Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8](OCC3CCN(C)CC3)=[C:9](OC)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1([CH3:36])[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:35])[CH:30]=2)[NH:25]1>>[CH3:23][C:24]1([CH3:36])[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:35][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:30]=2)[NH:25]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: CC1=CC(C)(C)Nc2ccc(O)cc21
Product: CC1=CC(C)(C)Nc2ccc(Oc3ncnc4ccccc34)cc21
Yield: 110.3 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 10), was reacted with 2,2,4-trimethyl-1,2-dihydroquinolin-6-ol (95 mg, 0.5 mmol), (IZV. ACAD. NAVK. SSSR. Ser. Khim. 1981, 9, 2008), to give 6-methoxy-74(1-methylpiperidin-4-yl)methoxy)-4-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yloxy)quinazoline (140 mg, 74%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]([OH:16])=O)[CH:10]=2)=[C:5]([F:17])[CH:4]=1)#[N:2].[CH:18]1([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=3)[CH2:24][CH2:23]2)[CH2:20][CH2:19]1>>[CH:18]1([N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=3)[CH2:24][CH2:23]2)[C:14]([C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[F:17])[O:13][N:12]=2)=[O:16])[CH2:19][CH2:20]1
Reactant: N#Cc1ccc(-c2cc(C(=O)O)no2)c(F)c1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Product: CC(C)c1noc(N2CCC(N(C(=O)c3cc(-c4ccc(C#N)cc4F)on3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from 5-(4-cyano-2-fluoro-phenyl)-isoxazole-3-carboxylic acid and cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine following a procedure analogous to that described in Example 18. LC (method 18): tR=1.23 min; Mass spectrum (ESI+): m/z=465 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:4]([CH:26]=[O:27])[CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:28])=[O:15])=[C:4]([CH:26]=[O:27])[CH:3]=1
Reactant: COc1ccc(CN(CCCCCC(=O)O)c2ccc(Br)cc2C=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCCCCN(Cc1ccc(OC)cc1)c1ccc(Br)cc1C=O
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of 6-((4-bromo-2-formylphenyl)(4-methoxybenzyl)amino)hexanoic acid (32.0 g) and potassium carbonate (12.2 g) in DMF (300 ml) was added dropwise a solution of iodomethane (14.6 g) in DMF (100 ml) under nitrogen atmosphere at 0° C. After returning to room temperature, the reaction mixture was stirred for 2 hours, then water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water five times and with saturated brine once, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to give methyl 6-((4-bromo-2-formylphenyl)(4-methoxybenzyl)amino)hexanoate (30.5 g) as a brown oily material.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]=[N+]=[N-])=[CH:15][CH:14]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:24])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:24])[CH:3]=1
Reactant: CCc1nc2c(C)cc(Cl)nc2n1-c1ccc(CCN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2c(C)cc(Cl)nc2n1-c1ccc(CCN)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.6 %

Procedure:
To a stirred solution of 2-[4-(5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide (step 6, 57 mg, 0.2 mmol) in THF (5 mL) was added triphenylphosphine (47 mg, 0.2 mmol) at room temperature. After completion of the addition, the stirring was continued for an additional 3 h at the same temperature. To the resulting mixture was added water (0.1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated to give colorless solids. Purification by preparative TLC (dichloromethane/methanol/triethylamine=10:1:1) gave 13 mg (25%) of the title compound as colorless solids: MS (EI) m/z 313 (M+).
Reaction SMILES: [C:1]1([CH:7]([OH:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(C)=O.O.S(=O)(=O)(O)O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]1([C:7]([C:8]#[CH:9])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CC(O)c1ccccc1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: C#CC(=O)c1ccccc1

Procedure:
A solution of 1-phenyl-2-propyne-1-ol (34.2 g) in 50 ml acetone is cooled down to 0°, stirred under N2 and treated dropwise, over a period of 3 hours with a solution of chromium trioxide (17.5 g) in water (50 ml) and concentrated sulfuric acid (14.8 ml), keeping the temperature below 5° at all times. After the addition is complete, the mixture is stirred for another hour at 5°. The reaction mixture is then diluted with water (100 ml) and extracted with two 250-ml portions of ether. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and stripped to give a yellow product. A small amount dried on a porous plate gives a m.p. of 45°-47°.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:10]=[C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Br
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C(F)(F)F)cc1-c1ccccc1
Yield: 63.6 %

