Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:11]=[C:10]([NH2:12])[O:9][N:8]=2)[CH2:3][CH2:2]1.C(C1C=C(N[C:22](=[O:30])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)ON=1)(C)C>>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:11]=[C:10]([NH:12][C:22](=[O:30])[O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:9][N:8]=2)[CH2:5][CH2:6]1
Reactant: Nc1cc(C2CCOCC2)no1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Product: O=C(Nc1cc(C2CCOCC2)no1)Oc1ccccc1
Yield: 56 %

Procedure:
Prepared from 3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-amine (170 mg, 1.01 mmol) according to the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to afford phenyl 3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-ylcarbamate as a colorless solid (164 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 7.93 (brs, 1H), 7.39-7.45 (m, 2H), 7.18-7.32 (m, 3H), 6.09 (s, 1H), 4.02-4.08 (m, 2H), 3.48-3.57 (m, 2H), 2.96 (m, 1H), 1.78-1.89 (m, 4H); LC-MS (ESI) m/z 289 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]2[CH2:11][CH2:10]2)[CH:3]=1.CC1(C)C(C)(C)[O:16][B:15](B2OC(C)(C)C(C)(C)O2)[O:14]1.C(Cl)Cl.CS(C)=O>C(OCC)(=O)C>[CH:9]1([O:8][C:4]2[CH:3]=[C:2]([B:15]([OH:16])[OH:14])[CH:7]=[CH:6][CH:5]=2)[CH2:11][CH2:10]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Brc1cccc(OC2CC2)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1cccc(OC2CC2)c1
Yield: 37.2 %

Procedure:
A mixture of 1-bromo-3-cyclopropoxybenzene (1.36 mmol, 0.289 g), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.11 mmol, 0.321 mmol), PdCl2dppf.DCM (0.14 mmol, 0.112 g), KAcO (6.11 mmol, 0.600 g) in a DMSO (3 ml) was heated at 130° C. for 45 minutes, under argon atmosphere in a microwave oven. Ethyl acetate was added and filtered through celite. The organic phase was washed with water and evaporated. The crude mixture was purified by reverse phase using a water/AcN/MeOH system gradient affording 0.090 g (yield 23%) of the expected product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13]C(C)(C)C)=O)[CH2:7]1)[CH3:2].O1CCOCC1.C(N(CC)[CH:29]([CH3:31])[CH3:30])(C)C.C1(C(Cl)=O)CC1>Cl.C(OCC)C.ClCCl>[CH:29]1([C:11]([N:8]2[CH2:9][CH2:10][C@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18])[CH2:7]2)=[O:13])[CH2:31][CH2:30]1
Reactant: CCOC(=O)C[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: O=C(Cl)C1CC1
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CCN(C(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a round bottom flask, a solution of 1,1-dimethylethyl (3R)-3-[2-(ethyloxy)-2-oxoethyl]-1-pyrrolidinecarboxylate (2.08 mmol) in 4M HCl in dioxane (10 mL, 40 mmol) was stirred at room temperature for 1 h. Analysis of an aliquot by LCMS confirmed complete removal of the BOC group from the starting material. The reaction was concentrated in vacuo to give a pale yellow liquid, which was dissolved in diethyl ether and concentrated to dryness in vacuo to yield a white solid. A solution of this intermediate as the HCl salt in dichloromethane (100 mL) was treated with N,N-diisopropylethylamine (4.16 mmol) and stirred for 5 min at room temperature. The yellow solution was treated with cyclopropanecarbonyl chloride (2.287 mmol) dropwise by syringe. The solution was allowed to warm to room temperature and stirred for 1 h. The reaction was diluted with dichloromethane (100 mL) and was washed with water, dried over magnesium sulfate, and concentrated in vacuo to give the title compound as a yellow oil (quantitative). MS(ES)+ m/e 226.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.Cl.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1>C(O)C.O1CCOCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([NH2:16])[N:3]=[C:2]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)[CH:7]=2)[CH:13]=1
Reactant: Cc1ccc(N)cc1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccc(Nc2cc(-c3cc(Cl)ccc3C)nc(N)n2)cc1
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a stirred suspension of the hydrochloride salt of 4-chloro-6-(5-chloro-2-methyl-phenyl)-pyrimidin-2-yl-amine (0.01 g, 0.0344 mmol) in ethanol (5 ml) was added a solution of hydrogen chloride in dioxane (4.0 M, 0.01 ml) followed by p-tolylamine (0.074 g, 0.068 mmol). The mixture was heated under reflux for 75 minutes. After evaporation of volatiles under reduced pressure, the residue was treated 1.0 M hydrochloric acid (10 ml) and stirred for 30 minutes. After filtration the solid was dissolved in methanol (5 ml) and treated with a solution of sodium carbonate in water (1.0 M, 1.0 ml). After stirring for 30 minutes volatiles were evaporated under reduced pressure. The residue was treated with water (10 ml) and stirred for 15 minutes. Filtration provided the title compound (0.011 g, 98% yield) as a white powder. 1H NMR (DMSO-d6) δ 2.27 (s, 3H, CH3), 2.34 (s, 3H, CH3), 6.07 (s, 1H, Ar), 6.33 (s, 2H, NH2), 7.10 (d, 2H, J=8.3 Hz, Ar), 7.30 (d, 1H, J=8.2 Hz, Ar), 7.35-7.40 (m, 2H, Ar), 7.61 (d, 1H, J=8.4 Hz, Ar), 9.09 (s, 1H, NH).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]#[N:29])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)(C)(C)C.[O-]S([O-])(=O)=O.[Ca+2]>>[C:28]([CH2:27][CH2:26][CH2:25][CH2:24][NH:15][O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)N(CCCCC#N)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O=C(O)C(F)(F)F
Product: N#CCCCCNOCc1ccccc1

