Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][CH2:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.CCOC(C)=O.[Fe]>[NH2:1][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][CH2:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCC3)C1
Temperature: 80 °C
Yield: 127.8 %

Procedure:
A mixture of tert-butyl [(3S)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (43 mg, 0.12 mmol), iron powder (106 mg, 1.90 mmol) and NH4Cl (127 mg, 2.37 mmol) in EtOH (0.69 mL) and water (0.11 mL) was heated in a sealed tube at 80° C. for 1 h. The mixture was diluted with EtOAc and the resulting solution was washed with saturated aq. Na2CO3, dried over Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound as a brown-orange powder (51 mg, 100%). LCMS calc. for C18H29N4O2 (M+H)+: m/z=333.2. Found: 333.1.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:16]([O:18][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH3:17]>CN(C=O)C.[I-].[K+]>[CH2:16]([O:18][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:17]
Reactant: CCOC(=O)CCCCCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCn1c2ccccc2c2ccccc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
Carbazole (2.0 g, 12.0 mmol) and sodium hydride (60 wt. % in mineral oil, 0.29 g, 12.0 mmol) were placed under argon and dissolved in DMF (5 mL). After stirring for 30 minutes, 6-bromo-hexanoic acid ethyl ester (2.0 mL, 12.0 mmol) and potassium iodide (10 mg) were added to the reaction. The reaction was heated to 80° C. for 2 h. The reaction was then quenched with water (30 mL) followed by addition of ethyl acetate (30 mL). The organic layer was isolated and the aqueous layer extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (2×20 mL), brine (15 mL), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (0-80% gradient of ethyl acetate in hexane) afforded the title compound (2.7 g, 73%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.13 (d, 2H, J=7.7 Hz), 7.56 (d, 2H, J=8.2 Hz), 7.42 (m, 2H), 7.26 (m, 2H), 4.34 (t, 2H, J=7.0 Hz), 4.13 (q, 2H, J=7.1 H), 2.29 (t, 2H, J=7.3 Hz), 1.93 (m, 2H), 1.70 (m, 2H), 1.45 (m, 2H), 1.25 (t, 3H, J=7.1 Hz). 13C NMR (100 MHz, DMSO): δ 173.1, 140.4, 126.1, 122.5, 120.7, 119.0, 109.6, 60.0, 42.5, 33.8, 28.7, 26.4, 24.7, 14.5. ESI-HRMS (m/z): [M+H]+ calcd. for C20H23NO2, 310.1802. found, 310.1792.
Reaction SMILES: C[CH:2]1[N:11]2[C:6]3[C:7](=[CH:16][CH:17]=[C:18](C4NN=NN=4)[C:5]=3[CH2:4][CH2:3]1)[C:8](=[O:15])[C:9]([C:12]([OH:14])=[O:13])=[CH:10]2.C1(N=C=O)C=CC=CC=1>O>[O:15]=[C:8]1[C:7]2=[CH:16][CH:17]=[CH:18][C:5]3=[C:6]2[N:11]([CH2:2][CH:3]=[CH:4]3)[CH:10]=[C:9]1[C:12]([OH:14])=[O:13]
Reactant: CC1CCc2c(-c3nnn[nH]3)ccc3c(=O)c(C(=O)O)cn1c23
Solvent: O=C=Nc1ccccc1
Solvent: O
Product: O=C(O)c1cn2c3c(cccc3c1=O)C=CC2
Temperature: 150 °C

Procedure:
A mixture of 1.0 g of 6,7-dihydro-5-methyl-1-oxo-8-(5-tetrazolyl)-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 5 ml (46 mmole) of phenyl isocyanate was heated at 150° C. for one hour. The mixture was then cooled and water was added. The solid was separated by filtration and recrystallized twice from aqueous N,N-dimethylformamide to provide 6,7-dihydro-5-methyl-8-[2-(5-N-anilino)-1,3,4-oxadiazolyl)]-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid solvated with N,N-dimethylformamide m.p. >300° C. Analysis: Calculated for C22H18N4O4.C3H7NO: %C, 63.1; %H, 5.3; %N, 14.7; Found: %C, 63.1; %H, 5.3; %N, 15.1.
Reaction SMILES: C([C:3]([C:10](OCC)=O)=[CH:4][C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)#N.C(O[CH2:19][C:20]1[NH:21]C(C(OCC2C=CC=CC=2)=O)=CC=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:8]1[CH:9]=[C:5]([CH2:4][C:3]2[NH:21][CH:20]=[CH:19][CH:10]=2)[NH:6][CH:7]=1
Reactant: CCOC(=O)C(C#N)=Cc1ccc[nH]1
Reactant: CC(=O)OCc1ccc(C(=O)OCc2ccccc2)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1c[nH]c(Cc2ccc[nH]2)c1

