Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(O)CC>O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: Nc1ccc2ccc(-c3ccc(Cl)cc3)nc2n1
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: O
Solvent: CCCO
Product: O=C(Nc1ccc2ccc(-c3ccc(Cl)cc3)nc2n1)c1cccc(Cl)c1
Temperature: 4 °C
Yield: 30.6 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-chlorobenzoic acid (1.6 g), N,N'-carbonyldiimidazole (1.6 g) and 2-amino-7-(4-chlorophenyl)-1,8-naphthyridine (1.8 g). The product obtained by precipitation in water (2.2 g; m.p. approximately 190° C.) is dissolved in boiling propanol (400 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with propanol (3×5 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(4-Chlorophenyl)-1,8-naphthyridin-2-yl]-3-chlorobenzamide (0.85 g), m.p. 222°-224° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](Cl)=[O:13])([CH3:4])([CH3:3])[CH3:2].C([NH:26][NH:27][CH:28]([CH3:30])[CH3:29])(OCC1C=CC=CC=1)=O.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:13])[N:27]([CH:28]([CH3:30])[CH3:29])[NH2:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)Cl
Reactant: CC(C)NNC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 65.7 %

Procedure:
Carbamoyl chloride 1 (4 mmol, crude), prepared as described above, was combined with carbazide 4 (3.50 mmol; 0.728 g) and triethylamine (0.557 ml; 4.00 mmol) in dry THF (2 ml). The mixture was heated at reflux for 7 hours, then filtered and evaporated to a thick oil. This was dissolved in benzene (10 ml) and hydrogenated with 10% Pd(C) (0.35 g) at 1 atm. for 6 hours. Filtration of the catalyst and evaporation gave a light yellow oil which was purified by flash chromatography on silica gel (CH2Cl2 --CH3OH, 50:1). There was obtained pure carbazide 5 (0.622 g; 2.30 mmol; 66%) as a light yellow solid. Recrystallization from hexanes gave a sample, mp 87°-91° C. TLC (silica gel; CH2Cl2 --CH3OH; 20:1) Rf=0.4. MS m/e 271 (M+). Analysis: Calculated for C13H25N 3 O3 : C, 57.54; H, 9.29; N, 15.48. Found: C, 57.67; H, 9.46; N, 15.44. NMR (CDCl3): δ1.08 (3H,d, J=6); 1.13 (3H, d, J=6); 1.43 (9H,s); 1.7-2.2 (4H,m); 2.4-2.7 (2H,m); 3.3 (2H,bs); 4.07 (1H, septet, J=6); 4.3-4.5 (1H,m). lR(CHCl3): 3600-3300, 1730, 1630 cm-1. [α]D =15.9°±b 0.5°. [α]d =15.9°±0.5°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20](Cl)=[CH:21][N:22]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:29][C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[C:35]([CH3:39])[NH:36]2)=[CH:32][CH:31]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:29][C:30]4[CH:38]=[C:37]5[C:33]([CH:34]=[C:35]([CH3:39])[NH:36]5)=[CH:32][CH:31]=4)=[CH:21][N:22]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Cl)cnnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc2ccc(O)cc2[nH]1
Product: COc1cc2c(Oc3ccc4cc(C)[nH]c4c3)cnnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using an analogous procedure to that described in Example 8, 7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-chloro-6-methoxycinnoline (204 mg, 0.5 mmol) was reacted with 6-hydroxy-2-methylindole (100 mg, 0.55 mmol) to give 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-6-yloxy)cinnoline. The crude product was then treated with TFA to give 6-methoxy-4-(2-methylindol-6-yloxy)-7-(piperidin-4-ylmethoxy)cinnoline (10 mg, 4%).
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3]C1.[F:13][C:14]1[C:21]([CH3:22])=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[F:13][C:14]1[C:21]([CH3:22])=[C:20]([N:6]2[CH2:7][CH2:8][C@:4]([CH2:1][CH3:3])([OH:12])[C@@H:5]2[CH2:9][CH3:11])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: Cc1c(F)ccc(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(F)c2C)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-diethylpyrrolidin-3-ol 0.5 oxalate (200 mg), 2,4-difluoro-3-methylbenzonitrile (279 mg) and lithium carbonate (220 mg), the title compound was obtained as pale-yellow oil (yield: 151 mg, yield: 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24]([OH:26])=O)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][N:35]([CH3:40])[S:36]([NH2:39])(=[O:38])=[O:37]>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24]([NH:39][S:36](=[O:38])(=[O:37])[N:35]([CH3:40])[CH3:34])=[O:26])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:31])[F:32])[CH:3]=1
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: CN(C)S(N)(=O)=O
Product: CN(C)S(=O)(=O)NC(=O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-N-(dimethylsulfamoyl)acetamide was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid (Example 4) and N,N-dimethylsulfamide following General Procedure L.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[C:11]1([C:17]2([CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26])[O:21][CH2:20][CH2:19][O:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]([C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:17]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:18][CH2:19][CH2:20][O:21]2)[C:4](=[O:9])[O:3]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)CCCC1(c2ccccc2)OCCO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)CCCC2(c3ccccc3)OCCO2)C(=O)O1
Reaction time: 0.17 h
Yield: 93.2 %

