Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:4]1[C:5]([NH:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH2:28][N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][C:30]4=[O:36])=[C:20]([CH:23](OC)[O:24]C)[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3].C([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1.O.C(Cl)Cl>[C:2]([C:4]1[C:5]([NH:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH2:28][N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][C:30]4=[O:36])=[C:20]([CH:23]=[O:24])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C=O)nc32)ncc1C#N
Reaction time: 2 h

Procedure:
Concentrated hydrochloric acid (0.40 ml) was added to a solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 80, 470 mg, 0.808 mmol) in THF (3 ml) and water (1 ml) at room temperature. After stirring for 3 h at room temperature saturated aqueous NaHCO3 was added, the mixture extracted with DCM (3×), the organic layers dried over Na2SO4 and evaporated. The residue was sonicated with EtOAc (6 ml) and pentane (6 ml) and then filtered. The white solid obtained was then dissolved in DCM (6 ml), EtOAc added (3 ml), the solution warmed, sealed and allowed to stand at room temperature for 2 h. Filtration and drying gave the title compound as a white solid.
Reaction SMILES: C=O.[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:12][CH2:13][O-].[Na+].Cl>CN(C)C=O>[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:6][C:7]2[C:12]3[C:13](=[CH:11][CH:3]=[CH:4][CH:5]=3)[CH2:9][CH:8]=2)=[CH:4]1
Reactant: CC[O-]
Reactant: C1=Cc2ccccc2C1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=C(CC2=CCc3ccccc32)c2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
Formalin (37% solution; 3.5 g, 43.1 mmol) was added to a mixture of indene (10.0 g, 86.2 mmol) and EtONa (2.9 g, 43.1 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was stirred at room temperature for 12 hours. A solution of HCl (1 M, 50 mL) was added. The mixture was extracted with CH2Cl2 (2×100 mL) and the organic phases combined, washed with a saturated solution of NaCl and then with water, dried over MgSO4, filtered and finally concentrated to yield a viscous brown liquid (89% yield by GC). Vacuum distillation yielded pure bis-(3-indenyl)methane as a yellow viscous oil (b.p. 160-180° C. at 1.2 mmHg, 3.65 g, 35% yield), which can be recrystallized from pentane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[C:9]([CH:11]=[O:12])[C:8]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:7](Br)[CH:6]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC#N.O.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=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>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:9]([CH:11]=[O:12])[CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: COCCOCOc1c(Br)cc(CC(=O)OC)cc1C=O
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: O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COCCOCOc1c(C=O)cc(CC(=O)OC)cc1-c1ccccc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
The arylbromide (5) (118 mmol, 42.6 gr) was dissolved in about 430 ml of toluene in a 1 L flask to which 150 ml of 2M K2CO3 was added followed by 5.0 g (0.037 eq) of Pd(PPh3)4. After the addition of phenylboronic acid (2.0 eq, 29 gr) the flask was heated to 70° C. and the mixture stirred for 5 hours. HPLC of the reaction mixture indicated that the arylbromide had completely reacted and a dominant less polar moiety (89% pure, r.t.=8.5 min., 1-90% MeCN/H2O, 0.1% TFA) was observed.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:13][CH2:14][C:15]3[C:16]([OH:23])=[N:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])=[C:9]([CH3:24])[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:6]=2[N:7]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[OH:23][C:16]1[C:15]([CH2:14][NH:13][C:11]([C:10]2[C:5]3[CH:4]=[N:3][C:2]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:7][C:6]=3[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:9]=2[CH3:24])=[O:12])=[C:20]([CH3:21])[CH:19]=[C:18]([CH3:22])[N:17]=1
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Product: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(N4CCOCC4)ncc23)c(O)n1
Yield: 70.5 %

