Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:11]=2[C:12]2[CH:13]([CH2:25][Cl:26])[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:16]=2[CH:17]=1)C1C=CC=CC=1.N#N>CCOC(C)=O.C1COCC1.[Pd]>[C:21]([O:20][C:18]([N:15]1[C:16]2[CH:17]=[C:9]([OH:8])[C:10]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:11]=3[C:12]=2[CH:13]([CH2:25][Cl:26])[CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(OCc1ccccc1)c1ccc(C#N)cc21
Agent: [Pd]
Agent: N#N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(O)c1ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.1 %

Procedure:
A solution of 22 (71.5 mg, 0.159 mmol) and 10% Pd-C (40 mg) in anhydrous EtOAc (5 mL) was degassed with a stream of N2 for 30 s. The resulting mixture was placed under an atmosphere of H2 and stirred at 25° C. for 2.5 h. The mixture was diluted with THF (1 mL) and filtered through Celite (EtOAc wash). The solvent was removed in vacuo. Chromatography (SiO2, 1.5×6 cm, 20% EtOAc-hexane) afforded 23 (57.1 mg, 57.1 mg theoretical, 100%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ8.25 (d, 1H, J=8.7 Hz, C6-H), 7.97 (s, 1H, C9-H), 7.87 (br s, 1H, C4-H), 7.42 (dd, 1H, J=1.5, 8.7 Hz, C7-H), 6.67 (br s, 1H, OH), 4.23 (d, 1H, J=11.4 Hz, C2-H), 4.14 (dd, 1H, J=8.8, 11.8 Hz, C2-H), 3.95 (m, 1H, C1-H), 3.82 (dd, 1H, J=3.2, 11.3 Hz, CHHCl), 3.46 (dd, 1H, J=9.8, 11.2 Hz, CHHCl), 1.59 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ154.2, 153.1, 142.9, 129.4, 127.8, 125.2, 123.2, 122.8, 119.3, 114.7, 111.0, 101.7, 82.5, 53.3, 46.3, 41.3, 28.4; IR (film) vmax 3315 (br), 2964, 2923, 2227, 1676, 1585, 1421, 1369, 1331, 1235, 1141, 729 cm-1 ; FABHRMS (NBA) m/z 358.1076 (M+ +H, C19H19ClN2O3 requires 358.1084).
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]\[S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[CH3:2].CN1CCOCC1.C(Cl)(Cl)=O.[N-:38]=[N+:39]=[N-:40].CN(C)C(=[NH2+])N(C)C>ClCCl.C1(C)C=CC=CC=1.[Cl-].[Na+].O.O>[CH3:2][C:1]1[N:4](/[CH:5]=[CH:6]\[S:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:40]=[N:39][N:38]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)N/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(=[NH2+])N(C)C
Agent: O=C(Cl)Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nnnn1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
(Z)-1-Acetamido-2-triphenylmethylthioethene, e44, (1.07 g) in dry dichloromethane (30 ml) containing N-methylmorpholine (3.5 ml, 3.22 g) was cooled to -30° and treated with phosgene in toluene (8.4 ml, 12.5% w/w). After warming to room temperature and stirring for 30 minutes tetramethylguanidinium azide (600 mg) in dichloromethane (6 ml) was added. After 45 min. a further quantity of tetramethylguanidinium azide (300 mg) in dichloromethane was added. After a further 45 min. the reaction mixture was warmed with water (2×300 ml), followed by saturated brine. After drying (MgSO4) the dichloromethane was evaporated in vacuo. Toluene (30 ml) was added and evaporated in vacuo (2×) and the residual material was crystallised from ethyl acetate/hexane to give (Z)-1-(5-methyltetrazol-1-yl)-2-triphenylmethylthioethene (827 mg), m.p. 208°-210°, νmax. (CHCl3) 1600, 1490, 1445, 1410 cm-1, δ(CDCl3) 2.54 (3H, s), 6.15 (1H, d, J 9 Hz), 6.59 (1H, d, J 9 Hz), 7.35 (15 H, s) p.p.m. (Found: C, 71.65; H, 5.20; N, 14.41%. C23H20N4S requires C, 71.9; H, 5.21; N, 14.6%).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][CH:11]2[CH:15]([OH:16])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)[N:4]=1.[ClH:25].C(OCC)C>C(OCC)(=O)C>[ClH:25].[ClH:25].[CH3:24][N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][CH:11]2[CH2:12][NH:13][CH2:14][CH:15]2[OH:16])[N:4]=1
Reactant: Cc1cc(N(C)C)nc(NC2CN(C(=O)OC(C)(C)C)CC2O)n1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1cc(N(C)C)nc(NC2CNCC2O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl (3RS,4RS)-3-(4-dimethylamino-6-methylpyrimidin-2-ylamino)-4-hydroxypyrrolidine-1-carboxylate (1.0 g) was dissolved in ethyl acetate (10 mL), followed by addition of a solution (7.5 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred at room temperature for 2 h. Diethyl ether was added to the solution, and the precipitated crystals were collected by filtration to obtain the title compound (0.89 g).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:43])[C:7](=[CH2:42])[CH2:8][C@H:9]([OH:41])[C@@H:10]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:11][C@@H:12]([CH:30]([CH3:32])[CH3:31])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4]>CO>[CH2:1]([NH:5][C:6](=[O:43])[C@H:7]([CH3:42])[CH2:8][C@H:9]([OH:41])[C@@H:10]([NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:11][C@@H:12]([CH:30]([CH3:31])[CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Solvent: CO
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C
Reaction time: 5 h