Procedure:
As illustrated in Reaction Scheme 2, Step 1, an equimolar amount or a slight excess of a 2-(2-cyano 2-ethoxycarbonyl-ethen-1-yl)pyrrole derivative, shown as a compound of formula 201, is reacted with a 2-acetoxymethyl-5-benzyloxycarbonylpyrrole derivative of formula 202 in an organic solvent, preferably toluene, in the presence of a catalytic amount of p-toluenesulfonic acid to give the dipyrromethane of formula 203. The benzyl protecting group of the dipyrromethane 203 is then removed by palladium-catalyzed hydrogenation, as shown in Step 2, to give the corresponding dipyrromethane-2-carboxylate derivative of formula 204. As shown in Step 3, compound 204 is then decarboxylated in the presence of trifluoroacetic acid (“TFA”) to form the unstable dipyrromethane of formula 205. This compound is then reacted in situ (Step 4) with ah excess amount of a 2-chloromethyl-5-(2-cyano 2-ethoxycarbonyl-ethen-1-yl)pyrrole of formula 206, in an organic solvent in the presence of a catalytic amount of tin(IV) chloride, to form the non-symmetric tripyrrane of formula 207. The ethylcyanoacrylate groups are then cleaved with alkali to give the non-symmetric tripyrrane α,α′-dialdehyde of Formula I.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C:5](=[O:21])[CH2:4][O:3]1.[ClH:22]>O1CCOCC1.C(O)(C)C>[ClH:22].[NH:11]1[CH2:12][CH2:13][CH:8]([CH2:7][N:6]2[C:5](=[O:21])[CH2:4][O:3][C:2]2=[O:1])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2C(=O)COC2=O)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: O=C1COC(=O)N1CC1CCNCC1
Reaction time: 17 h

Procedure:
A suspension of 12.51 g (41.95 mmol) of 1,1-dimethylethyl 4-[(2,4-dioxo-1,3-oxazolidin-3-yl)methyl]piperidine-1-carboxylate, obtained in step 2.2., in 65 ml of dioxane is admixed with 38.10 ml (209.75 mmol) of a solution of hydrochloric acid (5N) in isopropanol. Stirring is continued at approximately 60° C. for 17 hours. The suspension is allowed to return to ambient temperature. The solid formed is collected by filtration and then washed repeatedly with ether and dried under vacuum at approximately 70° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10]C(=O)C(F)(F)F)=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: O=C(NCCc1ccc(Br)cc1[N+](=O)[O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NCCc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of 4.856 g of N-[2-(4-bromo-2-nitrophenyl)ethyl]-2,2,2-trifluoroacetamide in 56 mL of methanol was added 3.417 mL of 5 mol/L sodium hydroxide solution. After being stirred at room temperature overnight, and at 50° C. overnight, the reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and water, and the mixture was separated. After the aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed with brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give 3.44 g of 2-(4-bromo-2-nitrophenyl)ethylamine.
Reaction SMILES: Cl[CH:2]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C=O>[CH:15]1([CH:2]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[C:3]2[O:4][C:5]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COc1ccc2oc(C(Cl)C3CCCCC3)c(C)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2oc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(C)c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a mixture of 2-[chloro(cyclohexyl)methyl]-5-methoxy-3-methyl-1-benzofuran (748 mg) synthesized in Example A27(4), methyl 4-aminobenzoate (385 mg), sodium iodide (764 mg) and N,N-dimethylformamide (15 mL) was added sodium carbonate (541 mg), and the mixture was stirred at 80° C. overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate/hexane) to give a yellow oil. To a mixture of the obtained oil, tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred with heating under reflux for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (40 mL), and 1N hydrochloric acid (20 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (745 mg, 74%) as a pale-brown solid.
Reaction SMILES: C([NH:9][C@@H:10]1[C:16](=[O:17])[N:15]2[C@H:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:29])[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.[CH:30]1[C:42]2[CH:41]([CH2:43][O:44][C:45](Cl)=[O:46])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1>>[O:29]=[C:13]1[CH2:12][CH2:11][C@H:10]([NH:9][C:45]([O:44][CH2:43][CH:41]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:34]3[C:42]2=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:46])[C:16](=[O:17])[N:15]2[C@H:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)c3ccccc3)C(=O)N12
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(=O)N12
Yield: 89 %

