Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[O:10])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=1.S(=O)(=O)([OH:24])N.Cl([O-])=O.[Na+].CCOC(C)=O>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:24])=[O:10])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=1
Reactant: NS(=O)(=O)O
Reactant: CCOC(=O)c1cccc(-c2c(C=O)cccc2OC)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(-c2c(OC)cccc2C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
Aldehyde 4a (0.512 g., 1.80 mmol, 1 equiv.) is dissolved in 17 mL of THF and 13 mL of H2O. The solution is cooled to 0° C. Sulfamic acid (0.525 g., 5.41 mmol, 3 equiv. ) is then added, followed by a solution of sodium chlorite (80% tech., 0.612 g., 5.41 mmol, 3 equiv. ) in 4 mL of H2O. The mixture is stirred for 15 min. at 0° C., and then poured into EtOAc and water. The aqueous layer is extracted thrice with EtOAc, and the combined organic-phase is washed with brine. The organic phase is dried (MgSO4) and then concentrated in vacuo to afford 2-methoxy-3'-carboethoxy-[1,1'-biphenyl]-6-carboxylic acid (5a) as a pale yellow oil (0.583 g., 1.80 mmol, 100%): 1H NMR (300 MHz, CDCl3) δ 10.17 (br, 1H, C2H), 8.02 (ddd, J=2, 2, 8 Hz, 1H, ArH), 7.94 (s, 1H, ArH), 7.56 (d, J=8 Hz, 1H, ArH), 7.41 (m, 3H, ArH), 7.15 (d, J=8 Hz, 1H, ArH), 4.19 (q, J=7 Hz, 2H, CO2CH2), 3.,73 (s, 3H, OCH3), 1.39 (t, J=7 Hz, 3H, CH2CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:12](O)[CH2:13][CH3:14].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>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCOc1ccc([N+](=O)[O-])c(F)c1

Procedure:
To a solution of the 3-fluoro-4-nitrophenol (32 mmol, 5.0 g), 1-propanol (48 mmol, 3.9 mL), and triphenylphosphine (64 mmol, 16.8 g) in CH2Cl2 (160 mL) at 0° C. was added DIAD (64 mmol, 12 mg). The reaction mixture was concentrated in vacuo. The product was isolated by flash chromatography on silica eluting with 5% EtOAc in hexanes. H1 NMR (500 MHz, CDCl3): δ 8.13 (t, J=8.7 Hz, 1H), 6.81-6.75 (m, 2H), 4.05 (d, J=6.4 Hz, 2H), 1.90 (m, 2H), 1.10 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]2[C:16](Cl)=[C:15]([C:18]#[N:19])[N:14]([CH2:20]CC)[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1.[C-]#N.[K+].[C:28]([Cu])#[N:29]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]2[C:16]([C:28]#[N:29])=[C:15]([C:18]#[N:19])[N:14]([CH3:20])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: C#CCOc1cc(-n2c(Cl)c(C#N)n(CCC)c2=O)c(F)cc1Cl
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(-n2c(C#N)c(C#N)n(C)c2=O)c(F)cc1Cl

Procedure:
The product of Example 3, 1-(4-chloro-2-fluoro-5-propargyloxyphenyl)-5-chloro-4-cyano-3-methyl-1,3-dihydro-2H-imidazol-2-one (V) (0.14 9, 0.4 mmol) was stirred in 20 mL dimethylformamide. To this mixture was added KCN (0.13 g, 2.0 mmol) and the resulting mixture was heated to reflux for ten minutes, however some starting material remained. The mixture was again heated to reflux one hour with the addition of CuCN (0.18 g, 2.0 mmol). The mixture was cooled, poured onto water, and extracted three times with 50 mL ethyl acetate. The organic solution was dried over MgSO4, filtered, and evaporated, then chromatographed to give approximately 30 mg of a glassy oil. Recrystallization with ethyl ether/hexane gave 22 mg of 1-(4-chloro-2-fluoro-5-propargyloxyphenyl)-4,5-dicyano-3-methyl-1,3-dihydro-2H-imidazol-2-one (VI) (m.p. 124°-6° C.).
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)(=[O:9])=[O:8].CCN(CC)CC.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[F:49][C:50]([F:60])([F:59])[C:51]1[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=1>C1COCC1>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:56][CH2:55][C:54]1[CH:53]=[CH:52][C:51]([C:50]([F:49])([F:59])[F:60])=[CH:58][CH:57]=1)=[O:15])(=[O:8])=[O:9]
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2nncs2)c1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1cccc(S(=O)(=O)Nc2nncs2)c1
Temperature: 35 °C
Reaction time: 18 h

