Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12].C1COCC1.B.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[Br:1][CH:2]([CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: CC(Br)CCCCCCCCC(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(Br)CCCCCCCCCO
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A flask containing 10-bromoundecanoic acid (25.0 g, 94.2 mmol) was charged with dry THF (250 ml), immersed in an ice/water bath and fitted with an addition funnel. The addition funnel was charged with borane-THF solution (1.0M, 113 ml, 113 mmol) which was added to the stirred reaction mixture over a period of 45 minutes. 3 hrs after the addition was completed, the reaction was poured into a stirred mixture of EtOAc (500 ml) and 10% aqueous potassium carbonate (300 ml). After vigorously stirring for 0.5 hr, the layers were separated. The organic phase was washed with water (250 ml) and brine (250 ml), dried (Na2SO4), filtered and evaporated in vacuo. Flash column chromatography (silica, 1:4; EtOAc:hexanes) provided 10-bromo-undecan-1-ol (20.8 g, 88%).
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].O.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>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2ccccc2)c(-c2ccc(Cl)s2)n1
Temperature: 140 °C

Procedure:
A biphasic mixture of 30 mg (0.068 mmol) of 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione, 10 mg (0.081 mmol) of phenylboronic acid, 4.0 mg (0.0034 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2 mL of 1,4-dioxane and 0.5 mL of 2 M aqueous Na2CO3 was heated in a microwave at 140° C. for 20 min. The reaction mixture was cooled to rt, diluted with 5 mL of water and extracted twice with CH2Cl2 and twice with a 3:1 mixture of CHCl3 and iPrOH. The combined organic extracts were concentrated and the crude products separated by C-18 prep HPLC to give 1-{2-[4-(5-chlorothiophen-2-yl)-5-phenylpyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione: MS (M+H)+ 442; and 5,5-dimethyl-1-{2-[5-phenyl-4-(5-phenylthiophen-2-yl)pyrimidin-2-ylamino]ethyl}imidazolidine-2,4-dione: MS (M+H)+ 484.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[C@@H:5]([C:16]([OH:18])=O)[CH2:4][CH2:3]1.[NH2:19][CH:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:21]([OH:25])[C:22]([NH2:24])=[O:23].O[NH-].O=[N-]>>[NH2:24][C:22](=[O:23])[C:21](=[O:25])[CH:20]([NH:19][C:16]([C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[C:9]([F:15])=[CH:10][CH:11]=[CH:12][C:13]=1[F:14])=[O:18])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1c(F)cccc1F
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1c(F)cccc1F

Procedure:
Coupling of (R)-5-oxo-1-(2,6-difluorobenzyl)-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:5][C@@:4]1([CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH2:24]([N:26]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:25]>>[CH2:24]([N:26]([CH:37]1[CH2:42][CH2:41][N:40]([CH2:1][C@H:3]2[CH2:5][C@@:4]2([CH2:12][N:13]([CH3:23])[S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:39][CH2:38]1)[C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:25]
Reactant: CN(C[C@@]1(c2ccccc2)C[C@@H]1C=O)S(=O)(=O)c1ccccc1
Reactant: CCN(C(=O)OCc1ccccc1)C1CCNCC1
Product: CCN(C(=O)OCc1ccccc1)C1CCN(C[C@H]2C[C@@]2(CN(C)S(=O)(=O)c2ccccc2)c2ccccc2)CC1

