Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:22](S(C2C=CC=CC=2)(=O)=O)[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.ClCCl.[CH3:35][N:36]([CH3:53])[CH2:37][CH2:38][N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])[O-].[K+].[K+]>O.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].O1CCOCC1>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:4]3[CH:3]=[C:2]([C:42]4[CH:41]=[N:40][N:39]([CH2:38][CH2:37][N:36]([CH3:53])[CH3:35])[CH:43]=4)[NH:22][C:5]3=[N:6][CH:7]=2)[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: CN(C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(CCc2cnc3[nH]c(-c4cnn(CCN(C)C)c4)cc3n2)cc(OC)c1
Temperature: 88 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
A stirred mixture of 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (from example 1, step 4, 20.0 mg, 0.0398 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (1.30 mg, 1.59 μmol), N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanamine (8.44 mg, 0.0318 mmol), and potassium phosphate (13.5 mg, 0.0637 mmol) in water (0.2 mL)/1,4-dioxane (0.4 mL) was heated at 88° C. After 1 hour, the volatiles were removed under vacuum and the residues were dissolved in methanol (2.0 mL). Potassium carbonate (8.8 mg, 63.7 μmol) was added and the reaction mixture was warmed up to 60° C. After 1 hour, the reaction mixture was cooled to ambient temperature and was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (3.0 mg) as its TFA salt. LCMS calculated for C23H29N6O2 (M+H)+: m/z=421.2. Found: 421.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH2:12](O)[CH3:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:12][CH3:13])=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(C)nc(Cl)c1
Yield: 86 %

Procedure:
A solution of 2-chloro-6-methyl-4-pyridinecarboxylic acid (2 g, 12 mmol) in ethanol (100 ml) and concentrated sulphuric acid (10 ml) was heated at reflux for 2 hours. The volatiles were removed by evaporation and the residue was dissolved in methylene chloride. The solution was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1/9) to give ethyl 2-chloro-6-methyl-4-pyridinecarboxylate (2 g, 86%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=2)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17](=[O:40])[CH2:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:15][O:16][C:17](=[O:40])[CH2:18][CH:19]1[CH2:20][CH2:21][CH:22]([C:25]2[CH:26]=[CH:27][C:28]([C:2]3[CH:3]=[CH:4][C:5]([NH:8][C:9]4[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=4)=[CH:6][N:7]=3)=[CH:29][CH:30]=2)[CH2:23][CH2:24]1
Reactant: Cn1ccc(Nc2ccc(Br)nc2)n1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccn(C)n4)cn3)cc2)CC1
Temperature: 80 °C

Procedure:
To a solution of (6-bromo-pyridin-3-yl)-(1-methyl-1H-pyrazol-3-yl)-amine (0.15 g, 0.6 mmol, 1.0 equiv) and {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.23 g, 0.7 mmol, 1.1 equiv) in 5 Ml DME was added 0.5 Ml saturated potassium carbonate solution followed by 5 mg Pd(PPh3)4 catalyst. The reaction was then heated to 80° C. for 2 h. Removal of volatiles in vacuo followed by silica gel chromatography (20% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.26 (m, 2 H) 1.54 (qd, J=12.59, 2.40 Hz, 2 H) 1.68 (br. S., 1 H) 1.87 (d, J=11.12 Hz, 5 H) 2.31 (d, J=6.57 Hz, 2 H) 3.66 (s, 3 H) 3.82 (s, 3 H) 5.86 (s, 1 H) 7.33 (d, J=8.34 Hz, 2 H) 7.59 (d, J=2.02 Hz, 1 H) 7.80 (d, J=8.84 Hz, 1 H) 7.93 (d, J=8.34 Hz, 2 H) 7.97 (dd, J=8.84, 2.78 Hz, 1H) 8.65 (d, J=2.27 Hz, 1 H) 8.83 (s, 1 H); (M+H)+ 405.2.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([O:13][C:14]([C:16]1([NH2:25])[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)=[O:15])[CH3:12].CCN(C(C)C)C(C)C.CC(O)C.C(Cl)Cl>C(Cl)Cl>[CH2:11]([O:13][C:14]([C:16]1([NH:25][C:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:10])[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)=[O:15])[CH3:12]
Reactant: O=C(O)c1ncccc1F
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)C1(NC(=O)c2ncccc2F)Cc2ccccc2C1
Reaction time: 0.03 h

