Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([CH3:26])([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:9](N[C@H](C2C=CC=CC=2)CO)=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:28]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([CH3:26])([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:9]([OH:10])=[O:28])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)CC[C@@](C)(C(=O)N[C@@H](CO)c1ccccc1)c1ccc(F)cc1
Solvent: C1COCCO1
Product: CC(C)CC[C@@](C)(C(=O)O)c1ccc(F)cc1
Yield: 100 %

Procedure:
A solution of the product of Example 22D (6.15 g, 17.2 mmol) in dioxane (100 mL) was treated with 4 M sulfuric acid solution (100 mL), and the mixture was warmed at reflux for 48 h. The solution was cooled and extracted with dichloromethane (3×). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford the title compound (4.16 g, 100%) as an amber oil. 1H NMR (300 MHz, CDCl3): δ 0.86 (t, J=6.43 Hz, 6 H) 1.05 (m, 2 H) 1.51 (m, 4 H) 1.96 (m, 2 H) 7.02 (m, 2 H) 7.34 (m, 2 H). Specific Rotation: [□]D−10.6°(c 2.15, EtOH).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[NH:11]([C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][N:3]=1)[NH2:12]
Reactant: NN
Reactant: Cc1cnc(Br)cc1C
Solvent: CCO
Solvent: O
Product: Cc1cnc(NN)cc1C

Procedure:
3.8 g (18.4 mmol, purity 90%) of the compound from Example 20A are initially charged in 12.5 ml of ethanol. 8.9 ml (9.2 g, 183.8 mmol) of hydrazine hydrate are added, and the mixture is reacted in a single-mode microwave oven (CEM Explorer) at 170° C. (100 Watt) for 2 h. The reaction solution is then concentrated, and the residue is taken up in ethyl acetate and washed in each case once with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18]([OH:20])=O)=[C:8]2[N:3]1[CH:4]=[CH:5][C:6]1[CH:23]=[CH:22][S:21][C:7]=12.S(Cl)(Cl)=O.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[Cl-].[Na+]>O1CCOCC1.O>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:18]([C:9]2[CH:10]=[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:2](=[O:1])[N:3]3[C:8]=2[C:7]2[S:21][CH:22]=[CH:23][C:6]=2[CH:5]=[CH:4]3)=[O:20])[CH2:31][CH2:30]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2ccc3ccsc3c12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CN1CCN(C(=O)c2cc(-c3ccccc3)c(=O)n3ccc4ccsc4c23)CC1
Temperature: 25 °C

Procedure:
1.93 g of 7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylic acid were converted into the acid chloride with 2.65 ml of thionyl chloride as described. This acid chloride was taken up in 80 ml of dioxane, treated with 2.7 ml of N-methylpiperazine, and the mixture was then stirred at room temperature until the reaction was completed and poured into 200 ml of water. The aqueous phase was saturated with sodium chloride and extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. By recrystallization from toluene there was obtained 1-methyl-4-[(7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizin-10-yl)carbonyl]piperazine as yellow crystals of m.p. 233°-234° (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[NH:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[C:6]=2[N:22]=1.[N:23]1([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:34]3[CH:35]=[CH:36][C:31]([O:30][CH2:29][CH2:28][N:23]4[CH:27]=[CH:26][N:25]=[CH:24]4)=[CH:32][CH:33]=3)=[N:22][C:6]1=2
Reactant: OB(O)c1ccc(OCCn2ccnc2)cc1
Reactant: Fc1ccc(F)c(CN2CCCNc3ncc(Br)nc32)c1Cl
Product: Fc1ccc(F)c(CN2CCCNc3ncc(-c4ccc(OCCn5ccnc5)cc4)nc32)c1Cl

Procedure:
The entitled compound can be prepared from 2-Bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine and 4-(2-(1H-imidazol-1-yl)ethoxy)phenyl boronic acid as described in example 1 or 30.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]([N:35]3[CH2:36][CH2:37][N:32]([C:30]4[S:29][N:28]=[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:31]=4)[CH2:33][CH2:34]3)=[O:20])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccc(-n2ccnc2)cc1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(-n2ccnc2)cc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl [4-(1H-imidazol-1-yl)phenyl]carbamate (200 mg, 0.598 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (147 mg, 0.598 mmol), diisopropylethylamine (0.104 ml, 0.598 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (71.0 mg, 35.4%) as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([CH3:17])[CH2:15][OH:16]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)CO)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CO)N1CCNCC1
Reaction time: 3 h

