Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[C:13]1([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH2:28])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl.[CH3:37][O:38][C:39](=[O:60])[C@@H:40]([NH2:59])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49](=[O:58])[C:50]2[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][C:51]=2[Cl:57])=[CH:44][CH:43]=1>ClCCl>[CH3:37][O:38][C:39](=[O:60])[C@@H:40]([NH:59][C:2]([NH:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:21])=[O:20])=[O:4])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49](=[O:58])[C:50]2[C:51]([Cl:57])=[CH:52][CH:53]=[CH:54][C:55]=2[Cl:56])=[CH:44][CH:43]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: Nc1ccccc1S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)Nc1ccccc1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 148.2 %

Procedure:
To a stirred solution of triphosgene (0.084 g, 0.28 mmol) in dichloromethane (1 ml) at 0° C. was slowly added a solution of 2-benzenesulfonylphenylamine (0.2 g, 0.87 mmol) in dichloromethane (1 ml) and the mixture was stirred at 0° C. for 15 minutes. After that, triethylamine (0.17 g, 1.74 mmol) in dichloromethane (2 ml) was added dropwise at 0° C. and the reaction was allowed to stir at room temperature for 3 h. To this solution a mixture of (S)-2-amino-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester hydrochloride (0.35 g, 0.87 mmol) and triethylamine (0.9 g, 0.87 mmol) in dichloromethane (2 ml) was slowly added and the resulting reaction mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified by column chromatography (Flash Biotage, dichloromethane:ethyl acetate 3:1) to yield the title compound (0.26 g, 50%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([C:12](=[N:14][OH:15])[CH3:13])=[N:9][N:8]=2)[CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([C:12](=[N:14][O:15][C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH3:13])=[N:9][N:8]=2)[CH:2]=1
Reactant: CC(=NO)c1nnc(-c2cccnc2)s1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(=NOc1ncccn1)c1nnc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.8 %

Procedure:
A solution of 1-[5-(3-pyridyl)-1,3,4-thiadiazol-2-yl]ethanone oxime (0.1 g, 0.436 mmol) in acetonitrile (5 ml) was stirred at ambient temperature and treated with cesium carbonate (0.43 g, 1.31 mmol) and 2-chloropyrimidine (0.079 g, 0.654 mmol). The reaction mixture was allowed to stir at ambient temperature and monitored by TLC and LC/MS. After 2 days, the mixture was concentrated in vacuo. The residue was stirred with ethyl acetate, filtered and the ethyl acetate concentrated in vacuo. Purification by recrystallisation gave a single isomer of 1-[5-(3-pyridyl)-1,3,4-thiadiazol-2-yl]-N-pyrimidin-2-yloxy-ethanimine (70 mg, 23%) in form of beige crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CN(C=O)C.[NH:39]1[C:43]2[CH:44]=[CH:45][C:46]([NH2:48])=[CH:47][C:42]=2[N:41]=[N:40]1.Cl>CCO>[NH:39]1[C:43]2[CH:44]=[CH:45][C:46]([NH:48][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=6[F:32])[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)=[CH:47][C:42]=2[N:41]=[N:40]1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4[nH]nnc4c3)n2)c1)c1c(F)cccc1F
Temperature: 80 °C
Yield: 74.5 %