Procedure:
Step AAH (3): To a soln of 2,2-dimethyl-1,3-dioxane-4,6-dione (329 mg, 2.281 mmol) in dichloromethane (10 mL) was added DMAP (405 mg, 3.32 mmol). After stirring for 10 min, a solution of 4-(2-phenyl-1,3-dioxolan-2-yl)butanoyl chloride (2.07 mmol) in dichloromethane was added at 0° C. under nitrogen. The mixture was stirred at rt for 3 his. The crude reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc. The organic layer was sequentially washed with 1.0 N aqueous HCl, 1.0 N aqueous NaOH, and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to 2,2-dimethyl-5-(4-(2-phenyl-1,3-dioxolan-2-yl)butanoyl)-1,3-dioxane-4,6-dione (700 mg, 1.93 mmol, 93% yield).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH2:24][CH3:25])=[C:6]([CH:12]([NH:15][C:16](=[O:22])[O:17][C:18](C)(C)C)CO)[C:7]([F:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].C(Cl)(Cl)=O>ClCCCl.C1(C)C=CC=CC=1>[C:1]([C:4]1[C:5]([O:23][CH2:24][CH3:25])=[C:6]([CH:12]2[CH2:18][O:17][C:16](=[O:22])[NH:15]2)[C:7]([F:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(CO)NC(=O)OC(C)(C)C
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1C1COC(=O)N1
Temperature: 80 °C

Procedure:
tert-Butyl [1-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-2-hydroxyethyl]carbamate (234 mg, 0.62 mmol) (from Step 8) was dissolved in 1,2-dichloroethane (12 mL) and a solution of 2.0 M phosgene in toluene (0.93 mL) was added. The mixture was heated to 80° C. for 1.5 hours. Evaporation and purification on silica gel using ethyl acetate in hexanes (0-85%) gave the desired compound, 175 mg, 93%. LCMS calculated for C13H14ClFNO4 (M+H)+: m/z=302.1; found: 302.1.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[CH:26]1([S:29](Cl)(=[O:31])=[O:30])[CH2:28][CH2:27]1>>[CH:26]1([S:29]([N:2]2[CH2:3][CH2:4][CH:5]([N:8]3[N:12]=[C:11]([CH2:13][O:14][C:15]4[CH:16]=[CH:17][C:18]([N:21]5[CH:25]=[N:24][N:23]=[N:22]5)=[N:19][CH:20]=4)[CH:10]=[N:9]3)[CH2:6][CH2:7]2)(=[O:31])=[O:30])[CH2:28][CH2:27]1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Product: O=S(=O)(C1CC1)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1

Procedure:
The title compound was synthesized using Intermediate 15 and cyclopropanesulfonyl chloride in a similar manner as described in Example 39. 1H NMR (DMSO-d6): δ 9.45 (1H, s), 8.28 (1H, d), 8.03 (1H, d), 7.73 (1H, s), 7.58 (1H, dd), 5.28 (2H, s), 4.62 (1H, m), 3.87 (2H, m), 3.12 (2H, m) 2.31 (5H, m), 1.86 (2H, m), 1.02 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=2.[CH2:15]1COCC1.IC>>[CH3:15][N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc2[nH]c(C)cc2c1
Solvent: CI
Product: COC(=O)c1ccc2c(c1)cc(C)n2C
Reaction time: 40 h

