Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:32])[CH2:9][C:10](=[O:31])[CH:11]=[C:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:30])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=3)[CH2:14][CH2:13]2)[CH:5]=[N:6][CH:7]=1.C(O)(=O)C.C(OCC)(=O)C>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:32][C:12]3([CH2:13][CH2:14][N:15]([C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=4)[CH2:16][CH2:17]3)[CH2:11][C:10](=[O:31])[CH:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1cc(C(=O)N2CCC(=CC(=O)CC(=O)c3cncc(F)c3)CC2)ccc1OC(C)C
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2CCC3(CC2)CC(=O)C=C(c2cncc(F)c2)O3)ccc1OC(C)C
Temperature: 120 °C
Yield: 91.2 %

Procedure:
A mixture of 1-(5-fluoro-3-pyridyl)-4-[1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidylidene]butane-1,3-dione (100 mg, 0.23 mmol) in acetic acid (1.7 mL, 30 mmol) was heated at 120° C. for 1 h. The reaction mixture was cooled to 25° C. and repartitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine, dried over magnesium sulfate, and concentrated to dryness. The crude product was purified on silica gel utilizing a gradient of 60-100% ethyl acetate in hexanes to yield 10-(5-fluoro-3-pyridyl)-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one (92 mg). 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.61 (d, J=2.7 Hz, 1H), 7.74 (ddd, J=9.0, 2.7, 1.9 Hz, 1H), 7.28-7.24 (m, 2H), 6.84 (d, J=9.0 Hz, 1H), 6.09 (s, 1H), 4.58 (dt, J=12.1, 6.1 Hz, 1H), 3.42 (br s, 2H), 2.68 (s, 2H), 2.27-2.22 (m, 6H), 1.75 (m, 3H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 438.20, found 439.3 (M+1)+; Retention time: 1.78 minutes (3 min run).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2].[H-].[Na+].[CH3:23][N:24]1[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]=[C:25]1S(C)(=O)=O.O>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:25]3[N:24]([CH3:23])[C:28]4=[N:29][CH:30]=[CH:31][CH:32]=[C:27]4[N:26]=3)=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(F)cc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a stirred solution of 1-ethyl-6-fluoro-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) in DMF (4 mL) was added 60% sodium hydride (13.2 mg) at room temperature. The mixture was stirred at room temperature for 30 min, and then 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (85 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on NH-silica gel eluting with AcOEt/Hexane. Crystallization from AcOEt/Hexane gave the title compound (96 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][NH2:31].CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18]([NH:31][CH2:30][C:26]4[S:25][CH:29]=[CH:28][N:27]=4)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2]
Reactant: NCc1nccs1
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCc4nccs4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), thiazol-2-ylmethyl-amine and DIEA to give 4-ethoxy-6-[4-oxo-2-[(thiazol-2-ylmethyl)-amino]-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile. LC-MS m/e 422 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[O:15]1[CH2:17][CH:16]1[CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:17][CH:16]([OH:15])[CH2:18][CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH2:11][CH2:10]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C1c2ccccc2C(=O)N1CCC1CO1
Product: O=C1c2ccccc2C(=O)N1CCC(O)CN1CCN(c2cccc(Cl)c2Cl)CC1

Procedure:
A sample of 2.1 g (9.0 mmol) 1-(2,3-dichlorophenyl)-piperazine in 40 mL 2-PrOH was reacted in the microwave (pressure vessel, Pmax 150 W, cooling, 90° C., 20 min) with 2.0 g (9.0 mmol) 25. The solvent was removed in vacuo and the foamy residue was washed with 10 mL 2-PrOH. Yield: 2.96 g (73%). 1H NMR (CDCl3): δ 1.79 (m, 2H), 2.42 (m, 2H), 2.56 (s, 2H), 2.79 (m, 2H), 3.02 (s, 4H), 3.60 (s, 1H), 3.74-3.83 (m, 3H), 6.90 (m, 1H), 7.06-7.11 (m, 2H), 7.67 (m, 2H), 7.81 (m, 2H). 13C NMR (CDCl3): δ 33.9, 35.3, 51.4, 53.4, 63.8, 64.5, 118.2, 122.7, 124.1, 127.0, 131.6, 133.4, 133.4, 150.4, 167.7.
Reaction SMILES: B(O)(O)O.[OH:5][N:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][C:7]1([CH3:24])[CH3:23].[C:25](#N)[CH3:26].OO>O.B(O)(O)O.C1CCCCC1>[CH:26]1([O:5][N:6]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([O:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][C:7]2([CH3:24])[CH3:23])[CH2:25][CH2:9][CH2:8][CH2:7][CH2:23]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC#N
Agent: OB(O)O
Agent: OO
Solvent: C1CCCCC1
Solvent: O
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1
Temperature: 52 °C
Yield: 68 %