Procedure:
To a slurry of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (103 mg, 0.223 mmol.) in 1 mL of EtOH/0.5 mL of DMF, 1H-1,2,3-benzotriazol-5-amine (32 mg, 0.245 mmol) and 5 μL of conc. HCl, the reaction contents were heated to 80° C. After heating for 18 h, the reaction mixture was cooled to rt and partitioned between DCM and sat. aq. NaHCO3. The layers were separated, extracted the aqueous layer with DCM (2×10 mL), the organic layers were pooled, dried over MgSO4, filtered, reduced in vacuo. Addition of TFA, followed by titration with Et2O afforded the desired product as a yellow solid 93 mg, 63% yield. 1H NMR (400 MHz, d6-DMSO): δ 10.91 (s, 1H); 9.91 (s, 1H); 8.54 (d, J=7 Hz, 1H); 8.52-8.49 (m, 2H); 8.31 (d, J=5 Hz, 1H); 7.99 (s, 1H); 7.82 (t, J1=10 Hz, 2H); 7.60-7.53 (m, 2H); 7.50-7.45 (m, 2H); 7.37 (d, J=8 Hz, 1H); 7.23 (t, J=9 Hz, 2H); 7.13 (t, J=7 Hz, 1H); 6.55 (d, J=5 Hz, 1H). HRMS calculated C30H20F2N9O [M+H]+ 560.1759, found 560.1763.
Reaction SMILES: [O:1]1[C:5](CO)=[CH:4][CH:3]=[C:2]1[CH2:8]O.N1C=CC=CC=1.S(Cl)([Cl:18])=O.[CH:20]([Cl:23])(Cl)Cl>>[Cl:18][CH2:8][C:2]1[O:1][C:5]([CH2:20][Cl:23])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: ClC(Cl)Cl
Reactant: OCc1ccc(CO)o1
Solvent: c1ccncc1
Product: ClCc1ccc(CCl)o1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of furan-2,5-dimethanol (25 mg, 0.2 mol) and pyridine (38.4 g, 0.48 mol) in a dry chloroform (120 mL) was added dropwise a solution of thionyl chloride (52.4 g, 0.44 mol) in dry chloroform (80 mL) at -40° C. (Ar) for 1.5 h. After addition, the mixture was stirred at -40° C. for 0.5 h then warmed to 0° C. for 0.5 h. After quenching with ice water (300 mL), the organic phase was washed with 5% sodium hydroxide (10 mL), dried, then evaporated to give a light brown oil. The brownish oil was distilled under vacuum (80°-82° C., 0.5 mm Hg) to give a colorless liquid which solidified at room temperature. Yield; 24 g (75%); M.P. 27°-28° C. (M.P. 27°-28° C., K. Yu. Noritskii, V. P. Volkoo, and Yu. K. Yuiey, Zhur. Obscher. Khim., 1961, 31, 538.)
Reaction SMILES: N1C=CC=CC=1.C(N(CC)CC)C.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:30][C:24]3[C:25](=[O:29])[NH:26][CH:27]=[CH:28][C:23]=3[CH:22]=2)=[CH:17][CH:16]=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>ClCCl>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([N:26]2[CH:27]=[CH:28][C:23]3[CH:22]=[C:21]([C:18]4[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=4)[S:30][C:24]=3[C:25]2=[O:29])=[CH:34][CH:33]=1
Reactant: O=c1[nH]ccc2cc(-c3ccc(Cl)cc3)sc12
Reactant: OB(O)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2ccn1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.1 %

Procedure:
Add pyridine (0.62 mL, 7.64 mmol) and triethylamine (0.53 mL, 3.82 mmol) to a mixture of 2-(4-chloro-phenyl)-6H-thieno[2,3-c]pyridin-7-one (0.5 g, 1.91 mmol), 4-bromobenzeneboronic acid (1.15 g, 5.73 mmol), cupric acetate (1.05 g, 5.73 mmol), and 4A molecular sieves (0.4 g) in dichloromethane (38 mL). Stir the mixture at RT for 2 days. Dilute the mixture with CH2Cl2, wash twice with a solution of 5% NH4OH/H2O, and H2O. Dry the organics over Na2SO4, filter, wash with Et2O, and concentrate. Purify the crude material by flash chromatography eluting with 10-15% EtOAc/CH2Cl2 to give 0.2 g (25%) of the title compound. LC-ES/MS m/z (81Br, 35Cl) 417.8 [M+H]+.
Reaction SMILES: [CH:1]([N:4]([CH3:35])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OCC3C=CC=CC=3)[C:12]2=[O:27])[C@H:7]([CH2:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:6]1)([CH3:3])[CH3:2].Br.CC(O)=O>CCOCC>[NH2:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@H:8]2[CH2:9][CH2:10][C@@H:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:35])[CH2:6][C@H:7]2[CH2:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[C:12]1=[O:27]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 128.5 %

Procedure:
The entirety of benzyl (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate prepared in Step 2 (250 mg, 0.5 mmol) was charged with 30% HBr/AcOH (5 mL). The reaction vessel warms and a vigorous gas evolution occurs. The mixture was stirred for 25 min at RT and then the flask was placed in a cool water bath before the addition of 20 mL of Et2O. The resulting solid was collected, washed with Et2O twice, and concentrated in vacuo to give (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (240 mg, 91% yield). MS found: (M+H)+=374.
Reaction SMILES: C1(C)C=CC=CC=1.CS(O[CH2:13][C:14]1[S:22][C:21]2[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][C:16]=2[CH:15]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>C(OCC)(=O)C>[N:36]1([CH2:13][C:14]2[S:22][C:21]3[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][C:16]=3[CH:15]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(COS(C)(=O)=O)cc2C1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2sc(CN3CCCC3)cc2C1
Temperature: 25 °C
Yield: 35 %

