Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ClCCl.C(C1C=C(CC[N:26]2[CH2:31][CH2:30][C:29]([CH2:33][N:34]([CH3:45])[C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=3)([OH:32])[CH2:28][CH2:27]2)C=CC=1)#N.[CH3:46][S:47]([C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57]([OH:59])=O)=[CH:52][CH:51]=1)(=[O:49])=[O:48]>O>[OH:32][C:29]1([CH2:33][N:34]([CH3:45])[C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)[CH2:30][CH2:31][N:26]([C:57](=[O:59])[CH2:56][C:53]2[CH:52]=[CH:51][C:50]([S:47]([CH3:46])(=[O:48])=[O:49])=[CH:55][CH:54]=2)[CH2:27][CH2:28]1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: COC(=O)c1ccc(N(C)CC2(O)CCN(CCc3cccc(C#N)c3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(N(C)CC2(O)CCN(C(=O)Cc3ccc(S(C)(=O)=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 129.8 %

Procedure:
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.68 g) was added to a dichloromethane solution (15 mL) of the compound (0.90 g) obtained in Step 3 of Example 25 and 4-methylsulfonylphenylacetic acid (0.76 g) and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into cold water (80 mL) and then separated, and the aqueous layer was extracted with dichloromethane. The organic layer was combined and washed with water and brine successively, and then dried over anhydrous sodium sulfate. After the solvent was removed under reduce pressure, the residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol=8:1) to obtain the titled compound (1.36 g) as crystals.
Reaction SMILES: [C:1]([O-:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:19](O)[CH2:20][CH2:21][CH3:22].C1(C)C=CC=CC=1>O>[C:1]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCO
Reactant: CCCCCCCCCCCCCCCC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)OCCCC

Procedure:
A reaction mixture of 1 mole of palmitate acid and 3 moles of n-butanol is transferred into a reaction flask. The reaction flask is equipped with a modified Dean and Stark distillation set-up, magnetic stirrer, condenser, dropping funnel and heating plate. 1 mole of toluene is added to the reaction mixture. 40 weight percent of acidic ion exchange resin (based on weight of acidic ion exchange resin/weight of palm fatty acid used) is added to the reaction mixture when it has reached the temperature 120° C. Concentration of active sites for the acidic ion exchange resins used is not less than 1.7 equivalents per litre or not less than 4.7 equivalents per kilogram. Heating continued for not more than 5 hours. Water formed as by-product of the esterification reaction is removed continuously by means of distillation with the aid of toluene while toluene is recycled continuously back to the reaction mixture.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1ccc(I)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(I)c(O)c1
Reaction time: 18 h
Yield: 447.9 %

Procedure:
A solution of 140 g (530 mmol) of 3-hydroxy-4-iodobenzoic acid and 20.2 g (110 mmol) of para-toluenesulfonic acid in 900 ml of methanol is refluxed for 18 hours. After cooling, 700 ml of water are added and the medium is stirred for 18 hours. The product precipitates and is filtered off. After drying under vacuum at 50° C., 137 g (93%) of methyl 3-hydroxy-4-iodobenzoate are obtained in the form of a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].O.C([OH:42])C>C(OCC)(=O)C.O>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:42])[CH:7]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccnc(Cl)c3)cc2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1cc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc([N+](=O)[O-])cc3)cc2)cc[nH]1

Procedure:
2-Chloro-4-{4-[4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazol-2-ylmethyl]-phenyl}-pyridine (1.6 g, 3 mmol) was refluxed with 6M NaOH in 1/1 water/ethanol (10 mL, 60 mmol) for 2 to 4 hours, followed by regular ethyl acetate/water workup and silica gel column chromatography to give the intermediate 4-{4-[4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazol-2-ylmethyl]-phenyl}-1H-pyridin-2-one, which was then treated as described in general procedure L [using iodocyclohexane (0.78 mL, 6 mmol)] to give 1-cyclohexyl-4-{4-[4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazol-2-ylmethyl]-phenyl}-1H-pyridin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][OH:19])[O:15][C:14]2=[O:20])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.O[C:22]1[CH:26]=[CH:25][O:24][N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][O:19][C:22]3[CH:26]=[CH:25][O:24][N:23]=3)[O:15][C:14]2=[O:20])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(-n2ccnc2)c(F)c1
Reactant: Oc1ccon1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(-n2ccnc2)c(F)c1
Reaction time: 2 h
Yield: 59.8 %

