Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][C@@H:45]3[CH3:54])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][C@@H:45]3[CH3:54])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(CN3CCN(S(C)(=O)=O)C[C@@H]3C)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 70 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of (S)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (9.6775 g, 12.77 mmol) in TFA (65 mL) was treated dropwise with trifluoromethanesulfonic acid (5.67 mL, 63.8 mmol) and the mixture was stirred for 1 h at 70° C. The volatile material was removed in vacuo, and the residual sticky oil was cooled to 0° C. (external ice bath). About 100 g ice was added, and the mixture was carefully quenched with 1 N NaOH(aq) until slightly basic. The mixture was stirred overnight, and the resulting yellow precipitate was collected by filtration and washed with isopropanol (100 mL). The collected yellow solid was purified by column chromatography (silica gel, 0% to 5% (2.0M ammonia in MeOH)/DCM, followed by repurification on silica gel, DCM to 40% EtOAc/DCM to EtOAc) to provide a yellow solid. This solid was washed with hot toluene several times to give (S)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (3.808 g, 58%) as a yellow solid. m/z (ESI, +ve ion) 518 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 11.95 (s, 1H), 8.67-8.75 (m, 1H), 8.41 (s, 1H), 8.38 (d, J=12.91 Hz, 1H), 8.27 (s, 1H), 7.90 (br s, 1H), 7.76 (br s, 1H), 3.93 (s, 3H), 3.91 (br s, 1H), 3.12-3.30 (m, 3H), 2.90 (d, J=14.28 Hz, 1H), 2.85 (s, 3H), 2.65-2.78 (m, 2H), 2.55-2.64 (m, 1H), 2.44 (s, 3H), 2.13-2.28 (m, 1H), 1.16 (d, J=6.06 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5]([NH2:7])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>COCCOCCOC>[CH3:1][O:2][C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5]#[N:7]
Reactant: COC(F)(F)C(F)(F)C(N)=O
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: COCCOCCOC
Product: COC(F)(F)C(F)(F)C#N
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A solution of 52.5 g (0.30 mol) of the amide from Part A in 200 ml of diglyme was stirred at -10° while 47.5 g (0.60 mol) of pyridine and then 63.0 g (0.30 mol) of trifluoroacetic anhydride were added. The cooling bath was removed, and the mixture was stirred at about 25° for 2 h. Evaporation of volatiles to 40° (4.5 mm) gave 42.7 g of crude product, which was distilled to afford 36.5 g (77%) of 3-methoxytetrafluoropropionitrile, b.p. 53°. IR (neat): 3.36 and 3.48 (sat'd CH), 4.42 (CN), 8-10μ (CF, C--O). NMR: 1H 3.78 ppm (s, OCH3): 19F -93.2 (t, JFF 6.3 Hz, 2F, CH2) and -108.8 ppm (t, JFF 6.3 Hz, 2F, CF2). Elemental analysis was consistent with the formula C4H3F4NO. ##STR54##
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[NH2:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:21]=1.C(O)(=O)C>CN(C=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:26]([C:22]1[CH:21]=[C:20]([NH:19][C:2]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[N:24]([CH3:25])[N:23]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: Cn1nc(C(C)(C)C)cc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2cc(C(C)(C)C)nn2C)c(C(=O)O)c1
Temperature: 150 °C
Yield: 32.8 %

