Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH2:13][C@@H:14]([O:17]C(=O)C)[CH2:15][CH3:16])[N:11]=[C:10]([NH:21][C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([O:32][CH3:33])[CH:23]=3)[N:9]=2)[CH:5]=[C:4]([CH3:34])[N:3]=1.[CH3:35][Mg]Br.[OH-].[Na+].[NH4+].[Cl-]>C1COCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3].CN1C(=O)CCC1>[CH3:34][C:4]1[CH:5]=[C:6]([C:8]2[N:12]([CH2:13][C@@H:14]([OH:17])[CH2:15][CH3:16])[N:11]=[C:10]([NH:21][C:22]3[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[C:24]([O:32][CH3:33])[CH:23]=3)[N:9]=2)[CH:7]=[C:2]([CH3:35])[N:3]=1
Reactant: C[Mg]Br
Reactant: CC[C@@H](Cn1nc(Nc2cc(OC)cc(C(F)(F)F)c2)nc1-c1cc(C)nc(Cl)c1)OC(C)=O
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC[C@H](O)Cn1nc(Nc2cc(OC)cc(C(F)(F)F)c2)nc1-c1cc(C)nc(C)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
NMP (1 ml; extra dry) and iron(III) acetylacetonate (35.33 g, 0.0001 mol) were added to a solution of intermediate D8 (498.08 g, 0.001 mol) in THF (10 ml; extra dry) and the mixture was cooled to 0° C. Methylmagnesium bromide (1.67 ml, 0.005 mol) was added slowly and the reaction mixture was stirred for 5 minutes at 0° C. Subsequently, the mixture was quenched with a saturated NH4Cl solution and extracted with CH2Cl2 (3×50 ml). The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvent was evaporated. The residue was redissolved in methanol and NaOH (800 mg, 0.020 mol) was added. The resulting mixture was stirred for 1 hour at room temperature. A saturated NH4Cl solution was added and the mixture was extracted with CH2Cl2 (3×50 ml). The combined organic layers were washed (brine), dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: (7 N NH3/MeOH)/CH2Cl2 gradiënt from 0/100 to 10/90. The product fractions were collected and the solvent was evaporated in vacuo. The residue was treated with heptane, yielding white crystals. These white crystals were filtered off and dried in vacuo. Yield: 0.632 g of compound E30 (83%; S-enantiomer).
Reaction SMILES: O[CH2:2][C:3]1([C:6]2[C:11]([O:12][CH2:13][O:14][CH3:15])=[CH:10][CH:9]=[C:8]([CH3:16])[C:7]=2[OH:17])[CH2:5][CH2:4]1.O1CCCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH3:15][O:14][CH2:13][O:12][C:11]1[C:6]2[C:3]3([CH2:2][O:17][C:7]=2[C:8]([CH3:16])=[CH:9][CH:10]=1)[CH2:4][CH2:5]3
Reactant: COCOc1ccc(C)c(O)c1C1(CO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: COCOc1ccc(C)c2c1C1(CC1)CO2
Yield: 67.3 %

Procedure:
To a solution of 2-[1-(hydroxymethyl)cyclopropyl]-3-(methoxymethoxy)-6-methyl-phenol (Intermediate 11, 65 mg, 0.27 mmol) in dry tetrahydrofuran (5 ml) triphenylphosphine (84 mg, 0.32 mmol) was added and the reaction mixture was stirred until complete dissolution of it. DIAD (0.056 ml, 0.285 mmol) was then added dropwise and the reaction mixture was stirred for 30 minutes at room temperature. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affording the title compound (40 mg) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:9][C:8](=[O:17])[N:7]=[C:6]1[S:18]C.[NH4+]=S.N1C=CC=CC=1.[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:9][C:8](=[O:17])[NH:7][C:6]1=[S:18]
Reactant: COCCn1c(-c2ccccn2)cc(=O)nc1SC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: c1ccncc1
Product: COCCn1c(-c2ccccn2)cc(=O)[nH]c1=S
Yield: 3.2 %