Procedure:
A 40 mL reaction vial which contains a stirring bar is charged with 3-Fluoropyridine-2-carboxylic acid (997 mg, 7.07 mmol) and dry DCM (15 mL). Stirring is initiated. After 2 min, the HTBU (2.7 g, 7.07 mmol) is added. After 5 min, 2-Amino-indan-2-carboxylic acid ethyl ester (1.45 g, 7.07 mmol) is added followed by DIPEA (2.50 mL, 14.5 mmol). The reaction is allowed to stir for 18 h. Analysis by tlc of the reaction mixture (silica, 5% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (50 mL). This is washed consecutively with water (3%, 25 mL), saturated aqueous NaHCO3 (2×25 mL) and brine (25 mL), and then dried over MgSO4, filtered and evaporated in vacuo to provide 4.15 g of light orange solid. This material is dissolved in 20 mL of DCM. This material is purified utilizing an ISCO Companion with an 80 g cartridge of silica. The gradient is 5% EtOAc in heptanes for 4 column volumes followed by a linear gradient to 60% EtOAc in heptanes over 10 column volumes. 14 mL fractions of UV active elutant are collected. Fractions 6 through 14 are combined and evaporated in vacuo. This yields 2.04 g white solid (2.04 g, 88%).
Reaction SMILES: [C:1]([N:18]1[CH2:21][CH:20]([C:22](O)=[O:23])[CH2:19]1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][C:56](=[C:59]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C:60]([NH:62][NH2:63])=[O:61])[CH2:55][CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>C(Cl)Cl.O>[C:46]([O:50][C:51]([N:53]1[CH2:54][CH2:55][C:56](=[C:59]([C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:60]([NH:62][NH:63][C:22]([CH:20]2[CH2:21][N:18]([C:1]([O:3][CH2:4][CH:5]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:12]4[C:17]3=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:2])[CH2:19]2)=[O:23])=[O:61])[CH2:57][CH2:58]1)=[O:52])([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(C(=O)NN)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=C(C(=O)NNC(=O)C2CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 101.6 %

Procedure:
To a solution of Fmoc-azetidine-3-carboxylic acid (0.495 g, 1.53 mmol) in CH2Cl2 (10 mL) was added HOBt (0.290 g, 2.14 mmol) and EDCI (0.411 g, 2.14 mmol), and the mixture was allowed to stir for 10 min. To this solution was added 4-(1-phenyl-1-hydrazinocarbonyl-methylene)piperidine-1-carboxylic acid tert-butyl ester (0.507 g, 1.53 mmol), the mixture was stirred for 1 h and then it was diluted with H2O and the layers separated. The aqueous phase was extracted with CH2Cl2 (×3) and the combined organic layers were washed (H2O, brine), dried (Na2SO4) and evaporated to give the title compound (0.99 g, 100%) which was of sufficient purity to be used as such in the following step:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][N:19]([CH3:39])[C:20]([C:22]3[O:23][C:24]4[CH:38]=[CH:37][CH:36]=[CH:35][C:25]=4[C:26]=3[CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:21])[CH:14]=2)[C:9]=1[Br:40].O.Cl>CO>[Br:40][C:9]1[C:10]2[C:15](=[CH:14][C:13]([CH2:18][N:19]([CH3:39])[C:20]([C:22]3[O:23][C:24]4[CH:38]=[CH:37][CH:36]=[CH:35][C:25]=4[C:26]=3[CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:21])=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[O:7][CH2:6][C:5]([OH:41])=[O:4]
Reactant: COC(=O)COc1ccc2cc(CN(C)C(=O)c3oc4ccccc4c3CCc3ccccc3)ccc2c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(Cc1ccc2c(Br)c(OCC(=O)O)ccc2c1)C(=O)c1oc2ccccc2c1CCc1ccccc1
Yield: 96 %