Procedure:
To a solution of 4-(2-hydroxy-1,1-dimethylethyl)piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.43 mmol) in DCM (3 mL) was added TFA (1 mL) and the resulting mixture stirred for 3 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as an off-white solid (62 mg, 91%). 1H NMR (CDCl3, 400 MHz): δ 3.32 (2H, s), 2.90 (5H, t, J=4.78 Hz), 2.38-2.13 (4H, m), 1.03 (6H, s)
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[OH:11])[CH2:8]2.CN(C)C1C=CC=CC=1.[C:21](Cl)([Cl:23])=[O:22].C(=O)=O>CCOCC.C1(C)C=CC=CC=1>[Cl:23][C:21]([O:11][CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)=[O:22]
Reactant: OC1C2CC3CC(C2)CC1C3
Reactant: O=C(Cl)Cl
Agent: O=C=O
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Temperature: 25 °C

Procedure:
15.2 g (0.10 mole) of 2-adamantanol and 12.1 g (0.10 mole) of N,N-dimethylaniline were dissolved in 200 ml of dry ether and added to 105 ml (0.20 mole) of phosgene in toluene (20%) over a period of 1 hour. The reaction flask was kept at 0° C. and was equipped with a stirrer and a dry ice condensor. The product was stirred at room temperature for another hour, after which the solution was cooled on ice and 10 ml of ice cold water was added carefully. The water and the toluene phases were quickly separated and the toluene was quickly washed with 50 ml of 0.5N HCl, 50 ml of 0.5N NaOH and 50 ml of H2O. The toluene solution was dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in dry n-hexane and filtered. The hexane was evaporated and the residue was distilled in vacuo to give 2-adamantanyl chloroformate bp15 135° C., nD19 1.521, IR (CO) 1770 cm-1.
Reaction SMILES: [C:1]1([C:7]2([NH2:11])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:12]=[C:13]1[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]1[CH2:30][C:31](O)=[O:32].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:12]=[C:13]1[C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]1[CH2:30][C:31]([NH:11][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:10][CH2:9][CH2:8]1)=[O:32]
Reactant: NC1(c2ccccc2)CCC1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NC1(c2ccccc2)CCC1
Reaction time: 8 h

Procedure:
A solution of 1-phenylcyclobutanamine (0.030 g, 0.204 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (0.055 g, 0.185 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.036 g, 0.185 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.31-7.39 (m, 7H), 7.17-7.31 (m, 8H), 6.42-6.44 (br s, 1H), 3.94 (s, 2H), 3.46 (t, J=6.5 Hz, 2H), 2.79 (t, J=6.5 Hz, 2H), 2.42-2.52 (m, 2H), 2.19-2.30 (m, 2H), 1.71-1.95 (m, 2H); MS (ESI−) m/z 423 (M−H)−.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:41][C@H:42]([C:50]([CH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15]([NH:41][C@H:42]([C:50]([CH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)CCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)CCc1ccccc1
Yield: 73.8 %

Procedure:
To a solution of Boc-D-Trp(CHO)-OH (0.92 g) in methylene chloride (15 ml) were added NMM (0.28 ml) and isobutyl chloroformate (0.36 ml) successively at -15° C., and the mixture was stirred for ten minutes. On the other hand, a solution of HCl.H-Phe-(CH2)2Ph (0.80 g) in methylene chloride (15 ml) was cooled at -30° C. and thereto was added NMM (0.28 ml). This solution was added to the above mentioned mixture at -50° C., and stirred for an hour at -50° C. and then stirred for 2 hours at room temperature. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with 2% hydrochloric acid, water, 2% sodium hydrogen carbonate solution, water, and saturated sodium chloride solution, and dried over magnesium sulfate. After evaporation, the residual white crystals were filtered and washed with n-hexane. The crystals were recrystallized from ethanol to give Boc-D-Trp(CHO)-Phe-(CH2)2Ph (1.16 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].O[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N(C(OCC)=O)(C(OCC)=O)N>C(OCC)(=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:2]([O:1][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:3]=1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)N(N)C(=O)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC)c(OCCN2CCOCC2)c1
Reaction time: 8 h

