Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:22]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br)#[N:23]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:22]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:6][CH:7]=1)#[N:23]
Reactant: N#Cc1ccccc1CBr
Reactant: NC(=O)c1cc(-c2ccc(O)cc2)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1COc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 50 mg, 0.24 mmol), K2CO3 (37 mg, 0.27 mmol) and tetrabutylammonium iodide (9 mg, 0.024 mmol) were taken up in DMF (2.4 mL). 2-Cyanobenzyl bromide (53 mg, 0.27 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by high-throughput purification to give 3-[4-(2-cyano-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (20.7 mg, 27%). LRMS (ESI+): m/z [M+CH3CN+H]+ 361.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:16]2[O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:4]2[C:9]([C:10]=1[C:11](=[O:13])[CH3:12])=[CH:8][C:7]([Cl:14])=[C:6]([Cl:15])[CH:5]=2.C[O-].[Na+]>CO>[Cl:1][C:2]1[N:3]([C@@H:16]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:4]2[C:9]([C:10]=1[C:11](=[O:13])[CH3:12])=[CH:8][C:7]([Cl:14])=[C:6]([Cl:15])[CH:5]=2
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)c(C(C)=O)c3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.3 %

Procedure:
2,5,6-Trichloro-3-acetyl-1-(5-O-acetyl-β-D-ribofuranosyl)indole (4.43, 232 mg, 0.53 mmol) was dissolved in dry MeOH (20 mL) to which was added sodium methoxide (35 mg, 0.65 mmol). The solution was stirred at room temperature for 45 min, and the solvent was then removed under vacuum. The residue was suspended in 10% aqueous NaHCO3 (50 mL) and the suspension extracted with EtOAc (2×50 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a white solid. The solid was recrystallized from boiling EtOAc/hexane to yield 170 mg (81%) of 4.46 as a white crystalline solid: mp 249-250 C; Rf 0.4 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.41 (s, 1H), 6.07 (d, 1H), 5.45-5.42 (m, 2H, D2O exch.), 5.30 (d, 1H, D2O exch.), 4.44 (q, 1H), 4.17 (d, 1H), 4.03 (d, 1H), 3.75 (b, 2H), 2.63 (s, 3H). 13C-NMR (125 MHz, DMSO-d6): δ 192.17, 133.10, 132.38, 126.21, 126.00, 125.73, 122.00, 115.44, 112.99, 88.97, 86.39, 71.63, 69.54, 60.97, 30.72. HRMS (ES) m/z calcd. for C15H14Cl3NO5□Na 415.9835, found 415.9843. Anal calcd for C15H14Cl3NO5: C, 45.65; H, 3.58; N, 3.55. Found: C, 45.75; H, 3.78; N, 3.61.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[Cl:17][CH2:18][CH2:19][CH2:20]I.[H-].[Na+].C(OCC)(=O)C>O1CCCC1>[Cl:17][CH2:18][CH2:19][CH2:20][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:13]([F:14])([F:15])[F:16])[C:9]([O:11][CH3:12])=[O:10]
Reactant: ClCCCI
Reactant: COC(=O)Cc1ccc(Cl)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(CCCCl)c1ccc(Cl)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of methyl (4-chloro-2-trifluoromethylphenyl)acetate (5.5 g) and 3-chloro-1-iodopropane (4.6 mL) in tetrahydrofuran (15 mL) was added dropwise to a suspension of sodium hydride (containing 60% in mineral oil, 955 mg) in tetrahydrofuran (50 mL) under ice-cooling. The reaction solution was stirred at the same temperature for 10 minutes and then at room temperature for three hours and 20 minutes. Ice water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The aqueous layer was reextracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Wakogel™ C-200; elution solvent:heptane:ethyl acetate=19:1) to obtain 5.30 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[OH:9][C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=1[C:17](=[O:19])[CH3:18]>CN(C=O)C>[CH3:1][O:16][C:14]1[CH:13]=[CH:12][C:11]([C:17](=[O:19])[CH3:18])=[C:10]([OH:9])[CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(O)cc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(C(C)=O)c(O)c1
Reaction time: 4 h