Procedure:
N-{[(1S,2S)-2-formyl-1-phenylcyclopropyl]methyl}-N-methylbenzenesulfonamide and benzyl ethyl(piperidin-4-yl)carbamate (incorporating by reference as needed Bioorg. and Med. Chem. Lett., 11 (2001), 2475) were reacted as per Preparation 10 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.67-7.55 (m, 5H), 7.39-7.21 (m, 10H), 5.07 (s, 2H), 3.67 (m, 1H), 3.57 (d, J=13.3 Hz, 1H), 3.17 (q, J=6.6 Hz, 2H), 2.99-2.93 (m, 1H), 2.76 (d, J=13.3 Hz, 1H), 2.75-2.68 (m, 1H), 2.52 (s, 3H), 2.29-2.19 (m, 1H), 1.87-1.38 (m, 7H), 1.11 (m, 1H), 1.04 (t, J=6.6 Hz, 3H), 1.07-1.03 (m, 1H), 0.90 (m, 1H). ES-LCMS m/z 576.2 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].Cl.[CH2:29]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])[CH3:30]>C(Cl)(Cl)Cl.O>[N+:25]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:15]=1[NH:35][CH2:34][CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:36])=[CH:23][CH:22]=[CH:21][CH:20]=2)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
Potassium carbonate (19.87 g, 143.8 mmol) and triethylamine (50.1 mL, 359 mmol) were sequentially added with stirring to a solution of 4-chloro-3-nitroquinoline (30.0 g, 144 mmol) in chloroform (200 mL). After 15 minutes, β-alanine ethyl ester hydrochloride (26.5 g, 173 mmol) was slowly added, and the reaction was stirred overnight at ambient temperature. Water (100 mL) was added, and the mixture was stirred for 15 minutes. The organic layer was separated, washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 27.4 g of ethyl N-(3-nitroquinolin-4-yl)-β-alaninate as a yellow solid, which was used without purification.
Reaction SMILES: C([O:5][C:6](=[O:41])[C@@H:7]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH2:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[N:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:19]=2)=[CH:14][CH:13]=1)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:26]1[CH2:27][CH2:28][CH2:29][NH:30][C:25]=1[NH:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:10]([NH:9][CH2:8][C@H:7]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:6]([OH:41])=[O:5])=[O:11])=[CH:17][CH:16]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(-c2cccc(Nc3ncccn3)c2)cc1)NS(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)c1ccc(-c2cccc(NC3=NCCCN3)c2)cc1
Reaction time: 2 h

Procedure:
A solution of 1-9 (175 mg, 0.305 mmol), TFA (3 mL) and CH2Cl2 (3 mL) was stirred at ambient temperature for 3.0 hours. The reaction was concentrated and then azeotroped with toluene (3×10 mL). The residue was dissolved in 5:1 AcOH/HCl (36 mL). 10% Pd/C (150 mg) was added and the mixture was shaken under 62 psi of hydrogen gas for 2.0 hours. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 10:1:1 EtOH/ NH4OH/H2O) to give 1-10 as a colorless oil.
Reaction SMILES: C1(CCOC2C=CC(C(NC(CC3C=CC(CCC)=CC=3)C(NCCO)=O)=O)=CC=2)CC1.[CH:33]1([CH2:36][O:37][C:38]2[CH:64]=[CH:63][C:41]([C:42]([NH:44]/[C:45](/[C:57]([NH:59][CH2:60][CH2:61][OH:62])=[O:58])=[CH:46]\[C:47]3[CH:52]=[CH:51][C:50]([O:53][CH:54]([F:56])[F:55])=[CH:49][CH:48]=3)=[O:43])=[CH:40][CH:39]=2)[CH2:35][CH2:34]1>>[CH:33]1([CH2:36][O:37][C:38]2[CH:64]=[CH:63][C:41]([C:42]([NH:44][CH:45]([CH2:46][C:47]3[CH:48]=[CH:49][C:50]([O:53][CH:54]([F:56])[F:55])=[CH:51][CH:52]=3)[C:57]([NH:59][CH2:60][CH2:61][OH:62])=[O:58])=[O:43])=[CH:40][CH:39]=2)[CH2:35][CH2:34]1
Reactant: O=C(NCCO)/C(=C/c1ccc(OC(F)F)cc1)NC(=O)c1ccc(OCC2CC2)cc1
Agent: CCCc1ccc(CC(NC(=O)c2ccc(OCCC3CC3)cc2)C(=O)NCCO)cc1
Product: O=C(NC(Cc1ccc(OC(F)F)cc1)C(=O)NCCO)c1ccc(OCC2CC2)cc1
Yield: 81 %

