Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[C:13]([CH3:24])[C:12](=[O:25])[N:11]2[CH2:26][CH2:27][N:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]=12.C(OC(=O)C)C>N1C=CC=CC=1>[CH2:29]([N:28]1[C:10]2=[C:9]([NH:8][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=3[F:23])=[C:13]([CH3:24])[C:12](=[O:25])[N:11]2[CH2:26][CH2:27]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(N)c2n(c1=O)CCN2Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(Br)cc2F)c(NS(=O)(=O)C2CC2)c2n(c1=O)CCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
Cyclopropanesulfonyl chloride (254 mg, 0.0002 mol) was added to a stirred solution of 8-amino-1-benzyl-7-(4-bromo-2-fluoro-phenylamino)-6-methyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (400 mg, 0.001 mol) in pyridine (4 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer was concentrated to afford the crude product. Purification by column chromatography on silica gel (80% ethylacetate in hexane), followed by preparative HPLC afforded 30 mg of the product (6% yield).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH2:13][C:14](=[O:18])[C:15]([OH:17])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[OH-].[Na+].CC(OC)(C)C>C1COCC1>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[C:5]([CH2:13][C@@H:14]([OH:18])[C:15]([OH:17])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)C(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
16.1 g (53.6 mmol) 3-(3,5-bis-trifluoromethyl-phenyl)-2-oxo-propionic acid in 9.5 (70.0 mmol) triethylamine and 100 mL THF were combined at −35° C. with a solution of 26.0 (81.1 mmol) (1R)—B-chlorodiisopinocampheylborane in 40 mL THF within 30 min, stirred for 1 h at this temperature and stirred overnight at RT. After the reaction had ended the reaction mixture was made alkaline at 0° C. with 160 mL 1 M NaOH, stirred for 15 min, combined with 100 mL TBME and the phases were separated. The organic phase was washed with 50 mL water and 50 mL 1 M NaOH. The combined aqueous phases were acidified with 4 M HCl, exhaustively extracted with TBME, the combined organic phases were dried over Na2SO4, suction filtered through activated charcoal and evaporated down i.vac. The product was reacted further without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]1[C:17](=[O:18])[C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][N:14]=[C:9]12)([O-:3])=[O:2]>C(O)(=O)C.Cl.O>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]1[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]=[C:9]12)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cnc2c3cccc([N+](=O)[O-])c3ccn2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cnc2c3cccc([N+](=O)[O-])c3ccn2c1=O
Temperature: 80 °C
Yield: 87.9 %

Procedure:
A suspension of ethyl 8-nitro-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (400 mg) in a mixture of acetic acid (20 ml) and 36% hydrochloric acid (4 ml) was heated at 80° C. for 5 hours. The mixture was cooled and diluted with water. The precipitated solid obtained was collected and dried to give 8-nitro-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylic acid (320 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:38])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[N:13]=[C:12]([C:17]4[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=4)[N:11]([CH:27]([CH3:29])[CH3:28])[C:10]=3[C@H:9]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[CH3:37])[CH:7]=1.[CH3:39][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>C1COCC1.CCOC(C)=O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:9]2([CH3:39])[C:10]3[N:11]([CH:27]([CH3:28])[CH3:29])[C:12]([C:17]4[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=4)=[N:13][C:14]=3[C:15](=[O:16])[N:8]2[C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH3:38])=[C:31]([CH3:37])[CH:32]=1