Procedure:
A solution of 0.100 g (0.360 mmol) of ferrous sulfate heptahydrate and 0.112 g (1.82 mmol) of boric acid in 4 ml of water is added to a mixture of 5.00 g (18.1 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 27 ml of acetonitrile, and 19 ml of cyclohexane. The mixture is heated to 52° C. A solution of 4.98 g (73 mmol) of 50% aqueous hydrogen peroxide is added dropwise over 2.75 hours to the reaction mixture while the temperature is brought to and maintained at reflux (63° C.). A solution of 0.051 g of ferrous sulfate heptahydrate and 0.042 g of boric acid in 2 ml of water is added to the reaction mixture 1.25 hours after the peroxide addition is started. After the peroxide is added, the reaction mixture is heated at reflux for 30 minutes, then allowed to cool slowly. Work-up and purification according to the procedure of Example 5 afford 4.42 g (68% yield) of the title compound, a colorless syrup, GC assay 99.3%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn([C@@H]3CCOC3)c2n1
Reactant: NCCc1ccc(O)cc1
Product: Oc1ccc(CCNc2nc(Cl)nc3c2ncn3[C@@H]2CCOC2)cc1

Procedure:
Following the procedure of Example 128b, (R)-2,6-dichloro-9-(tetrahydrofuran-3-yl)-9H-purine (b) was reacted with tyramine. The crude reaction mixture was purified by reverse-phase preparative HPLC. MS m/z 360.1 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:35]=[CH:34][S:33][CH:32]=2)[CH:26]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([C:15]([F:18])([F:17])[F:16])([OH:14])[C:10]([F:13])([F:12])[F:11])[CH3:2].[H-].[Na+].S(OC)(O[CH3:42])(=O)=O>CN(C)C=O>[CH2:1]([N:3]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:35]=[CH:34][S:33][CH:32]=2)[CH:26]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([C:15]([F:18])([F:17])[F:16])([O:14][CH3:42])[C:10]([F:11])([F:12])[F:13])[CH3:2]
Reactant: CCN(C/C=C/C#CC(O)(C(F)(F)F)C(F)(F)F)CCOCCOc1cccc(-c2ccsc2)c1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C/C=C/C#CC(OC)(C(F)(F)F)C(F)(F)F)CCOCCOc1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
159 mg of (E)-ethyl-N-(7,7,7-trifluoro-6-trifluoromethyl-6-hydroxy-2-hepten-4-ynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine was dissolved in 2 ml of dimethylformamide, and 24 mg of 60% oily sodium hydride was added. The mixture was stirred at room temperature for 10 minutes. To this solution was added 60 μl of dimethyl sulfate, and then the mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the residue to extract it. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated. The residue was purified by silica gel column chromatography [methylene chloride/methanol=70/1] to give 24 mg (yield 15%) of the captioned compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([C:6]#[C:7][C:8]2[CH:9]=[C:10]3[C@@:21]4([CH2:25][S:24][C:23]([NH:26]C(=O)OC(C)(C)C)=[N:22]4)[C:20]4[C:15](=[N:16][CH:17]=[C:18]([C:34]5[CH:35]=[N:36][C:37]([CH3:40])=[CH:38][CH:39]=5)[CH:19]=4)[O:14][C:11]3=[CH:12][CH:13]=2)[CH2:5][O:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([C:6]#[C:7][C:8]2[CH:9]=[C:10]3[C@@:21]4([CH2:25][S:24][C:23]([NH2:26])=[N:22]4)[C:20]4[C:15](=[N:16][CH:17]=[C:18]([C:34]5[CH:35]=[N:36][C:37]([CH3:40])=[CH:38][CH:39]=5)[CH:19]=4)[O:14][C:11]3=[CH:12][CH:13]=2)[CH2:3][O:4][CH2:5]1
Reactant: Cc1ccc(-c2cnc3c(c2)[C@]2(CSC(NC(=O)OC(C)(C)C)=N2)c2cc(C#CC4(C)COC4)ccc2O3)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cnc3c(c2)[C@]2(CSC(N)=N2)c2cc(C#CC4(C)COC4)ccc2O3)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
(S)-Tert-butyl 7-((3-methyloxetan-3-yl)ethynyl)-3-(6-methylpyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.027 g, 0.049 mmol) was taken up in 1.5 mL of DCM and TFA (0.057 mL, 0.735 mmol) was added. The reaction was heated to 50° C. and stirred for 2 h. The reaction was diluted with DCM and washed with saturated sodium bicarbonate solution. The aqueous layer was extracted with DCM, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford (S)-7-((3-methyloxetan-3-yl)ethynyl)-3-(6-methylpyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.017 g, 0.037 mmol, 37.6% yield) as a light yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.N1CCCCC1.[C:15]([CH2:17][C:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:25][CH:24]=1)=[O:19])#[N:16]>C(O)C>[C:15](/[C:17](=[CH:7]\[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)/[C:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:27][CH:28]=1)=[O:19])#[N:16]
Reactant: O=Cc1cccnc1
Reactant: COCOc1ccc(CCNC(=O)CC#N)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COCOc1ccc(CCNC(=O)/C(C#N)=C/c2cccnc2)cc1
Yield: 63.6 %

