Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].[CH3:16][Zn]C>O1CCOCC1.C1(C)C=CC=CC=1.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]>[CH3:16][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6]
Reactant: C[Zn]C
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)O)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A mixture of 3-bromo-4-(trifluoromethoxy)benzoic acid (923 mg, 3.24 mmol) and PdCl2(dppf) (95 mg, 0.13 mmol) were stirred in 1,4-dioxane (9 mL) in a three necked flask under argon atmosphere (a condenser was added to the flask). Dimethylzinc in toluene (3.2 mL of 2.0 M, 6.4 mmol) was added very slowly (caution: the reaction was very exothermic) and the mixture was stirred at room temperature for 1 hour before it was heated at 70° C. for 18 h. The mixture was cooled to room temperature before it was charged with additional dioxane (9 mL) and PdCl2(dppf) (100 mg). The mixture was cooled to 0° C. before additional dimethyl zinc in toluene (3.0 mL, 2.0M) was added. The ice bath was removed and the mixture was heated at 70° C. overnight. The mixture was cooled to room temperature and was quenched with methanol (2 mL) very slowly. The solution was diluted with ethyl acetate and was washed with 1N HCl (3×). The organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness to yield 3-methyl-4-(trifluoromethoxy)benzoic acid (56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([N+]([O-])=O)=[CH:12][C:11]=3[C:7]=2[C:6]([C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1.[ClH:22].O.N([O-])=O.[Na+]>O.Cl.Cl[Cu]>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:22])=[CH:12][C:11]=3[C:7]=2[C:6]([C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1
Reactant: Cl
Reactant: COc1ccc(C(=O)O)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(=O)O)c2c1oc1ccc(Cl)cc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Intermediate 29 (350 mg, 1.13 mmol) was suspended in mixture of concentrated hydrochloric acid:water (1: 1) (5 ml) and stirred at 50° C. for 30 min. The suspension was cooled to 0° C. and a solution of sodium nitrite (83 mg, 1.2 mmol) in water (2 ml) was added dropwise in 15 min. The reaction was stirred for 90 min. at 0-5° C. and then this suspension was added to a pre-cooled solution of CuCl (123 mg, 1.24 mmol) in concentrated HCl (5 ml). The reaction was allowed to come to room temperature and further heated to 80-90° C. for 2 h. The reaction mixture was then poured into water (100 ml) and the solid was filtered and then purified by column chromatography using 20% ethyl acetate-chloroform as the eluent to obtain 250 mg of the product as white solid; mp: 264-276° C.
Reaction SMILES: [S:1]([O:5][C:6]1[CH:23]=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15]([C:24](=[O:33])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH2:13]4)[CH2:10][CH2:9][C:8]=2[CH:7]=1)(=[O:4])(=[O:3])[NH2:2]>CCOC(C)=O.C(O)C.[Pt](=O)=O>[S:1]([O:5][C:6]1[CH:23]=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([C:24](=[O:33])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]=2[CH:7]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: CCCCCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCCNC(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Yield: 95.3 %