Procedure:
Potassium carbonate (27.2 g, 197 mmol) followed by methyl iodide (4.1 mL, 65.7 mmol) were added to a solution of 2′,4′-dihydroxyacetophenone (10.0 g, 65.7 mmol) in DMF (100 mL). The mixture was stirred for 4 hours and then partitioned between H2O and EtOAc. The organic layer was washed with satd NaHCO3, brine, dried over Na2SO4 and concentrated to a clear oil (11.0 g). 1H NMR (300 MHz, CDCl3): δ 2.60- (s, 3 H), 3.80 (s, 3 H), 6.40 (s, 1 H) 6.51 (d, J=2.45 Hz, 1 H), 7.62 (d, J=8.67 Hz, 1 H), 12.90 (s, 1 H).
Reaction SMILES: [OH:1][S:2]([OH:5])(=[O:4])=[O:3].[NH2:6][C:7]1[N:11]=[C:10]([SH:12])[NH:9][N:8]=1.OO>O>[S:2]([OH:5])([OH:4])(=[O:3])=[O:1].[NH2:6][C:7]1[N:11]=[C:10]([S:12][S:12][C:10]2[NH:9][N:8]=[C:7]([NH2:6])[N:11]=2)[NH:9][N:8]=1
Reactant: Nc1n[nH]c(S)n1
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: Nc1n[nH]c(SSc2nc(N)n[nH]2)n1
Reaction time: 8 h

Procedure:
Concentrated H2SO4 was added to a stirring mixture of 180.0 g 3-amino-1,2,4-triazole-5-thiol and 2958 g of water. A 30% hydrogen peroxide solution (87.8 g) was added and stirring was continued overnight. A peroxide test strip showed that all of the peroxide was consumed. The product is a solution of 3-amino-1,2,4-triazol-5-yl disulfide hydrogen sulfate.
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]([O:7][C:8](=[O:16])[CH2:9][C:10]1[N:11]=[C:12](N)[S:13][CH:14]=1)[CH3:6].[Br-:17].[Na+].Cl>O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:5]([O:7][C:8](=[O:16])[CH2:9][C:10]1[N:11]=[C:12]([Br:17])[S:13][CH:14]=1)[CH3:6]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: [Br-]
Agent: [Cu+2]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: CCOC(=O)Cc1csc(Br)n1
Reaction time: 0.33 h
Yield: 6 %

Procedure:
A solution of sodium nitrite (1.18 g, 0.0171 mol) in water (10 mL) was added dropwise to a mixture of (2-amino-thiazol-4-yl)acetic acid ethyl ester (2.60 g, 0.0140 mol), copper sulfate (6.84 g, 0.0429 mol), sodium bromide (5.89 g, 0.0573 mol) and 9 M hydrochloric acid aqueous solution (30 mL) at 0° C. over 10 minutes. After stirring at the same temperature for 20 minutes, the reaction solution was returned to room temperature over one hour and further stirred at room temperature for two hours. The reaction solution was diluted with water, filtered through celite and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography (n-hexane/ethyl acetate=1/0 to 9/1) to give the title compound (209.3 mg, 6%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:11][C:12]#[C:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:20]O>>[CH3:2][N:3]([CH2:11][C:12]#[C:13][CH2:14][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)[C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH3:20])=[O:8]
Reactant: CN(CC#CCN1CCCC1)C(=O)CCC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)CCC(=O)N(C)CC#CCN1CCCC1
Reaction time: 8 h
Yield: 63 %

Procedure:
Dowex 50 resin (200 mg) which had been activated with HCl was added to a solution of N-Methyl-N-[4-(1-pyrrolidinyl)-2-butynyl]-3-carboxypropanamide (101 mg, 0.40 mmol) in MeOH (2 mL) and the suspension was vigorously stirred overnight. The resin was filtered off and washed thoroughly with TFA. The combined MeOH and TFA washes were evaporated under a stream of N2, neutralized with 2M Na2CO3 solution and the product was extracted into EtOAc (3× mL). The organic layer was dried over Na2CO3, evaporated in vacuo and purified on silica gel (CHCl3 /MeOH/NH4OH, 40/10/1) to give 009 (66.8 mg, 63% yield). MS (CI-NH3), m/e 267 (MH+), 186, 172. 1H NMR (CDCl3) δ1.79 (br s, 4 H), 2.58 (br s, 4 H), 2.64 (m, 4 H), 2.98 & 3.07* (s, 3 H), 3.38 (s, 2 H), 3.68 (s, 3 H), 4.08 & 4.24* (s, 2 H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Temperature: 0 °C