Procedure:
Then, ethanol (10 ml), 3-pyridinecarbaldehyde (0.62 g, 5.8 mmol) and a drop of piperidine were added to the resulting 2-cyano-N-(4-methoxymethoxyphenethyl)acetamide (0.96 g, 3,87 mmol) and refluxed under heating for 19 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=19:1) and recrystallized to yield the titled compound (0.83 g, 64%). Properties: mp 105-106° C. (ethyl acetate-hexane)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O[CH2:33][CH2:34][CH2:35]OC1C(C2C=CC=CN=2)(C(N)=O)C1(C1C=CC=CC=1OC)C>C(O)CC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])[O:31][CH2:33][CH2:34][CH3:35])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1C1(C)C(OCCCO)C1(C(N)=O)c1ccccn1
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Solvent: CCCO
Product: CCCOC(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)c1ccccc1OC

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-methoxyphenyl)(propoxy)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and propan-1-ol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((3-hydroxypropoxy)(2-methoxyphenyl)methyl(pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][Zn]Cl>C1COCC1>[C:1]1([C:7]2[C:8]([C:16]3[CH:17]=[CH:18][C:19]([CH:20]([OH:21])[CH3:24])=[CH:22][CH:23]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Reactant: C[Zn]Cl
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Temperature: 100 °C

Procedure:
100 mg 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde (prepared as described for example 1) were dissolved in 2 mL THF and 1 mL of a 2M solution of MeZnCl was added. The mixture was heated (100° C., microwave) for 2 h, cooled to room temperature and extracted with a mixture of dichloromethane and water. The organic layers were dried over sodium sulphate and the solvent was evaporated. The crude product was purified by chromatography on silica gel (dichloromethane/ethyl acetate)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([O:36][CH2:37][O:38][CH3:39])[CH2:35][CH2:34][CH2:33]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([O:36][CH2:37][O:38][CH3:39])[CH2:35][CH2:34][CH2:33]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(C)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5cnn(C)c5)cc34)s2)CCC1
Temperature: 25 °C

Procedure:
A solution of Example 47A (0.074 g, 0.127 mmol) in methanol (1.5 mL) and 2 M aqueous sodium hydroxide solution (0.317 mL, 0.633 mmol) was heated at 75° C. for 15 minutes. The reaction was cooled to ambient temperature, and the pH adjusted to ˜7 with 10% aqueous HCl solution. The resulting suspension was extracted with ethyl acetate. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by flash chromatography on a silica gel column with a gradient of 0% to 3% methanol in dichloromethane to provide the title compound. ESI(+) m/z 429.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[S:14]([NH2:17])(=[O:16])=[O:15].ClS([N:22]=[C:23]=[O:24])(=O)=O.O>C(Cl)Cl>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[S:4][C:3]([S:14]([NH2:17])(=[O:15])=[O:16])=[C:2]([NH:1][C:23]([NH2:22])=[O:24])[CH:6]=2)=[CH:8][CH:9]=1
Reactant: Nc1cc(-c2ccc(F)cc2)sc1S(N)(=O)=O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: NC(=O)Nc1cc(-c2ccc(F)cc2)sc1S(N)(=O)=O
Yield: 38.4 %