Procedure:
A solution comprising about 210 mg of compound 5a (m=6) in about 6 ml of EtOAc and about 2 ml of ethanol (EtOH, 2 ml) was stirred over about 40 mg of platinum (IV) oxide (PtO2) under an atmosphere of hydrogen for 2.5 h. The catalyst was removed by filtration and the filtrate concentrated. The residue was purified by silica gel chromatography (Petroleum ether: EtOAc, 1:1), yielding pure compound 6a (201 mg, 95.3%).
Reaction SMILES: O1CCCC1.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH:11]=[CH:12][CH:13]=1.[H-].[Na+].[CH3:23][Si:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][O:27][CH2:28]Cl>O>[F:20][C:7]([F:6])([F:19])[C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[CH:16][N:17]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:31])([CH3:30])[CH3:23])[CH:18]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: FC(F)(F)c1cccc(-c2c[nH]cn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(-c2cccc(C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
To a 250 mL round bottom flask (fitted with rubber septum and nitrogen blanket and stir bar) add Tetrahydrofuran (30 mL; 368.66 mmoles; 30.00 mL; 26.58 g), 4-(3-Trifluoromethyl-phenyl)-1H-imidazole (1.047 g; 1.00 equiv; 4.93 mmoles; 1.05 g) and cool the mixture to 0° C. with stirring on and hold for 5 min. Add sodium hydride (0.138 g; 1.11 equiv; 5.46 mmoles; 138.00 mg) to the flask and stir the reaction for 20 min. Add 2-(trimethylsilyl)ethoxymethyl chloride (1.15 mL; 1.31 equiv; 6.49 mmoles; 1.15 mL; 1.08 g) and allow the reaction to warm to room temperature. Dilute the reaction with water and extract the mixture two times with ethyl acetate and discard the aqueous phase. Dry the material over Na2SO4, filter, and concentrate to dryness. Purify the crude mixture by flash chromatography on silica gel eluting with ethyl acetate/hexane from 10-60% EtOAc. Combine the appropriate fractions and concentrated to give 4-(3-Trifluoromethyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (1.178 g; 0.70 equiv; 3.44 mmoles; 1.18 g; 69.71% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17]2[NH:43][C:20]3=[N:21][C:22]([O:38][CH2:39][CH:40]([F:42])[F:41])=[C:23]([C:25](=[O:37])[NH:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([C:33]([F:36])([F:35])[F:34])[CH2:29][CH2:28]4)[CH:24]=[C:19]3[N:18]=2)[C:10]=1[Cl:44])(C)(C)C.Cl>O1CCOCC1.CO>[Cl:44][C:10]1[C:11]([NH:16][C:17]2[NH:43][C:20]3=[N:21][C:22]([O:38][CH2:39][CH:40]([F:41])[F:42])=[C:23]([C:25](=[O:37])[NH:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([C:33]([F:36])([F:34])[F:35])[CH2:29][CH2:28]4)[CH:24]=[C:19]3[N:18]=2)=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)F)nc3[nH]2)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)F)nc3[nH]2)c1Cl
Reaction time: 0.25 h

Procedure:
A mixture of N-{2,4-dichloro-3-[6-(trans-4-trifluoromethyl-cyclohexylcarbamoyl)-5-(2,2-difluoro-ethoxy)-3H-imidazo[4,5-b]pyridin-2-ylamino]benzyl}-carbamic acid tert-butyl ester (6.3 g, 9.3 mmol), 4 M HCl in dioxane (60 ml) and MeOH (5 ml) is stirred for 15 min. The mixture is concentrated, diluted with water and basified with conc. NH3. The precipitate is collected by filtration, washed with water, dried and purified via prep HPLC. The product fractions are concentrated, basified with conc. NH3, extracted with EtOAc. The organic phases are dried with Na2SO4 and concentrated to give the crude sub-title compound (4.8 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=2)[N:5]2[CH:20]=[C:21]([C:23]([O:25]CC)=[O:24])[N:22]=[C:4]2[CH:3]=1.[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].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.O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]3[CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=[C:4]3[CH:3]=[C:2]([C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][C:33]=3[Cl:35])[N:7]=2)=[N:13][CH:14]=1)#[N:19]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cn2c(NCCNc3ccc(C#N)cn3)nc(Cl)cc2n1
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: COCCOC
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C(=O)O)cn23)nc1
Temperature: 120 °C

Procedure:
1 g (2.59 mmol) of ethyl 7-chloro-5-({2-[(5-cyanopyridin-2-yl)amino]ethyl}amino)imidazo[1,2-c]pyrimidine-2-carboxylate (Example 59A), 580 mg (2.98 mmol) of (2,4-dichlorophenyl)boronic acid and 716 mg (5.18 mmol) of potassium carbonate are introduced into a mixture of 25 ml of 1,2-dimethoxyethane and 10 ml of water under argon, and the mixture is carefully degassed before 300 mg (0.26 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. The mixture is heated at 120° C. for 16 h. Filtration and subsequent purification by preparative HPLC result in 185 mg (14% of theory) of the product as a solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[C:17]([O:18][CH3:19])=[C:16]2[C:11]([CH2:12][CH2:13][NH:14][CH:15]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1.C(=O)([O-])O.[Na+]>CCOC(C)=O>[Cl:1][CH2:2][C:3]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[C:17]([O:18][CH3:19])[C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[CH:15]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc2c(c1OC)C(c1ccccc1)NCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1OC)C(c1ccccc1)N(C(=O)CCl)CC2
Reaction time: 2 h
Yield: 77.7 %