Procedure:
To a toluene solution (30 ml) of tert-butyl 2-((methylsulfonyloxy)methyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (5.3 mmol) was added potassium carbonate (26.5 mmol) and pyrrolidine (6.36 mmol) and the resulting reaction mixture was refluxed for 16 h. It was cooled to 25° C., diluted with ethyl acetate and the organic layer was successively washed with water and brine. After drying over sodium sulfate, the organic layer was evaporated under reduced pressure to give the crude product which was purified by column chromatography (5% methanol in dichloromethane). Yield: 35%.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:12][C:11]=1[F:27])=[O:5])=[N-]>ClCCCl.C1(C)C=CC=CC=1>[F:27][C:11]1[CH:12]=[C:13]([NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=[CH:15][C:10]=1[C@H:9]1[C@H:3]2[C@@H:8]1[CH2:7][O:6][C:4]2=[O:5]
Reactant: [N-]=[N+]=CC(=O)OC/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1F
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc([C@@H]2[C@H]3COC(=O)[C@H]32)c(F)c1)OCc1ccccc1

Procedure:
A solution of (2E)-3-(4-{[(benzyloxy)carbonyl]amino}-2-fluorophenyl)prop-2-enyl diazoacetate (13.9 g, 37.5 mmol) in 1,2-dichloroethane (150 mL) was added dropwise over 14 h to a refluxing solution of bis-(N-t-butylsalicylaldiminato)copper(II) (0.82 g, 1.9 mmol, prepared as described by R. G. Charles, J. Org. Chem. 1957, 22, 677) in 1.5 L of toluene. After the addition was complete, the reaction mixture was heated another hour at reflux, then cooled, filtered and concentrated. The crude oil was purified by column chromatography (0-50% ethyl acetate-hexanes) to provide the (racemic) title compound as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH2:8]C1(C)CCCCC1=O)([CH3:4])([CH3:3])[CH3:2].[C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])[CH3:26]>>[C:21]([C:18]1[CH:17]=[C:7]([CH2:8][CH2:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:27])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:19]=1[OH:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC1(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CCCCC1=O
Reactant: CC(=O)c1ccccc1
Product: CC(C)(C)c1cc(CCC(=O)c2ccccc2)cc(C(C)(C)C)c1O
Yield: 53 %

Procedure:
If, in this example, the 2-methylcyclohexanone is replaced by an equivalent quantity of acetophenone, an otherwise identical procedure gives phenyl (3,5-ditert.butyl-4-hydroxyphenylethyl) ketone in a yield of 53%.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:27])[N:10]([CH2:18][C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][C:36]([C:40]#[N:41])=[CH:37]2)=[CH:32][CH:31]=1>>[C:22]([C:21]1[CH:20]=[C:19]([CH2:18][N:10]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]([CH2:29][C:30]3[CH:39]=[C:38]4[C:33]([CH:34]=[CH:35][C:36]([C:40]#[N:41])=[CH:37]4)=[CH:32][CH:31]=3)[C:9]2=[O:27])[CH:26]=[CH:25][CH:24]=1)#[N:23]
Reactant: N#Cc1cccc(Cn2c(-c3ccccc3)c(-c3ccccc3)[nH]c2=O)c1
Reactant: N#Cc1ccc2ccc(CBr)cc2c1
Product: N#Cc1cccc(Cn2c(-c3ccccc3)c(-c3ccccc3)n(Cc3ccc4ccc(C#N)cc4c3)c2=O)c1

Procedure:
In a manner similar to Preparation 2 above, 3-[(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)methyl]benzonitrile was reacted with 7-(bromomethyl)naphthalene-2-carbonitrile to give 7-[[3-(3-cyanophenyl)methyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl]methyl]naphthalene-2-carbonitrile; NMR (CDCl3) 8.05 (s,1), 7.9 (d,1), 7.85 (d,1), 7.55 (m,3), 7.4 (m,2), 7.2 (m,9), 7.0 (m,3), 5.1 (s,2), 4.95 (s,2) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7](Br)[C:8](=[O:21])[C:9]([CH3:20])([CH3:19])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.O.O.O.O.C1(S(O)(=O)=O)C2C=CC=C(S(O)(=O)=O)C=2C=CC=1>C(#N)C.CC(C)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[C:8](=[O:21])[C:9]([CH3:20])([CH3:19])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(COc1ccc(Cl)cc1)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Solvent: CC#N
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(COc1ccc(Cl)cc1)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1
Yield: 67.3 %