Procedure:
To stirred solution of methyl 3-hydroxy-4-methoxybenzoate (2.00 g, 11.0 mmol), 4-(2-hydroxyethyl)morpholine (1.58 g, 12.0 mmol) and triphenylphosphine (3.17 g, 12.1 mmol) in ethyl acetate (60 mL) was added, dropwise, diethyl azodicarboxylate (1.9 mL, 12.1 mmol). The reaction was allowed to proceed overnight and then diluted with additional ethyl acetate and extracted with 1 N aqueous hydrochloric acid. The aqueous layer was washed with ethyl acetate, basified with concentrated ammonium hydroxide and then extracted with ethyl acetate. The organic extract was dried (sodium sulfate) and concentrated to afford 3.25 g of a 92:8 mixture of product (95%) and diethyl hydrazinedicarboxylate as an amber oil. This material was used without further purification in the next step: 1H NMR (CDCl3) δ 7.69 (dd, J=8.4, 2.0 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.20 (t, J=6.0 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.77-3.72 (m, 4H), 2.87 (t, J=6.0 Hz, 2H), 2.65-2.57 (m, 4H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([Cl:20])[C:4]=2[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>C(OCCO)C>[ClH:20].[F:1][C:2]1[CH:18]=[CH:17][C:16]2[NH+:15]([CH3:19])[C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([S:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[C:4]=2[CH:3]=1
Reactant: Cn1c2c3ccccc3nc-2c(Cl)c2cc(F)ccc21
Reactant: Sc1ccc(Cl)cc1
Solvent: CCOCCO
Product: C[NH+]1C2=c3ccccc3=NC2=C(Sc2ccc(Cl)cc2)c2cc(F)ccc21
Product: Cl
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of 2-fluoro-5-methyl-11-chloroquindoline from Example 24 (56 mg, 0.209 mmol) in 2-ethoxyethanol (5 mL) was added 4-chlorothiophenol (36 mg, 120 mol %). The reaction mixture was refluxed for 10 min, during which time the reaction mixture became orange and an orange precipitate formed. The reaction mixture was cooled to room temperature, filtered, and the solid was washed with ether and dried, affording 60 mg (73%) of the title compound, mp 254-256° C.; 1H NMR (DMSO-d6) δ 13.18 (s, 1H, NH), 9.00 (dd, 1H, J=4.4, J=5.2), 8.85 (d, 1H, J=8.4), 8.36 (d, 1H, J=8.0), 8.15 (t, 1H, J=7.2), 7.98 (d, 1H, J=8.0), 7.57 (t, 1H, J=7.2), 7.38-7.33 (m, 4H), 5.10 (s, 3H); 13C NMR (DMSO-d6) δ 161.64, 159.15, 146.27, 138.88, 138.15, 134.90, 132.65, 132.35, 132.07, 130.45, 129.66, 128.60, 126.98 122.77, 122.67, 121.67, 121.41, 114.55, 113.64, 109.83, 109.58, 41.29; MS (FAB, m/z) 393 (M+)
Reaction SMILES: [NH2:1][CH:2]1[CH:5]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])[N:4]([Si](C(C)(C)C)(C)C)[C:3]1=[O:18].C(N(C(C)C)CC)(C)C.[C:28](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O.O>[CH2:7]([O:6][CH:5]1[NH:4][C:3](=[O:18])[CH:2]1[NH:1][C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH:8]([CH3:9])[CH3:10]
Reactant: CC(C)COC1C(N)C(=O)N1[Si](C)(C)C(C)(C)C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)COC1NC(=O)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
A solution of (3RS,4RS)-3-amino-1-(tert-butyldimethylsilyl)-4-(isobutoxy)azetidin-2-one (0.2 g) was dissolved in dimethylformamide (8 mL), cooled in an ice bath, and treated with diisopropylethylamine (0.1 mL) followed by trityl chloride (167 mg, 0.6 mmol). The mixture was stirred for 18 h, diluted with water (40 mL) and extracted with ethyl acetate. The combined organic phase was dried (magnesium sulfate), concentrated, and the residue was chromatographed on silica gel eluted with 20% ethyl acetate:hexane to give the title compound. MS(ES) m/e 515 [M+H]+.
Reaction SMILES: C1C2C(COC(N[C@H](C(O)=O)CSC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.NCC[C:48]1[CH:55]=[CH:54][C:52](O)=[C:50]([OH:51])[CH:49]=1.C1C2C(CO[C:71]([NH:73][C@H:74]([C:96]([NH:98][CH2:99][CH2:100][C:101]3[CH:108]=[CH:107][C:105]([OH:106])=[C:103]([OH:104])[CH:102]=3)=[O:97])[CH2:75][S:76][C:77]([C:90]3[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=3)([C:84]3[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=3)[C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)=[O:72])C3C(=CC=CC=3)C=2C=CC=1.[F:109]C1(O)C=CC=CC1C(O)=O>>[F:109][C:48]1[CH:55]=[CH:54][CH:52]=[C:50]([OH:51])[C:49]=1[C:71]([NH:73][C@H:74]([C:96]([NH:98][CH2:99][CH2:100][C:101]1[CH:108]=[CH:107][C:105]([OH:106])=[C:103]([OH:104])[CH:102]=1)=[O:97])[CH2:75][S:76][C:77]([C:84]1[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=1)([C:90]1[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=1)[C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1)=[O:72]
Reactant: O=C(O)C1C=CC=CC1(O)F
Reactant: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCc1ccc(O)c(O)c1)OCC1c2ccccc2-c2ccccc21
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Product: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCc1ccc(O)c(O)c1)c1c(O)cccc1F