Procedure:
To a solution of Methyl 2-methyl-1H-indole-5-carboxylate (1000 mg, 5.29 mmol) in THF (53 ml) KOtBu (723 mg, 6.44 mmol) was added and subsequently Iodomethane (1.05 ml, 16.81 mmol) was added at rt. The reaction mixture was stirred at it for 40 hours. The orange reaction mixture was quenched with water/brine and extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to afford crude methyl 1,2-Dimethyl-1H-indole-5-carboxylate.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]3[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=[CH:42]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]3[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=[CH:42]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCCCCn3cnc4ccccc43)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)ccc(OCCCCCn3cnc4ccccc43)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-7-[5-(benzimidazol-1-yl)-pentyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[N:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[N:17][CH:16]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Clc1cnnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(-c2cnnc3ccccc23)c2ccccc12
Temperature: 80 °C
Reaction time: 60 h

Procedure:
1 mmol (175 mg) of 1H-indole-3-carboxylic acid methyl ester, 1.1 mmol (181 mg) of 4-chloro-cinnoline and 1.2 mmol (390 mg) of Cs2CO3 are suspended in 3 ml of dry DMF. The mixture is stirred for 60 h at 80° C. under argon, allowed to cool to room temperature, and diluted with water (20 ml). Part of the product precipitates and is filtered off, the filtrate is extracted twice with ethyl acetate (20 ml portions). The combined extracts are dried over anhydrous Na2SO4 and evaporated. The residue is combined with the precipitate and purified by prep. HPLC to yield 1-(cinnolin-4-yl)-1H-indole-3-carboxylic acid methyl ester (MS molpeak 304 (M+H, electrospray ionization)) as an off-white foam after freeze-drying.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.[OH-].[Na+].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:7]1[NH:6][C:5]2[CH:10]=[C:11]([Cl:12])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Yield: 90 %

Procedure:
Thoroughly dried 5,6-dichloro-1,3-dihydro-benzoimidazol-2-one (28.4 g, 0.14 mol) was suspended in POCl3 (75 mL). The reaction solution was heated to reflux temperature for 3 hours and cooled to room temperature. The solution was poured into crushed ice/water (1.5 L) slowly with sufficient stirring. The solution was neutralized to pH=7.0 with NaOH. The precipitated solid was collected by filtration, washed with water, and dried to afford the title compound (27.9 g, 90%). The crude product was used in the following reaction without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([O:22][CH3:23])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[O:24]=[C:25]1[C:28]2([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:27](O)=[CH:26]1>C(Cl)Cl>[O:24]=[C:25]1[C:28]2([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:27]([NH:1][C@@H:2]([CH2:7][C:8]2[CH:9]=[C:10]([O:22][CH3:23])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([O:14][CH3:15])[CH:13]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:26]1
Reactant: COC(=O)[C@@H](N)Cc1cc(OC)c(-c2ccccc2)c(OC)c1
Reactant: O=C1C=C(O)C12CCCCC2
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cc(OC)c(-c2ccccc2)c(OC)c1)NC1=CC(=O)C12CCCCC2
Reaction time: 48 h
Yield: 93.4 %