Procedure:
A mixture of 1 N NaOH (4 mL, 4 mmol) and (1-bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester (1.19 g, 2.02 mmol), prepared in the previous step, in 100 mL of methanol plus 4 mL of water was stirred under nitrogen at room temperature overnight. 1 N HCl (4 mL, 4 mmol) was added and the reaction concentrated under reduced pressure to remove the methanol. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (1.11 g, 96%) as an off-white solid, mp 119-122° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[N:10]([S:13]([C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14])=[C:11]=[O:12]>C(Cl)Cl>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:1][C:11]([NH:10][S:13]([C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14])=[O:12])[CH:7]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(C)nc(N)c1
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1cc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To 1.2 g of 2-amino-4,6-dimethylpyridine in 30 ml of methylene chloride at ambient temperature was added dropwise, with stirring 2.4 g of methyl 2-isocyanatosulfonylbenzoate. After stirring for one hour at room temperature a solid precipitated from the mixture. Filtration yielded 1.8 g of a crystalline white solid which melted at 181°-182° C. and showed absorption peaks by infrared spectroscopy at 1750, 1700, 1630 and 1580 cm-1. The nuclear magnetic resonance spectrum (60 mc) showed peaks at 7-8.6 δ (multiplet) for o-substituted benzene, 4.36 δ (singlet) for OCH3 and 2.76, 2.7 δ (singlets) for the two methyl groups on the pyridine ring.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:29][C:30]4[N:35]=[CH:34][C:33]5[O:36][CH2:37][CH2:38][O:39][C:32]=5[CH:31]=4)C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)[C:6]=2[CH:40]=1.Cl.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][CH:18]([NH:21][CH2:29][C:30]4[N:35]=[CH:34][C:33]5[O:36][CH2:37][CH2:38][O:39][C:32]=5[CH:31]=4)[CH2:19][CH2:20]3)[C:6]=2[CH:40]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1n[n+]([O-])c2ccc(Cl)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Yield: 167.1 %

Procedure:
A solution of 1,1-dimethylethyl {1-[2-(6-chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]-4-piperidinyl}(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)carbamate (81 mg, 0.141 mmol) in chloroform (1 ml) and MeOH (1 ml) was added 4M HCl in 1,4-dioxane (1 ml) and the reaction was stirred at rt for 0.5 h before evaporation, treatment with sat. aq NaHCO3 (50 ml). The reaction was then extracted with 20% MeOH in DCM (3×100 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the free base of the title compound as a yellow foam (60 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[CH3:26])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]([F:27])([F:28])[CH3:26])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8]
Reactant: CC(F)(F)c1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(F)(F)c1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a solution of 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(1,1-difluoroethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (59 mg, 0.098 mmol) in DCM (6 ml) was added TFA (2.0 mL) and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was purified via reverse phase HPLC to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(1,1-difluoroethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (28 mg, 0.060 mmol, 61% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.72 (s, 1H), 7.63 (s, 1H), 7.30-7.42 (m, 3H), 7.28 (s, 1H), 4.63 (s, 2H), 1.90 (t, 3H). LC-MS (ES+) m/z 469.08, [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19]Cl)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1.C(Cl)Cl.CO.N>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: ClCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Agent: N
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Brc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1