Procedure:
A mixture of crude 1-(2-methoxyethyl)-2-(methylthio)-6-(pyridin-2-yl)pyrimidin-4(1H)-one (100 mg, 0.36 mmol), ammonium sulfide solution (0.2 mL, 0.64 mmol) and pyridine (0.2 mL) was stirred in dioxane (2 mL) at 70° C. for 4 hours. The reaction mixture was diluted with water (10 mL), basified with 2M NaOH and washed with dichloromethane (3×10 mL). The aqueous layer was acidified to pH 6 with 2M HCl and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (3×10 mL), brine (3×10 mL), dried over MgSO4 and concentrated in vacuo. The crude material was purified by mass directed automatic purification using an acidic method to give the product as a brown solid (3 mg, 3%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1B(O)O>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:31]2[CH:30]=[CH:29][C:28]([F:27])=[CH:33][C:32]=2[F:34])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(F)cc2F)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 2,4-difluorophenyl-boronic acid, 5-(2,4-difluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of an off-white foam (yield=87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:31][N:32]1[CH2:36][CH2:35][CH2:34][C:33]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:10]4[CH2:11][CH2:12][CH:31]([N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[CH2:14][CH2:9]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COc1cc2c(Nc3ccc(Sc4ccccn4)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4ccccn4)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.34 mmol) of 4-[3-Chloro-4-(pyridin-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile and 264 mg (1.71 mmol) of 4-(1-pyrrolidinylpiperidine) are refluxed in 1-methyl 2-pyrrolidinone (1 mL) at 105° C. for 12 hours to yield the crude product. Purification by silica gel chromatography (95:5 methylene chloride/methanol) gives 126 mg of 4-[3-chloro-4-(pyridin-2-ylsulfanyl)-phenylamino]-6-methoxy-7-(4-pyrrolidin-1-yl-piperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 203-205° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:9][C:10]1[C:15]([C:16]([C:18]2[CH2:22][CH2:21][CH2:20][C:19]=2N2CCCC2)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1.C(O)(C)(C)C>C(N(CC)CC)C>[Cl:9][C:10]1[C:15]([C:16]([C:18]2[CH2:22][CH2:21][CH2:20][C:19]=2[NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C(C1=C(N2CCCC2)CCC1)c1cccnc1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC1=C(C(=O)c2cccnc2Cl)CCC1

Procedure:
Add equimolar amounts of ethyl glycinate hydrochloride, triethylamine, and (2-chloro-3-pyridinyl)-[2-(1-pyrrolidinyl)-1-cyclopenten-1-yl]methanone to t-butyl alcohol (170 ml per 0.020 mole of amine). Reflux the resulting mixture for 34 hrs, monitoring the reaction by thin-layer chromatography as needed. Cool the reaction mixture, and evaporate solvent. Wash a CHCl3 solution of the residue with water and with saturated aqueous NaCl solution. After drying the organic solution, evaporate the solvent to obtain the resulting enaminoketone, (2-chloro-3-pyridinyl)[2-(1-ethoxycarbonylmethanaminyl)-1-cyclopenten-1-yl]methanone, from isopropanol.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[C:28]2[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[N:32][CH:33]=2)[CH:12]=[CH:11][C:10]=1[C:44]1[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=1.Cl>CO>[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:26])([F:27])[F:25])=[CH:19][C:18]=2[C:28]2[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[N:32][CH:33]=2)[CH:12]=[CH:11][C:10]=1[C:44]1[CH:45]=[CH:46][C:47]([C:50]([F:53])([F:51])[F:52])=[CH:48][CH:49]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C)c2CNc2ccc(-c3ccc(C(F)(F)F)cc3)c(Cl)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(F)(F)F)cc(-c2ccc(C(=O)NCCC(=O)O)nc2)c1CNc1ccc(-c2ccc(C(F)(F)F)cc2)c(Cl)c1
Temperature: 25 °C