Procedure:
methanesulfonyl chloride (3.130 g, 2.115 mL, 27.32 mmol) was added to a stirred solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (5 g, 24.84 mmol) and Et3N (5.027 g, 6.924 mL, 49.68 mmol) in DCM (50 mL) cooled to 0° C. on an ice-bath. The reaction was allowed to warm to ambient temperature over 3 hours. The reaction mixture was washed with water and 1M HCl, dried (MgSO4), filtered and concentrated in vacuo to give tert-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate as a yellow oil (7.9 g, Quantitative yield—some residual solvent). 1H NMR (400.0 MHz, CDCL3) δ 1.49 (s, 9H), 1.60-1.57 (m, 1H), 2.04-1.79 (m, 3H), 3.08 (s, 3H), 3.38-3.32 (m, 1H), 3.50-3.43 (m, 1H), 3.70-3.60 (m, 2H) and 4.74 (br s, 1H) ppm;
Reaction SMILES: [CH2:1]([N:5]([CH2:39][CH2:40][CH2:41][CH3:42])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)=[C:8]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:43]([C:45]1[C:46](=[C:56]([C:59]#[N:60])[C:57]#[N:58])[O:47][C:48]([CH3:55])([C:51]([F:54])([F:53])[F:52])[C:49]=1[CH3:50])#[N:44]>C(O)C.O1CCCC1>[CH2:39]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:50][C:49]3[C:48]([CH3:55])([C:51]([F:54])([F:52])[F:53])[O:47][C:46](=[C:56]([C:57]#[N:58])[C:59]#[N:60])[C:45]=3[C:43]#[N:44])=[CH:16][CH:15]=2)=[C:8]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)s2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 60 °C
Yield: 82.5 %

Procedure:
In 12 ml of ethanol and 4 ml of tetrahydrofuran were dissolved 500 mg (0.84 mmol) of 5-[2-[4-dibutylamino-2-(tert-butyldiphenylsiloxy)phenyl]vinyl]thiophene-2-carboaldehyde and 234 mg (0.92 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred with heating at 60° C. for 4.5 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 576 mg of a dark reddish brown crystal (yield: 82.6%; mp: 186-187° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH3:17])[C:14](=[O:16])[NH:15][C:8]=23)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[CH3:17][N:13]1[C:9]2=[N:10][CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2]([NH:1][C:28]([NH:27][C:24]4[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=4)=[O:29])=[CH:3][CH:4]=3)=[C:8]2[NH:15][C:14]1=[O:16]
Reactant: Cn1c(=O)[nH]c2c(Oc3ccc(N)cc3)ccnc21
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Cn1c(=O)[nH]c2c(Oc3ccc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3)ccnc21
Yield: 83.7 %

Procedure:
Method H2 was used with 7-(4-aminophenoxy)-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (20 mg, 0.08 mmol) and 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (17 mg, 0.08 mmol) to afford the title compound as a solid (32 mg, 84%). 1H-NMR (δ, ppm, DMSO-d6): 3.30 (s, 3H, CH3), 6.40 (d, 1H, HPy,5, J=5.55 Hz), 7.13 (d, 2H, Harom,Ph,3+5, J=8.05 Hz), 7.54 (d, 2H, Harom,Ph,2+6), 7.61-7.65 (m, 2H, Harom′), 7.84 (d, 1H, HPy,6), 8.11 (s, 1H, Harom′), 8.97 (s, 1H, NHurea1), 9.20 (s, 1H, NHurea,3), 11.48 (s, 1H, NHPy3).
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[N:14]([CH:19]=[CH:20][N:21]=3)[CH:15]=[C:16]([Br:18])[N:17]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[Br:18][C:16]1[N:17]=[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:22])=[O:3])=[CH:10][CH:9]=2)[C:13]2[N:14]([CH:19]=[CH:20][N:21]=2)[CH:15]=1
Reactant: CCOC(=O)c1ccc(Nc2nc(Br)cn3ccnc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Nc2nc(Br)cn3ccnc23)cc1

Procedure:
A mixture of 4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid ethyl ester (30 mmol), 1N aqueous sodium hydroxide (50 mL), and ethanol (80 mL) is heated at reflux for 1.5 hr. The mixture is cooled and the ethanol removed in vacuo. The residue is diluted with iN sodium hydroxide (30 mL) and washed with ethyl acetate (2×100 mL). The aqueous layer is brought to pH 6 with 3N HCl, and the mixture filtered to give 4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid (7) as a light orange solid.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[CH3:30][C:31]1[N:36]=[C:35]([CH:37]=[O:38])[CH:34]=[CH:33][CH:32]=1>ClCCl>[CH3:30][C:31]1[N:36]=[C:35]([CH:37]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:6]=2)[OH:38])[CH:34]=[CH:33][CH:32]=1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cc1cccc(C=O)n1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cc1cccc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n1