Procedure:
A mixture of 2-bromo-5-methoxy benzoic acid (2.26 g, 9.79 mmol), potassium carbonate (1.49 g, 10.8 mmol), 5-amino-3-tert-butyl-1-methylpyrazole (1.50 g, 9.79 mmol), and copper (II) acetate (35 mg, 0.20 mmol) in DMF (20 mL) was heated (150° C.) in a sealed tube for 16 h. After cooling, the reaction mixture was diluted with water (10 mL) and acidified to pH=4 with acetic acid. This mixture was extracted with dichloromethane (3×20 mL), and then the combined organic extracts were washed with water (2×30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. HPLC purification of the residue (YMC propack C18 column, 150×20 mm ID, 30%-80% acetonitrile in water gradient) afforded the title compound (973 mg, 31%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.22 (br s, 1H), 9.24 (br s, 1H), 7.38 (d, 1H), 7.10 (dd, 1H), 6.80 (d, 1H), 5.95 (s, 1H), 3.70 (s, 3H), 3.55 (s, 3H), 1.21 (s, 9H); ES-MS m/z 304.2 (MH+), HPLC RT (min) 2.58.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]1([N:13]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH:21]=[C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:19][CH2:18]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO.[H][H]>[Pd].C(O)(=O)C>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:34]1([N:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[CH2:21][CH2:22]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: FC(F)(F)c1cccc(OC2=CCN(CCCN(c3ccccc3)c3ccccc3)CC2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(OC2CCN(CCCN(c3ccccc3)c3ccccc3)CC2)c1
Yield: 65.6 %

Procedure:
A mixture of 7.7 g. (0.014 moles) of 3,6-dihydro-N,N-diphenyl-4-[3-(trifluoromethyl)phenoxy]-1(2H)-pyridinepropanamine ethanedioate (1:1) (preparation described in Example 16), 90 ml. of methanol, 10 ml. of acetic acid and 0.5 g. of 20% Pd/c is shaken under 50 psi. of hydrogen at room temperature for about 4 hours. The reaction mixture is then filtered, and the solvent is evaporated. The residue is initially recrystallized from aqueous isopropanol, then recrystallized from aqueous isopropanol, and again recrystallized from aqueous ethanol to give 5.0 g of N,N-diphenyl-4[3-(trifluoromethyl)phenoxyl]-1-piperidinepropanamine ethanedioate (1:1), mp. 189°-190.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][CH:13]([NH2:15])[CH3:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:16][CH:17]([F:28])[C:18]1[C:22]([C:23](O)=[O:24])=[C:21]([F:26])[N:20]([CH3:27])[N:19]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH2:12][CH:13]([NH:15][C:23]([C:22]2[C:18]([CH:17]([F:28])[F:16])=[N:19][N:20]([CH3:27])[C:21]=2[F:26])=[O:24])[CH3:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Cn1nc(C(F)F)c(C(=O)O)c1F
Reactant: CC(N)Cc1ncc(C(F)(F)F)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Cc1ncc(C(F)(F)F)cc1Cl)NC(=O)c1c(C(F)F)nn(C)c1F
Reaction time: 8 h
Yield: 82.7 %

Procedure:
At ambient temperature, 150 mg (0.545 mmol) of 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]propan-2-amine, 116 mg (0.60 mmol) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid, 81 mg (0.60 mmol) of 1-hydroxybenzotriazole and 55 mg (0.545 mmol) of triethylamine are stirred together in 1 ml of dimethylformamide until dissolution. This solution is pourred over a 2 g-containing basic alumina Chem-Elut™ cartridge packed with 1.48 g of Si-DCC resin (1.09 mmol of DCC per g of resin) and left overnight at ambient temperature. The cartridge is then washed three times by 2 ml of acetonitrile. The solvents are removed and the crude amide is purified by column chromatography on silica gel (gradient heptane/ethyl acetate) to yield 187 mg (78% yield) of N-{1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]propan-2-yl}-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide as yellow solid (M+H=415).
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[F:22].[F:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[NH:32][C:31](=[O:34])[N:30]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[C:36]=1[CH3:50])[C:29]2=[O:51].C([O-])([O-])=O.[Cs+].[Cs+]>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].C(Cl)Cl.O1CCOCC1>[F:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([N:30]2[C:29](=[O:51])[C:28]4[C:33](=[C:24]([F:23])[CH:25]=[CH:26][CH:27]=4)[NH:32][C:31]2=[O:34])[C:36]=1[CH3:50])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)[nH]c2c(F)cccc2c1=O
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(F)c(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1c(-c2c(F)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)[nH]c2c(F)cccc2c1=O
Temperature: 88 °C
Yield: 18.3 %