Procedure:
Commercially available Nα-(9-Fluorenylmethoxycarbonyl)-S-trityl-L-cysteine (1.7 g, 2.9 mmol) was coupled with dopamine hydrochloride (825 mg, 4.3 mmol) according to the indications of general procedure F. The crude N-[Nα-(9-fluorenylmethoxycarbonyl)-S-trityl-L-cysteinyl]dopamine (618 mg, 0.86 mmol) was deprotected according to the indications of general procedure G. The resulting intermediate was then coupled with 2-fluorosalicylic acid (202 mg, 1.3 mmol) according to the indications of general procedure D. The final product was purified by flash chromatography using 99% CH2Cl2/1% AcOH and successively 5% then 10% AcOEt/CH2C2/1% AcOH to yield the desired derivative (260 mg, 48%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[O:15][CH:16]=[C:17]([C:19](O)=[O:20])[N:18]=1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:17]3[N:18]=[C:14]([CH3:13])[O:15][CH:16]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc(C(=O)O)co1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)co1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-methyloxazole-4-carboxylic acid (276 mg, 2.17 mmol), triethylamine (606 μL, 4.35 mmol), and BOP-Cl (203 mg, 2.17 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 4 hours. Next, 2M LiOH. H2O (3 mL) was added, and after 30 minutes water (10 mL) was added. The solid formed was filtered, washed with water (2×5 mL) and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyloxazole-4-carboxamide (165 mg, 56% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.15 (s, 1H), 9.68 (s, 1H), 8.63 (s, 1H), 8.37 (d, 1H), 7.67 (s, 1H), 2.52 (s, 3H); LCMS (APCI+) m/z 338.9, 341.0 (M+H)+, Retention time=3.21 minutes (Method 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][OH:22])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:23][CH3:24])[CH:3]=1.O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([O:35][CH3:36])=[O:34].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: COc1cc(F)ccc1-c1ccc2c(c1CO)C(C)=CC(C)(C)N2
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COC(=O)Cc1ccccc1OCc1c(-c2ccc(F)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
6-(4-Fluoro-2-methoxyphenyl)-5-hydroxymethyl-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-3, 100.1 mg, 0.31 mmol), methyl 2-hydroxyphenylacetate (76.1 mg, 0.46 mmol), tri-butylphosphine (114 μL, 0.46 mmol), and 1,1′-(azodicarbonyl)dipiperidine (117 mg, 0.46 mmol) were dissolved in anhydrous benzene (2 mL), and the mixture was stirred under argon atmosphere at room temperature for 1 hour. Hexane (5 mL) was added to the reaction mixture and unsoluble materials were filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (107.1 mg) as a colorless amorphous product. (Yield 74%)
Reaction SMILES: C([O:8][C:9](=[O:54])[C@H:10]([NH:22][C:23](=[O:53])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([CH2:36][NH:37][CH2:38][C@H:39]([OH:52])[C:40]3[CH:45]=[CH:44][C:43]([OH:46])=[C:42]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:41]=3)[CH2:32][CH2:31]2)=[CH:26][CH:25]=1)[CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])C1C=CC=CC=1>[Pd].C(O)C.C1CCCCC=1>[OH:52][C@H:39]([C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[C:42]([NH:47][S:48]([CH3:51])(=[O:49])=[O:50])[CH:41]=1)[CH2:38][NH:37][CH2:36][CH:33]1[CH2:32][CH2:31][N:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([NH:22][C@H:10]([CH2:11][C:12]([OH:14])=[O:13])[C:9]([OH:54])=[O:8])=[O:53])=[CH:25][CH:26]=2)[CH2:35][CH2:34]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(c3ccc(C(=O)N[C@H](CC(=O)OCc4ccccc4)C(=O)OCc4ccccc4)cc3)CC2)ccc1O
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(c3ccc(C(=O)N[C@H](CC(=O)O)C(=O)O)cc3)CC2)ccc1O
Yield: 12.3 %