Procedure:
A reaction similar to that described in Example (1 (1e) was conducted using 4-(cyclopropylmethoxy)-N-((Z)-2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (279 mg) to give 227 mg of the title compound (white powder).
Reaction SMILES: S1C=CC=C1.[Li]CCCC.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[Li]C1C=CC=CN=1.[C:25]1(=[O:30])[CH2:29][CH2:28][CH:27]=[CH:26]1>C(OCC)C.[Cu](I)I.CCOC(C)=O>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:27]1[CH2:28][CH2:29][C:25](=[O:30])[CH2:26]1
Reactant: O=C1C=CCC1
Reactant: Brc1ccccn1
Agent: I[Cu]I
Agent: [Li]CCCC
Agent: [Li]c1ccccn1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: c1ccsc1
Product: O=C1CCC(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
A solution of thiophene (0.50 g, 6.0 mmol), diethyl ether (50 mL), and n-BuLi (2.5 M, 2.20 mL, 5.50 mmol) was stirred at room temperature for 1 hour. The reaction mixture was cooled to <5° C. and copper iodide (1.05 g, 5.50 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. In a separate flask, a solution of 2-bromopyridine (0.87 g, 5.50 mmol) in diethyl ether (50 mL) was cooled to <−70° C. and n-BuLi (2.5 M, 2.20 mL, 5.50 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 10 minutes. The 2-lithiopyridine reagent was added to the first reaction mixture via cannula and stirred at room temperature for 1 hour. To the reaction mixture was added 2-cyclopenten-1-one (0.45 g, 5.50 mmol) in diethyl ether (10 mL) and the reaction mixture was stirred for 1 hour. The reaction was poured into EtOAc (150 mL) and washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated. The material was purified by flash column chromatography (20% EtOAc/hexanes), to provide the title compound (0.38 g, 43%). 1H NMR (CD3OD, 300 MHz) δ 2.10-2.19 (m, 1H), 2.13-2.66 (m, 5H), 3.56-3.68 (m, 1H), 7.27 (ddd, J=1.0, 5.1, 7.5 Hz, 1H), 7.38 (dd, J=1.02, 7.80 Hz, 1H), 7.76 (ddd, J=2.0, 7.80, 7.80 Hz, 1H), 8.47-8.50 (m, 1H); MS (DCI) m/z 162 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[CH:9][CH:8]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH3:39][C:40]1[C:44](B(O)O)=[C:43]([CH3:48])[O:42][N:41]=1>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.C1COCC1>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:13](=[C:14]2[CH2:15][C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH2:19]2)[C:10]2[CH:9]=[CH:8][C:7]([C:44]3[C:40]([CH3:39])=[N:41][O:42][C:43]=3[CH3:48])=[CH:12][CH:11]=2)=[CH:29][CH:28]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC(C)(C)C1
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: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
The Suzuki procedure described for 21 was employed using triflate 25 (200 mg, 0.425 mmol), Pd(Ph3P)4 (49 mg, 0.0425 mmol), 2 N aqueous Na2CO3 (425 uL, 0.85 mmol), (3,5-dimethyl-4-isoxazolyl)boronic acid (150 mg, 1.06 mmol), and THF (25 mL). The reaction mixture was refluxed for 24 h and cooled to RT. Standard work-up followed by column chromatography afforded 132 mg (74%) of the title product 28 as an off-white solid. 1H NMR (400 MHz, CDCl3): δ7.26-7.21 (m, 2H), 7.17-7.14 (m, 4H), 2.41 (s, 3H), 2.28 (s, 3H), 2.0 (s, 2H), 1.95 (s, 2H), 1.31 (s, 2H), 0.96 (s, 6H), 0.93 (s, 6H). LCMS (APCI): m/z 418 (M+H)+.
Reaction SMILES: C([O:4][C@H:5]([CH3:32])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:20](=[O:21])[C:19]2[N:18]([CH3:22])[C:16](=[O:17])[N:15](COC(=O)C(C)(C)C)[C:14]=2[N:13]([CH3:31])[C:11]1=[O:12])(=O)C.C[O-].[Na+].Cl>CO>[OH:4][C@H:5]([CH3:32])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:20](=[O:21])[C:19]2[N:18]([CH3:22])[C:16](=[O:17])[NH:15][C:14]=2[N:13]([CH3:31])[C:11]1=[O:12]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(n(C)c1=O)n(COC(=O)C(C)(C)C)c(=O)n2C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2c([nH]c(=O)n2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 30.7 %

