Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[S:15]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16]1.C([O-])([O-])=O.[K+].[K+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:17]1[CH:18]=[CH:19][S:15][CH:16]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: OB(O)c1ccsc1
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1cccc2cc(C=O)c(-c3ccsc3)nc12
Temperature: 100 °C
Yield: 93.1 %

Procedure:
A mixture of 2-chloro-8-methylquinoline-3-carboxaldehyde (258 mg, 1.26 mmol), 3-thiopheneboronic acid (193 mg, 1.51 mmol), K2CO3 (260 mg, 1.88 mmol), palladium(II) acetate (5.6 mg, 0.025 mmol) and triphenylphosphine (26.3 mg, 0.10 mmol) in water (2 mL) was degassed. 1,4-Dioxane (6 mL) was added and the mixture further degassed, then heated at 100° C. for 1 h under microwave irradiation. The reaction mixture was diluted with DCM (30 mL) and water (10 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 10% EtOAc in heptane) gave the title compound (297 mg, 93%) as a colourless crystalline solid. δH (CDCl3) 10.40 (s, 1H), 8.75 (s, 1H), 7.83 (d, J 9 Hz, 1H), 7.60-7.73 (m, 3H), 7.46-7.54 (m, 2H), 2.85 (s, 3H). LCMS (ES+) 254.2 (M+H)+, RT 4.29 minutes (Method 3).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([OH:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[C:18]1([CH3:28])[CH:19]=[CH:20][C:21]([S:24]([OH:27])(=[O:25])=[O:26])=[CH:22][CH:23]=1.[NH2:1][C@H:2]([C:7]([O:9][CH2:28][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:8])[CH2:3][C:4]([O:6][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
One embodiment of the invention, in a method for the preparation of PALA compounds, comprises the steps of reacting L-aspartic acid with benzyl alcohol and p-toluenesulfonic acid to obtain L-aspartic acid, dibenzyl ester p-toluenesulfonate, reacting the L-aspartic acid, dibenzyl ester p-toluenesulfonate with triethylamine, adding phosphonoacetyl chloride to produce PALA dibenzyl ester; and separating the PALA dibenzyl ester from unreacted phosphonoacetyl chloride. The PALA dibenzyl ester is separated in any suitable way. Since it is insoluble in water, the PALA dibenzyl ester and unreacted phosphonoacetyl chloride preferably are separated by washing the reaction mixture with water to remove the phosphonoacetyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[Br:23]Br>C(O)(=O)C>[NH2:1][C:2]1[C:3]([Br:23])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)(=[O:16])=[O:15]
Reactant: BrBr
Reactant: NC(=O)c1[nH]c2c(N)cccc2c1S(=O)(=O)N1CCOCC1
Solvent: CC(=O)O
Product: NC(=O)c1[nH]c2c(N)c(Br)ccc2c1S(=O)(=O)N1CCOCC1
Reaction time: 0.5 h

Procedure:
To a solution of 7-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 7 (109 mg, 0.336 mmol) in 5 mL of acetic acid was added a 3.3 M stock solution of bromine in acetic acid (0.12 mL, 0.40 mmol). After 30 minutes, the mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by preparative reversed phase HPLC provided the titled compound. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C13H16BrN4O4S (M+H+): 403.0070. Found 403.0069.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[OH:31].Cl.Cl[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[O:31][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: ClCCN1CCCC1
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(O)c3)nc2-c2ccc3ncccc3c2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(OCCN4CCCC4)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 60 °C
Reaction time: 6 h
Yield: 53.2 %

Procedure:
To a stirred solution of 2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol (Example 81) (80 mg, 0.195 mmol) in acetone (6 mL) and DMF (3 mL) were added 1-(2-chloroethyl)pyrrolidine hydrochloride (50 mg, 0.292 mmol) and K2CO3 (81 mg, 0.585 mmol). The mixture was stirred at 60° C. for 6 hours, cooled to room temperature, and diluted with H2O (10 mL). The mixture was extracted with CH2Cl2 (25 mL, 3 times), and then the organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC on NH silica gel (MeOH:CH2Cl2=1:50 (v/v) to 1:20 (v/v)) to afford the title compound (52.7 mg, 53%). 1H NMR (300 MHz, CDCl3) δ 1.78 (4H, pentet), 2.51 (3H, s), 2.63 (4, td), 2.93 (2H, t), 4.16 (2H, s), 7.18 (2H, t), 6.85-6.90 (1H, m), 6.94-7.07 (3H, m), 7.24 (1H, s), 7.36 (1H, d), 7.41 (1H, dd), 7.97 (1H, dd), 8.09-8.18 (3H, m), 8.92 (1H, dd), 10.01 (1H, bs). MS (ESI) m/z 508 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[C:4](I)[CH:3]=1.N#N.[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[C:4](/[CH:19]=[CH:18]/[C:17]([O:21][CH3:22])=[O:20])[CH:3]=1
Reactant: Fc1cc(-n2cnnn2)c(I)cc1Cl
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CC#N
Product: COC(=O)/C=C/c1cc(Cl)c(F)cc1-n1cnnn1
Temperature: 85 °C

