][CH:34]=[CH:35][C:13]=3[Cl:12])[CH:19]=[CH:20][CH:21]=2)[N:26]=[CH:25][C:24]=1[CH2:28][CH3:29])([OH:38])=[O:31]
Reactant: [O-][Cl+][O-]
Reactant: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1C=O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1C(=O)O
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of sodium dihydrogenphosphate (395 mg) and 2-methyl-2-butene (578 mg) in tert-butanol (6 ml) and water (1.5 ml) was added 8-(2,6-dichlorobenzoylamino)-3-ethyl-4-formylquinoline (615 mg) at ambient temperature, and to the mixture was portionwise added sodium chlorite (298 mg) at the same temperature. The mixture was stirred for 3 hours at the same temperature. The mixture was quenched by diluted hydrochloric acid and extracted with dichloromethane. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethyl acetate-n-hexane to give 4-carboxy-8-(2,6-dichlorobenzoylamino)-3-ethylquinoline (404 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH3:17])[CH:3]=1.CO>CCOC(C)=O.[Pd]>[F:16][C:14]1[CH:13]=[CH:12][C:11]([CH3:17])=[C:10]([C:4]2[CH:3]=[CH:2][N:7]=[CH:6][C:5]=2[NH:8][CH3:9])[CH:15]=1
Reactant: CNc1cnc(Cl)cc1-c1cc(F)ccc1C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNc1cnccc1-c1cc(F)ccc1C
Reaction time: 4 h

Procedure:
A solution of 6-chloro-4-(5-fluoro-2-methylphenyl)-N-methylpyridin-3-amine (0.2 g, 798 μmol, example 253, intermediate a) in EtOAc (1 mL) and MeOH (1.0 mL) under argon was treated with palladium on carbon (21.2 mg, 19.9 μmol) and stirred under an hydrogen atmosphere (0.5 bar overpressure) for 4 hours. Stirring was continued overnight at room temperature. The reaction mixture was filtered over Dicalite and evaporated. The residue was taken up in CH2Cl2 and saturated aqueous NaHCO3 solution and the layers were separated. The aqueous layer was extracted three times with CH2Cl2. The organic layers were dried over MgSO4, filtered and evaporated. Light brown solid (0.16 g; 92%). MS (ESI): m/z=217.11 [M+H]+.