Procedure:
N-(4-Cyanobutyl)-O-benzylhydroxylamine (5) was synthesized by adding trifluoroacetic acid (TFA, 16 mL) to (4) (2.59 g, 8.51 mmol), and the solution was stirred at room temperature for 20 minutes (Drierite tube). Excess TFA was removed by rotary evaporation, saturated NaHCO3 (50 mL) was added and the product was extracted into ether (3×50 mL). After a brine wash (50 mL), the organic extracts were concentrated to yield 1.77 g crude product. Column chromatography with 3% EtOH/CHCl3 furnished 1.31 g of (5) (75% yield): NMR δ 1.5-1.7 (m, 4 H), 2.16-2.35 (m, 2 H), 2.78-2.98 (m, 2 H), 4.66 (s, 2 H), 5.45 (br s, 1 H), 7.28 (s, 5 H). Anal. calcd. for C12H16N2O: C, 70.56; H, 7.90. Found: C, 70.51; H, 7.91.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10](O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:14][C:15]1[N:20]=[C:19]2[N:21]([CH:25]3[CH2:27][CH2:26]3)[C:22](=[O:24])[NH:23][C:18]2=[N:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([N:23]2[C:18]3=[N:17][CH:16]=[C:15]([Br:14])[N:20]=[C:19]3[N:21]([CH:25]3[CH2:26][CH2:27]3)[C:22]2=[O:24])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Reactant: O=c1[nH]c2ncc(Br)nc2n1C1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nc(Br)cnc32)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) solution of tert-butyl(trans-3-hydroxycyclobutyl)carbamate (0.250 g, 1.335 mmol), 6-bromo-1-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.334 g, 1.309 mmol) and triphenylphosphine (0.520 g, 1.983 mmol) in THF (10 ml) was added DIAD (0.400 ml, 2.032 mmol) dropwise via syringe. After 10 min the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH/EtOAc, evaporated onto silica gel and purified by flash chromatography (Isco (25 gram)) eluting with EtOAc:hexanes (0:1-1:1) to give a light-yellow solid. ESI MS 445.9, 447.8 [M+Na].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:19]1([C:22]2[C:27]([C:28](O)=[O:29])=[CH:26][N:25]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)[N:23]=2)[CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH:17][C:28]([C:27]2[C:22]([CH:19]3[CH2:21][CH2:20]3)=[N:23][C:24]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=3)=[N:25][CH:26]=2)=[O:29])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CCN)c1
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Product: CCOC(=O)C(C)(C)Oc1cccc(CCNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (example 55C]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-[3-(2-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:4])[NH2:2].Cl.C(O[C:19](=[NH:21])[CH3:20])C>>[NH:21]=[C:19]([NH:2][NH:1][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:4])[CH3:20]
Reactant: CCOC(C)=N
Reactant: COC(=O)c1cccc(C(=O)NN)c1
Agent: Cl
Product: COC(=O)c1cccc(C(=O)NNC(C)=N)c1