Procedure:
3-(3-Fluoro-4-(imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one (WO 96/23788; 280 mg, 1 mmol), 3-hydroxyisoxazole (94 mg, 1.1 mmol), and triphenylphosphine (330 mg, 1.25 mmol) were suspended by stirring in dry tetrahydrofuran (10 ml) under nitrogen at ambient temperature. Diisopropylazodicarboxylate (308 mg, 1.5 mmol) was added dropwise over 10 minutes. The suspension dissolved, and stirring was continued at the same temperature for 2 hours. The mixture was evaporated to dryness, and the residue purified by chromatography on a 20 g silica Mega Bond Elut® columns, eluting with a gradient increasing in polarity from 50 to 100% EtOAc in isohexane. Relevant fractions were combined and evaporated to give the desired product (206 mg). MS (ESP): 345 (MH+) for C16H13FN4O4.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:39][N:40]([CH3:45])[C:41](=[O:44])[CH:42]=[CH2:43].[H-].[Na+]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:43][CH2:42][C:41]([N:40]([CH3:45])[CH3:39])=[O:44])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: C=CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](OCCC(=O)N(C)C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1.5 h
Yield: 93.8 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (316 mg, 0.57 mmol) was treated with N,N-dimethylacrylamide (175 mg, 1.77 mmol) and sodium hydride (60% in oil, 36 mg, 0.91 mmol) in tetrahydrofuran (5.7 ml) in the same manner as shown in Example 4(1) (at 0° C. for 1.5 hours and then at room temperature for 1.5 hours), followed by work up and purification using column chromatography (hexane:ethyl acetate=2:1) to give the titled compound (352 mg, 93.9%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[F:13].C(NC(C)C)(C)C.[Li].CN(C)[CH:24]=[O:25].C(O)(=O)C>O1CCCC1.O>[F:13][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])[C:4]=1[CH:24]=[O:25]
Reactant: COCCOc1ccc(F)c(F)c1
Reactant: CN(C)C=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Product: COCCOc1ccc(F)c(F)c1C=O
Yield: 80.3 %

Procedure:
In a manner similar to the method described in example 52a, 1,2-difluoro-4-(2-methoxy-ethoxy)-benzene (6.3 g, 33.4 mmol) prepared in example 101a was reacted with lithium diisopropylamine (20.1 mL, 2.0 M in THF, 40.1 mmol), N,N-dimethyl-formamide (3.11 mL, 40.1 mmol) and quenched with acetic acid (8.1 g, 134 mmol) and water (41.2 mL) in tetrahydrofuran to give 2,3-difluoro-6-(2-methoxy-ethoxy)-benzaldehyde as yellow oil (Yield: 5.8 g, 80.6%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH:13]1[CH2:22][OH:23].Cl>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][CH:13]2[O:12][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OCC1COc2ccccc2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
A solution of toluene-4-sulphonyl chloride (60.25 g) in pyridine (75 ml) was added dropwise at 20° C. to a stirred solution of 1-(1,4-benzodioxan-2-yl)methanol (50 g) in pyridine (100 ml) and the mixture was stirred at ambient temperature for 18 hours then poured onto an excess of ice and hydrochloric acid (5M). The resulting solid was collected by filtration, washed well with water and dried in vacuo to give 1,4-benzodioxan-2-ylmethyl toluene-4-sulphonate as an off-white solid (82.3 g), m.p. 75°-78° C.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)CO.I[C:14]1[C:15]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][CH:17]=[CH:18][CH:19]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[C:32][CH:33]=[C:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[N:26]=1>C(O)CCC.CCOC(C)=O.[Cu]I>[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[C:32][CH:33]=[C:34]2[CH2:35][CH2:36][N:37]([C:14]3[C:15]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:38][CH2:39]2)[N:26]=1
Reactant: CCCOc1ncccc1I
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: OCCO
Solvent: CCCCO
Product: CCCOc1ncccc1N1CCC(=CC#Cc2cccc(C)n2)CC1
Temperature: 100 °C
Yield: 9.2 %

Procedure:
Into a flamed flask flushed with nitrogen a mixture of CuI (19.4 mg. 0.1 mmol)), K3PO4 (425 mg, 2 mmol), ethylene glycol (112 μL), 3-iodo-2-propoxypyridine (263 mg, 1 mmol) in 1 mL of n-Butanol were added 255 mg of the compound of Example 3 dissolved in 1 mL of n-Butanol. The suspension was heated at 100° C. for 5 h. The reaction mixture was then cooled to r.t., diluted with EtOAc, washed with aq., NaHCO3 and water, dried over Na2SO4 and evaporated to dryness in vacuo. After the work-up the residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with PE-EtOAc 8:2. affording the title product (32 mg, 10%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][C:7]=2[CH:16]=[O:17])[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=2[CH:16]=[O:17])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OCC2CC2)c(C=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=Cc1cc(C(=O)O)ccc1OCC1CC1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Methyl 4-(cyclopropylmethoxy)-3-formylbenzoate (2.6 g, 11.87 mmol) was dissolved in MeOH (40 mL), and NaOH 1 N (17 ml, 17.09 mmol) was added. The mixture was stirred at 40° C. for 4 hours. MeOH was evaporated under vacuum, and the reaction mixture was partitioned between EtOAc and HCl 1 M. The aqueous layer was extracted 3 times with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4, filtered and solvent removed under vacuum to give 2.42 g. (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][NH:18]C2C=CC=CC=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[CH:6]=2.S(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:16]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:5][CH:6]=3)=[N:18][N:17]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[CH:6]=2
Reactant: COC(=O)c1cc2nc(Cl)c(NNc3ccccc3)nc2cc1C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2nc(Cl)c3nnc(-c4ccccc4)n3c2cc1C