Procedure:
A 3M aqueous NaOH solution (0.13 mL, 0.39 mmol) was added to a THF (2.0 mL) and MeOH (1.0 mL) solution of ethyl 3-(5-(2-(((2-chloro-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)amino)methyl)-3-methyl-5-(trifluoromethyl)phenyl)picolinamido)propanoate (44 mg, 0.07 mmol) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture was acidified with 1N aqueous HCl and extracted with EtOAc. The combined organics were dried (Na2SO4), concentrated and purified via column chromatography to give the title compound.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.I[CH:31]([CH3:33])[CH3:32]>>[CH:31]([N:18]1[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[C:9]=2[CH3:28])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19]1(=[O:26])=[O:27])([CH3:33])[CH3:32]
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: CC(C)I
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2C(C)C)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and 2-iodo propane. 1H NMR (DMSO-d6) δ 7.91-7.88 (m, 1H), 7.63-7.53 (m, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.17-6.78 (m, 4H), 6.14 (s, 1H), 4.98 (s, 2H), 3.68 (sept., J=6.8 Hz, 1H), 2.43 (s, 3H), 1.34 (d, J=6.9 Hz, 3H), 1.02 (d, J=6.9 Hz, 3H); MS: ESI (negative): 397 (M−H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([CH:21]=[O:22])=[CH:19][C:18](=[O:23])[C:13]([C:14]([O:16]C)=[O:15])=[CH:12]2)=[C:7]([CH3:24])[CH:6]=1)(=O)C.Cl.C(=O)([O-])O.[Na+].[Cl-].[Na+]>C(#N)C>[CH:21]([C:20]1[N:11]([C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][C:7]=2[CH3:24])[CH:12]=[C:13]([C:18](=[O:23])[CH:19]=1)[C:14]([OH:16])=[O:15])=[O:22]
Reactant: COC(=O)c1cn(-c2ccc(OC(C)=O)cc2C)c(C=O)cc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CC#N
Product: Cc1cc(O)ccc1-n1cc(C(=O)O)c(=O)cc1C=O
Temperature: 25 °C
Yield: 76.1 %

Procedure:
To 0.95 g of methyl 1-(4-acetoxy-2-methylphenyl)-6-formyl-4-oxo-1,4-dihydronicotinate was added 5 ml of 6N hydrochloric acid, and they were reacted at 100° C. for one hour. The reaction mixture was cooled to room temperature, and adjusted to a pH of 7.5 with a saturated aqueous sodium hydrogencarbonate solution. Then, 100 ml of acetonitrile was added, and the aqueous layer was saturated with sodium chloride. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride and then dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 0.6 g of 6-formyl-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 230°-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=1.[I:28]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(Cl)Cl>CC#N.[Cl-].[Na+].O.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:14])[CH3:15])[N:5]2[N:25]=[CH:26][C:27]([I:28])=[C:4]2[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(I)cnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
To crude 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (7.9 g) in CH3CN (100 mL) was added N-iodosuccinimide (4.3 g, 19.2 mmol) and the resulting mixture was stirred at room temperature for 30 mins, at which time LC/MS confirmed full conversion of starting material to product. Saturated sodium thiosulfate solution (˜20 mL) was added and stirring continued for 5 minutes before the mixture was transferred to a separatory funnel using CH2Cl2 (30 mL) and H2O (30 mL). Brine (50 mL) was added and organics were extracted with CH2Cl2 (4×40 mL), dried (Na2SO4) and concentrated in vacuo to give crude 5-chloro-3-iodo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine as a light brown liquid (10.4 g). LCMS: 2.95 mins, m/z=555.1 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[O:7][CH2:8][CH2:9][N:10]1[CH2:28][CH2:27][C:13]2([O:18][CH2:17][CH2:16][N:15]([C:19]([C:21]3[N:22]=[C:23]([CH3:26])[S:24][CH:25]=3)=[O:20])[CH2:14]2)[CH2:12][CH2:11]1.FC(F)(F)C(O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:26][C:23]1[S:24][CH:25]=[C:21]([C:19]([N:15]2[CH2:14][C:13]3([CH2:27][CH2:28][N:10]([CH2:9][CH2:8][O:7][C:6]4[CH:5]=[C:4]([CH2:3][CH:2]=[O:1])[CH:31]=[CH:30][CH:29]=4)[CH2:11][CH2:12]3)[O:18][CH2:17][CH2:16]2)=[O:20])[N:22]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4cccc(CCO)c4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4cccc(CC=O)c4)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (9-(2-(3-(2-hydroxyethyl)phenoxy)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4-yl)methanone (example 24, step c) (0.152 g) in DCM (5 mL) was cooled in ice-water and treated with trifluoroacetic acid (0.039 mL) and stirred for 5 minutes. Dess-Martin periodinane (0.221 g) was added and the mixture was removed from the cooling bath and stirred at room temperature for 25 minutes. The reaction was quenched by the addition of saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (5 mL), and the resulting two-phase mixture was stirred for 10 minutes. The mixture was then extracted twice with ethyl acetate, and the combined organic extracts washed with brine. Acetic acid (0.1 mL) was added, and then the acidified extracts were dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the subtitled compound as a brown gum. Yield 0.118 g.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC>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.O1CCOCC1>[N:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:2]1[C:10]2[NH:9][C:8]([N:11]3[CH2:12][CH2:13][N:14]([C:17]4[C:22]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:15][CH2:16]3)=[N:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:28])[F:29])[CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(-c2ccccn2)c2[nH]c(N3CCN(c4ncccc4C(F)(F)F)CC3)nc2c1
Reaction time: 1 h