Procedure:
A mixture of 4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H -carbazole-1-carboxamide [Intermediate 27] (0.104 g, 0.285 mmol), 8-fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 17] (0.147 g, 0.370 mmol), Cs2CO3 (0.186 g, 0.570 mmol), and dioxane (1.6 mL) was subjected to 3 evacuate-fill cycles with nitrogen. The mixture was treated with PdCl2(dppf) DCM adduct (14 mg, 0.017 mmol), and subjected to two more evacuate-fill cycles with nitrogen. The mixture was heated at 88° C. overnight. The cooled mixture was diluted with EtOAc, washed sequentially with water and brine, and dried and concentrated. The residue was purified by reverse phase preparative HPLC. The appropriate fractions were treated with saturated aqueous NaHCO3 and concentrated to an aqueous residue which was extracted with EtOAc. The organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 50%, 65% and 75%), to provide 3-fluoro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a white solid (0.029 g, 18% yield). Mass spectrum m/z 537 (M+H—H2O)+. 1H NMR (500 MHz, DMSO-d6) δ 11.81 (br. s., 1H), 11.39 (d, J=1.4 Hz, 1H), 8.21 (br. s., 1H), 7.95 (dd, J=10.7, 2.1 Hz, 1H), 7.86-7.80 (m, 2H), 7.64 (t, J=9.2 Hz, 1H), 7.59 (br. s., 1H), 7.53-7.50 (m, 2H), 7.42-7.38 (m, 1H), 7.26-7.20 (m, 1H), 7.07-6.99 (m, 1H), 6.97-6.88 (m, 1H), 4.98 (d, J=9.7 Hz, 1H), 1.81-1.75 (m, 3H), and 1.48-1.41 (m, 6H).
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](O)=[O:4].B#B.O1CCCC1.O>O1CCCC1>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4]
Reactant: O=C(O)C(Br)c1ccccc1
Agent: B#B
Solvent: C1CCOC1
Solvent: O
Product: OCC(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 25 g of α-bromophenylacetic acid in 100 ml of dry tetrahydrofuran was added 151 ml of 1.0M diborane in tetrahydrofuran dropwise at 5° C. under argon over 30 minutes. This mixture was stirred overnight at room temperature, then cooled to 0° C. and 130 ml of tetrahydrofuran:water (1:1) was added dropwise. The mixture was then saturated with potassium carbonate and the tetrahydrofuran removed. The aqueous remainder was extracted three times with ether. The extracts were combined and dried. The residue was triturated with hexane and the solid collected giving the desired compound as white needles, mp 38°-39° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]#[N:15])=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:17][N:18]1[C:22](=[O:23])[C:21]2[C:24]([CH:30]([CH3:32])[CH3:31])=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[S:19]1(=[O:34])=[O:33].[F-].[K+].CN(C=O)C>O>[CH:30]([C:24]1[C:21]2[C:22](=[O:23])[N:18]([CH2:17][O:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:9]=[C:10]([C:14]#[N:15])[CH:11]=3)[S:19](=[O:34])(=[O:33])[C:20]=2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=1)([CH3:32])[CH3:31]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: N#Cc1cc(O)n(-c2ccc(Cl)cc2)n1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C#N)nn1-c1ccc(Cl)cc1)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
A mixture of 1-(4-chlorophenyl)-3-cyano-5-hydroxypyrazole (59.7 mg, 0.273 mmol), 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (93.7 mg, 0.27 mmol), KF (15.7 mg, 0.27 mmol) and DMF (5 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with ether (3×25 mL). The ether extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexane to afford 81 mg (62%) of 4-isopropyl-6-methoxy-2-[1-(4-chlorophenyl)-3-cyanopyrazol -5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-Cl--Ph; R2 =CN; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3), m.p. 135° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1[C:19]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([OH:31])=[O:30])=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)C(C)C)C.O[C:42]([CH3:47])([CH3:46])[C:43]([OH:45])=[O:44]>C(Cl)Cl.CN(C)C=O>[CH:16]1[C:17]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([O:31][C:42]([CH3:47])([CH3:46])[C:43]([OH:45])=[O:44])=[O:30])=[O:23])[C:19]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(O)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(OC(=O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 0 °C
Yield: 98.3 %