Reactant: COc1ncc(-c2nc3c(n2C(C)C)[C@@H](c2ccc(Cl)cc2C)N(c2cc(Cl)ccc2C)C3=O)c(OC)n1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: COc1ncc(-c2nc3c(n2C(C)C)C(C)(c2ccc(Cl)cc2C)N(c2cc(Cl)ccc2C)C3=O)c(OC)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product from example 76 (100 mg, 0.18 mmol) in THF (2 mL) at −78° C. was added KHMDS (217 μL, 0.22 mmol, 1M in THF) and the mixture was stirred at −78° C. for 15 min. Methyl iodide (34 μL, 0.54 mmol) was added and the mixture was allowed to warm to rt and the mixture was stirred at rt for 20 h. The reaction mixture was diluted with EtOAc and extracted with a 5% citric acid solution. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative HPLC, then the residue was lyophilized in dioxane. tR: 1.25 min (LC-MS 2); ESI-MS: 566.3/568.2 [M+H]+ (LC-MS 2).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]2[C:6]3[N:23]=[C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([O:34][CH3:35])[CH:26]=4)[N:21]=[CH:20][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[F:19])[C:4]=2[CH:3]=1.[OH-].[Na+:39]>C(O)C.O>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]2[C:6]3[N:23]=[C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([O-:31])=[O:30])=[C:27]([O:34][CH3:35])[CH:26]=4)[N:21]=[CH:20][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[F:19])[C:4]=2[CH:3]=1.[Na+:39]
Reactant: COc1cc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2OC)=NC3)ccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2OC)=NC3)ccc1C(=O)[O-]
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a stirred suspension of 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid (98.0 g, 190 mmol) in ethanol (2.0 L) was added 1.044 M Sodium hydroxide in water (199 mL). The resultant homogeneous solution was stirred for 1 hour, during which time a thick precipitate formed. The product was collected by filtration, and washed with ethanol (0.5 L) and diethyl ether (1.0 L). The resultant solid was dried in vacuo at 60-70° C. for 4 days to provide 88.6 g (86.8%) of sodium 4-([9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino)-2-methoxybenzoate as a light tan solid, mp 225° C. (decomp). 1H NMR (DMSO-d6) δ 9.86 (s, 1H), 8.60 (s, 1H), 8.29 (d, 1H), 7.79 (dd, 1H), 7.60 (br s, 1H), 7.40 (dd, 1H), 7.29 (d, 1H), 7.25-7.15 (m, 2H), 6.9 (br s, 2H), 4.9 (br s, 1H), 3.8 (br s, 1H), 3.70 (s, 3H), 3.35 (br s, 3H); MS m/z 519 (M+−Na+H, 100%); CHN Anal. Calcd. for C27H19ClFN4NaO40.33 EtOH−1.3H2O: C, 57.33; H, 4.10; N, 9.67. Found: C, 57.14; H, 3.99; N, 9.65.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:17][Si:18]([CH3:27])([CH3:26])[O:19][CH2:20][CH2:21][CH2:22][C:23](=O)[CH3:24]>C1COCC1>[CH:2]1([C:23]([CH:13]2[CH:12]=[CH:16][CH:15]=[CH:14]2)([CH2:22][CH2:21][CH2:20][O:19][Si:18]([CH3:27])([CH3:26])[CH3:17])[CH3:24])[CH:1]=[CH:5][CH:4]=[CH:3]1
Reactant: CCCCCC
Reactant: CC(=O)CCCO[Si](C)(C)C
Reactant: C1=CCC=C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(CCCO[Si](C)(C)C)(C1C=CC=C1)C1C=CC=C1
Temperature: 65 °C
Yield: 16.9 %

Procedure:
Freshly distilled cyclopentadiene (61.5 g, 0.93 mol) was placed in a one liter Schlenk flask and dissolved in dry THF (500 ml). n-BuLi 2.5 M in hexane (372 ml 0.93 mol) was slowly added to this solution at −78° C., yielding a white precipitate. The suspension was left to reach room temperature and then heated to 65° C. for one hour. The reaction mixture is thermostated at 20° C. and a solution of 5-trimethylsiloxypentan-2-one (72.5 g, 0.42 mol) in THF (100 ml) was slowly added. The yellow suspension obtained was heated at reflux for 16 h. The resulting brown suspension was filtered and the solid washed with hexane several times. Solvents were removed under vacuum and the orange oil obtained was distilled at 10−3 mbar and 84-89° C., obtaining a yellow oil (20.5 g, 17% yield). 1H NMR (CDCl3): Λ6.40-6.02 (C5H5, 6H), 3.55 (CH2, m, 2H), 2.97, 2.80 and 2.78 (C5H5, 4H), 1.82 (CH2, m, 2H), 1.42 (CH2, m, 2H), 1.40 (CH3, s, 3H), 0.10 ((CH3)3, s, 9H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:42][C:43]1[N:44]=[CH:45][NH:46][CH:47]=1)[C:3]([NH:5][C@@H:6]([CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C@@H:7]([OH:34])[CH2:8][C@@H:9]([CH:31]([CH3:33])[CH3:32])[CH:10]([OH:30])[CH2:11][N:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4].