Procedure:
A solution of 6-bromo-2-[4-(2-chloroethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (50 mg, 0.14 mmol), morpholine (0.037 ml, 0.42 mmol) in NMP (5 ml) and N-ethyldiisopropylamine (0.24 ml, 1.4 mmol) was heated at 120° C. for 6 h. Column chromatography on silica using methylene chloride/methanol/ammonia as eluent afforded the title compound.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[NH:23][C:24]([CH3:26])=[N:25][C:15]=3[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:29]I.O>CN(C)C=O.C(Cl)(Cl)Cl>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[N:23]=[C:24]([CH3:26])[N:25]([CH3:29])[C:15]=3[CH2:14][CH2:13]2)=[O:11])=[CH:27][CH:28]=1)([O-:5])=[O:4]
Reactant: CI
Reactant: Cc1nc2c([nH]1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc2c(n1C)CCN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a stream of argon, 144 mg of 60% sodium hydride was suspended in a small volume of N,N-dimethylformamide to which, with cooling on an ice bath, was then added dropwise a solution prepared by dissolving 500 mg of 6-(4-nitrobenzoyl)-2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine in 20 ml of N,N-dimethylformamide. After 1 hour of stirring at room temperature, the reaction solution was mixed with 0.11 ml of methyl iodide and stirred for 24 hours at room temperature. The reaction solution was mixed with water and chloroform, and the resulting organic layer was separated, washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After removing the solvent by distillation under a reduced pressure, the thus obtained residue was subjected to silica gel column chromatography to obtain 351 mg of 6-(4-nitrobenzoyl)-2,3-dimethyl-3,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine from the chloroform-methyl alcohol (30:1) eluate.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:27])=[C:11]([CH:24]=[CH:25][CH:26]=1)[C:12]([NH:14][CH2:15][C@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)O)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Si:1]([O:8][C:9]1[C:10]([F:27])=[C:11]([C:12]2[O:13][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][N:14]=2)[CH:24]=[CH:25][CH:26]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)NC[C@@H](O)c2ccccc2)c1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C2=NC[C@@H](c3ccccc3)O2)c1F
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a solution of 2-(3-tert-butyldimethylsilyloxy-2-fluorobenzamido)-1(S)-phenylethanol (4.6 g, 12 mmol) and triphenylphosphine (3.7 g, 14 mmol) in THF (50 ml) was added dropwise a solution of diethyl azodicarboxylate (2.2 ml, 42 mmol) in THF (20 ml). After stirring for 1 h, volatiles were removed by evaporation. The residue was purified by column chromatography on silica gel eluting with hexane-ethyl acetate (13:1 to 9:1) to afford the title compound (2.2 g, 50%) as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:34]([CH2:38][CH2:39][CH3:40])[CH2:35][CH2:36][CH3:37])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:33])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[C:25]([Cl:32])[CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10](O)=[O:11])[C:6]=1[CH3:7].[N:41]([CH2:44][C@@H:45]1[CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:47][NH:46]1)=[N+:42]=[N-:43]>>[N:41]([CH2:44][C@@H:45]1[CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:47][N:46]1[C:10]([C:9]1[CH:13]=[C:14]([CH:15]=[CH:16][C:8]=1[N:5]1[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([N:34]([CH2:38][CH2:39][CH3:40])[CH2:35][CH2:36][CH3:37])=[N:4]1)[C:17]([NH:18][S:19]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[C:25]([Cl:32])[CH:26]=[CH:27][CH:28]=2)[CH:23]=1)(=[O:21])=[O:20])=[O:33])=[O:11])=[N+:42]=[N-:43]
Reactant: [N-]=[N+]=NC[C@@H]1Cc2ccccc2CN1
Reactant: CCCN(CCC)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(Cl)c4c3)cc2C(=O)O)c(C)c1Cl
Product: CCCN(CCC)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(Cl)c4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])c(C)c1Cl

