Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=1)[CH:19]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:19][C:18]2[CH:21]=[C:14]([Br:13])[CH:15]=[CH:16][C:17]=2[F:22])=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2cc(Br)ccc2F)cc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (1.65 g, 10 mmol) and 5-bromo-2-fluoro-benzaldehyde (2.03 g, 10 mmol) in ethanol (20 mL) was heated to reflux for 2 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(5-bromo-2-fluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.76 g, 79%) as a white solid: LC/MS m/e calcd for C16H13BrFNO2 M+: 350.2, observed: 350.1, 352.1.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=2)[NH:9][C:8]=1Cl)=[O:6])[CH3:3].C([O-])=O.[NH4+]>CO.[Pd]>[CH2:2]([O:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=2)[NH:9][CH:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)[nH]c1Cl
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Product: CCOC(=O)c1c[nH]c(-c2ccnc(N)n2)c1
Yield: 49.8 %

Procedure:
To a suspension of 5-(2-Amino-pyrimidin-4-yl)-2-chloro-1H-pyrrole-3-carboxylic acid ethyl ester hydrochloride (33 g, 0.108 mol) in dry methanol (500 mL), ammonium formate (33 g, 0.523 mol) and 10% Pd/C (3.5 g, 0.0028 mol) were added. The reaction was refluxed for 10 hours. The catalyst was filtered through a pad of Celite rinsing the Celite with dichloromethane (100 mL) and then with methanol (100 mL). The organic fraction was concentrated to small volume (50 mL) diluted with dichloromethane (150 mL) and washed with water (1×200 mL) and the acqueous fraction extracted with dichloromethane (1×200 mL). The organic fractions were combined, dried over sodium sulfate, filtered, and concentered to yield 12.5 g (50%) of the title compound as an light brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12](=[O:24])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][O:28][C:29](=O)[O:30]C>C1COCC1.CCOC(C)=O>[CH3:27][O:28][C:29]([CH:11]1[C:12](=[O:24])[CH2:13][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15]2)=[O:30]
Reactant: COC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC(C1)N2C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1C(=O)CC2CN(C(=O)OC(C)(C)C)CC1N2C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 58.9 %

Procedure:
Compound W (15.91 g, 46.7 mmol) was dissolved in THF (100 mL). NaH (55% in oil, 4.71 g, 98 mmol) was added portionwise, followed by dimethylcarbonate (8.86 mL, 105 mmol). The reaction mixture was heated to reflux for 1 h. The mixture was cooled to 0° C. with an ice bath, and treated cautiously with ice-water (50 mL). The org. layer was diluted with EtOAc (200 mL), and washed with aq. 1M HCl (100 mL), and with brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:3→1:2→1:1→2:1) yielded the title compound (Rf=0.7, EtOAc/heptane 1:1) as a yellow oil (10.96 g, 58%). LC-MS: tR=1.03, ES+: 399.25.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](O)=[N:7][CH:6]=[C:5]2[O:13][CH3:14].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnc(O)c2ccc(F)cc12
Product: COc1cnc(Cl)c2ccc(F)cc12
Yield: 69.3 %

Procedure:
A solution of 6-fluoro-4-methoxyisoquinolin-1-ol (2.9 g, 15.01 mmol) in POCl3 (10 ml, 107 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in Hexanes as eluent. The product fractions were collected and the solvent removed under vacuum to give 1-chloro-6-fluoro-4-methoxyisoquinoline (2.2 g, 67% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.29 (dd, J=9.2, 5.4 Hz, 1H), 7.84-7.79 (m, 2H), 7.45 (ddd, J=9.3, 8.2, 2.6 Hz, 1H), 4.06 (s, 3H); MS m/z 212.0 (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1([O:33][C:34]([NH:36][OH:37])=O)C=CC=CC=1>C1COCC1>[OH:37][NH:36][C:34]([N:24]1[CH2:23][CH2:22][CH:21]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)[CH2:26][CH2:25]1)=[O:33]
Reactant: O=C(NO)Oc1ccccc1
Reactant: Cc1cnc(CN(C2CCNCC2)C2CCCc3cccnc32)c(C)c1
Solvent: C1CCOC1
Product: Cc1cnc(CN(C2CCN(C(=O)NO)CC2)C2CCCc3cccnc32)c(C)c1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 33.7 %

