Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Br:50][C:51]1[C:56](C)=[CH:55][C:54](O)=[CH:53][C:52]=1C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:17][C:54]2[CH:55]=[CH:56][C:51]([Br:50])=[CH:52][CH:53]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CCCCCCC(O)c1ccc(C(=O)OC)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-heptyl)-benzoic acid methyl ester (1000 mg, 4.0 mmol) in toluene (40 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 1514 mg, 6.0 mmol) at 0° C., followed by the additions of tributylphosphine (1.49 mL, 6.0 mmol) and 4-bromo-3,5-dimethyl-phenol (965 mg, 4.8 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4-bromo-phenoxyl)-heptyl]-benzoic acid methyl ester. The ester product (1800 mg) is taken into ethanol (5 mL), treated with sodium hydroxide (5N aqueous, 5 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (5 mL), extract with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4-bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoic acid (1790 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:21])[CH3:2].[CH3:22][O:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:25][CH2:24][O:23][CH3:22])=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:21])[CH3:2]
Reactant: COCCBr
Reactant: CCn1c(=O)ccc2cnc(Nc3ccc(O)cc3)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)ccc2cnc(Nc3ccc(OCCOC)cc3)nc21
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A mixture of 8-ethyl-2-(4-hydroxyphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (92 mg, 0.33 mmol), 2-methoxyethyl bromide (55 mg, 0.40 mmol) and potassium carbonate (360 mg, 2.61 mmol) in 5 mL of dimethylformamide was heated at reflux for 5 minutes. After cooling to room temperature, water was added, and the resultant solid collected by filtration. The solid was dissolved in ethyl acetate and the solution dried over magnesium sulfate, filtered, concentrated, and purified by flash chromatography eluting with ethyl acetate to provide 92 mg (56%) of 8-ethyl-2-[4-(2-methoxyethoxy)phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one, mp 169-171° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=CC=CC=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:19]1(=[O:29])[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.Cl>CCOCC.C1C=CC=CC=1>[C:5]1([C:9]2[CH:18]=[C:17]([CH:16]=[CH:11][CH:10]=2)[C:22]([C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[C:19]([OH:24])=[O:29])=[O:23])[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Brc1cccc(-c2ccc3ccccc3c2)c1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
Under an argon atmosphere, 132 g of magnesium were dispersed in 500 mL of ether. A solution of 142 g of 2-(3-bromophenyl) naphthalene in 500 mL of ether was added to the dispersion, and then the mixture was stirred at room temperature for 1 hour. A solution of 74 g of phthalic anhydride in 150 mL of benzene was added to the mixture, and then the resultant reaction solution was stirred for 3 hours under reflux. After having been cooled to room temperature, the reaction solution was poured into ice water, and then 1 L of 10% hydrochloric acid was added to the mixture. The organic layer was separated and extracted with an aqueous solution of potassium carbonate. The alkaline extract was acidified, and then the resultant solid was washed with boiling water. The resultant crude product was recrystallized with acetic acid. Thus, 121 g of 2-(3-phenylbenzoyl)benzoic acid were obtained (in 69% yield).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([CH:20]=1)=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24]Cl)[CH:16]=1)[CH:11]=2.[NH:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1>>[N:26]1([CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:19]([CH:20]=2)=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24][N:26]4[CH:30]=[CH:29][CH:28]=[CH:27]4)[CH:16]=2)[CH:11]=3)[CH:30]=[CH:29][CH:28]=[CH:27]1
Reactant: ClCCCOc1ccc2cc3ccc(OCCCCl)cc3nc2c1
Reactant: c1cc[nH]c1
Agent: Cl
Product: c1ccn(CCCOc2ccc3cc4ccc(OCCCn5cccc5)cc4nc3c2)c1

Procedure:
The compound is prepared from 3,6-bis(3-chloropropoxy)acridine hydrochloride and pyrrole as described in Example 44.
Reaction SMILES: C=O.Cl.CON=C[C@H:8]([F:33])[C@H:9]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C@@H:10]([Br:22])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[C:34](=O)([O-])[OH:35].[Na+]>CC(C)=O.C(OCC)(=O)C>[Br:22][C@@H:10]([CH2:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C@@H:9]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C@H:8]([F:33])[CH:34]=[O:35]
Reactant: O=C([O-])O
Reactant: CON=C[C@H](F)[C@H](OCc1ccc(OC)cc1)[C@@H](Br)COCc1ccc(OC)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(COC[C@H](Br)[C@@H](OCc2ccc(OC)cc2)[C@H](F)C=O)cc1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
4.2 mL of a 35% formaldehyde solution and 4.2 mL of 2 mol/L hydrochloric acid were added to a solution of 857 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime in 17 mL of acetone at room temperature, and the obtained mixture was then stirred at room temperature for 1.75 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40), so as to obtain 598 mg of colorless oily (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal and a water adduct thereof.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:15][C:14]2[C:16]([O:21][CH3:22])=[CH:17][CH:18]=[C:19]([CH3:20])[C:13]=2[C@H:12]([CH2:23][Br:24])[O:11]1)C1C=CC=CC=1.[H][H]>[Pt].CO.C(OCC)(=O)C>[Br:24][CH2:23][C@H:12]1[C:13]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([O:21][CH3:22])[C:14]=2[CH2:15][C@@H:10]([CH2:9][OH:8])[O:11]1
Reactant: COc1ccc(C)c2c1C[C@@H](COCc1ccccc1)O[C@H]2CBr
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C)c2c1C[C@@H](CO)O[C@H]2CBr
Reaction time: 8 h