Procedure:
Following a procedure analogous to that for the synthesis of Example 91, 2-(4-chloro-3-(dipropylamino)-5-methyl-1H-pyrazol-1-yl)-5-(8-chloronaphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 193B, 50 mg, 0.083 mmol) and (S)-3-(azidomethyl)-1,2,3,4-tetrahydroisoquinoline (Intermediate 92A, 17 mg, 0.091 mmol) were converted to the title compound. 1H NMR (CDCl3, 2:1 mixture of amide rotamers) δ 9.15 (s, 1H), 8.27-8.13 (m, 1.5H), 8.07-7.80 (m, 2H), 7.72 (d, J=7.5 Hz, 1.5H), 7.61-7.51 (m, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.28-7.11 (m, 3.5H), 7.08-6.98 (m, 1H), 6.94-6.82 (m, 0.5H), 5.34 (d, J=18.5 Hz, 1H), 4.38-3.93 (m, 3H), 3.48-3.36 (m, 2H), 3.32-2.72 (m, 5H), 2.24 (s, 1H), 2.16 (s, 2H), 1.60-1.12 (m, 4H), 0.94-0.62 (m, 6H); MS(ESI+) m/z 773.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]4)[N:2]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C[Si](C([Si](C)(C)C)(C(F)(F)F)C(N)=O)(C)C>O1CCOCC1.C(OCC)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]4)[N:2]=1
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cc4ccccc4cn3)ccc12
Agent: C[Si](C)(C)C(C(N)=O)(C(F)(F)F)[Si](C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cc4ccccc4cn3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a suspension of (+)-(4aR)-(10bR)-8-(3-isoquinolinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (80 mg, 0.230 mmol), in 1.0 mL of 1,4-dioxane was added DDQ (58 mg, 1.1 equiv.) followed by bistrimethylsilyltrifluoromethyl acetamide (270 mg, 4.5 equiv.), and the solution was stirred at room temperature for 2 h, then heated at 100° for 20 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 2M sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel (ethyl acetate eluent) to give, after trituration from ether/hexanes, 18mg (24%) of the title compound as a white solid. mp 248° (decomp.) FDMS m/e=340.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[O:16]=[C:15]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][CH2:13][NH:14]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccncc1
Product: N#Cc1cc(-c2ccncc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (64 mg, 85%), MS (ISP) m/z=303.5 [(M+H)+], mp 278.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available pyridin-4-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([C:3]([C:7]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:8]=1[C:9]([NH:11][C:12]1([C:21]([OH:23])=[O:22])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:10])=[CH:4][CH2:5][CH3:6])[CH3:2]>CCO.[Pd]>[CH2:1]([CH:3]([C:7]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:8]=1[C:9]([NH:11][C:12]1([C:21]([OH:23])=[O:22])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:10])[CH2:4][CH2:5][CH3:6])[CH3:2]
Reactant: CCC=C(CC)c1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Agent: [Pd]
Solvent: CCO
Product: CCCC(CC)c1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Yield: 27.4 %

Procedure:
To a solution of 2-[2-(-1-ethyl-but-1-enyl)-3-methyl-benzoylamino]-indan-2-carboxylic acid ethyl ester (129) (270 mg, 0.72 mmol) in absolute EtOH (15 mL) is added the catalyst, Pd—C (50% wetted powder, 10% Pd, 46 mg, 2.2% mmol) under argon. The resulting reaction mixture is moved to the Paar apparatus to run hydrogenation: 50 psi, 70° C., overnight. The catalyst is removed by the filtration through a pre-column (10 g silica gel) and washed by EtOH. The combined EtOH solution is concentrated in vacuo. The residue is purified by HPLC to give a pure product (130) as white solid (75 mg, 28%).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[CH3:14][O:15][C:16]1[C:17]([CH3:25])=[N+:18]([O-])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>ClCCl>[OH:4][CH2:25][C:17]1[C:16]([O:15][CH3:14])=[C:21]([O:22][CH3:23])[CH:20]=[CH:19][N:18]=1
Reactant: COc1cc[n+]([O-])c(C)c1OC
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1ccnc(CO)c1OC

Procedure:
Trifluoroacetic anhydride (4.0 ml) was added dropwise to a stirred solution of 3,4-dimethoxy-2-methylpyridine N-oxide (1.91 g) in dichloromethane (25 ml) and the mixture was left to stand at room temperature for 8 days during which time trifluoroacetic anhydride (4.77 ml) was added in two portions. The mixture was evaporated to dryness and the residue was purified by extracting a chloroform solution with aqueous sodium bicarbonate and elution from silica gel with methanol-chloroform (1:9) to give 2-hydroxymethyl-3,4-dimethoxypyridine (1.6 g).