Procedure:
A mixture of 4-bromo-6-trifluoromethyl-2-[4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1H-benzoimidazole (148 mg, 0.3 mmol, Example 7), 2-tributylstannylpyridine (148 mg, 0.5 mmol, Frontier), Pd(PPh3)4 (46 mg, 0.04 mmol, Aldrich) and 1,4-dioxane (1 mL) was subjected to microwave irradiation at 140° C. with stirring for 60 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 60% EtOAc/hexane, to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 493 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[NH:13][CH:14]=[CH:15][C:3]=12.[H-].[Na+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH:14]=[CH:15][C:3]=12
Reactant: CCOC(=O)c1cnc2[nH]ccc2c1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.4 %

Procedure:
To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.32 g, 5.88 mmol) in DMF (39 mL) at about 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.400 g, 10.00 mmol) and the reaction mixture was stirred at this temperature for about 15 min. A solution of 4-methylbenzene-1-sulfonyl chloride (2.24 g, 11.8 mmol) in DMF (17 mL) was added dropwise and the reaction mixture was allowed to warm to ambient temperature for about 2 h. The reaction mixture was concd under reduced pressure and the residue was partitioned between EtOAc and water (25 mL each). The aqueous layer was extracted with EtOAc (2×25 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The solid was triturated with heptane, and the precipitates were filtered to give ethyl 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.28 g, 102%, 90% purity) as a white solid: LCMS (Table 1, Method c) Rt=1.64 min; MS m/z: 379 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([OH:15])=O)=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([C:13]([Cl:18])=[O:15])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=S(Cl)Cl
Reactant: COc1cc2ccccc2cc1C(=O)O
Solvent: c1ccccc1
Product: COc1cc2ccccc2cc1C(=O)Cl

Procedure:
To 4.55 grams of (VII) slurried in 25 milliliters of benzene, 3.57 grams of thionyl chloride was added. The mixture was refluxed for several hours and the solvent was removed to yield a thick yellow resinous product, 3-methoxy-2-naphthoyl chloride (VIII).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].N1C=CC=CC=1.[NH2:16][C:17]1[C:31]([O:32][CH3:33])=[C:30]([CH3:34])[C:29]([O:35][CH3:36])=[CH:28][C:18]=1[C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][OH:27])=[O:20]>C(Cl)Cl>[CH3:34][C:30]1[C:29]([O:35][CH3:36])=[CH:28][C:18]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[CH2:26][OH:27])=[O:20])=[C:17]([NH:16][C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[C:31]=1[O:32][CH3:33]
Reactant: COc1cc(C(=O)N2CCCC2CO)c(N)c(OC)c1C
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C(=O)N2CCCC2CO)c(NC(=O)OCC(Cl)(Cl)Cl)c(OC)c1C
Reaction time: 6 h
Yield: 69.7 %