Procedure:
5% Platinum on carbon (1.0 g) is added to a solution of [1R,3S] 3-benzyloxymethyl-1-bromomethyl-3,4-dihydro-5-methoxy-8-methyl-1H-2-benzopyran (3.42 g, 8.7 mmol), from Step 2, in 150 mL of methanol and 5 mL of ethyl acetate. The reaction mixture is sealed under 4 atmospheres of hydrogen and shaken overnight. The reaction mixture is filtered to remove the catalyst and concentrated. The residue is purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH:26]([OH:29])[CH2:27][CH3:28])[CH2:21][CH2:20]1>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH:26]([OH:29])[CH2:27][CH3:28])[CH2:23][CH2:24]2)=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CCC(O)CN1CCC(CN)CC1
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(CC(O)CC)CC3)c2n1

Procedure:
The tilte compound (free base) was prepared according to the procedure described in the step 5 of Example 1 from 5-amino-6-chloro-2-ethylimidazo[1,2-a]pyridine-8-carboxilic acid (Example 4, Step 2) and 1-[4-(aminomethyl)piperidin-1-yl]butan-2-ol (Example 13, Step 2).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](Cl)(=[O:22])[CH3:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:20]([N:10]1[CH2:11][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:9]1)(=[O:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1CNCC1c1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(NC(=O)OC(C)(C)C)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cooled stirred solution of tert-butyl (4-phenylpyrrolidin-3-yl)carbamate (prepared as described in J. Med. Chem. 1993, 36, 4139 starting from (2E)-3-phenylprop-2-enoic acid) (1.0 eq.) in dry DCM (0.1M) were slowly added acetyl chloride (4.0 eq.) and DIPEA (4.0 eq.). The reaction mixture was stirred for 1 h at RT, then diluted with DCM, washed with sat. aq. NaHCO3 sol., water and brine. The solution was dried (Na2SO4), filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography eluting with 5-100% EtOAc/petroleum ether, then eluting with 0-10% MeOH/EtOAc affording the titled compound as yellow oil. MS (ES) C17H24N2O3 requires: 304, found: 305 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=O.[NH2:11][C:12]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:35][CH2:34][CH2:33][N:32]([CH:36]([CH3:38])[CH3:37])[CH2:31][CH2:30]2)=[CH:25][C:13]=1[C:14]([NH:16][CH2:17][C:18](=[O:24])[NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:15].C(N(CC)CC)C.C[Si](Cl)(C)C>C(Cl)Cl>[C:20]([NH:19][C:18](=[O:24])[CH2:17][N:16]1[C:14](=[O:15])[C:13]2[C:12](=[CH:28][CH:27]=[C:26]([N:29]3[CH2:35][CH2:34][CH2:33][N:32]([CH:36]([CH3:38])[CH3:37])[CH2:31][CH2:30]3)[CH:25]=2)[N:11]=[C:5]1[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)N1CCCN(c2ccc(N)c(C(=O)NCC(=O)NC(C)(C)C)c2)CC1
Reactant: O=C(Cl)c1cccc(F)c1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N1CCCN(c2ccc3nc(-c4cccc(F)c4)n(CC(=O)NC(C)(C)C)c(=O)c3c2)CC1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 6.5 %