Procedure:
3.5 g of N-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-methoxy-phenyl)-octanoic acid (N-butyl)amide are hydrogenated in 30 ml of absolute methanol in the presence of 20 mg of [Ru2Cl4 ((S)-Binap)2 ]-NEt3 at room temperature and 25 bar for 5 hours. The reaction mixture is filtered and the filtrate is concentrated by evaporation. The residue is purified by FC (200 g of silica gel, hexane/ethyl acetate=1:1). Title compound: Rf (hexane/ethyl acetate=1:1)=0.16; FAB-MS (M+H)+ =599.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:17].FC(F)(F)C(O)=O>>[O:17]=[C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]1[CH2:6][CH:2]=[O:1]
Reactant: O=c1ccc2ccccc2n1CC1OCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=CCn1c(=O)ccc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
To 0.88 g of 1-(1,3-dioxolan-2-ylmethyl)quinolin-2(1H)-one, 8.8 mL of a 90% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, thereto were added an aqueous saturated sodium hydrogen carbonate solution and ethyl acetate, and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, and the aqueous layer was extracted 5 times with ethyl acetate. The organic layer and an extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.55 g of (2-oxoquinolin-1(2H)-yl)acetaldehyde.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[OH:30][C:6]1[C:5]([C:3]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:10](=[O:23])[N:11]2[C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]
Reactant: NCCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2[C@@H](C)c2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: C[C@@H](c1ccccc1)n1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCCC(=O)O)ncc21
Temperature: 25 °C
Yield: 36.1 %

Procedure:
A mixture of (5)-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.1 mmol), 4-aminobutyric acid (825 mg, 8.0 mmol) and NaOMe solution (12 mL, 6.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 17 mg of the title compound. MS: (+) m/z 472.34 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:16](=[O:18])[NH:15][CH:14]=[CH:13][C:12]=3[NH:11][C:10]([CH3:19])=[C:9]2[C:20]([O:22][CH2:23][CH2:24][C:25]#[N:26])=[O:21])=[C:4]([O:27][C:28]([F:31])([F:30])[F:29])[CH:3]=1.C(OCC)(OCC)O[CH2:34][CH3:35]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[O:18][CH2:34][CH3:35])[NH:11][C:10]([CH3:19])=[C:9]2[C:20]([O:22][CH2:23][CH2:24][C:25]#[N:26])=[O:21])=[C:4]([O:27][C:28]([F:30])([F:29])[F:31])[CH:3]=1
Reactant: CC1=C(C(=O)OCCC#N)C(c2ccc(Br)cc2OC(F)(F)F)c2c(cc[nH]c2=O)N1
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Product: CCOc1nccc2c1C(c1ccc(Br)cc1OC(F)(F)F)C(C(=O)OCCC#N)=C(C)N2
Temperature: 130 °C
Reaction time: 7 h