Procedure:
A solution of (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (70 mg, 0.15 mmol) in morpholine (1.0 mL) was stirred at 150° C. for 30 minutes under microwave (pressure: 10.5 bar, equipment power: 150 W). The mixture was concentrated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford (R)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-2-morpholino-7-(1-phenylethyl)-7H-pyrrolo[23-d]pyrimidine-5-carboxamide (55 mg, 70.5%). LRMS (M+H+) m/z: calcd 500.25. found 500. HPLC purity (214 nm): 98.6%. 1H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 7.28 (dt, J=11.9, 7.7 Hz, 5H), 6.10 (dd, J=13.7, 6.5 Hz, 2H), 4.51 (s, 2H), 3.78-3.65 (m, 8H), 2.47 (s, 3H), 2.41 (s, 3H), 2.26 (s, 3H), 2.03 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][O:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH2:5].[C:28](=O)([O-])[O-].[K+].[K+].IC>C(#N)C.ClCCl>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][O:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:5][CH3:28]
Reactant: COC(=O)[C@@H](N)COC1(c2ccccc2)c2ccccc2-c2ccccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Solvent: ClCCl
Product: CN[C@@H](COC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.6 %

Procedure:
To a mixture of 0.8 g (2.2 mmol) of O-(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester (Example 4a, Step 2) and 1.2 g (8.9 mmol) of potassium carbonate in acetonitrile (5 mL) was added 0.17 mL (2.7 mmol) iodomethane and the mixture stirred at room temperature for 16 h. The mixture was dissolved in dichloromethane, filtered and after evaporation of the solvent the residue was chromatographed on silica gel with 60% ethyl acetate in hexanes to give 0.038 g (yield 4.5%) N-Methyl--O--(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester as an oil. 1H NMR (CDCl3, 300 MHz) δ: 7.67 (d, 2H), 7.45-7.10 (m, 11H), 3.73 (s, 3 H), 3.35-3.15 (m, 3H), 2.37 (s, 3H), 2.06 (s, 1H); 13C NMR (CDCl3, 75 MHz) 6: 173.2, 146.6, 146.4, 143.1, 140.6, 129.2, 129.1, 128.3, 128.1, 128.0, 127.1, 125.4, 125.3, 125.1, 119.9, 88.3, 63.8, 62.9, 51.7.
Reaction SMILES: [N:1]([C:4]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[N:12][C:11]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[CH:25]=2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[N+]=[N-]>ClC1C=CC=CC=1Cl>[F:32][C:26]1[CH:25]=[C:24]([C:11]2[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]3[NH:1][C:15]4[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=4[C:13]=3[N:12]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH3:31]
Reactant: COC(=O)c1ccc(-c2nc(-c3ccc(OC)c(F)c3)cc(C(=O)OC)c2N=[N+]=[N-])cc1
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1ccc2c(c1)[nH]c1c(C(=O)OC)cc(-c3ccc(OC)c(F)c3)nc12
Yield: 77.6 %