Procedure:
3-Fluorobenzoyl chloride (24 mg, 0.154 mmol, 0.019 mL) was added to an ice-water cooled solution of 2-amino-N-(tert-butylcarbamoylmethyl)-5-(4-isopropylperhydro-1,4-diazepin-1-yl)benzamide (INTERMEDIATE V.49) (60 mg, 0.154 mmol) and triethylamine (716 mg, 0.96 mL, 7.09 mmol) in DCM (2 mL). Stirring was continued for 15 min. Trimethylsilyl chloride (251 mg, 0.295 mL, 2.31 mmol) was added and the reaction mixture heated in the microwave at 150° C. for 7 min. The reaction mixture was diluted with DCM (10 mL) and washed with water. The organic phase was dried (MgSO4) and concentrated in vacuo. Crude product was purified by chromatography on silica gel with a gradient of DCM to DCM:MeOH:NH3 (95:4:1, v/v) as eluent. Further purification by preparative HPLC afforded N-tert-butyl-2-[2-(3-fluorophenyl)-6-(4-isopropylperhydro-1,4-diazepin-1-yl)-4-oxo-4H-quinazolin-3-yl]acetamide (EXAMPLE 7d) (5 mg, 10 μmol, 7%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11]CC(C)=C)=[CH:9][C:8]([CH3:16])=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[CH:17]=[O:18].[CH3:19][C:20]1[CH:28]=C(CC(C)=C)C(C)=C2[C:21]=1C=CN2C=O>CN(C)C1C=CC=CC=1.CCCCCC>[OH:11][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[C:8]([CH3:16])[C:9]=1[CH2:21][C:20]([CH3:28])=[CH2:19])[N:6]([CH:17]=[O:18])[CH2:5][CH2:4]2
Reactant: C=C(C)COc1cc(C)c2c(c1C)CCN2C=O
Reactant: C=C(C)Cc1cc(C)c2ccn(C=O)c2c1C
Solvent: CCCCCC
Solvent: CN(C)c1ccccc1
Product: C=C(C)Cc1c(C)c2c(c(C)c1O)CCN2C=O
Temperature: 220 °C
Reaction time: 7 h
Yield: 91 %

Procedure:
2,3-Dihydro-5-hydroxy group-4,7-dimethyl-6-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde 2,3-Dihydro-4,7-dimethyl-5-[(2-methyl-2-propenyl)oxy]-1H-indole-1-carbaldehyde (6.00 g, 24.4 mmol) was suspended in N,N-dimethylaniline (25 ml) and stirred under argon atmosphere at 220° C. for 7 hours. The reaction mixture was cooled and diluted with hexane (50 ml) and stirred for 30 minutes. The precipitated crystals were filtered and washed with hexane to obtain 5.45 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:10]2[CH:5]([CH2:6][C:7](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:9]2)[C:4](=[O:21])[NH:3]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1>CO.C(O)(=O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[N:30][C:7]2[CH2:6][CH:5]3[CH:10]([CH2:9][C:8]=2[NH:30][NH:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[C:2](=[O:1])[NH:3][C:4]3=[O:21])=[CH:25][CH:24]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CC2C(=O)NC(=O)C2C1
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NC(=O)C2CC(NNc3ccc(Cl)cc3)=C(N=Nc3ccc(Cl)cc3)CC12

Procedure:
8 g (24.4 mmole) 1,3,3a,4,7,7a-hexahydro-1,3-dioxo-5,6-bis(trimethylsiloxy)-isoindole and 11.4 g (80 mmole) 4-chlorophenyl hydrazine are boiled under reflux for 16 hours in 50 ml methanol and 50 ml glacial acetic acid. The crystals precipitated out after cooling are filtered off, after-washed several times with methanol, and dried. One obtains 5-[(4-chlorophenyl)-azo]-6-[N'-(4-chlorophenyl)-hydrazino]-1,3,3a,4,7,7a-hexahydro-1,3-dioxoisoindole in the form of yellow-green crystals.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[N:6][C:7]=1[Br:8].N([O-])=O.[Na+].[ClH:18]>O.Cl[Cu]>[Br:8][C:7]1[N:6]=[C:5]([NH:9][C:10](=[O:13])[O:11][CH3:12])[CH:4]=[CH:3][C:2]=1[Cl:18]
Reactant: Cl
Reactant: COC(=O)Nc1ccc(N)c(Br)n1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)Nc1ccc(Cl)c(Br)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a mixture of methyl 5-amino-6-bromopyridin-2-ylcarbamate (100 mg, 0.41 mmol) and CuCl (120 mg, 1.6 mmol) in HCl (28%, 10 mL) was added and NaNO2 (29 mg, 0.41 mmol) at 0° C. The mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give methyl 6-bromo-5-chloropyridin-2-ylcarbamate (80 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.38 (brs, 1H), 3.82 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][NH:13][C:12]3=O)=[CH:3][CH:2]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[CH:24]2>>[NH:26]1[C:27]2[C:23](=[CH:22][C:21]([NH:20][C:12]3[C:11]4[C:16](=[CH:17][CH:18]=[C:9]([CH:8]=[CH:7][C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[CH:10]=4)[N:15]=[CH:14][N:13]=3)=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: O=c1[nH]cnc2ccc(C=Cc3ccncc3)cc12
Reactant: Nc1ccc2[nH]ccc2c1
Product: C(=Cc1ccc2ncnc(Nc3ccc4[nH]ccc4c3)c2c1)c1ccncc1
Temperature: 60 °C
Yield: 74.3 %