[NH:48](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:49]([C:57](O)=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C=O>[CH:36]1([CH2:35][C@H:6]([NH:5][C:3](=[O:4])[C@H:2]([CH2:42][C:43]2[N:44]=[CH:45][NH:46][CH:47]=2)[NH:1][C:57](=[O:58])[C@H:49]([CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH2:48])[C@@H:7]([OH:34])[CH2:8][C@@H:9]([CH:31]([CH3:33])[CH3:32])[CH:10]([OH:30])[CH2:11][N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CC(C)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(O)CN(Cc1ccccn1)C(=O)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)Cc1ccccc1)C(O)CN(Cc1ccccn1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A mixture of 340 mg (0.52 mmol) of benzyl [(2RS,3S, 5S,6S)-6-[(S)-α-amino-4-imidazolepropionamido]-7-cyclohexyl-2,5-dihydroxy-3-isopropylheptyl]-(2-pyridylmethyl)carbamate, 225 mg (0.58 mmol) of Fmoc-Phe-OH, 0.132 ml (1.05 mmol) of 4-ethylmorpholine, 155 mg (1.15 mmol) of HOBT, 121 mg (0.63 mmol) of EDC and 10 ml of dimethylformamide is stirred at room temperature overnight. Thereafter, the reaction mixture is poured into 70 ml of ice-cold 2N sodium bicarbonate solution and extracted three times with 150 ml of ethyl acetate each time. The organic extracts are washed in succession with 70 ml of sodium bicarbonate solution and 70 ml of saturated sodium chloride solution, combined, dried and evaporated. The residue (640 mg) in 30 ml of methylene chloride and 1 ml of piperidine is stirred at room temperature for 2.5 hours. Then, the reaction mixture is evaporated and the residue (500 mg) is chromatographed on 50 mg of silica gel with a 14:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent. Recrystallization of the crude product obtained (320 mg) from methylene chloride/ether/hexane yields 280 mg of benzyl [(2RS,3S,5S,6S)-7-cyclohexyl-2,5-dihydroxy-3-isopropyl-6-[[N-(3-phenyl-L-alanyl)-L-histidyl]amino]heptyl]-(2-pyridylmethyl)carbamate as a white solid, melting point 94°.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:27]=[N:26][C:17]4[NH:18][C:19]5[CH:24]=[N:23][C:22](N)=[CH:21][C:20]=5[C:16]=4[CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(=O)(O)[O-].[Na+].[N:38]1C=CC=CC=1>CO.C(Cl)Cl.O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:27]=[N:26][C:17]4[NH:18][C:19]5[CH:24]=[N:23][C:22]([CH2:28][S:29]([NH2:38])(=[O:31])=[O:30])=[CH:21][C:20]=5[C:16]=4[CH:15]=3)=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: NS(=O)(=O)Cc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 50 °C
Yield: 38 %

Procedure:
A solution of 3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-amine (82.1 mg, 0.230 mmol) in pyridine (8.2 mL) was treated with methanesulfonyl chloride (58.7 μL, 0.758 mmol) and heated at 50° C. for 15 h. The cooled reaction mixture was treated with saturated sodium bicarbonate solution and diluted with 20% MeOH in DCM and water. The layers were separated, the aqueous phase extracted into 20% MeOH in DCM, and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by preparative HPLC (0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min) to afford the title compound as a tan solid (38 mg, 38%). 1H NMR (DMSO-D6, 400 MHz): 12.03 (s, 1H), 8.96 (d, J=2.1 Hz, 1H), 8.88 (d, J=2.1 Hz, 1H), 8.64 (s, 1H), 7.85 (s, 1H), 7.77 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 3.48 (s, 2H), 3.22 (s, 3H), 2.36 (m, 4H), 1.55-1.46 (m, 4H), 1.41 (m, 2H). LCMS (Method D): RT=7.37 min, M+H+=436.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20][C:21]3[N:30]=[C:29]([N:31]([CH3:33])[CH3:32])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([O:34][C:35]([F:38])([F:37])[F:36])[CH:3]=1.[H-].[Na+].I[CH3:42]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20][C:21]3[N:30]=[C:29]([N:31]([CH3:33])[CH3:32])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH2:15][CH2:14]2)[CH3:42])(=[O:10])=[O:9])=[C:4]([O:34][C:35]([F:36])([F:37])[F:38])[CH:3]=1
Reactant: CI
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CNS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CN(C)S(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
To a solution of trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide obtained in step H of example 1 (380 mg, 0.61 mmol) in DMF (2 mL) was added 60% sodium hydride in oil (24.6 mg, 0.61 mmol). The reaction mixture was stirred at ambient temperature for 80 min. The reaction mixture was cooled at 0° C. and iodomethane (38.3 μL, 0.61 mmol) was added and stirred at ambient temperature for 3 hr. The reaction was quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 25% EtOAc in hexane, and silica gel, 5% MeOH in CHCl3) to give trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-N-methyl-2-trifluoromethoxy-benzenesulfonamide (268 mg, 69%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[S:18][C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:11]=3[CH:10]=[N:9]2)[C:3]=1[CH:22]=[O:23].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57].C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[C:20](=[O:21])[C:19]4[S:18][C:17]5[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=5[C:11]=4[CH:10]=[N:9]3)[C:3]=2[CH:22]=[O:23])=[CH:30]1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 70 °C