Procedure:
To a solution of (3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (150.0 mg, 0.428 mmol) in THF (5 mL) was added hydroxylamine carboxylic acid phenyl ester (75 mg, 0.449 mmol) and stirred for 17.5 h at reflux. The mixture was cooled to ambient temperature and concentrated in vacuo. Purification by flash chromatography on silica gel using CH2Cl2/MeOH/NH4OH (89:10:1) followed by purification by radial chromatography using CH2Cl2/MeOH/NH4OH (94:5:1) afforded COMPOUND 369 (59 mg, 34%) as white solid. 1H NMR (CDCl3) δ1.54-1.72 (m, 3H), 1.81-2.05 (m, 5H), 2.23 (s, 3H), 2.37 (s, 3H), 2.53-2.79 (m, 5H), 3.85-4.07 (m, 5H), 6.95-7.00 (m, 2H), 7.14 (s, 1H), 7.25 (d, 1H, J=4.2 Hz), 8.10 (s, 1H), 8.40 (d, 1H, J=3.7 Hz); 13C NMR (CDCl3) δ 17.90, 18.58, 21.71, 29.04, 29.37, 30.08, 31.25, 43.84, 53.30, 57.64, 60.19, 121.29, 131.51, 133.03, 134.11, 136.25, 138.92, 145.97, 146.88, 158.41, 160.63; ES-MS m/z 410 (M+H). Anal Calcd. For C23H31N5O2.0.1(H2O).0.3CH2Cl2): C, 64.07; H, 7.34; N, 16.03. Found: C, 64.13; H, 7.44; N, 15.69.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.[Cl-].[Na+].O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:11][C:9]1[CH:10]=[C:2]2[N:7]([C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:5][C:4]([NH2:12])=[CH:3]2)[N:8]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2cc(N)nc(-c3ccccc3)n2n1
Temperature: 100 °C
Yield: 17.8 %

Procedure:
7-Chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J, 10 g, 55 mmol), phenylboronic acid (7.3 g, 60 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (1.0 g, 1.4 mmol) were mixed in dioxane (120 ml) and saturated NaHCO3 (60 ml). The mixture was then heated at 100° C. for 4 hours. After cooling to room temperature, Brine was added and the mixture was extracted with EtOAc five times. Combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO2) to give 2-methyl-7-phenylpyrazolo[1,5-c]pyrimidin-5-amine (10A, 2.2 g, 18%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ=7.95-7.85 (m, 2 H), 7.62-7.50 (m, 3 H), 6.70 (s, 2 H), 6.22 (s, 1 H), 5.81 (s, 1 H), 2.24 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13](Cl)=[O:14])=[C:11]([CH3:16])[O:10][N:9]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH2:34][C:35]([F:37])([F:38])[F:36])[CH2:25][CH2:26]2)=[O:14])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Reactant: NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Yield: 67.2 %