Procedure:
To a solution of 3-[(1,3,4-thiadiazol-2-ylamino)sulfonyl]benzoic acid (100 mg, 0.350, mmol, 1 eq) in THF (1 ml) was added Et3N (0.19 ml, 1.4 mmol, 4 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI HCl, 87 mg, 0.455 mmol, 1.3 eq), 1-hydroxybenzotriazole hydrate (HOBt, 61 mg, 0.455 mmol, 1.3 eq) and 4-(trifluoromethyl)benzylamine (0.075 ml, 0.525 mmol, 1.5 eq) at 0° C. The reaction mixture was stirred at 30-40° C. for 18 hours. The reaction mixture was extracted from 2M HCl into ethyl acetate, washed with sat sodium hydrogen carbonate, brine, dried over magnesium sulphate, filtered and evaporated in vacuo. The crude material was purified by preparative HPLC to yield the title compound.
Reaction SMILES: CP(C)C.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[I:23]C.O[CH2:26][CH:27]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1COCC1>[I:23][CH2:26][CH:27]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CI
Reactant: CCCCCCCCCCC(CO)NC(=O)OC(C)(C)C
Agent: CP(C)C
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCCCCCCCC(CI)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
Trimethylphosphine (1.0M, 1.33 mmol) was added dropwise to a stirred solution of (azodicarbonyl)dipiperidine [ADDP] (336 mg, 1.33 mmol) in abs. THF (25 ml) at 0° C. After 30 minutes, iodomethane (189 mg, 1.33 mmol) and tert-butyl N-[1-(R/S)-(hydroxy-methyl)undecyl]carbamate 46 (200 mg, 0.664 mmol) were added to the solution, which was subsequently stirred for 4 hours at room temperature. The precipitate was then filtered off and the solution evaporated to dryness. The residue was dissolved in ethyl acetate and the remaining hydrazide was precipitated from hexane and removed by filtration. Following evaporation, the residue was taken up in CH2Cl2 (50 ml), washed with water (2×25 ml) and with NaHCO3 (sat, aq) (1×25 ml), dried with MgSO4, filtered and evaporated. The residue was purified by column chromatography in hexane:ethyl acetate 4:1 (v/v) to give 62 (176 mg, 64%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C(N(CC)CC)C.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:1]([O:5][C:6](=[O:28])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=1)[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCc1cccc(Br)c1)Cc1ccc(C(C)(C)C)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCc1cccc(C#C[Si](C)(C)C)c1)Cc1ccc(C(C)(C)C)cc1
Temperature: 105 °C
Yield: 82.4 %

Procedure:
A mixture of the crude [2-(3-bromo-phenyl)-ethyl]-(4-tert-butyl-benzyl)-carbamic acid tert-butyl ester (515 mg, 1.154 mmol), bis(triphenylphosphine)palladium(II)chloride (32 mg, 0.0461 mmol), CuI (11 mg, 0.0577 mmol) and (trimethylsilyl)acetylene (251 μl, 1.73 mmol) in triethylamine (3.4 ml) was heated in a sealed tube at 105° C. over night. The mixture was then cooled to RT, diluted with sat. NaHCO3-solution and extracted three times with ethyl acetate. The combined ethyl acetate layers were then washed with water and brine and were dried (Na2SO4) and evaporated. The remaining residue was purified by chromatography (heptane/EtOAc 100:0 to 95:5) to obtain the title compound as a yellow gum (441 mg, 82%). MS (ISP) 464.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][N:20]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:21][N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)o1