Procedure:
To the mixture of 3c (30 mg, 0.11 mol) in CH2Cl2 (10 mL) was added chlorosulfonyl isocyanate (14 μL, 0.165 mmol). The resultant mixture was stirred at room temperature for 3 h, then mixed with water (0.5 mL). Separation using a reverse phase HPLC afforded 3d (20 mg, 58%) as a white solid: MS (ES) 316 (M+H)+; 1H NMR (400 MHz, CD3OD) δ8.02 (s, 1 H), 7.69 (m, 2 H), 7.20 (m, 2 H).
Reaction SMILES: C([NH:4][C:5]1[NH:6][C:7](=[O:27])[C:8]2[N:9]=[CH:10][N:11]([CH2:14][O:15][CH2:16][CH:17]([O:23]C(=O)C)[CH2:18][O:19]C(=O)C)[C:12]=2[N:13]=1)(=O)C.C(Cl)(Cl)Cl.CO.C>CN.O>[OH:23][CH:17]([CH2:18][OH:19])[CH2:16][O:15][CH2:14][N:11]1[CH:10]=[N:9][C:8]2[C:7](=[O:27])[NH:6][C:5]([NH2:4])=[N:13][C:12]1=2
Reactant: CC(=O)Nc1nc2c(ncn2COCC(COC(C)=O)OC(C)=O)c(=O)[nH]1
Agent: CN
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(ncn2COCC(O)CO)c(=O)[nH]1
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A solution of 1.14 g (3.0 mmole) of 2-acetamide-9-(2,3-diacetoxy-1-propoxymethyl)hypoxanthine (VIII) from Step B above was heated at reflux in 40% aqueous methylamine with stirring under N2 for 1 hour and then cooled. TLC (80:20:2 CHCl3 --CH3OH--H2O) showed complete conversion to the title compound (I). The light orange solution was treated with some charcoal and filtered through Super-Cel. Concentration of the filtrate gave a solid which was recrystallized from H2O (adjusted to about pH 6 with a few drops of CH3COOH) to yield 687 mg of cream-colored crystals, mp 246°-247° dec.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:9]([O:13][C:14](=[O:35])[NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:34])[C:23]2[CH:28]=[CH:27][C:26]([NH:29][CH3:30])=[C:25]([N+:31]([O-])=O)[CH:24]=2)[CH2:17]1)([CH3:12])([CH3:11])[CH3:10].[CH2:36]([N:38]1[C:42]2=[N:43][CH:44]=[CH:45][CH:46]=[C:41]2[CH:40]=[C:39]1[CH:47]=O)[CH3:37]>O.C(O)C.C(Cl)Cl.[O-]S([O-])(=O)=O.[Na+].[Na+]>[C:9]([O:13][C:14](=[O:35])[NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([C:23]2[CH:28]=[CH:27][C:26]3[N:29]([CH3:30])[C:47]([C:39]4[N:38]([CH2:36][CH3:37])[C:42]5=[N:43][CH:44]=[CH:45][CH:46]=[C:41]5[CH:40]=4)=[N:31][C:25]=3[CH:24]=2)=[O:34])[CH2:17]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CNc1ccc(C(=O)N2CCCC(NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Reactant: CCn1c(C=O)cc2cccnc21
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCn1c(-c2nc3cc(C(=O)N4CCCC(NC(=O)OC(C)(C)C)C4)ccc3n2C)cc2cccnc21
Temperature: 100 °C
Yield: 54 %

Procedure:
Sodium hydrosulfite (235 mg, 1.150 mmol) dissolved in water (1.500 mL) was added to a solution of tert-butyl(1-(4-(methylamino)-3-nitrobenzoyl)piperidin-3-yl)carbamate (145 mg, 0.383 mmol) and 1-ethyl-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (66.7 mg, 0.383 mmol) in ethanol (3 mL) at RT under nitrogen. The reaction mixture was heated to 100° C. in a microwave for 5 h. The reaction mixture was diluted with DCM (20 mL), Na2SO4 was added and the resultant suspension filtered and concentrated in vacuo to yield the crude product as a yellow oil. The crude product was purified by Biotage SP4 on a SNAP 25 g silica cartridge using a gradient of 0% (20% MeOH/DCM)/DCM→100% (20% MeOH/DCM)/DCM. Appropriate fractions were combined and evaporated under vacuum to give the title compound as a yellow solid (104 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[C:23](=[O:24])[NH:22][CH:21]=[CH:20][C:14]=3[N:15]=[C:16](SC)[N:17]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([NH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(OC(C)(C)C)=O.[ClH:39]>O1CCOCC1>[ClH:39].[NH2:32][CH:33]1[CH2:38][CH2:37][N:36]([C:16]2[N:17]=[C:12]([NH:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[C:13]3[C:23](=[O:24])[NH:22][CH:21]=[CH:20][C:14]=3[N:15]=2)[CH2:35][CH2:34]1
Reactant: COc1cc(Nc2nc(SC)nc3cc[nH]c(=O)c23)cc(OC)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(N3CCC(N)CC3)nc3cc[nH]c(=O)c23)cc(OC)c1