Procedure:
A solution of chloroacetyl chloride (177 mg) in EtOAc (12 mL) was added dropwise to a mixture of 7,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (350 mg), a saturated aqueous sodium hydrogen carbonate solution (50 mL), and EtOAc (50 mL) under stirring. After the dropwise addition was complete, the mixture was stirred for 2 hours and extracted with EtOAc. The extract was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-EtOH) to obtain 2-(chloroacetyl)-7,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (349 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16][SH:17])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:28]([S:31][CH2:32][CH:33]([CH3:37])[C:34](Cl)=[O:35])(=[O:30])[CH3:29]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16][S:17][C:34](=[O:35])[CH:33]([CH3:37])[CH2:32][S:31][C:28](=[O:30])[CH3:29])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CC(CS)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SCC(C)C(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Reaction time: 8 h

Procedure:
To a mixture of 3 g (0.01M) of N-(3-mercapto-2-methyl propanoyl)-N-cyclopentyl glycine-t-butyl ester, 1.2 g (0.012M) triethylamine in 100 ml methylene chloride was added a solution of 1.8 g (0.01M) of 3-acetylthio-2-methyl propanoyl chloride and stirring continued for 8 hours. It was then washed with water, dried over MgSO4 and evaporated to dryness leaving an oily residue which was purified by HPLC using ethyl acetate--hexane (1:3) as eluent.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]([OH:22])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:37][CH2:38][C:39]([NH:41][C@H:42]([C:45]([OH:47])=[O:46])[CH2:43][OH:44])=[O:40]>>[C:1]([O:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]([NH:37][CH2:38][C:39]([NH:41][C@H:42]([C:45]([OH:47])=[O:46])[CH2:43][OH:44])=[O:40])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)O
Reactant: NCC(=O)N[C@@H](CO)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@@H](CO)C(=O)O
Yield: 60.9 %

Procedure:
Starting from 2-hexadecanoyloxyhexadecanoic acid (128 mg) prepared by the method described in Preparation 7 and N-glycyl-L-serine (162 mg), N-[N-(2-hexadecanoyloxyhexadecanoyl)glycyl]-L-serine (100 mg) was obtained as powders according to a similar manner to that of Example 6.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][OH:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.CCOCC>C(Cl)Cl>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH:14]=[O:15])=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1ccc(CCCO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)Oc1ccc(CCC=O)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 3-(4-tert-butoxyphenyl)-propan-1-ol S4 (2.39 g, 11.5 mmol) in anhydrous CH2Cl2 (115 mL) under N2 was added PCC (3.73 g, 17.3 mmol). The reaction flask was fitted with a reflux condenser, and the reaction mixture was stirred under N2 for 90 min. Anhydrous Et2O (120 mL) was added to the reaction mixture, and a brown solid precipitated out. The resulting slurry was filtered through a pad of silica gel to remove the solid. The brown gum left in the reaction flask washed with Et2O (3×50 mL). The combined filtrate was concentrated to give a yellow oil (1.54 g, 65% crude yield) that was carried on to the next step without further purification. TLC Rf=0.50 (Hex/EtOAc, v/v, 7:3). 1H NMR (300 MHz, CDCl3): 9.82 (t, J=1.5 Hz, 1H), 7.08 (m, 2H), 6.91 (m, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.77 (t, J=7.5 Hz, 2H), 1.32 (s, 9H), FIG. 71. 13C NMR (75 MHz, CDCl3): 201.9, 154.0, 135.3, 128.8, 124.5, 45.6, 29.0, 27.7, FIG. 72. TOF-MS-ESI: [2M+Na]+ calculated 435.55 found 435.6.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N+:16]([O-])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+].O=P(Cl)(Cl)[Cl:25]>>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[Cl:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(ccc[n+]2[O-])c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: O=S(=O)(c1ccccc1)c1ccc2nccc(Cl)c2c1
Yield: 27 %