Procedure:
A solution of 2-(5-dimethylaminomethyl-2-furyl-methylthio)ethylamine (2.25 g, 0.105 mol) and 2-nitroamino-5-(3-pyridylmethyl)-4-pyrimidone (2.47 g, 0.100 mol) in ethanol (12 ml) was boiled under reflux for 22 hours and evaporated to dryness. The residue was washed with water to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone and this was treated with dilute ethanolic hydrogen chloride and dried. The residue was recrystallised from methanol/2-propanol and from methanol to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone trihydrochloride (2.61 g) m.p. 205°-208°.
Reaction SMILES: C([N:8]([CH3:31])[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:9]([CH2:31][NH:8][C:9]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(N(C)Cc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C#Cc2ccc(C3(NCCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 147.5 %

Procedure:
Using General Procedure I; a solution of ethyl 4-{4-[ 1-(benzyl-methylamino)-cyclopropyl]-phenylethynyl}-benzoate (Compound 115, 65.0 mg, 0.16 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 45.0 mg (75%) of the title compound as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:28]1[CH:29]=[N:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([NH:65][C:66]([C:68]3[S:69][C:70]([C:73]([CH3:76])([CH3:75])[CH3:74])=[CH:71][CH:72]=3)=[O:67])[C:42]([NH:44][CH:45]([CH:53]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:43])=[CH:36][CH:35]=2)=[N:32][CH:33]=1.O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:61]([O:60][CH:53]([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH:45]([NH:44][C:42](=[O:43])[C@@H:41]([NH:65][C:66]([C:68]1[S:69][C:70]([C:73]([CH3:75])([CH3:74])[CH3:76])=[CH:71][CH:72]=1)=[O:67])[CH2:40][C:37]1[CH:38]=[CH:39][C:34]([C:31]2[N:30]=[CH:29][C:28]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)=[CH:33][N:32]=2)=[CH:35][CH:36]=1)[C:46]([O:48][C:49]([CH3:52])([CH3:50])[CH3:51])=[O:47])([CH3:62])([CH3:63])[CH3:64]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)C(NC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)s1)C(OC(C)(C)C)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(NC(=O)[C@H](Cc1ccc(-c2ncc(-c3ccc(O)cc3)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)s1)C(OC(C)(C)C)c1ccccc1
Temperature: 80 °C
Yield: 99.4 %