Procedure:
2-Bromo-4-trifluoromethyl-benzoic acid (100 mg, 0.372 mmol) and phenylboronic acid (70 mg, 0.574 mmol) were dissolved in 6 mL dioxane and 3 mL 1N sodium carbonate solution. The mixture was evacuated and back-filled with argon several times to remove oxygen. 2-Dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (S-Phos, 31 mg, 0.075 mmol) and palladium acetate (8 mg, 0.036 mmol) were added and the reaction mixture was refluxed overnight. The mixture was diluted with ethyl acetate, water and 2N sodium carbonate solution. The mixture was extracted three times with 2N sodium carbonate solution and the aqueous layers washed with ethyl acetate. The combined organic layers were discarded. The combined aqueous layers were acidified with 2N HCl and extracted twice with dichloromethane. The organic layers were washed with brine, combined, dried over sodium sulfate, filtered and concentrated down. Purification of the residue by flash chromatography on gel with dichloromethane/methanol/acetic acid (100:0:0→90:10:0.5) yielded the title compound as a white solid (63 mg, 64%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][C:28]([F:31])([F:30])[F:29])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][C:28]([F:29])([F:30])[F:31])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC(F)(F)F)c4cc(F)ccc34)nc12
Agent: Cl
Solvent: CO
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CC(F)(F)F)c4cc(F)ccc34)nc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a mixture of N-tert-Butyl-2-(6-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (60 mg, 0.12 mmol) in 3 mL of methanol was added concentrated HCl (10 mL). The reaction mixture was heated to 50° C. and stirred overnight. The solvent was evaporated and the residue was triturated with tert-butyl methyl ether, filtered and dried to give N-tert-butyl-2-(6-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide as a yellow solid (30 mg, 58%). LCMS: (M+H)+=435; 1H NMR (300 MHz, DMSO): δ 12.86 (s, 1H), 9.04 (s, 1H), 8.52-8.47 (m, 1H), 8.41 (d, 1H, J=3.0 Hz), 7.89-7.83 (m, 2H), 7.26-7.23 (m, 1H), 5.62-5.53 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: Br[C:2]1[C:19]2[C:10](=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:39]1([C:45]#[CH:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[Al]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[C:39]1([C:45]#[C:46][C:9]2[C:10]3[C:19](=[CH:18][C:17]4[C:12]([CH:11]=3)=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:2]=[C:3]3[C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]3)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1c2ccccc2cc2cc3ccccc3cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Al]
Solvent: CCN(CC)CC
Product: C(#Cc1c2ccccc2cc2cc3ccccc3cc12)c1ccccc1

Procedure:
5-Bromonaphthacene (1.00 g, 3.26 mmol, prepared as described in Example 1, Step 1), 31 mg of copper(I) iodide (0.163 mmol), 85 mg of triphenylphosphine (0.33 mmol) and 114 mg of dichlorobis(triphenylphosphine)palladium(II) catalyst (0.163 mmol) were added to an oven-dried glass pressure tube equipped with a magnetic stirrer. Dry triethylamine (20 ml) was added and the mixture was degassed with nitrogen for 15 minutes. Phenylacetylene (0.5 g, 0.46 ml, 4.88 mmol) was then added by syringe. The tube was sealed and heated in an oil bath to 95° C. while covered with aluminum foil to exclude light (for the duration of the reaction and work up, exposure to light was minimized). The reaction mixture was heated for two hours, and then allowed to cool slowly. The tube contents were dark red with a white precipitate. Upon further cooling, a dark red precipitate formed. TLC analysis with 30% dichloromethane/hexanes showed that all 5-bromonaphthacene had been consumed.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:13]=[C:12]([CH:14]=[O:15])[N:11]([CH3:16])[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C([O-])([O-])=O.[K+].[K+].CI>CC#N.C(Cl)Cl.FC(C(O)=O)(F)F>[CH:14]([C:12]1[N:11]([CH3:16])[CH:10]=[C:9]([S:6]([NH:5][CH3:1])(=[O:8])=[O:7])[CH:13]=1)=[O:15]
Reactant: Cn1cc(S(=O)(=O)NC(C)(C)C)cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Solvent: ClCCl
Product: CNS(=O)(=O)c1cc(C=O)n(C)c1
Reaction time: 3 h