Procedure:
A mixture of 4-iodo-1-tritylimidazole (commercially available) (5.0 g, 11.5 mmol) in dichloromethane (50 mL) at −10° C. was treated with ethyl magnesium bromide (3.8 mL, 11.5 mmol, 3M in ether) and allowed to react for 90 m. A solution of 6-methyl-pyridine-2-carbaldehyde (Intermediate D1) (commercially available from Aldrich) (0.93 g, 7.7 mmol) in dichloromethane (10 mL) was added via syringe at −10° C. and stirred for 45 m. The mixture was quenched with water (50 mL) and with a saturated solution of ammonium chloride (60 mL). The residue was isolated in an aqueous workup, extracting with CHCl3 and purified by chromatography on silica gel with 5% NH3-MeOH:CH2Cl2 to give (6-Methyl-pyridin-2-yl)-(1-trityl-1H-imidazol-4-yl)-methanol (Intermediate D2) as a solid, 3.3 g (˜99%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=O)([OH:3])=[O:2].[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17].Cl>O1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:15]([C:14](=[O:19])[CH3:13])[C:16](=[O:18])[CH3:17])[CH:9]=[CH:10][C:11]=1[OH:12])([OH:3])=[O:2]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)C(=Cc1ccc(O)c(C(=O)O)c1)C(C)=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture containing 2 g 3-carboxy-4-hydroxybenzaldehyde, 4 ml 2,4-pentanedione and 20 ml tetrahydrofuran was saturated with hydrogen chloride gas. The solution was stirred for 2.0 h at 50° C. and evaporated to dryness in vacuo. The residue was crystallized from ethyl ether, mp. 112°-114° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)[C:21](=[O:22])[O:1]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(-c2cc3ccc(OC)cc3oc2=O)cc1
Yield: 89.2 %

Procedure:
A suspension of 2-hydroxy-4-methoxybenzaldehyde (6.10 g), 4-methoxyphenylacetylchloride (11.1 g) and potassium carbonate (20 g) in acetone (400 ml) was heated under reflux for 2 hours. The reaction mixture was evaporated to remove the solvent, followed by addition of water. The resulting precipitates were collected by filtration and dried under reduced pressure to give 7-methoxy-3-(4-methoxyphenyl)-chromen-2-one (10.1 g, Yield 89%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:26])[C@@H:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])([CH3:6])([CH3:5])[CH3:4].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([N:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:9]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:26])(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)N[C@H](CC(C)C)C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](CC(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of sodium hydride (0.68 g, 14.1 mmol) in dimethylformamide (60.0 mL), is added N-[4-methoxybenzenesulfonyl]-(D)-leucine t-butyl ester (5.02 g, 14.06 mmol) in dimethylformamide (10.0 mL). After stirring at room temperature for 20 minutes, benzyl bromide (1.67 mL, 14.06 mmol) is added, and the reaction is stirred overnight at room temperature. The reaction is then partitioned between ethyl acetate and acidic water (pH=5), the organic layer is dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (10% ethyl acetate/hexane) to give t-butyl 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-methylpentanoate.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1([CH:26]([OH:55])[CH2:27][NH:28][C:29]([C:31]2[N:32]=[N:33][C:34]([N:37]3[CH2:42][CH2:41][N:40]([C:43](=[O:54])[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:50]([F:53])([F:52])[F:51])[CH2:39][CH2:38]3)=[CH:35][CH:36]=2)=[O:30])[CH2:25][CH2:24]1>C(OCC)(=O)C>[CH:23]1([C:26](=[O:55])[CH2:27][NH:28][C:29]([C:31]2[N:32]=[N:33][C:34]([N:37]3[CH2:38][CH2:39][N:40]([C:43](=[O:54])[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:50]([F:53])([F:52])[F:51])[CH2:41][CH2:42]3)=[CH:35][CH:36]=2)=[O:30])[CH2:25][CH2:24]1
Reactant: O=C(NCC(O)C1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Product: O=C(NCC(=O)C1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Dess-Martin periodinane (0.55 g, 1.3 mmol) was added to a solution of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide (0.50 g, 1.07 mmol), the resulting reaction mixture was stirred at ambient temperature for 2 h, then diluted with ethyl acetate, sequentially washed with 10% Na2S2O3 solution, saturated NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography and recrystallized from ethyl acetate-hexanes to give the title compound in 87% yield (0.43 g). 1H NMR (300 MHz, CDCl3) δ 8.45-8.41, 8.02, 7.72, 7.63-7.51, 7.34, 7.00, 4.48, 4.47-3.28, 2.00-1.94, 1.18-1.11, 1.10-0.82. 13C NMR (75 MHz, CDCl3) δ 204.4, 167.6, 163.1, 159.8, 144.9, 134.2, 132.3, 129.5, 129.0, 127.5, 127.2, 126.9, 121.8, 118.1, 112.4, 49.5, 46.3, 44.6, 44.4, 41.2, 18.7, 11.4. MS (ES+) m/z 462.0 (M+1).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3](O)[CH2:2]1.ClC(F)C(N(CC)CC)(F)F.C(O)C>CN(C)C=O>[CH3:16][C:15]1[C:13](=[O:14])[N:12]=[C:10]2[N:9]([C@@H:1]3[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([O:11]2)[CH2:2]3)[CH:17]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CCN(CC)C(F)(F)C(F)Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cn2c(nc1=O)O[C@H]1C[C@H]2O[C@@H]1CO
Temperature: 70 °C
Yield: 60.3 %