Procedure:
A solution of Intermediate 5B (100 g, 324.4 mmol) in ACN (1000 mL) was degassed with N2. TEA (64 mL) and methyl acrylate (60 mL) were added and the reaction was further degassed. Pd(OAc)2 (8 g, 11.8 mmol) was added and the reaction was heated to 85° C. for 18 h. The reaction was concentrated and the residue was diluted with H2O. The aqueous layer was extracted with EtOAc and the combined organics were washed with brine. Purification by silica gel chromatography gave 25 g Intermediate 5C. MS (ESI) m/z: 283.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:34]1([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CN1C(=O)CCC1>[CH:34]1([NH:40][C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCCCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NC4CCCCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and cyclohexylamine in NMP. ES-MS m/e (%): 468 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([P:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8])=[O:5].[P:17]([O-:22])([O:20][CH3:21])[O:18][CH3:19]>>[P:17]([O:5][CH:4]([P:6]([O:9][CH3:10])([O:7][CH3:8])=[O:11])[C:3]1[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:2]=1[CH3:1])([O:20][CH3:21])([O:18][CH3:19])=[O:22]
Reactant: COP(=O)(OC)C(=O)c1cc(C)ccc1C
Reactant: COP([O-])OC
Product: COP(=O)(OC)OC(c1cc(C)ccc1C)P(=O)(OC)OC

Procedure:
A mixture of 5.0 g (20.7 mmol) dimethyl 2,5-dimethylbenzoylphosphonate and 2.73 g (24.8 mmol) dimethyl phosphite was heated at 110° for 5 h. The excess of dimethyl phosphite and the unreacted benzoylphosphonate were removed under vacuum. The yellow viscous residue was then purified by column chromatography with chloroform as the eluent. Dimethyl α-(dimethoxyphosphinyl)2,5-dimethylbenzyl phosphate was obtained as a white oil (2.06 g, 29%); GLC and TLC analysis showed the compound to be pure.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])[C:15]([OH:17])=O)=[CH:10][CH:9]=1.C(N(CC)C(C)C)(C)C.[NH2:33][C:34]1[CH:35]=[C:36]([CH2:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH:37]=[CH:38][C:39]=1[C:40]#[N:41]>ClCCl.CN(C=O)C.C1COCC1.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]([C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])[C:15]([NH:33][C:34]2[CH:35]=[C:36]([CH2:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH:37]=[CH:38][C:39]=2[C:40]#[N:41])=[O:17])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(C#N)c(N)c1
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]([C@H](C(=O)Nc1cc(CCC(=O)OC(C)(C)C)ccc1C#N)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 155 μl (0.31 mmol) of a 2 M solution of oxalyl chloride in dichloromethane and one drop of DMF were added to a solution of 41.3 mg (0.16 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid in 1.16 ml of dichloromethane. After 1 h of stirring at 0° C., the mixture was concentrated, the residue that remained was dissolved in 1 ml of THF, 32 μl (0.19 mmol) of N,N-diisopropylethylamine were added, the mixture was cooled to 0° C. and a solution of 42 mg (0.17 mmol) of tert-butyl 3-(3-amino-4-cyanophenyl)propanoate in 2 ml of THF was added. The reaction mixture was stirred at RT overnight. The mixture was then poured into 10 ml of water and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. The residue was purified by preparative HPLC. This gave 16.5 mg (22% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:26]=[O:27])=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[BH4-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:26][OH:27])=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1OC
Yield: 32.7 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-methoxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.1320 g) in ethanol (30 ml) was gradually added sodium borohydride (114 mg) under stirring and the resultant mixture was further stirred at room temperature for an hour. The resultant mixture was acidified with dilute hydrochloric acid. After removing ethanol from the mixture, water was added to the residue to solidify. The solid was collected by filtration, dried and washed with diethyl ether. The diethyl ether washings were concentrated to the volume of about 10 ml and stood at room temperature to give pale yellowish granules (372.5 mg) of diethyl 2-methyl-4-(2-methoxyphenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 125° to 126° C.
Reaction SMILES: C1(O)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[N+](=[C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:26]=2)[O:21][CH2:20]1)=[N-]>>[CH2:31]([O:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH:19]([O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)[C:28]2=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: [N-]=[N+]=C1COc2ccc(OCc3ccccc3)cc2C1=O
Reactant: COc1ccc(O)cc1
Solvent: Oc1ccccc1
Product: COc1ccc(OC2COc3ccc(OCc4ccccc4)cc3C2=O)cc1