Procedure:
Prepared analogously to the method described for intermediate product 1a) from methyl 3-hydrazinocarbonyl-benzoate and ethylacetimidate hydrochloride. White solid.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[C:6]2[N:7]([C:15]([CH2:18][CH3:19])=[N:16][N:17]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2>CN(C)C=O>[CH2:18]([C:15]1[N:7]2[C:8]3[C:13]([N:14]=[C:5]([NH:3][CH2:1][CH3:2])[C:6]2=[N:17][N:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:19]
Reactant: CCN
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Solvent: CN(C)C=O
Product: CCNc1nc2ccccc2n2c(CC)nnc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Monoethylamine was bubbled through a solution of 4-chloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline (1.2 g., 0.005 mole), the product of Example 4, in N,N-dimethylformamide (50 ml.) at 0° C. for about 2 minutes. The clear solution was stirred at 0° C. for 30 minutes and at room temperature for 2 hours. The reaction mixture was next poured over ice and the precipitate was separated by filtration, washed with water and air dried. Recrystallization from ethanol then afforded 1.0 g. (83% yield) of pure 1-ethyl-4-ethylamino-[1,2,4]triazolo[4,3-a]quinoxaline as a white solid (m.p. 235°-238° C.). Mass spectrum: m/e, 241 (P).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[N:13](C3CCCCO3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1OC
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1OC
Yield: 92.5 %

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (550 mg, 1.51 mmol) in methanol (30 mL) was added 6 N HCl (30 mL). The solution was stirred at room temperature for 3 hours when water (80 mL) was added and the suspension filtered to give after drying, the title compound (390 mg, 93% yield). ES-MS (m/z) 280 [M+1]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[C:7]([C@@H:9]([NH2:11])[CH3:10])[CH:8]=1.C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([F:13])([F:14])[F:15])=[C:7]([C@@H:9]([NH:11][C:45]([C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([C:24]4[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:34][CH:33]=2)[C:37]([CH3:49])=[C:38]3[CH3:48])=[O:46])[CH3:10])[CH:8]=1
Reactant: C[C@H](N)c1cc(F)ccc1C(F)(F)F
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cc(F)ccc3C(F)(F)F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(5-fluoro-2-(trifluoromethyl)phenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 589 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([OH:21])[CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([CH:23]=[O:24])=[CH:5][NH:6]2.O.[OH:26]P([O-])(O)=O.[Na+].Cl([O-])=O.[Na+].CC(=CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC#N.O.C(O)(C)(C)C>[F:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3([OH:21])[CH2:18][CH2:19][CH2:20]3)=[CH:15][CH:16]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([C:23]([OH:26])=[O:24])=[CH:5][NH:6]2
Reactant: O=Cc1c[nH]c2cc(F)c(-c3ccc(C4(O)CCC4)cc3)c(F)c12
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1c[nH]c2cc(F)c(-c3ccc(C4(O)CCC4)cc3)c(F)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.9 %