Procedure:
To a 100 ml flask were added (4-hydroxyphenyl)boronic acid (63 mg, 0.5 mmol), sodium carbonate decahydrate (217 mg, 0.8 mmol), tert-butyl 2-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanamido)-3-(tert-butoxy)-3-phenylpropanoate (290 mg, 0.4 mmol), Pd(dppf)Cl2 (28 mg, 0.04 mmol), dioxane (10.0 mL), and water (2.0 mL). The reaction mixture was heated to 80° C. overnight. The reaction mixture was dried under reduced pressure to remove the solvent and diluted in DCM (20 mL). The mixture was washed with aqueous NaHCO3 (3×10 mL). The combined organics were dried over Na2SO4 and evaporated to afford 309 mg (106%) of crude tert-butyl 3-(tert-butoxy)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)-3-phenylpropanoate INT-51 which was used without further purification. LCMS-ESI (m/z) calculated for C45H52N4O6S: 776.9. found 721 [M−tBuO]+, tR=11.03 min. (Method 14).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>C1COCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:13]([C:10]2[CH:11]=[N:12][C:7]([N:1]3[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]3)=[N:8][CH:9]=2)([OH:15])[CH3:14])=[CH:19][CH:18]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(=O)c1cnc(N2CCNCC2)nc1
Solvent: C1CCOC1
Product: CC(O)(c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
To a solution of 1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanone (1.8 g, 8.73 mmol) in dry THF (100 mL) was added (4-fluorophenyl)magnesium bromide (1 M in THF, 87.3 mL) at 0° C. under N2. The mixture was stirred at RT for 3 h, then quenched with ammonium chloride solution and extracted with dichloromethane (300 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by Combi-flash (dicholomethane:methanol=10:1) to give the title compound (1.02 g, 38%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([Cl:11])[CH:3]=1.[CH2:12]([O:14]C(OCC)OCC)[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C(O)CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:9])[O:14][CH2:12][CH2:13][O:10]2)=[C:4]([Cl:11])[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)c1ccc(Br)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Product: CC1(c2ccc(Br)cc2Cl)OCCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-(4-Bromo-2-chloro-phenyl)-ethanone (from step 2 below) (1.86 g, 5.66 mmol), below was dissolved in ethylene glycol (5 mL). Triethylorthoformate (0.71 g, 4.79 mmol), and tosic acid (0.02 g) were added and reaction was stirred under nitrogen for 24 hours at room temperature. The resulting reaction mixture was poured into NaHCO3 (10 mL) and extracted with EtOAC. The combined organics were washed with water (10 mL) and brine (10 mL) then dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (5% EtOAc in Hexanes) to yield the intermediate ether as a colorless oil (0.69 g, 58%). 1H NMR (CDCl3): δ 1.77 (s, 3H), 3.74-3.79 (m, 2H), 4.04-4.09 (m, 2H), 7.37 (dd, J=8.5, 1.9 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.55 (d, J=1.9 Hz, 1H). ESIMS (MH+): 278.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]([Cl:16])[CH:15]=1)[C:7]1([CH:12]=[CH:11][NH:10][CH2:9][CH2:8]1)[NH:6][C:5]2=[O:17]>C(O)(=O)C.O=[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]([Cl:16])[CH:15]=1)[C:7]1([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[NH:6][C:5]2=[O:17]
Reactant: O=C1NC2(C=CNCC2)c2c(Cl)cc(Cl)cc21
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C1NC2(CCNCC2)c2c(Cl)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
H2 was sent to the solution of 5,7-dichloro-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridin]-3-one (400 mg, 1.5 mmol), PtO2 (40 mg) in acetic acid (10 mL). The mixture was stirred at rt for 2 h. The mixture was filtered, the filtrate was neutralized with satd aq NaHCO3 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried and concentrated to give 5,7-dichlorospiro[isoindoline-1,4′-piperidin]-3-one (300 mg, 73%). 1H NMR (CD3OD): 1.36 (m, 2H), 2.76 (m, 2H), 2.94 (m, 2H), 3.12 (m, 2H), 7.67 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].Br[CH2:23][CH:24](OCC)OCC.C(O)C>O>[S:21]1[CH:24]=[CH:23][N:20]=[C:19]1[C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8]
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CCOC(CBr)OCC
Solvent: CCO
Solvent: O
Product: O=S(=O)(Nc1cccc2cc(-c3nccs3)[nH]c12)c1cccs1
Yield: 9 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.61 g), 1-bromo-2,2-diethoxyethane (0.32 mL) and ethanol (10 mL) was heated under reflux overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.06 g, yield 9%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 164-165° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[C:10](I)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH2:33]([Si:35]([C:40]#[C:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH2:38][CH3:39])[CH2:36][CH3:37])[CH3:34]>CN(C=O)C>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:40]([Si:35]([CH2:38][CH3:39])([CH2:33][CH3:34])[CH2:36][CH3:37])[O:23][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(I)c(OCc2ccccc2)ccn1Cc1ccccc1
Reactant: CC[Si](C#Cc1ccccc1)(CC)CC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)c1oc2c(c1-c1ccccc1)c(=O)ccn2Cc1ccccc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A 250-ml round bottom flask was charged with 1-benzyl-4-benzyloxy-3-iodo-2-pyridone (6.00 g, 14.40 mmol), dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (1.18 g, 1.44 mmol), DMF (60 mL), Hunig's base (3 mL, 17.30 mmol), triethylsilyl phenylacetylene (9.34 g, 43.10 mmol). The system was evacuated and purged with N2 three times, and the reaction was stirred at 110° C. for 12 hrs. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4 and the solvent was removed. The residue was purified by silica gel column chromatography, eluting with 50/50/1, EtOAc/Hexane/MeOH, to give 7-benzyl-3-phenyl-2-(triethylsily)furo[2,3-b]pyridine-4(7H)-one as a solid. MS (MH+) 416.0; Calculated 415 for C26H29NO2Si.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:28]([O:30]CC2C=CC=CC=2)=[O:29])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:7]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:6]=2.[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1[C:3]([C:28]([OH:30])=[O:29])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[C:7]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:6]=2
Reactant: Cc1nc2cc(OCc3ccccc3)c(OCc3ccccc3)cc2nc1C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc2cc(OCc3ccccc3)c(OCc3ccccc3)cc2nc1C(=O)O
Temperature: 80 °C
Reaction time: 20 h