Procedure:
To a solution of methyl(2S)-2-amino-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoate (0.80 g, 2.5 mmol) in DCM (10 ml) at room temperature was added 1-keto-3-hydroxyspiro[3,5]-non-2-ene (0.38 g, 2.5 mmol) and the mixture stirred for 48 h. Volatiles were removed in vacuo and the residue purified by column chromatography (SiO2, EtOAc) to give the title compound as a white solid (1.05 g, 92%). δH (CDCl3): 7.32-7.26 (3H, m), 7.12 (2H, d, J 8.2 Hz), 6.92 (2H, d, J 8.3 Hz), 5.90 (1H, br d, J 8.2 Hz), 4.60 (1H, s), 4.33 (1H, br), 3.86 (3H,s), 3.73 (6H, s), 3.30 (1H, dd, J 13.9, 5.3 Hz), 3.13 (1H, dd, J 13.9, 6.3 Hz), 1.82-1.33 (10H, m); m/z (ES+, 70V) 450.1 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:22])([CH3:21])[CH:15]=[C:14]2[CH2:23][NH:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:33]I>C1COCC1>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:22])([CH3:21])[CH:15]=[C:14]2[CH2:23][N:24]([CH3:33])[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CI
Reactant: COc1ccccc1-c1ccc2c(c1)C(CNC(=O)c1ccccc1)=CC(C)(C)N2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc2c(c1)C(CN(C)C(=O)c1ccccc1)=CC(C)(C)N2
Reaction time: 5 h

Procedure:
A round bottom flask equipped with a stir bar and under argon atmosphere was charged with NaH (60% in oil) (0.04 mmol, 1 equiv) and 1 mL of THF. Another vessel containing N-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]benzamide (Example 3) was diluted with THF and this solution was added to the NaH solution. Lastly, MeI (0.06 mmol, 1.5 equiv) was added and the reaction was stirred 5 hours under argon. The reaction was quenched with water and extracted with EtOAc. The combined organics were subsequently washed with brine and concentrated in vacuo. The residue was taken up in methylene chloride and adsorbed onto silica gel and flash chromatographed using 25% EtOAc/hexanes to elute product. The product fractions were pooled and concentrated in vacuo to afford 7.2 mg of the title compound as a oil.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.[CH3:13][CH2:14]OCC>C(O)(=O)C.C(Cl)Cl>[NH:7]1[C:1]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13]1
Reactant: NNc1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc2[nH]ccc2c1
Temperature: 50 °C
Yield: 275.1 %