Procedure:
was prepared in a similar manner to 211e, except 9-fluorenylmethylchloroformate was used instead of benzoylchloride to give a white glassy solid 211f (2.14 g, 89%): mp 190-192° C.; [α]D25 −81.5° (c 0.1, CH2Cl2). IR (KBr) 3335, 2977, 1731, 1678, 1450, 1421, 1246, 1156, 742; 1H NMR (CDCl3) δ7.60 (2H, m), 7.57 (2H, m), 7.50-7.26 (4H, m), 5.60 (1H, d, J=7.8), 5.28 (1H, m), 4.67 (2H, m), 4.38 (2H, m), 4.23 (1H, m), 3.59-3.41 (1H, m), 2.92-2.65 (2H, m), 2.41-2.21 (2H, m), 1.95-1.58 (4H, m), 1.47 (9H, s). MS(ES−, m/z) 520 (M++1, 97%), 179 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([NH:22][CH2:23][C:24]([OH:26])=O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH:29]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:34][CH:31]1[CH2:32][CH2:33][N:29]([C:24](=[O:26])[CH2:23][NH:22][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:28]=[CH:27][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:30]1
Reactant: OC1CCNC1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)N3CCC(O)C3)ccc21
Yield: 87.5 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]amide (102 mg) was prepared by following General Procedure F starting from {[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (100 mg), 3-pyrrolidinol (23 mg), HBTU (109 mg), and DIEA (63 uL). LC/MS: m/z 485.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 8.54 (q, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.82 (d, 1H), 7.67 (d, 1H), 7.51 (d, 1H), 7.39 (d, 1H), 5.04 (d, 1H), 4.32 (d, 1H), 4.15-3.97 (m, 2H), 3.63 (s, 3H), 3.62-3.51 (m, 2H), 3.50-3.33 (m, 2H), 2.05-1.70 (m, 2H).
Reaction SMILES: C[NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=O.NC1C=C[C:23]([OH:26])=CC=1.ClC1C=CN=C(C#N)C=1.CNC(C1C=C(Cl)C=CN=1)=O>>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:3]#[N:2])[CH:10]=2)=[C:13]([O:26][CH3:23])[CH:14]=1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: Nc1ccc(O)cc1
Agent: CNC(=O)c1cc(Cl)ccn1
Agent: N#Cc1cc(Cl)ccn1
Product: COc1cc(N)ccc1Oc1ccnc(C#N)c1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylamide, substituting 4-amino-2-methoxyphenol for 4-aminophenol, and 4-chloro-2-cyanopyridine for 4-chloropyridine-2-carboxylic acid methylamide. 1H-NMR (DMSO-d6) δ 8.50 (d, J=6.0 Hz, 1H), 7.49 (d, J=2.7 Hz, 1H), 7.00 (dd, J=5.7, 2.4 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.37 (d, J=2.4 Hz, 1H), 6.16 (dd, J=8.7, 2.7 Hz, 1H), 5.25 (s, 2H), 3.62 (s, 3H); MS LC-MS (M+H)+=242.1.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[NH2:15][C:16]1[CH:21]=[N:20][CH:19]=[C:18](Cl)[N:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:18]1[N:17]=[C:16]([NH2:15])[CH:21]=[N:20][CH:19]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Nc1cncc(Cl)n1
Product: Cc1onc(-c2ccccc2)c1C#Cc1cncc(N)n1
Yield: 34 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-amino-6-chloropyrazine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 47 mg, 34%) which was obtained as a brown solid. MS: m/e=277.2 [M+H]+.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2[N:29]([CH2:30][C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:28](=[O:37])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:38]4[CH2:44][CH2:43][CH2:42][N:41]([CH:45]([CH3:47])[CH3:46])[CH2:40][CH2:39]4)[CH:26]=3)[N:21]=2)[CH:16]=[CH:17][C:18]=1[F:19]>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2[N:29]([CH2:30][C:31]([NH:33][CH:34]([CH3:35])[CH3:36])=[O:32])[C:28](=[O:37])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:38]4[CH2:44][CH2:43][CH2:42][N+:41]([O-:6])([CH:45]([CH3:47])[CH3:46])[CH2:40][CH2:39]4)[CH:26]=3)[N:21]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)NC(=O)Cn1c(-c2ccc(F)c(Cl)c2)nc2ccc(N3CCCN(C(C)C)CC3)cc2c1=O
Solvent: ClCCl
Product: CC(C)NC(=O)Cn1c(-c2ccc(F)c(Cl)c2)nc2ccc(N3CCC[N+]([O-])(C(C)C)CC3)cc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.3 %