Procedure:
Replacing the phenol with a molar equivalent of 4-methoxyphenol, the method of Example 9 was employed to convert 3-diazo-6-benzyloxy-4-chromanone (22 g) to present title product, 6.8 g, m.p. 98°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cu](C#N)[C:20]#[N:21].[OH-].[NH4+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[N:21])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Reactant: N#C[Cu]C#N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.55 g, 5.0 mmol) in N,N-dimethylformamide (12.5 mL) was treated with copper cyanide (672 mg, 7.5 mmol). This mixture was heated at reflux for 21 h. The reaction mixture was cooled to 25° C. and poured into aqueous ammonium hydroxide (25 mL). The resulting solution was diluted with water (25 mL). This solution was extracted with ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous sodium chloride solution (3×75 mL), dried over sodium sulfate and magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.17 g, 91.3%) as a clear oil; EI-HRMS m/e calcd for C16H19NO2 (M+) 257.1415 found 257.1406.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:25][S:26]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 20 h

Procedure:
The alcohol from Example 1 (33.1 g) and 20 ml of triethylamine were dissolved in 350 ml of dichloromethane, cooled to 0° C., and treated with 11 ml methanesulfonyl chloride. After being stirred at room temperature for about 20 hours, the reaction mixture was diluted with dichloromethane (100 ml) and the organic layer was washed with three 50-ml portions of water and one of brine. Drying and concentration in vacuo gave the crude product which gradually crystallized upon standing. The solid was washed with diethyl ether, filtered, and dried to yield 12.0 g of 2-[2-(methylsulfonyloxy)ethyl]-N-(1,1-dimethylethyl)benzenesulfonamide as a white powder; m.p. 106°-108° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[F:14][C:15]([F:34])([F:33])[C:16]1[O:20][C:19]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[C:23]2=[O:32])=[CH:18][CH:17]=1>O1CCCC1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:24]2([OH:31])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:22]([CH2:21][C:19]3[O:20][C:16]([C:15]([F:34])([F:33])[F:14])=[CH:17][CH:18]=3)[C:23]2=[O:32])=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1ccc(Br)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a stirred solution of 3-bromophenol (4.4 g, 25.4 mmol) in tetrahydrofuran (100 mL) was added iso-propylmagnesium chloride (12.7 mL, 2 M tetrahydrofuran solution, 25.4 mol) slowly at 0° C. The mixture was allowed to stir for 30 min at 0° C., then the solvent was removed in vacuo. Dichloromethane (100 mL) was added, followed by the addition of a solution of 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione (5.0 g, 16.9 mol) in dichloromethane (100 mL) at 0° C. The mixture was stirred at ambient temperature for 16 h, quenched by the addition of saturated ammonium chloride solution. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The obtained solid was recrystallized from ethyl acetate/hexanes to afford 3-(4-bromo-2-hydroxyphenyl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (6.4 g, 81%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.49-5.83 (m, 9H), 5.13-4.71 (m, 2H); MS (ES+) m/z 449.9 (M−17), 451.9 (M−17).
Reaction SMILES: [N:1]1([NH:14][CH:15]([CH3:17])[CH3:16])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:30].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.O>[CH:15]([NH:14][N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:30])[C:4]=2[N:3]=[CH:2]1)([CH3:17])[CH3:16]
Reactant: [NH4+]
Reactant: CC(C)Nn1cnc2cnc3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)Nn1cnc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-(1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (1.36 g, 5.66 mmol) in 50 mL of chloroform was cooled in a cold water bath. The solution was treated with MCPBA (2.03 g, 7.07 mmol) over 5 min and then allowed to warm to ambient temperature. After 1 h, TLC showed complete conversion to the intermediate 5-N-oxide. The reaction mixture was again cooled with a cold water bath. The solution was treated with concentrated ammonium hydroxide solution (25 mL, 30%) and stirred rapidly to homogenize. The reaction mixture was treated with p-toluenesulfonyl chloride (1.13 g, 5.94 g) over 5 min and allowed to warm to ambient temperature. After 30 min, the reaction mixture was diluted with 50 mL of CHCl3 and 25 mL of water. An undissolved solid between the phases was filtered off, saved, and the phases were separated. The organic portion was washed with saturated NaHCO3 solution (30 mL), water (30 mL) and brine (30 mL). The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to yield a tan/orange solid. A high-performance liquid chromatography (HPLC) analysis of the filtered solid matched that of the solid from the concentrated organic extracts. The combined solid was recrystallized twice from MeOH to give 1.18 g of N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine as an off-white solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:25]([O:8][C:1](=[O:9])[C@@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C[C@@H](O)C(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(O)C[C@@H](O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64 %