Procedure:
A mixture of (2R)-2-{[4-(4-({[(2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)-amino]-phenyl}ethyl)amino]methyl}piperidin-1-yl)benzoyl]-amino}butanedioic acid dibenzyl ester (0.110 g, 0.14 mmol) and 0.11 g of 10% palladium on carbon in ethanol (3 mL) and cyclohexene (1 mL) was heated at reflux for 3 hours. When complete, the catalyst was filtered (Celite) and the cake was washed with hot methanol. The solvent was removed under reduced pressure, to give the title compound (0.010 g).
Reaction SMILES: [NH2:1][C:2]1NO[C:5]2[CH:11]=CC=C[C:6]=2[CH:7]=1.F[C:13](F)(F)[C:14](=O)[CH2:15][C:16]([O-:18])=O.S(=O)(=O)(O)O>>[NH:1]1[C:2]2[C:13](=[CH:11][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:15][C:16]1=[O:18]
Reactant: NC1=Cc2ccccc2ON1
Reactant: O=C([O-])CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=c1ccc2ccccc2[nH]1

Procedure:
Quinolinones (e.g., Structure 35) are prepared from benzoxazines (e.g., Structure 34) by the synthetic route outlined in Scheme VII. Scheme VII begins with an alkylation of a haloketone onto 2-amino-5-nitrophenol (Structure 1) with, for example, 2-bromobutanone, mediated by a base, for example, potassium carbonate, followed by treatment with a reducing agent, for example, sodium cyanoborohydride, in an acid, for example acetic acid, to afford a benzoxazine compound (e.g., Structure 32). The benzoxazine is alkylated at the benzoxazine nitrogen by treatment of a benzoxazine compound (e.g., Structure 32) with an aldehyde, its corresponding hydrate or hemiacetal, with for example, trifluoroacetaldehyde hydrate in the presence of a reducing agent, for example, sodium cyanoborohydride, in an acid, for example trifluoroacetic acid. This procedure affords an alkylated benzoxazine compound (e.g., Structure 33). The nitro derivative of the alkylated benzoxazine compound (Structure 33) is reduced to the corresponding aniline by catalytic hydrogenation or with a reducing agent, for example, zinc and calcium chloride, to afford benzoxazine compound (e.g., Structure 34). Knorr cyclization of an aminobenzoxazine (e.g., Structure 34) by heating with a β-ketoester or corresponding hydrate, with for example, 4,4,4-trifluoroacetoacetate, followed by treatment with an acid, for example, sulfuric acid, affords a quinolinone product (e.g., Structure 35).