Procedure:
To a solution of 1 (90 mg, 0.27 mmol) in acetic acid (2 mL) was added a solution of phenylhydrazine (0.026 mL, 0.27 mmol) in acetic acid (1 mL) and the mixture heated at 50° C. for 1 hour. The reaction was cooled to room temperature then boron trifluoride etherate (0.060 mL, 0.46 mmol) added and the reaction heated at 80° C. for 16 hours. The mixture was diluted with CH2Cl2 (25 mL) and washed with satd NaHCO3 (3×15 mL, caution: vigorous gas evolution). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluted with 40% EtOAc/hexanes, to give 2 (87 mg, 78% yield) as an off-white solid. Rt=1.96 min using Phenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 min gradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%. [M+H]=411.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:12][C:13]1[C:14]([C:34]2[CH:35]=[N:36][C:37](F)=[CH:38][CH:39]=2)=[CH:15][C:16]2[C:17]3[N:25]([C@H:26]4[CH2:29][C@@H:28]([O:30][CH3:31])[CH2:27]4)[C:24](=[O:32])[N:23]([CH3:33])[C:18]=3[CH:19]=[N:20][C:21]=2[CH:22]=1>C1COCC1>[F:12][C:13]1[C:14]([C:34]2[CH:35]=[N:36][C:37]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:38][CH:39]=2)=[CH:15][C:16]2[C:17]3[N:25]([C@H:26]4[CH2:29][C@@H:28]([O:30][CH3:31])[CH2:27]4)[C:24](=[O:32])[N:23]([CH3:33])[C:18]=3[CH:19]=[N:20][C:21]=2[CH:22]=1
Reactant: OCCCN1CCCC1
Reactant: CO[C@H]1C[C@@H](n2c(=O)n(C)c3cnc4cc(F)c(-c5ccc(F)nc5)cc4c32)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1C[C@@H](n2c(=O)n(C)c3cnc4cc(F)c(-c5ccc(OCCCN6CCCC6)nc5)cc4c32)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(Pyrrolidin-1-yl)propan-1-ol (46.9 mg, 0.36 mmol) was added to sodium hydride (29.1 mg, 1.21 mmol) in THF (4 mL) at ambient temperature over a period of 20 minutes. 7-Fluoro-8-(6-fluoropyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one (120 mg, 0.30 mmol) was added. The resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was quenched with water and the crude product purified by FCC, elution gradient 0 to 5% MeOH in DCM. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractious containing the desired compound were evaporated to dryness to afford the desired material (60.0 mg, 38.7%) as a off-white solid. NMR Spectrum: 1H NMR (300 MHz, MeOD) δ 1.90-2.00 (4H, m), 2.10-2.20 (2H, m), 2.81-3.00 (8H, m), 3.04-3.17 (2H, m), 3.28 (3H, s), 3.6 (3H, s), 3.85-3.96 (1H, m), 4.48 (2H, t), 5.00-5.13 (1H, m), 6.88 (1H, d), 7.82 (1H, d), 8.05 (1H, d), 8.43-8.50 (2H, m), 8.83 (1H, s) Mass Spectrum: m/z (ES+)[M+H]+=506.
Reaction SMILES: O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19].FC(F)(F)S(O[Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])(=O)=O>CN1CCCN(C)C1=O>[CH2:23]([O:22][C:16]([O:21][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])=[CH:17][CH:18]([CH3:20])[CH3:19])[CH3:24]
Reactant: CCOC(=O)CC(C)C
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=CC(C)C)O[Si](C(C)C)(C(C)C)C(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (100 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro 2 (1H)-pyrimidinone (140 ml) were mixed at -20° C. and lithium bis (trimethylsilyl) amide (1M in tetrahydrofuran, 100 ml) was added. The mixture was cooled to -70° C., ethyl isovalerate (18.75 ml) added and stirred for 1/2 hour at -70° C. Triisopropylsilyl trifluoromethane sulfonate was added and the mixture left to stir at -75° C. for 1/2 hour before warming to room temperature and stirring for 3 hours. The reaction mixture was quenched with aqueous sodium bicarbonate (8%, 150 ml) and extracted with hexane (1000 ml). The hexane extract was washed with water (4×500 ml), dried (MgSO4), filtered and concentrated in vacuo to afford a crude yellow oil containing the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH2:17]([O:19][C:20]([C:22]1([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])[CH3:18].Cl.CCN(C(C)C)C(C)C>C(O)C>[CH2:17]([O:19][C:20]([C:22]1([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23][CH2:24][N:25]([C:2]2[N:11]=[C:10]([OH:12])[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=2)[CH2:26][CH2:27]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Reactant: COc1cc2nc(Cl)nc(O)c2cc1OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)C1(Cc2ccccc2)CCN(c2nc(O)c3cc(OC)c(OC)cc3n2)CC1
Yield: 84.2 %

Procedure:
A mixture of 1.2 g (5 mmol) 2-Chloro-6,7-dimethoxy-quinazolin-4-ol (commercially available), 2.26 g (8 mmol) 4-Benzyl-piperidine-4-carboxylic acid ethyl ester; hydrochloride and 1.93 g (15 mmol) DIPEA in 80 mL ethanol was heated to reflux for 62 h. The mixture was concentrated, the precipitate filtered off and washed with ethanol and diethyl ether. The residue was dried. 1.9 g (87%) of the title compound was isolated as white solid. MS (m/e): 452.2 (MH+).
Reaction SMILES: CO[C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:20][CH:19]=4)=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=[O:4]>C(N)CN>[NH2:10][CH2:11][CH2:12][NH:13][C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][N:25]5[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]5)=[CH:20][CH:19]=4)=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Solvent: NCCN
Product: NCCNC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Yield: 55.8 %

Procedure:
A solution of 3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (152 mg, 0.380 mmol) in ethylenediamine (8.0 mL) was heated to 80° C. for 16 h in a sealed tube. The mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in DMSO and purified by preparative HPLC (2-60% MeCN/water modified with 0.1% ammonium hydroxide) to afford a light brown solid (45.4 mg, 28%). 1H NMR (DMSO-D6, 400 MHz): 9.19 (d, J=2.1 Hz, 1H), 8.99 (s, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.92 (s, 1H), 8.74 (m, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 3.41-3.33 (m, 2H), 2.76 (t, J=6.4 Hz, 2H), 2.38 (m, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (Method D): RT=6.45 min, M+H+=429.