Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH2:24][CH3:25])[C:21]([CH2:26][O:27][CH2:28][CH3:29])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1>[Pd].C(O)C>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]([CH2:26][O:27][CH2:28][CH3:29])[N:22]([CH2:23][CH2:24][CH3:25])[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=2[N:16]=1
Reactant: CCCn1c(COCC)nc2c(N)nc3cc(OCc4ccccc4)ccc3c21
Agent: [Pd]
Solvent: CCO
Product: CCCn1c(COCC)nc2c(N)nc3cc(O)ccc3c21
Reaction time: 18 h
Yield: 80 %

Procedure:
7-Benzyloxy-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (3.9 g, 9.99 mmol), prepared in Example 44, was mixed with ethanol and added to a Parr flask charged with 10% palladium on carbon (0.390 g) in ethanol. The flask was placed under hydrogen pressure and shaken for 18 hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with warm DMF. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to yield 2.4 g of 4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol as a white solid, mp>250° C.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[NH:11][C:10]([O:9][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])=[O:25])=[CH:18][CH:19]=2)=[CH:33][CH:32]=1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3)cc2)cc1

Procedure:
Following the procedure described in Example 17, Step 2, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester and 4-ethoxycarbonylphenylboronic acid were reacted to provide 4′-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-carboxylic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].CC([O-])(C)C.[K+].F[C:13]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1.O>[F:1][CH:2]([F:5])[CH2:3][O:4][C:13]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: OCC(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1OCC(F)F
Reaction time: 0.08 h

Procedure:
A mixture of 2,2-difluoroethanol (0.178 mL, 2.82 mmol) and KOtBu (0.319 g, 2.70 mmol) in 10 mL THF was stirred for 5 min, then ethyl 2-fluoro-5-nitrobenzoate (0.500 g, 2.35 mmol) was added and it was stirred at rt overnight. Additional 60 μL 2,2-difluoroethanol and 110 mg KOtBu were added and it was stirred for 2 h. The mixture was diluted with H2O, concentrated i.vac. and extracted 2× with EtOAc. The combined organic layers were dried with Na2SO4 and concentrated to furnish the subtitle compound. Yield: 0.52 g (81%); TLC: Rf=0.85 (silica gel, DCM:EtOH 99:1).
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9])[CH:5]([CH3:7])[CH3:6].C(N(CC)CC)C.[C:30](Cl)(=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C:30]([NH:3][C@@H:4]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[CH2:12][CH2:11]2)=[O:9])[CH:5]([CH3:6])[CH3:7])=[O:39])=[CH:32][CH:33]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(C2CCN(C)CC2)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N[C@@H](C(=O)N2CCC(C3CCN(C)CC3)CC2)C(C)C)cc1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
1-D-Valinyl-4-(1-methylpiperidin-4-yl)piperidine dihydrochloride (15.6 g, 44.1 mmol) is slurried in anhydrous CH2Cl2 (400 mL); and to the slurry is added triethylamine (19.7 mL, 141.0 mmol), followed by p-anisoyl chloride (7.9 mL, 52.9 mmol). The reaction is allowed to stir for about 30 min and then quenched with the addition of saturated NaHCO3 (300 mL), followed by the separation of the phases. The organic layer is washed with saturated NaHCO3 (2×300 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by chromatography over silica gel, eluting with 2.5% (2 M NH3 in MeOH)/CHCl3 to give 16.3 g (89%) of the title compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[F:23][C:24]1[C:25]([NH2:31])=[N:26][C:27](=[O:30])[NH:28][CH:29]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[NH2:31][C:25]1[C:24]([F:23])=[CH:29][N:28]([C:19]2[CH:20]=[CH:21][C:16]([N:14]3[CH:15]=[C:11]([CH2:10][NH:9][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])[N:12]=[CH:13]3)=[CH:17][CH:18]=2)[C:27](=[O:30])[N:26]=1
Reactant: Nc1nc(=O)[nH]cc1F
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Nc1nc(=O)n(-c2ccc(-n3cnc(CNC(=O)c4ccc(Cl)s4)c3)cc2)cc1F
Temperature: 130 °C
Yield: 18.7 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 (80 mg, 0.18 mmol), 5-fluorocytosine (60 mg, 0.46 mmol), 8-hydroxyquinoline (12 mg, 0.083 mmol) and K2CO3 (60 mg, 0.43 mmol) in DMSO (2 mL) was degassed with Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was heated at 130° C. overnight. The mixture was then purified by HPLC to give the titled compound (15 mg). MS 445.2 and 447.2 (M+H, Cl pattern).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.CO.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[CH:30]1([C:33]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:15]=[CH:16][C:17]=2[CH3:18])[N:5]=3)=[O:34])[CH2:32][CH2:31]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc2nc(N)sc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of benzyl {3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}carbamate (25.1 g, 61.9 mmol) in pyridine (200 mL) was added cyclopropanecarbonyl chloride (9.47 mL, 105 mmol) at 0° C., and the mixture was stirred at room temperature for 30 min. Methanol (100 mL) and potassium carbonate (8.55 g, 61.9 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration, and washed successively with methanol (200 mL), water (100 mL), methanol (100 mL) and hexane (100 mL) to give the title compound (23.9 g, 81%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:8][CH:7]=1.O>CN(C)C=O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH3:3])=[CH:10][CH:11]=1
Reactant: OCCCCc1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 88 %