Procedure:
21.6 g (0.05 mole) of crude 1,4-bis-(4-chlorophenoxy)-1-bromo-3,3-dimethyl-butan-2-one were stirred under reflux with 14 g (0.2 mole) of imidazole in 100 ml of acetonitrile for 17 hours. The mixture was then concentrated by distilling off the solvent under reduced pressure. The residue was taken up in 400 ml of methylene chloride and the mixture was extracted by shaking three times with 800 ml of water each time, dried over sodium sulphate and concentrated. The residue was taken up in 100 ml of acetone, and 9 g (0.05 mole) of 1,5-naphthalenedisulphonic acid tetrahydrate in 50 ml of acetone were added dropwise. The precipitate formed was filtered off and suspended in 200 ml of methylene chloride. 400 ml of saturated sodium bicarbonate solution ere added, the mixture was stirred for 30 minutes and the organic phase was separated off. After distilling off the solvent, 14.1 g (67% of theory) of 1,4-bis-(4-chlorophenoxy)- 3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one were obtained as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[C:21](O)(=[O:23])C>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:21]=[O:23])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 40 %

Procedure:
A mixture of 208.4 g (1.0 mol) of 2,4-di-tert-butylphenol and 283.2 g (2.0 mol) of HMT in 500 mL of glacial acetic acid was heated at 130 C. with stirring for 2 hours. A solution of 500 mL of 20% (vol/vol) aqueous sulfuric acid was then added and the resulting solution was refluxed for 0.5 hour. The solution was cooled to around 60°-80° C. and the organic phase was separated from the aqueous phase. The organic phase was recrystallized twice from 150-200 mL of cold (0°-5° C.) methanol to give 93 to 107 g (40-46% yield) of pure 3,5-di-tert-butylsalicylaldehyde of greater than 95% purity by HPLC. mp 60°-62° C. 1H-NMR (60 MHz, CDCl3): δ9.8 (s,1H); 7.6 (d,1H); 7.3 (d,1H); 1.2-1.5 (d,18H). IR (KBr): 3400, 2980, 1650 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:33]([O:35][CH3:36])=[O:34])=[N:11][N:12]([CH:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:19][NH:20][C:21]([O:23]C(C)(C)C)=O)[C:13]=1C(OC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:10]([C:33]([O:35][CH3:36])=[O:34])=[N:11][N:12]2[CH:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:19][NH:20][C:21](=[O:23])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CNC(=O)OC(C)(C)C)n1nc(C(=O)OC)c(OCc2ccccc2)c1C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CNC(=O)c2c(OCc3ccccc3)c(C(=O)OC)nn21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl 4-(benzyloxy)-1-{2-[(tert-butoxycarbonyl)amino]-1-(ethoxycarbonyl)ethyl}-1H-pyrazole-3,5-dicarboxylate (6.97 g, 13.78 mmol) in CHCl3 (150 mL) was added TFA (30 mL). The reaction was allowed to stir at room temperature overnight. The solvent was removed in vacuo, and the residue was partitioned between saturated aqueous NaHCO3 solution and CHCl3. The aqueous layer was extracted three times with CHCl3, and the combined organic extracts were dried over Na2SO4. Concentration in vacuo afforded a yellow oil which was dissolved in EtOAc (30 mL) and sonicated. The resulting precipitate was collected by filtration to afford the title product as a white solid. The filtrate was further purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA), and collection and concentration of the appropriate fractions afforded additional title product as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.38 (d, J=5.2 Hz, 1H), 6.45-7.43 (m, 2H), 7.38-7.30 (m, 3H), 5.55 (d, J=4.0 Hz, 1H), 5.26 (dd, J=11.2, 40.0 Hz, 2H), 4.23-4.14 (m, 2H), 3.97 (dd, J=5.0, 13.8 Hz, 1H), 3.79 (s, 3H), 3.71 (dd, J=5.4, 13.8 Hz, 1H), 1.18 (t, J=7.0 Hz, 3H); ES MS (M+H)=374.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][C:8](=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:20][C:21](=[O:23])[CH3:22])C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:20][C:21]([CH3:22])=[O:23])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc2c1OCC2=O
Solvent: Cc1ccccc1
Product: COc1cccc2c(CC(C)=O)coc12