Procedure:
A solution of 0.8 g (3.3 mmol) N-(tert-butyl)-5-formyl-1-methyl-1H-pyrrole-3-sulfonamide, 1.2 g (9.8 mmol) K2CO3 and 1 mL (16 mmol) CH3I in CH3CN was heated at 60° C. overnight. Solvent was removed, and the residue was partitioned between EtOAc and water. The organic layer was separated and washed with brine. Drying (MgSO4) and removal of solvent to give material that slowly solidified. The material was dissolved in 2 mL 1:1 CH2Cl2-TFA with stirring for 3 h. Solvent was removed to give the title compound as a solid, 1H NMR (DMSO) δ 9.8 (s, 1H), 7.9 (s, 1H), 7.45 (s, 1H), 7.4 (s, 1H), 4.1 (s, 3H), 2.6 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[C:29]([O:36][C:37]([F:40])([F:39])[F:38])[CH:28]=1>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([Br:26])=[CH:28][C:29]=4[O:36][C:37]([F:40])([F:38])[F:39])=[S:35])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: FC(F)(F)Oc1cc(Br)ccc1N=C=S
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)Nc5ccc(Br)cc5OC(F)(F)F)c4c(c23)C1=O
Temperature: 25 °C
Yield: 94 %

Procedure:
200 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.60 mmole) were dissolved in 15 ml of acetonitrile. 357 mg (2 molar equivalents) of 4-bromo-2-(trifluoromethoxy)phenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 356 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=94%) which was characterized as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([O:21]CC)=[O:20])[C:5]2=[O:24].[OH-:25].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Cl>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([OH:25])=[CH:11][CH:10]=3)[C:5](=[O:24])[C:6]([C:19]([OH:21])=[O:20])=[CH:7]2)=[CH:13][CH:14]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2ccc(O)cc2c1=O
Temperature: 150 °C
Yield: 100 %

Procedure:
Compound D (500 mg, 1.28 mmol, 1.00 eq), potassium hydroxide (216 mg, 3.84 mmol, 3.00 eq), tris(dibenzylideneacetone)dipalladium(0) (70.4 mg, 0.0769 mmol, 0.0600 eq) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (65.3 mg, 0.154 mmol, 0.120 eq) were suspended in a mixture of 1,4-dioxane (3.2 mL) and water (3.2 mL) in a microwave vial and heated in a microwave reactor at 150° C. for 15 minutes. The reaction was neutralized with 2N HCl and the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to afford 383 mg (99%) of the title compound as a brown solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.75-7.72 (m, 2H), 7.67 (d, J=2.7 Hz, 1H), 7.51 (t, J=8.7 Hz, 2H), 7.26 (d, J=9.1 Hz, 1H), 6.99 (d, J=9.2 Hz, 1H); ES-MS [M+1]+: 300.2.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[O:11]1[CH2:15]CC[CH2:12]1.CN(C)C=O.COCCl>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:12][O:11][CH3:15])=[CH:8][N:9]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: C1CCOC1
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(Cl)nc1
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
Sodium hydride, 60% dispension in mineral oil (3:2, Sodium hydride:Mineral Oil, 2.32 g) was added portion wise to a solution of 6-Chloro-pyridin-3-ol (5.00 g, 38.6 mmol) in a mixture of Tetrahydrofuran (10.0 mL, 123 mmol) and N,N-Dimethylformamide (20.0 mL, 258 mmol). The mixture formed was stirred for 15 min and Chloromethyl Methyl Ether (3.66 mL, 48.2 mmol) was added dropwise. The above mixture was stirred for 6 hours (monitored by LCMS), poured into water and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated in vacuum. Purified on 40 g silica column eluting with 10-40% ethyl acetate in heptane to give 6.33 g of 2-chloro-5-(methoxymethoxy)pyridine.
Reaction SMILES: [CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:5]2C(=O)OC(C)(C)[O:7][C:6]2=[O:14])[CH2:3][CH2:2]1>CN(C=O)C.O.O>[CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH2:5][C:6]([OH:14])=[O:7])[CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C(C(c2cccc(O)c2)C2CC2)C(=O)O1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CC(c1cccc(O)c1)C1CC1
Yield: 100 %