Procedure:
The title compound was synthesised according to the procedure described in Example 8 but using 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride instead of the crude 3-(4-fluorophenyl)isoxazole-4-carbonyl chloride and Compound 12B instead of Compound 8B. Washing the reaction mixture with 2 N sodium hydroxide, followed by the usual work-up and purification by flash chromatography (chloroform-2 N ammonia in methanol 100:3) afforded the title compound (67.2%) as an oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]2[CH2:21][CH:20]2[CH2:22][OH:23])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(Cl)(Cl)Cl.C(#N)C.I([O-])(=O)(=O)=[O:35].[Na+]>O.[Ru](Cl)(Cl)Cl.O>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]2[CH2:21][CH:20]2[C:22]([OH:35])=[O:23])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Oc1ccccc1C1CC1CO)c1ccc(C(F)(F)F)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=C(O)C1CC1c1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of 2-[2-(hydroxymethyl)cyclopropyl]phenyl 4-(trifluoromethyl)-benzenesulfonate (0.70 g, 1.9 mmol), carbon tetrachloride (2.5 mL), acetonitrile (2.5 mL), water (3.8 mL), sodium periodate (1.8 g, 8.4 mmol) and ruthenium choride hydrate (75 mg, 0.4 mmol) is stirred at room temperature overnight. The reaction is partitioned between ethyl acetate and dilute HCl. The organic layer is filtered through anhydrous sodium sulfate, evaporated and purified on silica gel in ethyl acetate-methylene chloride-acetic acid mixtures. The product, 2-[2-({[4-(trifluoromethyl)phenyl]sulfonyl}oxy)phenyl]cyclopropanecarboxylic acid, is obtained as a mixture of isomers. A yield of 95% is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]=[C:9]=[O:10])[CH:3]=1.CO[CH:13](OC)[CH2:14][NH2:15]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:14][NH:15][C:9]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(CN)OC
Reactant: O=C=Nc1cccc(Br)c1
Solvent: ClCCl
Product: O=c1[nH]ccn1-c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-bromo-3-isocyanatobenzene (1.0 mL, 8.01 mmol) and [2,2-bis(methyloxy)ethyl]amine (0.86 mL, 8.01 mmol) in CH2Cl2 (15 mL) was stirred at room temperature for 16 hr. The solution was concentrated in vacuo and the residue taken up in a mixture of CH3CN (10 mL) and H2O (3 mL). TFA (3 mL) was added and the solution stirred at room temperature for 4 hr. The solution was concentrated in vacuo, the residue taken up in EtOAc then washed with satd NaHCO3, H2O, and brine. The organics were then dried over Na2SO4, concentrated in vacuo and the residue recrystallized from EtOAc to give 1-(3-bromophenyl)-1,3-dihydro-2H-imidazol-2-one as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.60 (d, J=3.0 Hz, 1H), 7.03 (d, J=3.0 Hz, 1H), 7.34-7.36 (m, 2H); 7.70-7.72 (m, 1H), 8.06 (s, 1H), 10.39 (br s, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[O:12])[CH2:4][CH2:3]1.C[N+]1([O-])CCOCC1>ClCCl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[N+:28]([C:25]1[CH:26]=[CH:27][C:9]([NH:8][CH:5]2[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]2)=[C:10]([CH:24]=1)[C:11]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]2[O:19][CH2:20][O:21][C:17]=2[CH:16]=1)=[O:12])([O-:30])=[O:29]
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@H](O)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: O=C1CCC(Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of 2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (100 mg) in dichloromethane (3 mL) and acetonitrile (0.4 mL) were added tetrapropylammonium perruthenate (4.25 mg), 4-methylmorpholine N-oxide (42.5 mg) and molecular sieves (4 Å, 0.2 g). The resulting mixture was stirred for 2 hours at ambient temperature. The mixture was subjected to a silica gel chromatography eluting with ethyl acetate to give 5-nitro-2-(4-oxocyclohexylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide (92 mg) as a solid substance.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:20])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[CH:10][CH:9]=[CH:8][CH:7]=2.[N:21]1[C:29]([NH2:30])=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[N:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:30][C:29]1[N:21]=[CH:22][N:23]=[C:24]2[C:28]=1[N:27]=[CH:26][N:25]2[CH2:2][C:3]1[O:4][C:5](=[O:20])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=c1oc(CBr)c(-c2ccccc2F)c2ccccc12
Reactant: Nc1ncnc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ncnc2c1ncn2Cc1oc(=O)c2ccccc2c1-c1ccccc1F
Yield: 64.5 %

Procedure:
The title compound was made in a similar way as that of the compound of example 1, using 3-(bromomethyl)-4-(2-fluorophenyl)-1H-isochromen-1-one (intermediate C2, 60 mg, 0.180 mmol), 9H-purin-6-amine (48.7 mg, 0.360 mmol) and K2CO3 (49.8 mg, 0.360 mmol) to give the title compound (45 mg, 64.5%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([OH:14])[C:8]([OH:15])=[N:7]2)=[N+:2]=[N-:3].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[N:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[N+:16]([O-:18])=[O:17])[N:10]=[C:9]([OH:14])[C:8]([OH:15])=[N:7]2)=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])O
Reactant: [N-]=[N+]=Nc1ccc2nc(O)c(O)nc2c1
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1cc2nc(O)c(O)nc2cc1[N+](=O)[O-]
Temperature: 24 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
2 g 6-azido-2,3-dihydroxyquinoxaline is suspended in 100 ml glacial acetic acid. To the suspension is added 16 ml fuming nitric acid at 24° C. The mixture is stirred at 24° C. for 4 h giving a precipitate of 1.9 g (78%) 6-azido-2,3-dihydroxy-7-nitroquinoxaline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[NH2:19])(=[O:10])=[O:9])[CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>N1C=CC=CC=1.C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[NH:19][S:29]([C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)(=[O:31])=[O:30])(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Nc1ccc(F)cc1N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Br)cc1S(=O)(=O)Nc1ccc(F)cc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.2 %