Procedure:
A solution of 6-benzenesulfonyl-quinoline 1-oxid (135 mg, 0.47 mmol) in POCl3 (4 mL) was heated at 90° C. for 2 h after which the solution was poured on ice, ammonium hydroxide was added and extraction with DCM. The organic phase was dried (NaSO4), the volatiles were evaporated and the residue was purified by column chromatography (SiO2, ethyl acetate:petroleum ether, 1:1) to yield a white solid (39 mg, 27%). MS m/z: 305 [M+H+].
Reaction SMILES: [C:1]([C:3]1([OH:13])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)#[CH:2].C([Li])CCC.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]([OH:25])[C:2]#[C:1][C:3]2([OH:13])[CH2:12][CH2:11][C:6]3([O:7][CH2:8][CH2:9][O:10]3)[CH2:5][CH2:4]2)=[CH:22][CH:21]=1
Reactant: C#CC1(O)CCC2(CC1)OCCO2
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(C#CC1(O)CCC2(CC1)OCCO2)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 8-ethynyl-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 1) (5.03 g, 27.6 mmol) in tetrahydrofuran (100 mL), 2.63 M n-butyllithium (solution in n-hexane, 22.1 mL, 57.9 mmol) was added dropwise at −72° C. for 15 minutes, and the obtained solution was stirred at the same temperature for 60 minutes. Thereafter, 4-chlorobenzaldehyde (4.06 g, 28.9 mmol) was added dropwise at −72° C. for 10 minutes, and the obtained solution was stirred at the same temperature for 60 minutes. The reaction solution was allowed to warm to room temperature and poured into saturated aqueous ammonium chloride solution. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (8.13 g, 25.2 mmol, 91%) as an amorphous product.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C(N(CC)CC)C>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=4[C:26]([F:25])([F:36])[F:37])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
As described for Example 9, a mixture of 0.377 g (1.44 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.15 g of triethylamine and 0.300 g (1.44 mmol) of 2-trifluoromethylbenzoyl chloride is stirred at room temperature for 2 hours and then washed with 1N HCl 1M NaHCO3, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filtrate evaporated to give a solid. Crystallization from dichloromethane-hexane gives 0.41 g of crystals, m.p. 191°-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C@H:10]([C:12]([OH:14])=[O:13])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[C:20]([O:19][C:17]([CH2:16][O:13][C:12](=[O:14])[C@H:10]([CH3:11])[NH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[C@H](Nc1ccc(Cl)c(Cl)c1)C(=O)O
Product: C[C@H](Nc1ccc(Cl)c(Cl)c1)C(=O)OCC(=O)OC(C)(C)C

Procedure:
Following General Procedure AE above and using N-(3,4-dichlorophenyl)alanine (from Example AB above) and tert-butyl bromoacetate (Aldrich), the title compound was prepared as a solid. The reaction was monitored by silica gel tlc (Rf=0.57 in 25% EtOAc/hexanes). Purification was by recrystallization from ethanol.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[C:5]([F:19])[CH:6]=[CH:7][C:8]=2[F:18])[C:3]1=[O:20].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[F:18][C:8]1[CH:7]=[CH:6][C:5]([F:19])=[C:4]2[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:11][N:2]([NH:1][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]2=[O:20]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nn1nc(-c2ccccn2)c2c(F)ccc(F)c2c1=O
Solvent: ClCCl
Product: O=C(Nn1nc(-c2ccccn2)c2c(F)ccc(F)c2c1=O)c1ccccc1