Procedure:
The title compound (250 mg, 1.0 mmol) from Example 20 was activated in an analogous method to Example 21 and combined with 5 -aminoindole (171 mg, 1.3 mmol). The reaction mixture was heated at 60° C. overnight and then cooled to room temperature. The resin was filtered off and the solution was concentrated in vacuo. The crude residue was chromatographed on silica gel in 10% acetone/ethyl acetate to provide 270 mg (74%) of the product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:20])[CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][CH2:12][CH2:11][CH2:10]1.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>CC(C)=O.O>[CH3:7][N:8]([CH3:20])[CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C1CCCNc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Yield: 97.1 %

Procedure:
38.8 g of potassium carbonate was added to a solution of 50 g of 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 400 ml of acetone and 200 ml of water. To the solution was added 40 g of p-nitrobenzoyl chloride with ice-cooling and stirring. The resulting mixture was stirred overnight at room temperature. The reaction mixture was mixed with an appropriate amount of water. The resulting crystals were collected by filtration and dried to obtain 71 g of 5-dimethylamino-1-(4-nitro-benzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[CH3:34][N:35]1[CH:39]=[C:38]([NH2:40])[C:37]([CH3:41])=[N:36]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O1CCOCC1>[CH:30]1([O:29][C:4]2[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=3[N:7]=[C:2]([NH:40][C:38]3[C:37]([CH3:41])=[N:36][N:35]([CH3:34])[CH:39]=3)[N:3]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCC4)c23)cc1
Reactant: Cc1nn(C)cc1N
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Nc4cn(C)nc4C)nc(OC4CCC4)c23)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
To a degassed mixture of 4-(2-chloro-4-cyclobutoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide (1 equiv), 1,3-dimethyl-1H-pyrazol-4-amine (1 equiv) and sodium tert-butoxide (2 equiv) in 1,4-dioxane (0.15 M) was added chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II), (0.06 equiv) and dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine (0.06 equiv). The reaction was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to afford the title compound (37% yield). MS (ESI) m/z 562.3 [M+1]+.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]=[C:5]1[CH3:12])([CH3:3])[CH3:2].[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1.C1C=CC2N(O)N=NC=2C=1.CN(C=O)C>O>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:9]([C:7]3[N:6]=[C:5]([CH3:12])[N:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=3)=[O:11])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: Cc1nc(C(=O)O)cn1C(C)C
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1C(C)C
Yield: 79.3 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) using 1-isopropyl-2-methyl-1H-imidazole-4-carboxylic acid (0.303 mmol, 51 mg), (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.253 mmol, 70.4 mg) and only a catalytic amount of HOBt (0.025 mmol, 3.41 mg). DMF (2 ml) was used as the solvent in the reaction. The work up was done by adding water to the reaction mixture and extracting it three times with DCM. The combined organics were washed twice with water. The organic phase was evaporated and the residue was purified by flash chromatography. 86 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.06 (d, 3H), 1.34 (d, 6H), 2.35 (s, 3H), 4.23-4.47 (m, 4H), 7.02 (d, 1H), 7.62 (s, 1H), 7.86 (d, 1H), 7.90-7.96 (m, 1H), 8.00 (s, 1H), 8.04 (d, 1H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=O)([CH3:3])[CH3:2].[N-:21]=[C:22]=[O:23].[K+].C(O)(=O)C>O>[CH:1]([N:4]1[C:5]2[C:6](=[CH:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:21][C:22]1=[O:23])([CH3:3])[CH3:2]
Reactant: [N-]=C=O
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2)c(NC(C)C)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2c(-c3ccc(F)cc3)nc(=O)n(C(C)C)c2c1

Procedure:
A solution of 8.5 g. of 2-isopropylamino-4-methyl-4'-fluoro-benzophenone and 4.2 g. of potassium isocyanate in 100 ml. of glacial acetic acid is stirred at 60°-70°C. for 20 hours. The resulting mixture is treated with a mixture of ice and water and extracted three times with methylene chloride. The organic phases are combined, washed twice with water, once with sodium bicarbonate solution and again with water followed by drying and evaporation in vacuo. The residue is dissolved in a small amount of methylene chloride and precipitated by adding pentane. The resulting solid is redissolved in methylene chloride, treated with charcoal and diethyl ether exchanged for the methylene chloride to obtain a solid which is dried in a high vacuum at 60°C. to yield 1-isopropyl-7-methyl-4-(p-fluorophenyl)-2(1H)-quinazolinone, m.p. 172°-174°C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1B(O)O>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: OB(O)c1cc(F)ccc1F
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cc(F)ccc1F

Procedure:
The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2,5-difluorophenyl-boronic acid (CAS RN 193353-34-3) and using preparative HPLC for the chromatographic purification. Off-white solid (36%). MS (ESI): m/z=461.2 [M+H]+.