Procedure:
To a solution of 5-bromo-N-(4-fluoro-2-aminophenyl)-2-methoxybenzenesulfonamide (0.1 mmol) in pyridine (0.5 mL) and DCM (2 mL), 4-chlorobenzenesulfonyl chloride (0.12 mmol) was added. The reaction mixture was stirred at room temperature for 4 h and then diluted with ethyl acetate (10 mL). The contents were washed with 10% aqueous HCl (10 mL) and brine (10 mL), dried over sodium sulfate, and concentrated under vacuum. The residue obtained was purified by column chromatography eluting with hexanes/ethyl acetate (1:1) followed by ethyl acetate to give 43 mg of 5-bromo-N-[2-(4-chlorobenzenesulfonylamino) -4-fluorophenyl]-2-methoxybenzenesulfonamide. LC: Tr 1.10 min, MS: 551.8 (M+1)+
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[CH2:15][N:16]([CH2:27][C:28]([F:31])([F:30])[F:29])[S:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:18].C(N(CC)C(C)C)(C)C.[C:41](Cl)(=[O:43])[CH3:42]>ClCCl>[C:41]([N:12]1[CH2:13][CH2:14][CH:9]([C:7]2[CH:6]=[CH:5][C:4]([CH2:15][N:16]([CH2:27][C:28]([F:31])([F:29])[F:30])[S:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:19])=[O:18])=[C:3]([F:2])[CH:8]=2)[CH2:10][CH2:11]1)(=[O:43])[CH3:42]
Reactant: O=S(=O)(Cc1ccccc1)N(Cc1ccc(C2CCNCC2)cc1F)CC(F)(F)F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ccc(CN(CC(F)(F)F)S(=O)(=O)Cc3ccccc3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
To a solution of N-[[2-fluoro-4-(4-piperidyl)phenyl]methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide hydrochloride (100 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.62 mmol) in dichloromethane (1.5 mL) was added acetyl chloride (24 mg, 0.31 mmol) and the reaction was stirred at ambient temperature for 2 hours. The reaction was then concentrated and purified by preparative reverse phase HPLC to yield 33.3 mg of N-[4-(1-Acetyl-piperidin-4-yl)-2-fluoro-benzyl]-C-phenyl-N-(2,2,2-trifluoro-ethyl)-methanesulfonamide. 1H NMR (400 MHz, DMSO) δ 7.44-7.38 (m, 5H), 7.38-7.32 (m, 1H), 7.14-7.04 (m, 2H), 4.60 (s, 2H), 4.56-4.47 (m, 1H), 4.41 (s, 2H), 4.07-3.83 (m, 3H), 3.16-3.04 (m, 1H), 2.87-2.74 (m, 1H), 2.63-2.51 (m, 1H), 2.01 (s, 3H), 1.86-1.68 (m, 2H), 1.67-1.49 (m, 1H), 1.49-1.29 (m, 1H). LCMS (m/z) ES+ 487.1 [M+1]+.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[O:17]=[C:18]([CH2:24][C@@H:25]([O:31][C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33])[C@@H:26]([CH3:30])[CH2:27][CH:28]=[CH2:29])[C:19]([CH3:23])([CH3:22])[CH:20]=[O:21].O>CCOCC.C1COCC1>[O:17]=[C:18]([CH2:24][C@@H:25]([O:31][C:32]([O:34][CH2:35][C:36]([Cl:37])([Cl:38])[Cl:39])=[O:33])[C@@H:26]([CH3:30])[CH2:27][CH:28]=[CH2:29])[C:19]([CH3:23])([CH3:22])[C@@H:20]([OH:21])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: C=CC[C@H](C)[C@@H](CC(=O)C(C)(C)C=O)OC(=O)OCC(Cl)(Cl)Cl
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@H](C)[C@@H](CC(=O)C(C)(C)[C@@H](O)CC(=O)OC(C)(C)C)OC(=O)OCC(Cl)(Cl)Cl
Temperature: -30 °C
Reaction time: 1 h