Procedure:
To a stirring solution of (R)-1-(5-acetoxyhexyl)-9-pivaloyloxymethyl-3,7-dimethyluric acid (0.10 g, 0.22 mmol) in methanol (5 ml) was added solid sodium methoxide (48 mg, 0.88 mmol) in one portion. After stirring at room temperature for 4 days, the mixture was treated with 5% aqueous hydrochloric acid solution (0.25 ml) and concentrated under a stream of nitrogen and mild heating. The residue was purified by preparative thin layer chromatography (250 micron silica gel plate) eluting with 7% methanol-dichloromethane to provide (R)-1-(5-hydroxyhexyl)-3,7-dimethyluric acid (20 mg, 30 % yield) as awhite solid.
Reaction SMILES: [CH3:1][C:2]1[C:14]([OH:15])=[C:13]([CH3:16])[CH:12]=[C:11]2[C:3]=1[CH:4](O)[CH2:5][C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1.C1(S(N)(=O)=O)C=CC=CC=1.S(=O)(=O)(O)O>C1COCC1>[CH3:1][C:2]1[C:14]([OH:15])=[C:13]([CH3:16])[CH:12]=[C:11]2[C:3]=1[CH:4]=[CH:5][C:6]1([O:10]2)[CH2:7][CH2:8][CH2:9]1
Reactant: Cc1cc2c(c(C)c1O)C(O)CC1(CCC1)O2
Agent: NS(=O)(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: Cc1cc2c(c(C)c1O)C=CC1(CCC1)O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a cold solution of 5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-4,6-diol (200 mg) and phenyl sulfonamide (1.35 g) in THF (15 mL) was added dropwise a sulfuric acid solution in THF (2 drops, 98% sulfuric acid, 5 mL THF). The mixture was allowed to stir 30 minutes at 0° C. and then at room temperature for another 30 minutes. The solution was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate (2×10 mL). The combined organic solutions were washed with water and dried over Na2SO4. Upon removal of solvents to dryness, the crude products were purified using flash column chromatography (0-20% ethyl acetate in hexanes) to yield 5,7-dimethylspiro[chromene-2,1′-cyclobutan]-6-ol as an off-white solid (106 mg).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:19]=[N:18][N:17]([C:31](=[O:33])[CH3:32])[CH:16]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6]1
Reactant: CC(=O)Cl
Reactant: Fc1ccccc1Cn1ncc2cnc(Nc3cn[nH]c3)nc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)n1cc(Nc2ncc3cnn(Cc4ccccc4F)c3n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-fluorobenzyl)-N-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (56 mg, 0.18 mmol), (Example 88), in DCM (2 mL) were added triethylamine (384, 1.5 eq) and acetyl chloride (154, 1.2 eq). After stirring for 30 min at rt, the reaction mixture was quenched with water. The aqueous phase was extracted with DCM and the combined organic phases dried over sodium sulfate and concentrated in vacuo. The residue was purified with the preparative HPLC to give the title product. 1H NMR (d6-DMSO) δ 10.25 (s, 1H), 9.03 (s, 1H), 8.67 (s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.41-7.31 (m, 2H), 7.26-7.12 (m, 2H), 5.60 (s, 2H), 2.63 (s, 3H); LC-MS method B, (ES+) 352.0, RT=9.09 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:6][O:7][C:8]([NH:10][C@H:11]([C:20](OC)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:9].[OH2:29].O.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].Cl>C(O)C.N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:6]([O:7][C:8]([NH:10][C@H:11]([CH2:20][OH:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:9])=[O:29]
Reactant: O
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccc(OC)c(OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(C(=O)OC(=O)N[C@H](CO)Cc2ccc(O)cc2)cc1OC
Temperature: 25 °C
Yield: 60.6 %

Procedure:
In a mixture of 80 ml of ethanol and 30 ml of pyridine, 6.54 g of methyl N-(3,4-dimethoxybenzyloxycarbonyl)-tyrosinate was dissolved. To the solution, 4.41 g of calcium chloride dihydrate was added. Then, to the mixture, 2.27 g of sodium borohydride was slowly added while stirring at room temperature. The resulting mixture was stirred for three hours and neutralized with 3% hydrochloric acid. After addition of 250 ml of water, the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 3.82 g of N-(3,4-dimethoxybenzoyloxycarbonyl)-tyrosinol. The crystals were recrystallized from ethanol to give small needles with mp. 152°-155° C. Analysis, calculated for C19H23NO6C 63.14, H 6.42, N 3.88, found C 63.30, H 6.29, N 3.99.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([O:11][CH:12]([O:16][C:17]([NH:19][C:20]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21]2)=[O:18])[CH:13]([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)C>[Pd].C(O)C>[CH3:14][CH:13]([CH3:15])[CH:12]([O:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[O:16][C:17]([NH:19][C:20]1([C:23]([OH:25])=[O:24])[CH2:21][CH2:22]1)=[O:18]
Reactant: CC(C)C(OC(=O)/C=C/c1ccccc1)OC(=O)NC1(C(=O)O)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)C(OC(=O)CCc1ccccc1)OC(=O)NC1(C(=O)O)CC1