Procedure:
A solution of methyl 3-azido-6-(3-fluoro-4-methoxyphenyl)-2-(4-(methoxycarbonyl)phenyl)isonicotinate (1.06 g, 2.43 mmol) in 1,2-dichlorobenzene (30 mL) was heated under reflux for 5 minutes. Removal of the solvent followed by flash silica gel chromatography (elution with hexane containing 15% EtOAc) afforded dimethyl 2-(3-fluoro-4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4,7-dicarboxylate (0.77 gm). MS (ESI) m/z 409.1 (M+H). 1H NMR (DMSO-d6) δ ppm 11.86 (1H, br. s.), 8.29-8.47 (3H, m), 8.11 (1H, dd, J=13.12, 2.14 Hz), 7.97-8.06 (1H, m), 7.92(1H, d, J=8.24 Hz), 7.32 (1H, t, J=8.85 Hz), 4.09 (3H, s), 3.95 (3H, s), 3.94 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[N:19]([CH3:20])[C:18](S(C)(=O)=O)=[N:17][N:16]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH:37]([OH:39])[CH3:38])[CH:33]=2)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[N:19]([CH3:20])[C:18]([O:39][CH:37]([C:34]3[CH:33]=[C:32]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=4)[O:36][N:35]=3)[CH3:38])=[N:17][N:16]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)c1cc(-c2cccc(Cl)c2)on1
Reactant: Cn1c(-c2ccnc(OCc3ccccc3)c2)nnc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(Oc1nnc(-c2ccnc(OCc3ccccc3)c2)n1C)c1cc(-c2cccc(Cl)c2)on1
Temperature: 65 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
The title compound from example 29.1 (103 mg, 0.298 mmol), the title compound from example 7.1 (100 mg, 0.4471 mmol) and cesium carbonate (291 mg, 0.894 mmol) were combined in a screw cap vial which was purged with nitrogen. Dimethylformamide (3 mL) was added and the reaction was stirred at 65° C. overnight. The reaction mixture was then cooled to room temperature, diluted with water and extracted three times with dichloromethane. The combined organics were dried over magnesium sulfate, filtered and concentrated, then chromatographed in dichloromethane followed by ethyl acetate on silica gel to give the title compound (129.4 mg, 58%).
Reaction SMILES: Br[C:2]1[C:3]([C:17]#[N:18])=[CH:4][C:5]([F:16])=[C:6]([NH:8][C@H:9]([CH:13]2[CH2:15][CH2:14]2)[C:10]([NH2:12])=[O:11])[CH:7]=1.Cl.[NH2:20][C:21]1[S:25][N:24]=[C:23]([CH3:26])[CH:22]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]([C:3]1[C:2]([NH:20][C:21]2[S:25][N:24]=[C:23]([CH3:26])[CH:22]=2)=[CH:7][C:6]([NH:8][C@H:9]([CH:13]2[CH2:15][CH2:14]2)[C:10]([NH2:12])=[O:11])=[C:5]([F:16])[CH:4]=1)#[N:18]
Reactant: Cc1cc(N)sn1
Reactant: N#Cc1cc(F)c(N[C@@H](C(N)=O)C2CC2)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N[C@@H](C(N)=O)C3CC3)c(F)cc2C#N)sn1
Reaction time: 18 h
Yield: 39.6 %

Procedure:
A mixture of (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-2-cyclopropylacetamide (87 mg, 0.278 mmol), 5-amino-3-methylisothiazole hydrochloride (63 mg, 0.418 mmol), K2CO3 (120 mg, 0.869 mmol), BINAP (40 mg, 0.064 mmol) and Pd(OAc)2 (20 mg, 0.089 mmol) in dioxane (2 mL) was degassed with argon, then was stirred at 120 C for 18 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-2-cyclopropylacetamide (38 mg).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16]([CH3:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[S:19]([OH:22])(=O)=[O:20])(=[O:3])[CH3:2].S1(CCCC1)(=O)=O.P(Cl)(Cl)([Cl:32])=O>>[C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16]([CH3:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[S:19]([Cl:32])(=[O:22])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)O)ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)Cl)ccc12
Temperature: 40 °C
Yield: 81 %

Procedure:
100 g of 1-acetoxy-5-acetaminonaphthalene-2-sulfonic acid was added to 500 ml of sulfolane, and 200 ml of phosphorus oxychloride was dropwise added thereto at 40° C. while stirring. After continuing stirring for about 1 hour, the reaction mixture was poured into 2 liters of ice water, and the precipitated crystals were collected by filtration, washed with water until the filtrate did not show acidity, and air-dried as such for 24 hours to obtain 70 g (81% yield) of product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]#[CH:23])[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.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.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]#[C:23][C:28]3[CH:29]=[CH:30][C:25]([I:24])=[CH:26][CH:27]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc2nc(C3CCCN3C(=O)OC(C)(C)C)[nH]c2c1
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(C#Cc3ccc(I)cc3)cc2[nH]1
Temperature: 100 °C
Yield: 74.6 %