Procedure:
Oxalyl chloride (1.17 mL, 13.3 mmol) was added dropwise to a solution of (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (Fmoc-Pro-OH) (3.00 g, 8.89 mmol) and N,N-dimethylformamide (34 μL, 0.445 mmol) in methylene chloride (36 mL) with stirring at 0° C. under a nitrogen atmosphere, and the reaction mixture was then stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the resulting residue was mixed with methylene chloride (36 mL), N-ethyldiisopropylamine (DIPEA) (4.66 mL, 26.7 mmol) and 2-hydroxy-2-methylpropanoic acid (2.78 g, 26.7 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was washed with 1 N hydrochloric acid twice and a saturated aqueous sodium chloride solution twice, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carbonyl)oxy)-2-methylpropanoic acid (Fmoc-Pro-HOGly(Me)2-OH) (Compound SP636) (3.70 g, 8.74 mmol, 98%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1>>[C:18]([N:13]1[C:12]([C:32]2[CH:33]=[CH:34][S:30][CH:31]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C(C)(C)C)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccsc1
Product: CC(C)(C)n1nc2c(c1-c1ccsc1)CCNCC2
Yield: 65.2 %

Procedure:
The title compound (83 mg) was prepared according to Example 215 using 204 mg of 2-(tert-butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 215, Step A) and 177 mg of 3-thiopheneboronic acid. MS (ESI): exact mass calculated for C15H21N3S, 275.15; found, m/z 276.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.59-7.57 (m, 1H), 7.43-7.42 (m, 1H), 7.08-7.06 (m, 1H), 3.38-3.36 (m, 2H), 3.25-3.23 (m, 2H), 3.13-3.11 (m, 2H), 2.56-2.54 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: O[C:2]1([C:22]([F:25])([F:24])[F:23])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[C:4]([C:15]2[S:19][C:18]([S:20][CH3:21])=[N:17][N:16]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH:6]=[C:2]([C:22]([F:25])([F:24])[F:23])[N:3]=[C:4]2[C:15]2[S:19][C:18]([S:20][CH3:21])=[N:17][N:16]=2)=[CH:8][CH:9]=1
Reactant: CSc1ccc(N2CC(O)(C(F)(F)F)N=C2c2nnc(SC)s2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CSc1ccc(-n2cc(C(F)(F)F)nc2-c2nnc(SC)s2)cc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A mixture of 4-hydroxy-1-[4-(methylthio)phenyl]-2-[2-(methylthio)-1,3,4-thiadiazol-5-yl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (0.52 g, 1.28 mmol) and p-toluenesulfonic acid monohydrate (0.1 g) in toluene (20 mL) was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The crude residue was redissolved in ethyl acetate and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration, and concentration in vacuo, the crude mixture was purified by chromatography on silica gel using hexane/ethyl acetate to give the title product (0.4 g, 80%) as a white solid; 1H NMR δ (DMSO-d6) 8.38 (1H, s), 7.51 (2H, d, J=8.7 Hz), 7.38 (2H, d, J=8.3 Hz), 2.76 (3H, s), 2.55 (3H, s); 13C NMR δ (DMSO-d6) 168.8, 157.4, 140.4, 138.0, 133.0, 131.0(q), 127.2, 126.4, 125.7, 122.0(q), 16.4, 14.4.
Reaction SMILES: [CH3:1][N:2]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[C:25]([CH3:33])[CH:24]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:9]([OH:11])=O.[NH2:34][OH:35]>>[OH:35][NH:34][C:9]([C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[N:2]([CH3:1])[S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[C:25]([CH3:33])[CH:24]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])=[O:11]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@@H]3CCCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@@H]3CCCC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 77 %