Procedure:
A dry 100 mL round-bottomed flask equipped with a magnetic stir bar and a rubber septum was charged with 1-{[1-((2E)-3-phenylprop-2-enoyloxy)-2-methylpropoxy]carbonylamino}cyclopropanecarboxylic acid (18) (0.62 g, 1.8 mmols) and 10% palladium on carbon in a 1: I mixture of ethylacetate and ethanol. The reaction was done at 1 atm pressure under a hydrogen balloon at ca. room temperature. After the reaction was complete, the solution was filtered through Celite and the solvents removed in vacuo using a rotary evaporator. The dry, crude residue was dissolved in a small amount of a mixture of 60% (v/v) acetonitrile/water (ca. 10 mL), and the solution filtered through a 0.2 μm nylon syringe filter. Final purification was achieved by mass-guided preparative HPLC. After lyophilization of the solvents, the title compound (19) was obtained as a yellow semisolid (70% yield). 1H NMR (CDCl3, 400 MHz): δ=7.33 (t, 2H), 7.20 (m, 3H), 6.61 (d, 1H), 6.05 (s, 0.35H), 5.35 (s, 0.65H), 2.98 (t, 2H), 2.71 (m, 2H), 2.01 (m, 1H), 1.65 (m, 2H), 1.36 (m, 2H), 0.98 (d, 6H). MS (ESI) m/z 371.92 (M+Na)+; 348.01 (M−H)−.
Reaction SMILES: C1C=CN=CC=1.[FH:7].[N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10](N)[CH:9]=1.N([O-])=O.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:7][C:10]1[CH:9]=[N:8][C:17]2[C:12]([CH:11]=1)=[N:13][CH:14]=[CH:15][CH:16]=2
Reactant: Nc1cnc2cccnc2c1
Reactant: F
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Fc1cnc2cccnc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 2 mL of hydrogen fluoride/pyridine, 145 mg of 1,5-naphthyridin-3-amine was added at 0° C., 76 mg of sodium nitrite was added to the reaction mixture, and stirred at 0° C. for 1 hour. The reaction mixture was stirred at 60° C. for 1 hour, and neutralized with a saturated aqueous sodium hydrogen carbonate solution at 0° C., chloroform was then added thereto, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60N made by KANTO CHEMICAL CO., INC., and an eluent of chloroform:methanol=20:1 to obtain 77 mg of 3-fluoro-1,5-naphthyridine as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:40]C(=O)OC(C)(C)C)[CH2:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]4[N:30]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:29]5[CH:36]=[CH:37][CH:38]=[CH:39][C:28]=5[N:27]=4)[CH2:21]3)=[O:19])=[CH:11][CH:10]=2)[N:8]=1)[CH3:2].ClCCl.[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54]>CO.CC#N.O>[NH2:40][C@H:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[N:8]=[C:4]([O:3][CH2:1][CH3:2])[S:5][CH:6]=2)=[CH:14][CH:13]=1)[CH2:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]2[N:30]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:29]3[CH:36]=[CH:37][CH:38]=[CH:39][C:28]=3[N:27]=2)[CH2:21]1)=[O:19].[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54]
Reactant: CCOc1nc(-c2ccc(C[C@H](CC(=O)N3CCC[C@@H](c4nc5ccccc5n4CCCOC)C3)NC(=O)OC(C)(C)C)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CC#N
Product: CCOc1nc(-c2ccc(C[C@@H](N)CC(=O)N3CCC[C@@H](c4nc5ccccc5n4CCCOC)C3)cc2)cs1

Procedure:
tert-Butyl (R)-1-(4-(2-ethoxythiazol-4-yl)phenyl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (97B) (0.091 mmol max, crude oil) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (2 mL) and trifluoroacetic acid (2 mL) were then added and the solution was stirred at room temperature for 2 hrs. The solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in methanol (3 mL), filtered, and then purified by preparative LC/MS (10-55% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in CH3CN (1 mL) and water (2 mL). The resultant solution was frozen and lyophilized to afford (R)-3-amino-4-(4-(2-ethoxythiazol-4-yl)phenyl)-1-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)butan-1-one (200) as its trifluoroacetic acid salt as a white flocculent solid (0.061 mmol, 0.041 g, 67% yield over 2-steps). ESI-MS: 562.2 m/z (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.66 (m, 1H) 1.67-2.12 (m, 5H) 2.28-2.44 (m, 2H) 2.56-2.95 (m, 4H) 2.94-3.28 (m, 7H) 3.84-4.05 (m, 1H) 4.09 (d, J=1.77 Hz, 5H) 4.44-4.61 (m, 1 H) 7.09-7.60 (m, 7H) 7.70-7.93 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:3]1=2.S(=O)(=O)(O)O.[CH3:25]O>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:25])=[O:18])=[CH:16][C:3]1=2
Reactant: CO
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2

Procedure:
Reflux 8 gm. of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-carboxylic acid in 600 cc. of methanol containing 1 cc. of sulfuric acid for 19 hours. Cool and separate the solids by filtration to obtain the title product. (m.p. 130°-131° C.).