Procedure:
To a solution of D-malic acid (18.8 g., 140.2 mmole) in 150 ml. of freshly-distilled THF was added dicyclohexylcarbodiimide (DCC, 1.1 equiv.) and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was filtered to remove the precipitate of dicyclohexylurea which formed. The precipitate was washed with two 50 ml. portions of THF and the washings were combined with the filtrate. To the combined filtrate and washings were added two equivalents of benzyl alcohol and the solution was stirred overnight at room temperature. The reaction mixture was evaporated to remove the solvent and the residual oil containing the monoester was dissolved in 100 ml. of ethyl acetate. The solution was extracted with three 50 ml. portions of a 10% solution of sodium carbonate in water and the extracts were combined, acidified to pH 2 and extracted with three 50 ml. portions of ethyl acetate. The extracts were combined, washed with 25 ml. of brine, dried over magnesium sulfate, filtered, and then evaporated to dryness to yield D-malic acid monobenzyl ester as an oil in 64% yield.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([CH3:11])[CH:7]=1)(=[O:3])[CH3:2].CC(O)=O.[Br:16]N1C(=O)CCC1=O.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>>[C:1]([O:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([CH3:11])[C:7]=1[Br:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(C)no1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCc1onc(C)c1Br
Temperature: 110 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of (3-methylisoxazol-5-yl)methyl acetate (0.979 g, 6.31 mmol) in AcOH (10 mL, 175 mmol) was added N-bromosuccinimide (1.30 g, 7.30 mmol) and H2SO4 (0.65 mL, 12.19 mmol). The reaction was heated to 110° C. After 1 h, the reaction mixture was cooled to room temperature and carefully poured into a beaker containing ice and saturated NaHCO3. The bi-phasic was vigorously stirred and basic solution (pH ˜8-9) was extracted with EtOAc (2×15 mL). The organic layer was washed with 2% sodium thiosulfate, washed with brine (20 mL), dried over Na2SO4, and concentrated to give a light yellow oil. The oil was purified on Biotage system (isocratic elution 10% EtOAc:90% Hexanes) to give the titled compound (1.30 g, 5.55 mmol, 88% Yield) as a colorless yellow oil. LC/MS m/z 234 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)C(C)C)(C)C.[F:20][C:21]([F:36])([F:35])[C:22]([O:25][C:26](=O)[O:27]C1C=CC=CN=1)([CH3:24])[CH3:23]>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C@@H:2]([NH:1][C:26]([O:25][C:22]([CH3:24])([CH3:23])[C:21]([F:36])([F:35])[F:20])=[O:27])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: CC(C)(OC(=O)Oc1ccccn1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C(F)(F)F)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To an ice-cooled solution of (S)-methyl 2-amino-3,3-dimethylbutanoate (0.411 g, 2.262 mmol) in DCM (20 mL) was added N,N-Diisopropylethylamine (1.182 mL, 6.79 mmol). The formed solution was stirred for 5 min before addition of carbonic acid pyridin-2-yl ester 2,2,2-trifluoro-1,1-dimethyl-ethyl ester (1.24 g, 4.98 mmol, from step 1a) in DCM (10 mL). The final light yellow solution was stirred at room temperature overnight. The reaction mixture was washed with 5% citric acid aqueous solution, 0.1 M NaOH aqueous solution, and brine, then dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by silica gel column, eluted with (4:1) hexane-EtOAc to afford a colorless oil as the product (673 mg, 99%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([Br:12])[N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>>[Br:12][C:10]1[N:11]=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)=[N:14][S:13][C:9]=12
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(F)cc3)c2c1O
Product: O=C(O)CNC(=O)c1nc(Br)c2snc(-c3ccc(F)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-bromo-3-(4-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 423.9, 426.0 (M−1).