Procedure:
5-(Cyclopropyl(3-hydroxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 66.6T (14.64 g, 50.43 mmol) in DMF/water (10/1) (220 mL) was heated at 90° C. overnight. The reaction was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give 66.6U as a clear oil (10.40 g, 100%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:61])[N:10]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH2:47][C:48]3[N:49]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:50]=[CH:51][N:52]=3)[CH2:33][C:34]3[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:36]=[CH:37][N:38]=3)=[O:31])=[CH:26][CH:25]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15]C(OC(C)(C)C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH2:47][C:48]2[N:49]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:59])([CH3:58])[CH3:60])[CH:50]=[CH:51][N:52]=2)[CH2:33][C:34]2[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:45])([CH3:44])[CH3:46])[CH:36]=[CH:37][N:38]=2)=[O:31])=[CH:28][CH:29]=1)[C:9](=[O:61])[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCCCN(Cc1ccc(C(=O)N(Cc2nccn2COCC[Si](C)(C)C)Cc2nccn2COCC[Si](C)(C)C)cc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCOCn1ccnc1CN(Cc1nccn1COCC[Si](C)(C)C)C(=O)c1ccc(CN(CCCCN)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To the compound 6 (225 mg), a solution of 25% trifluoroacetic acid in dichloromethane (6 mL) was added. The reaction mixture was stirred at room temperature for one hour. The reaction mixture was concentrated and the residue was added by 1N sodium hydroxide and then extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol:28% ammonia water=80:10:1) to obtain the title compound (92 mg) having the following physical properties.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[C:32](=[O:33])[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24]5)[C:18]=4[CH3:34])=[CH:15][N:14]=[C:13]([C:35]([NH2:37])=[O:36])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:38][Mg]Br>O1CCCC1>[OH:3][C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[C:32](=[O:33])[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24]5)[C:18]=4[CH3:34])=[CH:15][N:14]=[C:13]([C:35]([NH2:37])=[O:36])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)([CH3:38])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Solvent: C1CCOC1
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
To a solution of 7-acetyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (45 mg, 0.092 mmol) in tetrahydrofuran (10 mL) at 0° C. was added methylmagnesium bromide (0.154 mL, 0.462 mmol). The mixture was stirred at room temperature for 30 min. Additional methylmagnesium bromide (0.100 mL, 0.300 mmol) was added at 0° C., and the mixture was stirred at room temperature for another 30 min. The reaction was quenched with water (10 mL) and the mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (25 mL) and dried over anhydrous MgSO4. The organic solution was concentrated under vacuum, and the residue was purified by reverse phase HPLC. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×35 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (20.9 mg, 0.041 mmol, 44.1% yield) as a pale yellow solid. LCMS (M+H)+=504.0. 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropisomer) δ: 11.74 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.30 (s, 1H), 7.98 (m, 1H), 7.92 (m, 1H), 7.80 (m, 1H), 7.75 (m, 1H), 7.58 (m, 1H), 7.24 (m, 1H), 5.12 (s, 1H), 1.83 (s, 3H), 1.50 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH2:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:30]([NH:37][C:38]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Reactant: O=C=NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccccc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (62.8 μL, 0.36 mmol) in DCM (2 mL) was added benzyl isocyanate (44.2 μL, 0.36 mmol). The resulting mixture was reacted under the same conditions as described for example 10 to give the title compound as a white solid. MS (ESI, positive ion) m/z: 411 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>C(OCC)(=O)C.C1CCCCC1.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>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)cn2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.3.). Starting with 3 g (8.06 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(5-bromo-2-pyridyl)-1-piperazine-carboxylate, obtained in step 3.3., 4.59 g (24.17 mmol) of 3-(trifluoromethyl)phenylboronic acid, 6.84 g (32.23 mmol) of hydrated potassium phosphate and 0.93 g (0.806 mmol) of tetrakis(triphenylphosphine)palladium, and after chromatography on silica gel, eluting with a 30/70 mixture of ethyl acetate and cyclohexane, 2.22 g of product are obtained in the form of a white solid.