Procedure:
Tert-butyl acetate (0.865 mL) is added to a solution of lithium diisopropylamide (7.52 mmol) in 30 mL of ether at −78° C., and the mixture is stirred for 1 hour. A solution of bis(1,2:5,6-di-O-isopropylidene-α-L-glucofuranos-3-O-yl)cyclopentadienyltitanium chloride (8.34 mmol) in 90 mL of ether is added dropwise over 40 minutes, and the reaction is stirred for an additional 30 minutes at −78° C., warmed to −30° C. and kept for 45 minutes, then recooled to −78° C. A solution of (5R,6S)-3-oxo-5-(2,2,2-trichloroethoxycarbonyl-oxy)-2,2,6-trimethyl-8-nonenal (2.4 g) in 15 mL of ether is added over 10 minutes and the reaction is continued for 2 hours before addition of 14 mL of 5 M water in THF. The mix is stirred for 1 hour, then filtered through Celite. The filtrate is washed with sat. aq. NaCl, and the brine layer is back extracted with ether. The organic phases are combined, dried with Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:38][CH2:39][CH3:40])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[C:33]([S:36][CH3:37])[S:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27].CO.C1COCC1.[OH-].[Li+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[C:4]([CH2:38][CH2:39][CH3:40])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[C:33]([S:36][CH3:37])[S:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27]
Reactant: CCCc1c(OCCCOc2ccc(-c3csc(SC)n3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(-c3csc(SC)n3)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2
Yield: 93.9 %

Procedure:
The compound of Example 27 (48 mg, 81.9 μmol) was added to 3.0 ml of 4:1 methanol/THF, and 0.17 ml of 1M lithium hydroxide was added. The mixture was allowed to react at room temperature for 2.75 hours. The reaction mixture was poured into ethyl acetate/water, and the ethyl acetate layer was washed with brine, dried over sodium sulfate and concentrated to give the product (44 mg, 76.9 μmol, 94% yield). High resolution mass spectrum, m/e 527.2159 (calculated for C29H37NO4S2 (M-CO2), 527.2164).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)[C@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1c1ccccc1
Reactant: N#Cc1cccc(CBr)c1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](OCc2cccc(C#N)c2)[C@H]1c1ccccc1

Procedure:
This compound was prepared from 1-t-butyloxycarbonyl-3-hydroxy-2-phenylpiperidine (Description 1c) and α-bromo-m-tolunitrile according to the procedure described in Example 1d. 1H NMR (360 MHz, CDCl3) δ 1.49 (9H, s, (CH3)3), 1.6-1.72 (2H, m), 1.87-1.99 (2H, m), 2.72 (1H, dt, J=13, 4 Hz, NCHH), 3.80-3.95 (2H, m, CHO+NCHH), 4.65 (2H, q, J=12 Hz, OCH2), 5.69 (1H, brs, CHPh), 7.1-7.5 (9H, m, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.P(Cl)(Cl)([Cl:29])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[Cl:29]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 85 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
1-(6-Bromo-4-hydroxyquinolin-3-yl)ethanone (2.2 g, 8.27 mmol) was suspended in phosphoryl chloride (30 mL) and the reaction was heated to 85° C. and stirred for 3 h. After this time the reaction mixture was cooled to room temperature and slowly poured into a 2:1 solution of satd. aq. sodium bicarbonate/ethyl acetate that was cooled to 0° C. The organic layer was separated, washed with satd. aq. sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (710 mg, 72%) as a light brown solid: ESI MS m/z 280 [C11H7BrClNO+H]+.
Reaction SMILES: [Br:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][C:7]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:8]=3[C@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:31][C:32]([F:39])([F:38])[C:33](OCC)=[O:34].O>CO>[Br:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][C:7]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:8]=3[C@H:9]3[C@H:14]([NH:15][C:33](=[O:34])[C:32]([F:39])([F:38])[F:31])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of (−)-(cis)-7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (2.32 g, 6.09 mmol) in a mixture of methanol (80 mL) and triethylamine (5.1 mL, 36.3 mmol), ethyl trifluoroacetate (4.3 mL, 36.3 mmol) was added and the resulting mixture was stirred at ambient temperature for 2 h. Water (120 mL) was added and stirred for additional 10 min. The formed precipitate was filtered off to yield the title compound (2.74 g, 94%).