Procedure:
The compound of Example 27A (4.9 g, 10.0 mmol) was added to a solution of potassium hydroxide (2.2 g, 40.0 mmol) in ethanol/water (80 ml/16 ml) and the mixture was stirred at 80° C. for 20 hours and then cooled (5° C.). The precipitate was collected by suction, washed with ether (4.3 g) and then suspended in water (100 ml). After correction of the pH of this suspension to 2 by the addition of 2N HCl stirring was continued at room temperature for 20 minutes and the crystallized title compound was isolated by suction, washed with water and dried in vacuo over P2O5. Yield: 3.4 g (85%); mp 198°-200° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](C(N)=O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]([C:18]2[C:19](=[O:31])[N:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]([CH3:24])[C:22]=2[CH3:23])=[O:17])=[CH:13][CH:14]=1.O.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CC#[N:53]>CCOC(C)=O>[NH2:53][C:3]1[C:2]([Cl:1])=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3Cl)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: CC#N
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3Cl)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
To a solution of 3-chloro-4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridin-3-yl)oxy)picolinamide (290 mg, 0.6 mmol) in EtOAc (4 mL), CH3CN (4 mL), and H2O (2 mL) was added PhI(OAc)2 (234 mg, 0.72 mmol). The reaction was stirred at 0° C. for 30 minutes, then warmed up to rt and continued to stir for 12 hours. The mixture was filtered through a CELITE® pad, which was washed with DCM (30 mL). The filtrate was washed with water (20 mL), then concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=50/1) to give the title compound as a light beige solid (120 mg, 44.7%).
Reaction SMILES: O=[C:2]([CH3:17])[CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]([NH2:40])[CH3:39]>C(Cl)Cl>[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]([NH:40][CH:2]([CH3:17])[CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH3:39]
Reactant: CC(=O)CCCN1C(=O)c2ccccc2C1=O
Reactant: CC(N)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(CCCN1C(=O)c2ccccc2C1=O)NC(C)c1ccccn1

Procedure:
Using General Procedure B: Reaction of 2-(4-oxo-pentyl)-isoindole-1,3-dione (Abdel-Monem, M M et al. J. Med. Chem. 1974, 17, 447-451) in CH2Cl2 and 1-pyridin-2-yl-ethylamine with NaBH(OAc)3 gave 2-[4-(1-pyridin-2-yl-ethylamino)-pentyl]-isoindole-1,3-dione as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30](O)=O)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.[NH:33]([C:35](=[S:37])[NH2:36])[NH2:34].O(Cl)Cl.[P+5]>O1CCOCC1>[NH2:36][C:35]1[S:37][C:30]([C:29]2[C:22]3[C:21]([NH:20][C@H:18]([C:7]4[N:8]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:9](=[O:11])[C:10]5=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]5[N:6]=4)[CH3:19])=[N:26][CH:25]=[N:24][C:23]=3[NH:27][CH:28]=2)=[N:34][N:33]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)O)c34)n(-c3ccccc3)c(=O)c12
Reactant: NNC(N)=S
Agent: ClOCl
Agent: [P+5]
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5nnc(N)s5)c34)n(-c3ccccc3)c(=O)c12
Temperature: 110 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
(S)-4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (50 mg, 0.12 mmol) was treated with hydrazinecarbothioamide (20 mg, 0.22 mmol) and phosphorus (V) oxychloride (12.5 μl, 0.13 mmol) in 1,4-dioxane (1 ml) according to the method described in Example 120 but stirring at 110° C. overnight. The residue was purified using SP1® Purification System (reverse phase, 0% to 100%, water-methanol/acetonitrile 1:1) to give 11 mg (19% yield) of the title compound.