Procedure:
3-Chloroperoxybenzoic acid (19 mg, 0.078 mmol) was added to a stirred solution of 2-[2-(3-chloro-4-fluorophenyl)-6-(4-isopropylperhydro-1,4-diazepin-1-yl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 6k) (40 mg, 0.078 mmol) in DCM (5 mL). The reaction mixture was stirred for 10 min at room temperature. The reaction mixture was diluted with DCM (10 mL) and washed with aqueous sodium bicarbonate solution (10 mL). The organic phase was dried (Na2SO4), concentrated under reduced pressure and purified by chromatography on silica gel with a gradient of DCM to DCM:MeOH (4:1, v/v) as eluent to afford 4-(2-(3-chloro-4-fluorophenyl)-3-(2-(isopropylamino)-2-oxoethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-1-isopropyl-1,4-diazepane 1-oxide (EXAMPLE 12a) (25 mg, 0.047 mmol, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:25][CH:26]([CH3:28])[CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:25]([N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:21])[F:22])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:11])=[O:12])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CBr
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccccc2C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 76.5 %

Procedure:
A mixture of 4-nitro-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (1.90 g, 5.49 mmol), 1-bromo-2-methyl propane (1.19 mL, 10.97 mmol) and K2CO3 (1.51 g, 10.97 mmol) in DMF (20 mL) was heated at 100° C. for 18 hours. The cooled mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-30% EtOAc in cyclohexane) gave N-isobutyl-4-nitro-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (1.69 g, 77%). 1H NMR (300 MHz, CDCl3) δ 8.34 (d, J=8.8 Hz, 2H), 7.88 (d, J=8.8 Hz, 2H), 7.78-7.70 (m, 1H), 7.61-7.47 (m, 2H), 7.23-7.16 (m, 1H), 3.48-3.31 (m, 2H), 1.76-1.60 (m, 1H), 0.88 (dd, J=10.1, 6.6 Hz, 6H). LCMS (m/z, Method A) ES+ no mass ion observed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[CH:24]=[C:25]([S:29]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[CH:24]=[C:25]([S:29]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])(=[O:30])=[O:31])[CH:26]=[CH:27][CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (118 mg, 0.4 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (148 mg, 0.48 mmol) (example B.6) according to general procedure II. Obtained as a yellow solid (46 mg, 22%). MS (ISP) 521.5 f (M+H)+]; mp 202–204° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]4[CH2:32][CH2:33][CH2:34][C@H:28]4[CH2:27]3)=[N:23][N:24]=2)[CH:3]=1.[CH3:35][O:36][C:37]1[C:42]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][N:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Pd](Cl)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]>[CH2:27]1[N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:40]4[CH:41]=[C:42]([NH:43][S:44]([CH3:47])(=[O:45])=[O:46])[C:37]([O:36][CH3:35])=[N:38][CH:39]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][N:8]4[S:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:12])=[O:13])=[N:24][N:23]=2)[CH2:31][CH2:30][N:29]2[CH2:32][CH2:33][CH2:34][C@@H:28]12
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CN4CCN5CCC[C@H]5C4)o3)cc(Br)cc21
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Product: COc1ncc(-c2cc(-c3nnc(CN4CCN5CCC[C@H]5C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Temperature: 100 °C
Yield: 77.7 %