Procedure:
The title compound (Compound 3; MS m/z: 398 (M+H)+) was prepared as described in Example 1g starting from 4-(3,5-dimethoxyphenylamino)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one (40 mg, 0.29 mmol) and 4-(boc-amino) piperidine and treating with 4 N HCl in dioxane (17 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.CI.[C:17](=O)([O-])[O-].[K+].[K+]>CC(C)=O.[OH-].[Na+]>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[C:8]([O:12][CH3:17])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(=O)oc2c(C)c(O)ccc12
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2c(C)cc(=O)oc2c1C
Yield: 66 %

Procedure:
A solution of 4,8-dimethyl-7-hydroxycoumarin (0.190 g, 1.00 mmol) and methyl iodide (0.180 g, 1.30 mmol) in 50 ml of dry acetone was heated at reflux in the presence of 0.5 g of potassium carbonate for 14 hours. The solution was then cooled and filtered. The filtrate was evaporated under reduced pressure to yield a beige solid. The beige solid was taken up in 20% sodium hydroxide (aqueous) and collected by vacuum filtration. The crude product was recrystallized from methanol to yield shiny white crystals, m.p. 162°-164° C., 135 mg, 66% yield. 1H-NMR: 2.27 (s, 3H, C8 --CH3), 2.4 (d, 3H, C4 --CH3, J=1.2 Hz), 3.9 (s, 3H, OCH3), 6.1 (q, 1H, C3 --H, J=1.2 Hz), 6.8-6.9 (d, 1H, C6 --H, J=8.8 Hz), 7.4- 7.5 (d, 1H, C5 --H, J=8.8 Hz).
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[O:3].Cl.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[NH:15][NH2:16]>Cl.O>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[NH:15][N:16]=[C:1]([OH:5])[CH:2]=[O:3]
Reactant: O=CC(=O)O
Reactant: NNc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: O
Product: O=CC(O)=NNc1ccc(Cl)cc1Cl
Yield: 69 %

Procedure:
In a manner similar to that disclosed by HO House, et al (Organic Synthesis, Vol V, 258-263) the reaction of 3.4 g (0.046 mole) of glyoxylic acid in 40 mL of 2.5 N hydrochloric acid and 60 mL of water with a solution of 9.8 g (0.046 mole) of 2,4-dichlorophenylhydrazine hydrochloride in 30 mL of water produced 7.4 g of 2-oxoacetic acid 2,4-dichlorophenylhydrazone as a solid (m.p. 160° C., dec.).
Reaction SMILES: [F:1][C:2]1([F:25])[C@@H:11]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[O:10][C@H:5]([O:6]C(=O)C)[C@H:4]([O:17][C:18](=[O:20])[CH3:19])[C@H:3]1[O:21][C:22](=[O:24])[CH3:23].C(OCC)(=O)C.[BrH:32]>C(O)(=O)C>[Br:32][C@@:5]1([O:10][C@H:11]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[C:2]([F:25])([F:1])[C@H:3]([O:21][C:22](=[O:24])[CH3:23])[C@H:4]1[O:17][C:18](=[O:20])[CH3:19])[OH:6]
Reactant: Br
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C1(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@](O)(Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)C1(F)F
Temperature: 0 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
300 mg (0.8 mmol) of tetraacetate 46 are dissolved in 13 ml of 33% strength HBr in glacial acetic acid and left to stand at room temperature for 6 hours. The reaction solution is then poured into a mixture of 10 g of ice and 10 ml of ethyl acetate. The organic phase is washed twice more with aqueous NaCl solution, filtered through a little silica gel and concentrated. The residue is separated by chromatography on silica gel (ethyl acetate/heptane 1:1). 112 mg (35%) of 47 are obtained as a colorless solid. C12H15BrF2O7(389.15) MS(DCl): 389.2 (M+H+).