Procedure:
Sodium hydride (purity: 55%, 434 mg) and methyl iodide (0.62 mL) were added to a solution of 4-(4-bromophenyl)butan-1-ol obtained in Reference Example 5-21(1) in N,N-dimethylformamide (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 7.5 hours. Water was added to the reaction solution, followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1→20:1→10:1) to give the title compound (1.06 g, 88%).
Reaction SMILES: FC1C=CC(C(Cl)=O)=CC=1.C[O:12][C:13](=[O:46])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([N:34]([C:42](=[O:44])[CH3:43])[C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:26][C@@H:25]2[CH3:45])=[O:23])=[CH:18][CH:17]=1.[Li+].[OH-]>C1COCC1.CO>[C:42]([N:34]([C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C@H:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH:15]=[CH:14][C:13]([OH:46])=[O:12])=[CH:17][CH:18]=2)=[O:23])[C@@H:25]([CH3:45])[CH2:26]1)(=[O:44])[CH3:43]
Reactant: COC(=O)C=Cc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: O=C(Cl)c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C=CC(=O)O)cc2)c2ccccc21
Yield: 94.1 %

Procedure:
(2S,4R)-3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-acrylic acid was prepared following general procedure C, substituting 3-(4-chlorocarbonyl-phenyl)-acrylic acid methyl ester for 4-fluorobenzoyl chloride. The ester was hydrolyzed as follows. To a solution of (2S,4R)-3-(4-{4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-acrylic acid methyl ester (112 mg, 0.239 mmol) in THF/MeOH (2 ml, 2 ml) was added LiOH (4 ml: 1.0 M in H2O). Upon consumption of the starting unit (1 hour), the mixture was neutralized with aq. HCl (1.0 M), partioned with EtOAc (10 ml) and separated. The organic layer was separated and concentrated whereby the resulting oil was subjected to silica gel chromatography (2% MeOH in EtOAc to 10% MeOH in EtOAc) to afford the title compound (110 mg, 99%).
Reaction SMILES: N(S([O-])(=O)=O)(S([O-])(=O)=O)[O].[K+].[K+].Cl.[Cl:14][C:15]1[C:24]([Cl:25])=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH2:22]2)=[CH:17][CH:16]=1>C(=O)([O-])[O-].[Na+].[Na+]>[Cl:14][C:15]1[C:24]([Cl:25])=[C:23]2[C:18]([CH2:19][CH2:20][N:21]=[CH:22]2)=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(c1Cl)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2c(c1Cl)C=NCC2
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a mixture of 1 liter 5 percent aqueous sodium carbonate and 62.6 g. (0.233 mole) potassium nitrosodisulfonate was added 21.9 g. (0.092 mole) 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride and then 0.1 liter 5 percent aqueous sodium carbonate. The reaction mixture was stirred at room temperature for 23 hours. The reaction mixture was then extracted with methylene chloride (3×250 ml.). The combined extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to afford a crude intermediate. The crude intermediate was recrystallized from ethyl acetate to yield 7,8-dichloro-3,4-dihydroisoquinoline as a yellow solid with a melting point of 56°-60° C. 7,8-Dichloro-3,4-dihydro isoquinoline was converted to the desired 7,8-dichloro-1-isopropyl-1,2,3,4-tetrahydroisoquinoline via a Grignard reaction with isopropylmagnesium iodide. 7,8-Dichloro-1-isopropyl-1,2,3,4-tetrahydroisoquinoline hydrochloride has a melting point of 196°-200° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([O:21]C)=[O:20])[C:11](=[O:18])[N:12](CC(C)C)[N:13]=2)=[CH:4][C:3]=1C.[F:24]C1C=C(C(=O)CC(C(OCC)=O)(O)C(OCC)=O)C=CC=1F>>[C:19]([C:10]1[C:11](=[O:18])[NH:12][N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([F:24])[CH:4]=2)[CH:9]=1)([OH:21])=[O:20]
Reactant: CCOC(=O)C(O)(CC(=O)c1ccc(F)c(F)c1)C(=O)OCC
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(CC(C)C)c1=O
Product: O=C(O)c1cc(-c2ccc(F)c(F)c2)n[nH]c1=O
Yield: 88.9 %