Yield: 53 %

Procedure:
A round bottom flask was charged with 124a, 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (271 mg, 0.58 mmol), PdCl2(dppf) (50 mg, 0.06 mmol), K3PO4.3H2O (323 mg, 1.16 mmol), THF (15 mL), and H2O (5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 70° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on flash column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 124b as a yellow solid (200 mg, 53%). LCMS: [M+H]+ 651
Reaction SMILES: C[Mg]I.[Br:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Br:19])[CH:13]=3)[C:8](=O)[C:7]=2[CH:6]=1.[CH3:21]C(O)=O>C1COCC1.CCOC(C)=O>[Br:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Br:19])[CH:13]=3)[C:8](=[CH2:21])[C:7]=2[CH:6]=1
Reactant: CC(=O)O
Reactant: O=c1c2ccc(Br)cc2oc2ccc(Br)cc12
Agent: C[Mg]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1c2ccc(Br)cc2Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Referring to Scheme 10, methylmagnesium iodide (14.12 mL, 3 M in Et2O, 42.4 mmol) was added to a stirred solution of 2,6-dibromo-9H-xanthen-9-one (7-2) (10 g, 28.2 mmol) in THF (30 mL) at 0° C. The reaction mixture was allowed to warm up to rt and stirred for 2 h. The reaction mixture was cooled to 0° C. and quenched with saturated NH4Cl solution (250 mL) and stirred for 30 min. The volatiles were removed in vacuo. The residue was taken up in CHCl3 (200 mL), and the organic layer was separated and the aqueous phase was extracted with CHCl3 (2×200 mL) and combined organics was dried over MgSO4, filtered and solvents removed in vacuo to crude product (9.46 g). The crude reaction was taken up in EtOAc (200 mL) and AcOH was added (20 mL) and the reaction mixture was stirred at room temperature for 3 h, the volatiles removed in vacuo and the residue was precipitated from isohexanes to give 2,6-dibromo-9-methylene-9H-xanthene (9-1) (6.43 g, 64.7% yield).
Reaction SMILES: C1COCC1.[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[CH2:7].C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]([F:46])([F:45])[C:23]([F:44])([F:43])[C:24]([F:42])([F:41])[O:25][C:26]([F:40])([C:31]([F:39])([F:38])[O:32][C:33]([F:37])=[C:34]([F:36])[F:35])[C:27]([F:30])([F:29])[F:28]>C(O)C(O)C>[F:36][C:34]([F:35])([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:6]=[CH2:7])=[CH:9][CH:10]=1)[CH:33]([F:37])[O:32][C:31]([F:38])([F:39])[C:26]([F:40])([O:25][C:24]([F:41])([F:42])[C:23]([F:43])([F:44])[C:22]([F:21])([F:45])[F:46])[C:27]([F:30])([F:29])[F:28]
Reactant: C=Cc1ccc(O)cc1
Reactant: FC(F)=C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(O)CO
Product: C=Cc1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
In the dry box, THF (50 mL) and 4-vinylphenol (5.00 g of a 10% solution in propylene glycol) were added to an oven dry RB flask equipped with a stirrer, Potassium carbonate (0.35 g, 0.0025 mol) was then added. 1,1,1,2,2,3,3-Heptafluoro-3-(1,1,1,2,3,3-hexafluoro-3-(1,2,2-trifluorovinyloxy)propan-2-yloxy)propane (2.70 g, 0.00625 mol) was then added via the addition funnel and the reaction allowed to stir at room temperature. The reaction mixture was heated to a gentle reflux under nitrogen overnight. An aliquot was withdrawn and concentrated under vacuum and analyzed via proton NMR which showed the complete conversion to be 1-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)-4-vinylbenzene. The cooled reaction mixture was then concentrated at reduced pressure taken up in methylene chloride washed with water (˜25 mL) separated, then dried over anhydrous sodium sulfate. The separated organic phase was then concentrated at reduced pressure and then column chromatograph on silica gel obtaining 1.15 g (about 50.0%) of the theoretical yield) of product.