Procedure:
A mixture of 7-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol) and 1-triphenylphosphoranylidene-2-propanone (4.77 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and later with 25% ethyl acetate. The product, 1-(7-methoxy-1-benzofuran-3-yl)acetone, was obtained as a red oil. Yield: 1.4 g (68%); (M+H): 205.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:7][C@@H:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5]1.B(Br)(Br)Br.C[OH:27]>C(Cl)Cl>[CH:15]([OH:14])=[O:27].[NH2:2][CH2:3][C@H:4]1[C:13]2[C:8](=[C:9]([OH:14])[CH:10]=[CH:11][CH:12]=2)[CH2:7][C@@H:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5]1
Reactant: COc1cccc2c1C[C@@H](c1ccccc1)C[C@H]2CN
Reactant: CO
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: NC[C@@H]1C[C@H](c2ccccc2)Cc2c(O)cccc21
Product: O=CO
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
[1R,3S] 1-Aminomethyl-5-methoxy-3-phenyl-1,2,3,4-tetrahydronaphthalene hydrochloride (0.16 g, 0.53 mmol), from Step 1, was suspended in 5 mL of methylene chloride and the suspension was cooled to -78° C. in a dry ice/acetone bath. Boron tribromide (19 mL of a 1 M solution in methylene chloride, 19 mmol) was added and the reaction mixture was allowed to warm to ambient temperature, kept at ambient temperature for 1.5 h then cooled to -78° C. Methanol (3 mL) was added to the reaction mixture and it was again allowed to warm to ambient temperature then concentrated in vacuo. The residue was dissolved in methanol and reconcentrated. The residue was redissolved in methanol and the methanol solution was chromatographed on a silica gel column eluted with ethyl acetate:formic acid:water (18:1:1, v/v/v) to give 0.11 g (70% yield) of the title compound as a white powder, m.p. 110°-112° C.; 1H NMR (d6 -DMSO) δ1.7 (q, 1H), 2.1-2.25 (m, 1H), 2.35-2.5 (m, 1H), 2.75-2.90 (m, 2H), 2.9-3.05 (m, 1H), 3.05-3.2 (m, 1H), 3.25-3.35 (m, 1H), 6.07 (d, 1H), 6.81 (d, 1H), 7.0 (t, 1H), 7.2-7.3 (m, 1H), 7.3-7.4 (m, 4H), 8.38 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[S:10](Cl)(=[O:12])=[O:11])#[N:2].[CH3:14][NH2:15]>O>[CH3:14][N:15]1[C:1](=[NH:2])[C:3]2[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=2[S:10]1(=[O:12])=[O:11]
Reactant: N#Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CN
Solvent: O
Product: CN1C(=N)c2c(Cl)cccc2S1(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7.1 g of 2-cyano-3-chlorobenzenesulphonylchloride were added to a solution of 9 ml of methylamine in approx. 15 ml of water cooled at 0° C. After stirring at 0°-10° C. for 1 hour, the solid was sucked off, washed with water and dried in air. The desired product was obtained in a yield of 5,5 g; melting-point 140°-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[OH:18])=[C:4]([F:20])[CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:21])=[C:4]([F:20])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)cc2F)c(O)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Nc2ccc(Cl)cc2F)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of compound 2a (0.59 g, 2 mmole) in anhydrous acetone (10 mL) were added potassium carbonate (0.69 g, 5 mmole) and iodomethane (0.28 mL, 4.4 mmole) and refluxed 8 hr. After cooled to room temperature, the reaction mixture was filtered through Celite and concentrated. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][NH:8][C:9]1[C:18]2[CH:17]=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[N:12]=[C:11]2[C:20](=[O:25])[NH:21][NH:22][C:23](=[O:24])[C:10]=12)=[O:5])C.Cl>>[C:4]([CH2:6][CH2:7][NH:8][C:9]1[C:18]2[CH:17]=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[N:12]=[C:11]2[C:20](=[O:25])[NH:21][NH:22][C:23](=[O:24])[C:10]=12)([OH:5])=[O:3]
Reactant: CCOC(=O)CCNc1c2ccc(Cl)cc2nc2c(=O)[nH][nH]c(=O)c12
Agent: Cl
Product: O=C(O)CCNc1c2ccc(Cl)cc2nc2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A mixture of 10-(2-ethoxycarbonylethylamino)-7-chloro-2,3-dihydropyridazino[4,5-b]quinoline-1,4-dione (0.08 g, 0.22 mM) and 1N hydrochloric acid was refluxed for 1 hr and then cooled to room temperature and filtered. The collected orange solid was washed with water and air dried to provide (0.07 g, 97%) the title compound as an orange powder, mp 356°-359° C.; MS(CI): 335 (M+H). Analysis for C14H11ClN4O4.0.3 H2O: Calculated: C, 49.4; H, 3.44; N, 16.47 Found: C, 49.3; H, 3.23; N, 16.25