Procedure:
To a solution of 4,6-difluoro-5-[4-(1-hydroxy-cyclobutyl)-phenyl]-1H-indole-3-carbaldehyde (37.0 mg, 0.11 mmol) in a mixture of MeCN (2 mL), tert-butanol (1 mL) and water (2 mL) was added sodium phosphate monobasic hydrate (214.0 mg, 1.55 mmol), sodium chlorite (114.0 mg, 1.26 mmol) and 2-methyl-2-butene (1.0 mL, 6.85 mmol). The reaction mixture was stirred at room temperature for 24 hours, acidified with 1N aqueous citric acid solution (1 mL) and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The resulting yellow gum was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 60% H2O/40% MeCN in 8.5 min, 60% H2O/40% MeCN linear to 0% H2O/100% MeCN in 0.5 min, HOLD at 0% H2O/100% MeCN to 10.0 min. Flow: 25 mL/min) to afford the title compound (9.4 mg, 24%). MS (ES+) 344.1 (M+H)+. Retention time=2.48 minutes (Waters Atlantis dC18 4.6×50, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:32]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)O)=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]([CH3:31])[CH3:30])[CH:21]=[N:22][C:15]=2[N:14]([CH3:41])[C:13]1=[O:42])(C(C)(C)C)(C)C.[CH:43](O)=[O:44]>[Zn]>[CH:43]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH2:32][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]([CH3:30])[CH3:31])[CH:21]=[N:22][C:15]=2[N:14]([CH3:41])[C:13]1=[O:42])=[O:44]
Reactant: CC(C)c1ccccc1-c1cnc2c(c1C(O)c1ccc(Cl)cc1)c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Reactant: O=CO
Agent: [Zn]
Product: CC(C)c1ccccc1-c1cnc2c(c1Cc1ccc(Cl)cc1)c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 100 °C
Yield: 48 %

Procedure:
To a solution of 3-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-((4-chlorophenyl) (hydroxy)methyl)-6-(2-isopropylphenyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 20, step 6, 50 mg, 0.086 mmol) in HCOOH (5 mL) was added Zn dust (56.6 mg, 0.86 mmol). The reaction was heated at 100° C. for 3 h, cooled to RT and filtered. The filtrate was concentrated and dried to give 3-(5-(4-chlorobenzyl)-6-(2-isopropylphenyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (20 mg, 48.0% yield) as a brown oil. LCMS: [MH+—OH] 506 and TR=2.062 min. Used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[CH:22]3)[C:16]([CH2:29][CH3:30])=[C:15]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:46])C(=O)C1>CC#N>[CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[C:22]3[Cl:46])[C:16]([CH2:29][CH3:30])=[C:15]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(-c2ccc3c(ccn3C)c2)nc(OCc2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCc1c(-c2ccc3c(c2)c(Cl)cn3C)nc(OCc2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of methyl 2,4-bis(benzyloxy)-5-ethyl-6-(1-methyl-1H-indol-5-yl)nicotinate (131 mg, 0.26 mmol), prepared in Example 359, step 1, in MeCN (2 mL) was added NCS (35 mg, 0.26 mmol) at 0° C. The reaction was stirred at 0° C. for 1 h before it was allowed to warm to room temperature. The reaction progress was monitored by LC-MS. Upon completion, the reaction was quenched with water then extracted by CH2Cl2 (3×20 mL). The solvent was removed to give the crude product which was purified by flash column chromatography (0-10% EtOAc in hexanes) to afford the desired product (100 mg, 71%).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][NH:5][CH:4]=1)#[N:2].[O:8]1CCC[CH2:9]1.C=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[OH:8][CH2:9][N:5]1[CH:6]=[CH:7][C:3]([C:1]#[N:2])=[CH:4]1
Reactant: C1CCOC1
Reactant: N#Cc1cc[nH]c1
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Product: N#Cc1ccn(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
670 mg of 3-cyano-1H-pyrole, 10 ml of tetrahydrofuran and 10 ml of formaldehyde 36% in water were mixed. 0.1 ml of tetrabutylammonium hydroxide 10% in water was added at room temperature, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 1-hydroxymethyl-3-cyano-1H-pyrole.
Reaction SMILES: ClC1C=C(Cl)C=C(Cl)C=1[O:10][C:11](=O)[CH2:12][C:13](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:14].[NH2:26]/[C:27](/[CH3:34])=[CH:28]\[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(OCC)(=O)C.CCOCC>BrC1C=CC=CC=1>[CH2:32]([O:31][C:29]([C:28]1[C:13]([OH:14])=[CH:12][C:11](=[O:10])[NH:26][C:27]=1[CH3:34])=[O:30])[CH3:33]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: Brc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)c1c(O)cc(=O)[nH]c1C
Temperature: 155 °C