Reaction SMILES: Cl.[N:2]1([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:36][CH3:37])=[C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)[N:21]=[C:20](Cl)[N:19]=1.C(N(CC)CC)C.C(OCC)C>C(O)CCC>[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:36][CH3:37])=[C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)[N:21]=[C:20]([N:13]2[CH2:14][CH2:15][CH2:16][N:10]([C:8]([N:2]3[CH2:3][CH2:4][O:5][CH2:6][CH2:7]3)=[O:9])[CH2:11][CH2:12]2)[N:19]=1
Reactant: O=C(N1CCCNCC1)N1CCOCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: CCOCC
Product: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2cc1OCc1ccccc1
Yield: 69.2 %

Procedure:
1-(4-Morpholinecarbonyl)-1,4-diazepane hydrochloride (16 g, 0.075 mol) and 4-amino-6-benzyloxy-2-chloro-7-methoxyquinazoline (15 g, 0.048 mol) were added to a solution of triethylamine (20 ml, 0.144 mol) in n-butanol (200 ml) and the reaction stirred at reflux for 1 hour. On cooling, the mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (400 ml) and water (400 ml). The phases were separated and the organic layer dried (MgSO4), filtered and evaporated under reduced pressure to give a cream coloured solid. Trituration with diethyl ether gave the title compound as a solid (16.35 g, 70%). Rf 0.50 (0.880 aqueous ammonia:methanol:dichloromethane 1:7:92, v/v). MS m/z 493 (MH)+. 1H-NMR (CDCl3): δ=2.03 (2H, m), 3.18 (4H, m), 3.34 (2H, t), 3.56 (2H, m), 3.65 (5H, m), 3.85 (2H, m), 4.00 (4H, m), 5.00 (1H, bs), 5.18 (2H, s), 6.87 (1H, bs), 7.37 (4H, m), 7.47 (3H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[CH2:10][CH:11]([C:16]([F:19])([F:18])[F:17])[CH2:12][C:13]([OH:15])=O)=[CH:4][CH:3]=1.NC1C=CC=CC=1.C1(=O)OC(=O)CCC1.C(Cl)(=O)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:20])[CH2:10][CH:11]([C:16]([F:19])([F:18])[F:17])[CH2:12][C:13]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(CC(=O)Nc1ccc(Br)cc1)C(F)(F)F
Agent: O=C1CCCC(=O)O1
Solvent: CC(=O)Cl
Solvent: Nc1ccccc1
Product: O=C1CC(C(F)(F)F)CC(=O)N1c1ccc(Br)cc1
Yield: 78.5 %

Procedure:
Into a 50 ml 1-necked, round-bottomed flask containing a stir bar were placed 2.50 g (7.96 mmol) N-(4'-bromophenyl)-3-(trifluoromethyl)glutaramic acid (prepared as described in Example 1 from the appropriate aniline and glutaric anhydride) and acetyl chloride (15 ml). The mixture was heated to reflux for 6 hours resulting in a dear, light grey solution. The acetyl chloride was removed via atmospheric distillation through a short path distillation head. The resulting light grey crystalline solid was triturated with hexanes, filtered and washed with hexanes to yield an off-white crystalline solid which was dried in vacuo at 50° C. to yield 2.10 g (89% yield) of product, m.p. 163°-4° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[CH3:20][CH:21](O)[CH3:22]>>[CH:21]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)([CH3:22])[CH3:20]
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: CC(C)O
Reactant: Nc1cnccn1
Product: CC(C)Oc1ccc2ncnc(Nc3cnccn3)c2c1

Procedure:
The compound of Example 23 was manufactured by the same method as in Example 22, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-hydroxy-quinazoline, 2-propanol and 2-aminopyrazine.