Procedure:
A solution of 2,2,2-trichloroethyl chloroformate (1.38 g, 6.5 mmol) in distilled DCM (25 mL) was added dropwise over 0.5 hours to a solution of anhydrous pyridine (1.03 g, 13 mmol) and 191 (1.91 g, 6.5 mmol) in distilled DCM (25 mL) at 0° C. After 6 hours at room temperature, the reaction mixture was diluted with anhydrous DCM (100 mL) and washed with 1 N HCl (2×100 mL), H2O (100 mL), brine (100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent yielded a brown oil which was purified by flash column chromatography (silica gel, EtOAc) to afford the product (192) as a yellow glass (2.13 g, 4.53 mmol, 70%); 1H NMR (270 MHz, CDCl3) δ7.59 (br s, 1H), 6.56 (s, 1H), 4.78 (br s, 2H), 4.25-4.23 (m, 1H), 3.82-3.79 (m, 3H+1H), 3.69-3.63 (m, 3H+1H), 3.52 (m, 1H), 3.42-3.33 (m, 1H), 2.13-2.06 (m, 3H+1H), 1.88-1.64 (m, 3H); 13C NMR (67.8 MHZ, CDCl3) δ169.95, 156.82, 156.67, 154.02, 153.34, 131.92, 121.74, 119.33, 103.94, 95.43, 74.42, 66.04, 61.01, 60.60, 60.27, 55.73, 50.46, 28.53, 24.47, 9.13.
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[C:16]([Cl:20])=[CH:17][C:18](Cl)=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[Cl:21])[C:6]1=[O:22])[CH:2]=[CH2:3].[C:23]([O:27][C:28](=[O:35])[NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C(#N)C>[C:23]([O:27][C:28](=[O:35])[NH:29][C@H:30]1[CH2:34][CH2:33][N:32]([C:18]2[CH:17]=[C:16]([Cl:20])[C:13]3[C:14](=[O:15])[N:5]([O:4][CH2:1][CH:2]=[CH2:3])[C:6](=[O:22])[C:7]4[C:12]=3[C:11]=2[C:10]([Cl:21])=[CH:9][CH:8]=4)[CH2:31]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: C=CCON1C(=O)c2ccc(Cl)c3c(Cl)cc(Cl)c(c23)C1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCON1C(=O)c2ccc(Cl)c3c(N4CC[C@H](NC(=O)OC(C)(C)C)C4)cc(Cl)c(c23)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.6 %

Procedure:
A suspension of 2-allyloxy-4,6,7-trichlorobenzo[de]isoquinoline-1,3-dione (0.44 g, 1.2 mmol, from Example I4), (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (0.3 g, 1.5 mmol), triethylamine (0.2 g, 2.0 mmol), and 20 mL of acetonitrile was stirred at room temperature for 6 hours. The solvent was removed in vacuo and the residue partitioned between water and dichloromethane. The organic layer was dried and evaporated in vacuo. The residue was chromatographed on silica gel (ICN 230-400 mesh) eluting with dichloromethane/ethyl acetate (80:20) to give 0.35 g of the title compound, mp 123-125° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=3[N:7]([CH2:11][CH3:12])[CH:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:41]=[N+:42]=[N-:43])(=O)=O)(C)C.C(O)(=O)C>C1COCC1>[N:41]([C:9]1[N:10]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]2[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=2[N:7]([CH2:11][CH3:12])[CH:8]=1)=[N+:42]=[N-:43]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: CCN1C=CN=C(C2CC2)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN1C=C(N=[N+]=[N-])N=C(C2CC2)c2ccccc21
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
To a stirring solution of 5-cyclopropyl-1-ethyl-1H-benzo[e][1,4]diazepine (6.4 g, 0.028 mol) in THF (125 ml) cooled to −78° C. was added potassium tert-butoxide (2.05 eq, 0.057 mol, 57.2 ml of a 1 M solution in THF) dropwise over 15 min. A solution of 2,4,6-triisopropylphenyl-sulfonylazide (9.5 g, 0.031 mol) in THF (100 ml) was added over 5 min. The solution was stirred for 10 min, acetic acid (7.7 ml,0.123 mol) was added and the reaction warmed to 30° C. for 2 hour. The reaction was concentrated the residue dissolved in dichloromethane (200 mL) and washed with satd. NaHCO3 (200 ml). The aqueous layer was back extracted with dichloromethane (100 ml). The organic layers were combined, dried with Na2SO4 and evaporated to a foam. The foam was chromatographed over silica eluting with 30% ethyl acetate:hexane. The appropriate fractions were collected and evaporated under reduced pressure to give 5.83 g of a powder. MP=158-160° C.