Procedure:
A mixture of malonic acid bis(2,4,6-trichloro-phenyl)ester (13.3 g, 0.03 mol) and ethyl 3-aminocrotonate (3.87 g, 0.03 mol) in bromobenzene (25 mL) is heated at 155° C. for 30 minutes. The mixture is cooled to room temperature. Ethyl acetate (50 mL) and ether (50 mL) are added. The solid is collected and purified by filtration through a short silica gel column (25% ethyl acetate/ether) to give 4-hydroxy-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester. 1H NMR: (CDCl3) 5.85 (s, 1H), 4.38 (q, 2H), 2.68 (s, 3H), 1.39 (t, 3H).
Reaction SMILES: [NH:1]([C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([O:24]CC1C=CC=CC=1)=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4].C([O-])=O.[NH4+]>[Pd].CN(C=O)C>[NH:1]([C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])=[O:4]
Reactant: O=C(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 51.7 %

Procedure:
Trt-Gly-Gly-Phe-Gly-OBzl (670 mg), 10% Pd-C (100 mg), and ammonium formate (200 mg) were added to DMF (5 ml) and stirred for three hours. The reaction mixture was filtered, the filtrate was evaporated to dryness under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=8: 1 solution) to obtain the title compound (300 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([N:43](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:27][CH:28]=[C:29]([CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[O:34])[C:24]=4[O:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11].Cl.O1CCOCC1>>[C:37]1([CH2:36][O:35][C:33](=[O:34])[NH:32][CH2:31][CH2:30][C:29]2[C:24]3[O:23][CH:22]=[C:21]([C:17]4[CH:16]=[C:15]5[C:20](=[CH:19][CH:18]=4)[N:12]([C:10](=[O:11])[CH2:9][C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH2:13][CH2:14]5)[C:25]=3[C:26]([NH2:43])=[N:27][CH:28]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(CCNC(=O)OCc2ccccc2)c2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncc(CCNC(=O)OCc2ccccc2)c2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
A mixture of bis(1,1-dimethylethyl) {3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-[2-({[(phenylmethyl)oxy]carbonyl}amino)ethyl]furo[3,2-c]pyridin-4-yl}imidodicarbonate (149 mg, 0.190 mmol) and 4.0 M HCl in dioxane (2.0 mL, 8.00 mmol) was stirred at room temperature under Nitrogen for 4 hr. The crude reaction mixture was then concentrated in vacuo and azeotroped once with acetonitrile. The residue was taken up in DCM and passed through a PL-HCO3 MP-resin cartridge, rinsing with more DCM. The filtrate was then concentrated in vacuo to give the free base of phenylmethyl[2-(4-amino-3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-7-yl)ethyl]carbamate (105 mg, 0.162 mmol, 85% yield) as an off-white foam (purity estimated at 90%). LC/MS (ES) m/z=583.6 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d 2.86 (t, J=7.07 Hz, 2H), 3.22-3.34 (m, 4H), 3.96 (s, 2H), 4.31 (t, J=8.34 Hz, 2H), 5.02 (s, 2H), 5.38 (s, 2H), 7.14-7.44 (m, 12H), 7.68 (s, 1H), 7.93 (s, 1H), 8.12 (d, J=8.34 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:10]=1C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.S(=O)(=O)(O)[OH:27]>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:10]=1[OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Oc2ccccc2)ccc1OCc1ccccc1
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CO
Product: Oc1cc(Oc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Benzyloxy-5-phenoxybenzaldehyde (22.25 g, 73 mmol) is dissolved in methanol (200 mL) and treated with hydrogen peroxide (31% in water, 32.0 mL) and concentrated sulfuric acid (15.0 mL). The mixture is stirred overnight at room temperature and evaporated. The residue is dissolved in saturated aqueous sodium chloride solution and extracted with ether. The organic phase is dried over magnesium sulfate and evaporated. Purification of the residue by silica-gel flash chromatography gives 2-benzyloxy-5-phenoxyphenol as a colorless solid.