Procedure:
According to the procedure of Example 10, Step 2, the reaction of 111 mg of trans-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-anecarboxylic acid with hydroxylamine provided 71 mg of trans-N-hydroxy-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxamide in 77% yield. MS: 484.1 (M+H)+
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C1C=CC=CC=1.[CH:15]1[C:28]2[C:19](=[N:20][CH:21]=[C:22]3[C:27]=2[CH:26]=[CH:25][CH:24]=[CH:23]3)[CH:18]=[CH:17][CH:16]=1>O>[Cl:3][C:25]1[CH:24]=[CH:23][C:22]2[C:27]([CH:26]=1)=[C:28]1[C:19]([CH:18]=[CH:17][CH:16]=[CH:15]1)=[N:20][CH:21]=2
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: O
Product: Clc1ccc2cnc3ccccc3c2c1
Yield: 96 %

Procedure:
Phosphorus oxychloride (15 ml) and dimethylaniline (0.63 ml) were added to phenanthridine (2.0 g), followed by refluxing for 3 hours. The solution was poured into H2O to generate a solid, and the obtained solid was extracted with chloroform, followed by drying with sodium sulfate. After filtration, the filtrate was evaporated to dryness under reduced pressure. The obtained solid was purified by column chromatography (eluent: chloroform) (amount: 2.1 g, yield: 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([CH:14]2[CH2:16][CH2:15]2)=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:12][CH:14]2[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: O=C(C1CC1)N1CCCC1Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc(CC2CCCN2CC2CC2)cc1

Procedure:
Dissolve 3.0 g of 2-(4-chlorobenzyl)-1-cyclopropylcarbonylpyrrolidine in 30 ml of tetrahydrofuran, and add the thus-prepared solution (dropwise, within 10 minutes at 0°, with stirring) to a suspension of 0.43 g of lithium aluminum hydride (=lithium hydrido-aluminate) in 10 ml of tetrahydrofuran. Subsequently, boil the resulting reaction mixture under reflux for 1 hour. After cooling, cautiously add 50 ml of water thereto and extract the product 3 times with, in each case, 30 ml of diethyl ether. Combine the ether solutions and wash the combined extract with saturated sodium chloride solution. Dry the washed ether phase over sodium sulfate, evaporate off the solvent and distil the residue twice under a vacuum to obtain 1.65 g (58% of theory) of the title compound (b.p. 108° at 0.006 mm of Hg).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28]>C[O-].[Na+].CO>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][C@@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:7]
Reactant: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](NC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O)C(=O)O
Yield: 72 %

Procedure:
A mixture of 4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (0.20 g) and L-alanine (0.75 g) in 0.5 M NaOMe/MeOH (11.3 ml) was heated to reflux for 36 h. After cooling, reaction mixture was concentrated. The residue was suspended in water (50 ml) and extracted with ethyl acetate (50 ml) which was discarded. The aqueous layer was acidified by 2 N HCl aqueous solution. Extracted with ethyl acetate (2×50 ml). Combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound (0.15 g). MS-(−)-ion: M−1=367.1.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1)[CH3:2].Cl.[CH3:16]O>C(=O)(O)[O-].[Na+]>[CH3:16][O:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]2[N:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=2[CH:8]=1)=[O:14]
Reactant: CO
Reactant: CCn1nnc2ccc(C(=O)O)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCn1nnc2ccc(C(=O)OC)cc21
Temperature: 65 °C

Procedure:
3-Ethyl-3H-benzotriazole-5-carboxylic acid (0.15 g) was diluted with methanol and treated with HCl (gas). The reaction was then heated to 65° C. for 18 hours. The mixture was allowed to cool to 23° C. and was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated to give 3-ethyl-3H-benzotriazole-5-carboxylic acid methyl ester (0.143 g).