Procedure:
Following the procedure of Example 1 (4), ethyl 4-(3,4-difluorophenyl)-2-ethoxycarbonyl-2-hydroxy-4-oxo-butanoate was reacted to yield the title compound as a pale yellow crystalline powder (yield: 88.9%).
Reaction SMILES: [CH2:1]([CH:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=O)[CH:2]([CH3:4])[CH3:3].C(OC(=O)C)(=O)C>>[CH2:1]([CH:5]1[CH2:6][C:7](=[O:9])[O:13][C:11](=[O:12])[CH2:10]1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)CC(CC(=O)O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)CC1CC(=O)OC(=O)C1

Procedure:
A 1 liter four-necked flask equipped with a mechanical stirrer, thermometer pocket and condenser, was charged with 3-isobutyl glutaric acid (250 g) and acetic anhydride (62.7 g) The reaction mixture was refluxed at 135°-145° C. for 2.5-3 hours, followed by distilling out the unreacted acetic anhydride at 147°-155° C., and then the distillation was continued under vacuum to ensure removal of traces of unreacted acetic anhydride. The residue was cooled to 25°-30° C. to obtain 220-225 g of 3-isobutylglutaric anhydride.
Reaction SMILES: Br[C:2]1[C:3]([C:9](=[O:15])[C:10]([O:12]CC)=[O:11])=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[O:36][CH2:35][CH2:34][CH2:33]3)O1.C(O)C>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].O>[O:36]1[C:37]2[CH:38]=[CH:39][C:30]([C:2]3[C:3]([C:9](=[O:15])[C:10]([OH:12])=[O:11])=[C:4]([CH3:8])[S:5][C:6]=3[CH3:7])=[CH:31][C:32]=2[CH2:33][CH2:34][CH2:35]1
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Reactant: CCOC(=O)C(=O)c1c(C)sc(C)c1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1sc(C)c(-c2ccc3c(c2)CCCO3)c1C(=O)C(=O)O
Temperature: 95 °C
Yield: 100 %