Procedure:
A mixture of 2-(6-ethynyl-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.321 mmol), 1,4-Diiodo-benzene (529 mg, 1.61 mmol), tetrakis(triphenylphosphine)palladium (37 mg, 0.03 mmol), copper(I) iodide (12 mg, 0.06 mmol) and triethylamine (0.135 mL, 0.96 mmol) in 2 ml DMF was heated to 100° C. in the microwave for 1 hour. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-[6-(4-Iodo-phenylethynyl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (123 mg, yield 75%). LCMS-ESI−: calc'd for C24H24IN3O2: 513.37. Found: 531.8 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2I)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Cl:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(OC(C)C)OC(C)C)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.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>[Cl:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:13]=2[NH:12][C:4]2[C:5]([CH3:11])=[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=2)[NH:9][CH:8]=[CH:7]3)[C:19]#[N:20])=[CH:28][CH:27]=1
Reactant: Cc1c(Nc2c(I)cncc2C#N)cc(Cl)c2[nH]ccc12
Reactant: CC(C)OB(OC(C)C)c1ccc(OCCCl)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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1c(Nc2c(C#N)cncc2-c2ccc(OCCCl)cc2)cc(Cl)c2[nH]ccc12
Temperature: 80 °C
Yield: 84.8 %

Procedure:
To a stirred solution of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-iodonicotinonitrile (534 mg, 1.3 mmol) in DME (30 mL) was added diisopropyl 4-(2-chloroethoxy)phenylboronate (754 mg, 2.6 mmol), sodium carbonate solution (2.7 mL of 2M solution, 5.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.15 mmol) under nitrogen atmosphere and the reaction mixture was heated at 80° C. for 6 h and cooled to room temperature. Ethyl acetate was added and the organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane) to give 5-[4-(2-chloroethoxy)phenyl]-4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]nicotinonitrile as a yellow solid (482 mg, 84%). HPLC retention time: 10.7 min.(g) and MS: 437.2 (M+H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]3)=[N:8][CH:9]=1)=[S:3].Br[CH:31]([CH3:35])[C:32](=O)[CH3:33]>C(O)C>[CH3:35][C:31]1[N:1]=[C:2]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]4)=[N:8][CH:9]=2)[S:3][C:32]=1[CH3:33]
Reactant: CC(=O)C(C)Br
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cn3)ccc21
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc(C)c(C)s4)cn3)ccc21
Temperature: 80 °C
Yield: 82.8 %

Procedure:
A mixture of ethyl [(1S)-5-(3-{[5-(aminocarbonothioyl)-2-pyridinyl]oxy}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 259, 90 mg, 0.22 mmol) and 3-bromo-2-butanone (40 mg, 0.26 mmol) in ethanol (9 mL) was heated under argon at 80° C. for 18 h, and then concentrated under reduced pressure. The product (85 mg, 84%) was isolated after purification by silica gel chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 8.54 (dd, 1H), 8.05 (dd, 1H), 7.02 (d, 1H), 6.83 (d, 1H), 6.78 (d, 1H), 6.69 (dd, 1H), 4.51 (t, 2H), 4.18-4.10 (m, 4H), 3.48 (qt, 1H), 2.92-2.75 (m, 2H), 2.69 (dd, 1H), 2.42-2.30 (m, 8H), 2.29-2.20 (m, 2H), 1.80-1.68 (m, 1H), 1.27 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](O)(=O)[CH2:14][CH:15]([CH3:17])[CH3:16].O>ClCCl>[CH3:16][CH:15]([CH3:17])[CH2:14][C:13]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C)CC(=O)O
Reactant: Nc1cnc2ccccc2c1S
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1nc2cnc3ccccc3c2s1
Temperature: 140 °C