Procedure:
7.30 g (13.19 mmol) of the compound from Example 34A are suspended in 150 ml of triethyl orthoformate and heated to 130° C. Then, over a total period of 7 hours, 15 drops of concentrated sulfuric acid are added each hour to the reaction mixture. It is then stirred at the same temperature overnight. After cooling, excess orthoester is removed in a rotary evaporator, and the crude product is purified by column chromatography (silica gel; mobile phase: cyclohexane/ethyl acetate 1:1). 4.59 g (64% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][OH:11].[CH:12]1([CH2:15]Br)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:12]1([CH2:15][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH2:9][CH2:10][OH:11])[CH2:14][CH2:13]1
Reactant: BrCC1CC1
Reactant: OCCOc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCOc1ccccc1OCC1CC1
Yield: 114.5 %

Procedure:
2-Hydroxy-1-(2-hydroxyethyloxy)benzene (4 g, 26.0 mmol), cyclopropylmethyl-bromide (5.0 g, 37.0 mmol), and potassium carbonate (5.0 g, 36.2 mmol) were combined in acetone (80 mL) and the mixture was refluxed for 18 hours. The mixture was cooled and filtered. The filtrate was evaporated and the residue was dissolved in ether. The solution was washed with water 2N sodium hydroxide, and then brine, and dried over magnesium sulfate. Evaporation gave 2-cyclopropylmethyloxy-1-(2-hydroxyethyloxy)benzene (6.2 g) as an oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:7][C:8]2[O:12][C:11]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][C:9]=2[C:21]=1[C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][C:5]1[C:6]([C:26]([CH3:27])([CH3:29])[CH3:28])=[CH:7][C:8]2[O:12][C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][C:9]=2[C:21]=1[C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:3])[CH3:2]
Reactant: CCCCCCC=Cc1cc2c(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)cc2o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCc1cc2c(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)cc2o1
Reaction time: 3 h
Yield: 94.7 %

Procedure:
5-Acetoxy-4,6-di-tert-butyl-2-(1-octenyl)benzofuran (3.1 g) was dissolved in ethyl acetate containing 10% acetic acid (50 ml) and, after addition of 10% Pd on carbon (0.3 g), the solution was stirred under a hydrogen atmosphere for 3 h. After filtering off the Pd on carbon, the filtrate was concentrated under vacuum. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 5-acetoxy-4,6-di-tert-butyl-2-Octylbenzofuran [2.95 g (yield, 96%)] as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:23]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)=[O:14])[CH:10]=[CH:9][C:8]=1[CH3:19])=[O:5].[CH3:31]OC(OC)OC>>[CH:16]1([NH:15][C:13](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([CH3:19])=[C:7]([N:6]3[C:4](=[O:5])[C:3]4[C:2](=[C:23]([N:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)[CH:22]=[CH:21][CH:20]=4)[N:1]=[CH:31]3)[CH:12]=2)[CH2:17][CH2:18]1
Reactant: COC(OC)OC
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cccc(N2CCN(C)CC2)c1N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(N3CCN(C)CC3)cccc2c1=O