Procedure:
A solution of ethyl 2-(4-bromo-2,5-dimethylthiophen-3-yl)-2-oxoacetate (17c) (1.0 g, 3.43 mmol), sodium carbonate (1.46 g, 13.7 mmol), and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (1.16 g, 4.46 mmol) in a mixture of toluene (9 mL), ethanol (3 mL) and water (3.5 mL) was bubbled with nitrogen for 5 minutes. Palladium tetrakis(triphenylphosphine) (0.2 g, 0.17 mmol) was added and the reaction mixture was heated at 95° C. overnight. Water (5 mL) was added and the organic layer was extracted with 1N sodium hydroxide (5 mL). The combined aqueous layers were washed with ethyl acetate (10 mL), acidified with 1M hydrochloric acid until pH 2 and extracted with dichloromethane (2×10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide the desired product (42a) (1.09 g, 3.43 mmol, 100%) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[F:1][C:2]1[CH:7]=[C:6]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[CH:5]=[CH:4][C:3]=1[CH2:17][N:18]1[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)CC1
Reactant: Cc1cccc(Br)n1
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: C1COCCO1
Solvent: O
Product: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)n1
Temperature: 75 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A 25 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen and charged with tert-butyl 4-[[2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine-1-carboxylate (1.50 g, 3.57 mmol, 1.00 equiv), 2-bromo-6-methylpyridine (0.916 g, 5.32 mmol, 1.49 equiv), Tetrakis(triphenylphosphine)palladium (0.413 g, 0.360 mmol, 0.10 equiv), potassium carbonate (1.50 g, 10.8 mmol, 3.04 equiv), dioxane (15 mL) and water (3 mL). The resulting solution was stirred overnight at 75° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (3×20 mL) and the organic layers were combined, washed with brine (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to yield 1.10 g (80% yield) of tert-butyl 4-[[2-fluoro-4-(6-methylpyridin-2-yl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 386 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][C:32]([CH3:37])([CH3:36])[CH2:31]1>>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][C:32]([CH3:36])([CH3:37])[CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CC1(C)CC(CCCCBr)CCO1
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCOC(C)(C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 223 from N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 4-(4-bromobutyl)-2,2-dimethyltetrahydro-2H-pyran but conducting the alkylation over 1.5 hours at 60° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([N+:17]([O-])=O)=[CH:4][N:3]=1.C(O)(=O)C>[Zn].CO>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([NH2:17])=[CH:4][N:3]=1
Reactant: COc1ccc(Oc2nc(Cl)ncc2[N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(Oc2nc(Cl)ncc2N)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
To a stirred solution of Compound 1b (7.72 g; 27.4 mmol) in a mixture of glacial acetic acid (60 mL) and MeOH (120 mL) was added zinc dust (5.38 g; 82.2 mol) in portions at ambient temperature. The reaction mixture was stirred at room temperature for 20 h. The resultant mixture was filtered through a microglass filter and the filtrate was neutralized to pH 7 with 2 N KOH(aq). The mixture was partitioned between CH2Cl2 and H2O. The organic phase was washed sequentially with H2O and brine, and dried over Na2SO4. The mixture was filtered and the solvent was removed under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 1c (5.52 g; 80% yield) as an orange-red solid. 1H-NMR (400 MHz, CDCl3): δ 7.94 (s, 1H), 7.12-7.14 (m, 2H), 6.95-6.97 (m, 2H), 3.85 (s, 3H); MS: m/z 252.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C1C[C@@H](C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To (S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid (4 g, 17.60 mmol) dissolved in DMF (100 mL) at 0° C. were added benzyl bromide (2.51 mL, 21.12 mmol) and cesium carbonate (6.31 g, 19.36 mmol). The solution was stirred 16 h at RT then was concentrated. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 1:1). MS (UPLC/MS): 218 [MH−tBu]+, tR (HPLC conditions f): 2.44 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:29])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:28].FC1C=CC=C(F)C=1NC(=O)NC1C=CC(C2C=C(C(O)=O)ON=2)=CC=1C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:29])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:28]
Reactant: CCOC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)c(C)c2)no1
Agent: Cc1cc(-c2cc(C(=O)O)on2)ccc1NC(=O)Nc1c(F)cccc1F
Product: Cc1cc(-c2cc(C(=O)O)on2)ccc1NC(=O)Nc1ccc(F)cc1F

Procedure:
The title compound was prepared using ethyl 3-(4-(3-(2,4-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxylate following the same procedure as described for preparation of the compound of step 7 of Example 98. The title compound was obtained as a white solid (91%) after drying in vacuo; 1H NMR (300 MHz, DMSO-d6) δ: 2.30 (s, 3H), 7.01-7.06 (m, 1H), 7.27-7.34 (m, 1H), 7.66 (S, 1H), 7.71-7.74 (d, J=8.7 Hz, 1H), 7.78 (s, 1H), 8.08-8.17 (m, 2H), 8.48 (s, 1H), 9.11 (s, 1H); IR (KBr) 3289, 3076, 2926, 1709, 1651, 1594, 1557, 1502, 1426, 1285, 1230, 1142, 1100, 964, 851 cm−1.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14](OCC)=[O:15])[N:2]=1.[Li+].[BH4-].O>C1COCC1>[OH:15][CH2:14][C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2c(cn1)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 9 h
Yield: 81.4 %

Procedure:
Compound 10 (7.0 g, 31 mmol) was dissolved in anhydrous THF (900 ml) followed by the addition of LiBH4 (3.4 g, 155 mmol). The mixture was stirred at room temperature for 9 h and then cooled. Water (100 ml) was added into the mixture and stirred overnight. Then the solvent was removed in reduced pressure. With the addition of water (500 ml), extraction was conducted with dichloromethane (1 L) and then with ethyl acetate. The organic phases were combined, concentrated in vacuum and purified by silica gel column chromatography with ethyl acetate/methane (3:1) as the eluent to afford white solids (5.0 g, 82%), and mp 228-230° C. (reference[2]: 225-228° C.).