Procedure:
To a solution of 6-bromo-4-{5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylmethyl]-1,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)-1H-indazole (100 mg, 0.184 mmol) was added N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (72.5 mg, 0.221 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (36 mg, 0.049 mmol) and potassium phosphate tribasic (126 mg, 0.594 mmol). The mixture was heated under microwave irradiation at 100° C. for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The residue was dissolved in DCM and added to the top of a 10 g silica SPE cartridge that was subsequently eluted with 0-15% MeOH/DCM over 20 mins. The product-containing fractions were combined and the solvent removed in vacuo to give the title compound as an orange oil (95 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:14][N:13]([C:15]([C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][N:21]=2)=[O:16])[CH2:12]1)[CH:5]=O.Cl.[CH3:29][C:30]1([OH:34])[CH2:33][NH:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][N:32]2[CH2:33][C:30]([OH:34])([CH3:29])[CH2:31]2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:12][N:13]([C:15]([C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][N:21]=2)=[O:16])[CH2:14]1
Reactant: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)c(Cl)c1
Reactant: CC1(O)CNC1
Agent: Cl
Product: CC1(O)CN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)c(Cl)c2)C1
Yield: 56 %

Procedure:
Using a similar protocol as described in Example 70 employing 78A and 3-methylazetidin-3-ol hydrochloride as starting materials afforded 34 mg (56%) of 78 as a solid. 1H NMR (500 MHz, CDCl3): δ 1.50 (s, 3H), 3.07 (d, 2H), 3.30 (d, 2H), 3.57 (s, 2H), 4.39 (m, 1H), 4.65 (m, 1H), 4.81 (m, 1H), 5.13 (m, 2H), 5.29 (s, 1H), 6.59 (m, 2H), 7.13 (d, 1H), 7.35 (s, 1H), 7.53 (t, 2H), 7.59 (t, 1H), 8.16 (d, 2H), MS (APCI+) m/z 455 [M+H]+, LC purity: 93%.
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10]([O:13]C(=O)C)=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH:4]1[C:8]2=[N:9][C:10]([OH:13])=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: CC(=O)Oc1ccc2ccn(C(C)=O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Oc1ccc2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.9 %

Procedure:
A mixture of acetic acid 1-acetyl-1H-pyrrolo[2,3-b]pyridin-6-yl ester (4.0 g, 18.3 mmol) and potassium carbonate (10.45 g, 75.7 mmol) in methanol/water (50%, 260 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated to half its volume and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 10% methanol/dichloromethane) afforded 1H-pyrrolo[2,3-b]pyridin-6-ol (1.52 g, 62%): LC/MS m/e calcd for C7H6N2O [M+H]+ 135.14, observed 135.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH:13]C1C=CC=C2C=1N=CC=C2.[OH-].[K+].C(O)(C)(C)C>[Cu]I.O.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Oc1cccc2cccnc12
Reactant: Cc1c(I)cc(Cl)cc1C(=O)O
Agent: [Cu]I
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: Cc1c(O)cc(Cl)cc1C(=O)O
Temperature: 100 °C
Reaction time: 24 h
Yield: 404.9 %

Procedure:
To 5-chloro-3-iodo-2-methylbenzoic acid (10.0 g, 33.7 mmol), copper(I) iodide (0.70 g, 3.68 mmol), 8-hydroxyquinoline (1.0 g, 6.89 mmol), and potassium hydroxide (9.5 g, 169 mmol) was added tert-butanol (30.0 mL), dimethyl sulfoxide (30 mL) and water (3.0 mL). The reaction was purged with nitrogen, then heated to 100° C. and stirred for 24 h. The reaction was allowed to cool to room temperature and poured into 1 N HCl (200 mL) and EtOAc (250 mL). The flask was rinsed with water. The mixture was stirred for 30 min, filtered through a pad of Celite®, and rinsed with EtOAc. The EtOAc layer was removed, washed with aqueous sodium bisulfate and brine, dried (MgSO4), filtered and evaporated under vacuum to give 5-chloro-3-hydroxy-2-methylbenzoic acid (6.5 g, 27.9 mmol, 83% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (br. s., 1H), 10.18 (s, 1H), 7.17 (d, J=2.27 Hz, 1H), 6.98 (d, J=2.02 Hz, 1H), 2.26 (s, 3H). MS(ES) [M+H]+ 186.9.