Procedure:
Using an analogous procedure to that described in Example 1, 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-(4-methylpiperazine-1-yl)benzamide was reacted with trimethylorthoformate. There was thus obtained the title compound; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.67 (m, 2H), 2.13 (s, 3H), 2.24 (s, 3H), 2.50 (m, 4H), 2.84 (m, 1H), 3.31 (m, 4H), 7.33 (d, 1H), 7.48 (m, 2H), 7.78 (m, 2H), 7.88 (d, 1H), 8.25 (s, 1H), 8.41 (d, 1H); Mass Spectrum: M+H+ 418
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].O>ClCCl>[CH2:22]([O:21][C:19]([O:10][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=1[F:1])=[O:20])[CH3:23]
Reactant: Oc1ccc(F)c(F)c1F
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)Oc1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
7.40 g (50.0 mmol) of 2,3,4-trifluorophenol was dissolved in 50 mL of dichloromethane, 8.30 mL (60.0 mmol) of triethylamine and 5.74 mL (60.0 mmol) of ethyl chloroformate were added under ice-cooling and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution and the mixture was extracted once with chloroform. The organic layer was washed once with an aqueous saturated solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 9.83 g of O-ethoxycarbonyl-2,3,4-trifluorophenol (yield: 89%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1>[CH3:35][C:20]1[C:21]([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:34])=[CH:22][CH:23]=[CH:24][C:19]=1[C:8]1[C:7]2[C:6]3[C:14](=[CH:15][C:3]([CH2:2][NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:4][CH:5]=3)[NH:13][C:12]=2[C:11]([C:16]([NH2:18])=[O:17])=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CN)ccc4c23)cccc1N1Cc2ccccc2C1=O
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CNS(C)(=O)=O)ccc4c23)cccc1N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A solution of 7-(aminomethyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 33-1, 60 mg, 0.065 mmol) and TEA (23 μL, 0.163 mmol) in THF (1.3 mL) was treated with methanesulfonyl chloride (5.6 μL, 0.072 mmol) and the mixture was stirred at rt overnight. The mixture was concentrated and purified by preparative HPLC. The appropriate effluent fractions were concentrated and partitioned between EtOAc and NaHCO3 (aq). The organic phase was dried and concentrated, and the residue was purified further by column chromatography (eluting with a gradient from 40:60 hexane-EtOAc to EtOAc) to provide 4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-7-(methylsulfonamidomethyl)-9H-carbazole-1-carboxamide as an off-white solid (7 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ 11.57 (1 H, s), 8.19 (1 H, br. s.), 8.02 (1 H, d, J=7.7 Hz), 7.81 (1 H, d, J=7.7 Hz), 7.73 (1 H, s), 7.69 (2 H, d, J=3.7 Hz), 7.61-7.65 (1 H, m), 7.54-7.61 (2 H, m), 7.51 (2 H, t, J=7.7 Hz), 7.35 (1 H, dd, J=7.5, 1.1 Hz), 7.00-7.08 (2 H, m), 6.93-6.99 (1 H, m), 4.88-5.05 (2 H, m), 4.26 (2 H, d, J=5.9 Hz), 2.87 (3 H, s), 1.84 (3 H, s). Mass spectrum m/z 539.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]1[CH2:13][CH:14]3[NH:19][CH:18]([C:7]2=1)[CH2:17][CH2:16][CH2:15]3.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1>>[CH3:22][C:23]1[N:24]=[CH:25][C:26]([CH2:29][CH2:30][N:9]2[C:10]3[C:6](=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:12][CH:11]=3)[C:7]3[CH:18]4[NH:19][CH:14]([CH2:13][C:8]2=3)[CH2:15][CH2:16][CH2:17]4)=[CH:27][CH:28]=1
Reactant: FC(F)(F)Oc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Reactant: C=Cc1ccc(C)nc1
Product: Cc1ccc(CCn2c3c(c4cc(OC(F)(F)F)ccc42)C2CCCC(C3)N2)cn1

Procedure:
The coupling of 2-trifluoromethoxy-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (148 mg, 0.500 mmol; Example 140A) and 2-methyl-5-vinylpyridine (119 mg, 1.00 mmol; IBScreen) was performed according to the procedure described in Example 114B to afford the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 1.09-1.22 (m, 1H), 1.29-1.39 (m, J=7, 7 Hz, 1H), 1.46 (d, J=14 Hz, 1H), 1.75 (d, J=14 Hz, 1H), 2.26-2.44 (m, 3H), 2.48 (s, 3H), 2.95-3.04 (m, 1H), 3.05-3.13 (m, 1H), 3.47 (dd, J=18, 7 Hz, 1H), 4.22-4.31 (m, 1H), 4.34-4.43 (m, 2H), 5.29 (s, 1H), 6.99 (d, J=8 Hz, 1H), 7.23-7.31 (m, 2H), 7.51 (d, J=9 Hz, 1H), 7.60 (s, 1H), 8.37 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 416 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][N:14]=[C:15]([C:22]#[N:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(O)=[O:2].CN(C)C=O.S(Cl)([Cl:31])=O>>[Cl:31][C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][N:14]=[C:15]([C:22]#[N:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:2]
Reactant: N#CC(=NOS(=O)(=O)c1ccc(C(=O)O)cc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#CC(=NOS(=O)(=O)c1ccc(C(=O)Cl)cc1)c1ccccc1
Temperature: 50 °C