Procedure:
The product of part C, 2-amino-5,8-difluoro-4-(2-pyridyl)-(2H)-1-phthalazinone (0.01 mol) is stirred overnight with benzoylchloride in dichloromethane at room temperature. The product is recrystallized to yield the title compound (R1=benzyl, Y1=—NH—C(O), R2=2-pyridyl, A=benzene, R3=F, F, m=2, p=0).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]([F:23])([F:22])[C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1.Cl.[CH:25]1([NH:28][C:29](=[O:42])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[CH2:37][CH2:38][NH:39][CH2:40][CH:41]=3)[N:31]=2)[CH2:27][CH2:26]1>ClCCl>[CH:25]1([NH:28][C:29]([C:30]2[N:31]=[C:32]([C:36]3[CH2:37][CH2:38][N:39]([S:18]([C:14]4[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:23])([F:22])[F:10])[CH:13]=4)(=[O:20])=[O:19])[CH2:40][CH:41]=3)[CH:33]=[CH:34][CH:35]=2)=[O:42])[CH2:26][CH2:27]1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C(NC1CC1)c1cccc(C2=CCNCC2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CC1)c1cccc(C2=CCN(S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)n1
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
Diisopropyl ethyl amine (66 ml, 0.36 mmol) and 3-(trifluoromethyl)benzene sulfonyl chloride (6) (44 mg, 0.18 mmol, Aldrich) were sequentially added to a suspension of compound 5 (50 mg, 0.18 mmol) in dichloromethane at 0° C. while stirring. The reaction was completed within 0.5 hour and the crude product was purified without work-up on CombiFlash® with a gradient of 50-100% EtOAc in hexane to provide the title compound 7 as a white solid (50 mg, yield 64%). 1H NMR (400 MHz, CD3OD): δ 8.15 (m, 2H), 8.02-7.83 (m, 4H), 7.67 (dd, 1H, J=1.2, 7.6 Hz), 6.78 (m, 1H), 3.92 (m, 2H), 3.45 (m, 2H), 2.87 (m, 1H), 2.77 (m, 2H), 0.86 (m, 2H), 0.70 (m, 2H); MS: 452 (M+H+), 474 (M+Na).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([Br:24])[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([Br:24])[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(Br)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1CN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(Br)nc23)C2CC2)C1
Reaction time: 3 h

Procedure:
A solution of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (0.104 g, 0.195 mmol, contains some 2-chloro impurity), 1 mL of dichloromethane and 1 mL of TFA was stirred for 3 h, then concentrated to a pale yellow oil. The oil was dissolved in 0.5 mL of dichloromethane and 0.5 mL of ethylene diamine, and the yellow solution was stirred for 1.25 h, then partitioned between 5 mL of water and 10 mL of ethyl acetate. The aqueous layer was extracted with 10 mL of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated to give 0.087 g of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a pale yellow residue, which was used without further purification. MS: (M+Na)+=427. A major impurity is 2-chloro-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide. MS: (M+Na)+=381. Approximate 3:1 ratio of Br:Cl.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)C(C)C)(C)C.Cl[S:15]([C:18]1[CH:19]=[C:20]([C:24]2[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:36]([O:38][CH3:39])=[O:37])[CH:30]=3)[N:25]=2)[CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:16]>ClCCl>[CH3:2][N:3]([CH3:4])[S:15]([C:18]1[CH:19]=[C:20]([C:24]2[C:33]([CH3:34])([CH3:35])[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:36]([O:38][CH3:39])=[O:37])[CH:30]=3)[N:25]=2)[CH:21]=[CH:22][CH:23]=1)(=[O:16])=[O:17]
Reactant: CNC
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Cl)c1)=N2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N(C)C)c1)=N2
Yield: 25 %

Procedure:
To a stirred solution of dimethylamine hydrochloride (82 mg, 1.0 mmol) and N,N-diisopropylethyl amine (388 mg, 3.0 mmol) in dichloromethane (4 mL) was added a solution of methyl 2-(3-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (394 mg, crude product) in dichloromethane (4 mL). The mixture was purified on preparative Thin layer chromatography to afford 100 mg of methyl 2-(3-(N,N-dimethylsulfamoyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate, which was used directly.