Procedure:
3-Aminoquinoline-4-thiol (4.6 g) was added to polyphosphoric acid (80 g). Isovaleric acid (3.5 mL) was added and the reaction mixture was heated at 140° C. for 2 hours. The reaction mixture was poured into a mixture of ice and water (300 mL). The mixture was filtered through a layer of Celite® filter aid to remove some insoluble material. The filtrate was made alkaline with 50% sodium hydroxide while cooling with ice and then extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide an oil. The oil was dissolved in dichloromethane and then placed on a layer of silica gel and eluted with 1:1 ethyl acetate:hexanes. The eluant was concentrated under vacuum to provide 2-(2-methylpropyl)thiazolo[4,5-c]quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:13][C:14]1[C:15]([F:27])=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([S:20](Cl)(=[O:22])=[O:21])[CH:19]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:13][C:14]1[C:15]([F:27])=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([S:20]([NH:12][C:9]2[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)(=[O:22])=[O:21])[CH:19]=1
Reactant: Nc1ccc(Cl)c2cccnc12
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(F)c(Cl)cc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 12 %

Procedure:
In a similar fashion using route 14 general procedure 27, using 5-chloro-quinolin-8-ylamine (Intermediate 27) (750 mg, 4.2 mmol), 5-chloro-4-fluoro-2-nitro-benzenesulfonyl chloride (Intermediate 218) (1.5 g, 5.4 mmol), DMAP (cat), pyridine (8 ml) and DCM (15 ml) gave the title compound (210 mg, 12%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][CH2:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1.ClCCl.CO>O1CCCC1>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][CH2:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)NCc1ccccc1
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
Benzyl isocyanate (59 μL, 0.48 mmol) was added at ambient temperature to a suspension of 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmol) in tetrahydrofuran (60 mL). A solution was obtained in less than 30 minutes and thin layer chromatography (9:1 dichloromethane:methanol) showed one major new spot with a higher Rf and only a trace of starting material. Aminomethyl resin (280 mg) was added and the reaction mixture was stirred for 15 minutes. The solvent was removed under vacuum. The residue was purified by column chromatography to provide 0.16 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-benzylurea as a white solid. Analysis: Calculated for C25H31N7O: % C, 67.39; % H, 7.01; % N, 22.00; Found: % C, 67.43; % H, 6.92; % N, 22.02.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([C:10]([NH:13][C:14](=[O:23])[O:15][C@H:16]2[C@@H:21]3[CH2:22][N:18]([CH2:19][CH2:20]3)[CH2:17]2)([CH3:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:3]>[Pd]>[N:18]12[CH2:22][C@H:21]([CH2:20][CH2:19]1)[C@H:16]([O:15][C:14](=[O:23])[NH:13][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=1)([CH3:12])[CH3:11])[CH2:17]2
Reactant: C=C(C)c1cccc(C(C)(C)NC(=O)O[C@@H]2CN3CC[C@H]2C3)c1
Agent: [Pd]
Product: CC(C)c1cccc(C(C)(C)NC(=O)O[C@@H]2CN3CC[C@H]2C3)c1
Yield: 32.5 %

Procedure:
Using general procedure F, (+/−)-(3S,4S)-1-azabicyclo[2.2.1]heptan-3-yl 2-(3-(prop-1-en-2-yl)phenyl)propan-2-ylcarbamate (110 mg, 0.350 mmol) and palladium (20 mg, 20 wt. % on carbon) gave the title compound as an off-white solid (36 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 7.25-7.19 (m, 3H), 7.11 (d, J=8.0 Hz, 1H), 5.19 (s, 1H), 4.91 (s, 1H), 3.44 (t, J=4.0 Hz, 2H) 3.19 (br s, 1H), 3.02 (br s, 1H), 2.89 (m, 2H), 2.69 (br s, 1H), 2.39 (br s, 1H), 1.91 (br s, 1H), 1.66 (br s, 7H) 1.26 (d, J=4.0 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ 128.5 (2×), 124.8, 123.1 (2×), 122.4 (2×), 77.4, 60.6, 59.4, 55.5, 41.5, 34.5, 29.9, 29.9, 29.5, 24.3 (2×), 21.6 ppm. Purity: >95% UPLCMS (210 nm); retention time 0.88 min; (M+1) 317.