Procedure:
4 g of the product of Example 14 are suspended in 20 g of thionyl chloride, and 0.5 ml of dimethylformamide are added. The reaction mixture is then heated to 50° C. until the evolution of gas ceases (2 hours) and a clear solution has formed. Part of the excess thionyl chloride is evaporated off, affording a crystaline product which is isolated by filtration and recrystallised from dichloromethane. Melting point: 193°-195° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH:21]([C:22]([NH:24][OH:25])=[O:23])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].Cl>O1CCOCC1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH:21]([C:22]([NH:24][OH:25])=[O:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CCC2C(=O)NO)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC#CCOc1ccc(S(=O)(=O)N2CCNCCC2C(=O)NO)cc1

Procedure:
To the product of Example 291, tert-butyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-5-[(hydroxyamino)carbonyl]-1,4-diazepane-1-carboxylate (0.32 g, 0.68 mmol), was added 4N hydrochloric acid in dioxane (9 mL). After 10 min the reaction mixture was concentrated in vacuo. Trituration of the residue with diethyl ether gave 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-diazepane-5-carboxamide as an off-white powder (0.27 g). Electrospray Mass Spec 368.2 (M+H)+.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[CH:26][C:25]([CH3:28])=[N:24]2)=[CH:19][C:18]=1O.N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH:27]=[CH:26][C:25]([CH3:28])=[N:24]2)=[CH:21][C:22]=1[O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9]
Reactant: Cc1ccn(-c2ccc(F)c(O)c2)n1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccn(-c2ccc(F)c(OS(=O)(=O)C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
To an ice cooled solution of trifluoromethanesulfonic anhydride (0.29 mL, 1.72 mmol) in DCM (10 mL) was added 2-fluoro-5-(3-methylpyrazol-1-yl)phenol (which may be prepared as described in Description 68) (288 mg, 1.5 mmol) followed by pyridine (0.6 mL, 7.49 mmol). The reaction was stirred at 00° C. for 10 minutes, then allowed to warm to room temperature over 1 hour, then the reaction was stirred overnight at room temperature. Additional trifluoromethanesulfonic anhydride (0.29 mL, 1.72 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was diluted with DCM (30 mL) and subsequently poured into an aqueous solution of citric acid (10% w/w, 50 mL), and the layers were separated. The aqueous was then re-extracted with DCM (30 mL). The combined organics were dried through a phase separator, and concentrated in vacuo. The residue was loaded onto a silica column (10 g, SNAP cartidge), which was eluted with a gradient of EtOAc:isohexane, 0% to 30%. Fractions containing desired product were combined and concentrated in vacuo, to give [2-fluoro-5-(3-methylpyrazol-1-yl)phenyl]trifluoromethanesulfonate (D69) (308 mg, 0.9024 mmol, 60.2% yield);
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[N:17]=[CH:16][C:15]2[CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[NH:20][C:14]=2[CH:13]=1.Br[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[H-].[Na+]>CN(C=O)C.O.CCOC(C)=O>[Br:11][C:12]1[N:17]=[CH:16][C:15]2[CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[N:20]([CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:14]=2[CH:13]=1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: BrCC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3cnc(Br)cc3n2CC2CCCCC2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
NaHMDS (1 M solution in THF, 217 mL, 0.217 mmol) was added to a solution of 6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 50 mg, 0.180 mmol) in DMF (790 mL). The reaction mixture was then stirred for 10 minutes at room temperature before the addition of (bromomethyl)cyclohexane (38 mL, 0.271 mmol) and was stirred overnight at 60° C. NaH (60% in mineral oil) (14.4 mg, 0.361 mmol) and bromomethylcyclohexane (76 mL, 0.542 mmol) were then added. The reaction mixture was stirred for 1 hour at 60° C. before being diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was purified via Biotage silica gel column chromatography eluting with (DCM/EtOAc 99/1 to 80/20) to afford the title product as a colourless oil (40 mg, 59%). 1H NMR (500 MHz, CDCl3) d 0.84-0.94 (m, 2H), 1.06-1.17 (m, 3H), 1.43-1.50 (m, 2H), 1.61-1.69 (m, 3H), 1.70-1.78 (m, 1H), 3.95 (d, J=7.5 Hz, 2H), 4.02 (s, 3H), 6.52 (d, J=0.9 Hz, 1H), 7.41 (t, J=0.9 Hz, 1H), 7.57 (s, 1H), 7.66 (s, 1H), 8.58 (d, J=0.9 Hz, 1H). LC (Method B)-MS (ESI, m/z) tR 3.14 min, 373 [(M+H+), 100%].