Procedure:
Thymidine (85.4 g; 0.353 mol) was dissolved in 500 mL dry DMF (dimethyl formamide) and added to N-(2-chloro-1,1,2-trifluoroethyl)diethylamine (100.3 g; 0.529 mol) [prepared according to the method of D. E. Ayer, J.Med. Chem. 6, 608 (1963)]. This solution was heated at 70° C. for 30 minutes then poured into 950 mL ethanol with vigorous stirring. The product precipitated from this solution and was filtered. The ethanol supernatant was refrigerated then filtered to yield a total of 47.75 g (0.213 mol; 60.3%) of 2,3'-anhydrothymidine, mp=228°-230° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.C([O:14][C:15](=O)[C:16]([CH3:21])([CH3:20])[CH:17]([CH3:19])[CH3:18])C>C(C1C=CC=CC=1)C>[CH3:20][C:16]([CH3:21])([CH:17]([CH3:19])[CH3:18])[CH2:15][OH:14].[CH3:20][C:16]([CH3:21])([CH:17]([CH3:19])[CH3:18])[CH2:15][OH:14]
Reactant: CCOC(=O)C(C)(C)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCc1ccccc1
Product: CC(C)C(C)(C)CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 500 mL round-bottom-flask equipped with a stir bar was flushed with Ar and charged with 50 mL dry THF and a 1 M solution of LAH in Et2O (87.5 mL, 87.5 mmol, 0.625 equiv). The solution was cooled to 0° C. with an ice bath and the above ethyl ester (22.1 g, 140 mmol, 1.0 equiv) (approximately a 50% solution in ethylbenzene) was added dropwise at such a rate that the solution did not reflux (required 50 min). After addition of the ester, the reaction was stirred at 0° C. for 2 h and then at ambient temperature for 14 h. The reaction solution was re-cooled to 0° C. and carefully quenched by addition of EtOAc. 1 N NaOH was added until a granular precipitate formed (7.5 mL). The mixture was filtered on a pad of diatomaceous earth which was then washed 3×100 mL Et2O. The organics were combined and dried voer Na2SO4. The solution was decanted and concentrated in vacuo to yield 2,2,3-trimethyl-butanol-2,2,3-trimethyl-butanol as a nearly colorless oil (11.7 g of alcohol in 15.4 g of a mix with ethylbenzene). The crude product was used without further purification.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1.[CH3:17][NH:18][CH2:19][C:20]1[S:24][C:23]2[CH:25]=[CH:26][S:27][C:22]=2[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.O>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:18]([CH3:17])[CH2:19][C:20]2[S:24][C:23]3[CH:25]=[CH:26][S:27][C:22]=3[CH:21]=2)=[O:16])=[CH:8][CH:7]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1cc2sccc2s1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CN(Cc1cc2sccc2s1)C(=O)/C=C/c1ccc(N)nc1
Yield: 42.2 %

Procedure:
EDC (230 mg, 1.2 mmole) was added to a solution (E)-3-(6-aminopyridin-3-yl)acrylic acid (164 mg, 1.0 mmole), 2-(methylaminomethyl)thieno[3,2-b]thiophene (220 mg, 1.2 mmole), HOBt.H2O (162 mg, 1.2 mmole), and Et3N (0.35 mL, 2.5 mmole) in dry DMF (5 mL) at RT. After 18 hr the mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4) and concentrated. The solid was taken up in 1:1 MeOH/H2O and filtered. The filtrate was concentrated to approximately ⅓ volume. The precipitate was collected by filtration, washed with H2O, and dried in vacuo to afford the title compound (139 mg, 42%) as a light tan solid: 1H NMR (400 MHz, d6-DMSO) δ 8.15 (d, J=2.0 Hz, 1H), 7.83 (bd, 1H), 7.61 (d, J=5.2 Hz, 1H), 7.40 (m, 3H), 6.45 (m, 2H), 4.75 (s, 2H), 3.13 (s, 3H); for minor rotomer δ 5.00 (s, 2H), 2.95 (s, 3H); MS (ES) m/e 330 (M+H)+.