Procedure:
3.38 g of methyl 3-chloro-2-hydrazine-7-methylquinoxaline-6-carboxylate was dissolved in 30.0 mL of dichloromethane, and 7.09 g of bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate and 5.30 mL of triethylamine were added thereto under ice-cooling, followed by stirring at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by stirring at room temperature for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to obtain methyl 3-chloro-7-methyl-2-(2-phenylhydrazino)quinoxaline-6-carboxylate. The obtained methyl 3-chloro-7-methyl-2-(2-phenylhydrazino)quinoxaline-6-carboxylate was suspended in 50.0 mL of tetrahydrofuran, and 1.85 mL of thionyl chloride was added thereto at room temperature, followed by heating and refluxing overnight. The reaction liquid was left to stand at room temperature and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 2.06 g of methyl 4-chloro-8-methyl-1-phenyl[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate as a brown solid
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=12.S(=O)(=O)(O)O.[N+:17]([O-])([O-:19])=[O:18].[K+].[OH-].[Na+]>>[CH3:1][O:2][C:3]1[C:8]([N+:17]([O-:19])=[O:18])=[CH:7][N:6]=[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=12
Reactant: COc1ccnc2c1CCC2
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: COc1c([N+](=O)[O-])cnc2c1CCC2
Temperature: 80 °C
Yield: 41.4 %

Procedure:
4-Methoxy-6,7-dihydro-5H-cyclopenta[b]pyridine (2.90 g, 19.4 mmol) was mixed with concentrated sulfuric acid (17.0 g, 173 mmol) at 0° C., then a mixture of potassium nitrate (5.3 g, 52 mmol) in another portion of concentrated sulfuric acid (26.5 g, 270 mmol) was added slowly. The reaction mixture was heated at 80° C. for 4 h. The crude mixture was slowly poured onto crushed ice (50 g), and neutralized carefully with 50% aq. NaOH to pH 8-9. The resulting mixture was extracted with EtOAc five times. The combined organic extracts were dried and concentrated under reduced pressure to give the crude sub-title compound as brown gum (1.56 g, 41%), which was used without further purification. LCMS calc. for C9H11N2O3 (M+H)+: m/z=195.1. Found: 195.2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@@H:5]1[CH2:9][C@@H:8]([O:10][CH2:11][CH:12]=[CH2:13])[CH2:7][NH:6]1.[NH:15]([C:35]([CH3:37])=[O:36])[C@H:16]([C:25]([NH:27][C@H:28]([C:32](O)=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]1[CH2:9][C@@H:8]([O:10][CH2:11][CH:12]=[CH2:13])[CH2:7][N:6]1[C:32](=[O:33])[C@H:28]([CH:29]([CH3:30])[CH3:31])[NH:27][C:25](=[O:26])[C@H:16]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[NH:15][C:35](=[O:36])[CH3:37]
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: C=CCO[C@H]1CN[C@H](C(=O)OC)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCO[C@@H]1C[C@@H](C(=O)OC)N(C(=O)[C@@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(C)=O)C(C)C)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 33.5 %

Procedure:
4(R)-Allyloxyproline methyl ester hydrochloride (1.05 g, 4.75 mmol) and N-acetyl-Tyr-Val-OH (1.68 g, 5.21 mmol) were dissolved in 10 ml of a 1:1 mixture of dichloromethane and dimethylformamide and cooled to 0° C. Diisopropylethylamine (1 ml, 5.93 mmol) was added to the cooled mixture followed by the addition of N-hydroxybenzotriazole (0.769 g, 5.69 mmol) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.18 g, 6.2 mmol). After stirring for 2 hours, the mixture was warmed to room temperature and stirred for 16 hours. The reaction was poured into 150 ml of ethyl acetate and washed with 50 ml each of water, 10% sodium hydrogen sulfate, and 10% sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and evaporated to give a light yellow solid. This was purified by flash chromatography eluting with dichloromethane/methanol/pyridine (100:3:0.5) to give 780 mg of the title compound. 1H NMR (CD3OD) δ7.02-6.96 (2H, d), 6.67-6.63 (2H, d), 5.95-5.85 (1H, m), 5.34-5.27 (1H, d), 5.16-5.13 (1H, d), 4.53-4.38 (3H, m), 4.28-4.22 (1H, m), 4.12-3.97 (3H, m), 3.82-3.73 (1H, m), 3.72 (3H, s), 3.04-2.88 (2H, m), 2.85-2.72 (2H, m), 2.45-2.34 (1H, m), 2.08-1.95 (2H, m), 1.92 (3H, s), 1.00-0.92 (6H, 2×d).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[O:4][C:5]2[C:10]([CH:11]=1)=[C:9]([O:12]C)[CH:8]=[CH:7][CH:6]=2.B(Br)(Br)Br>ClCCl>[OH:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([CH3:1])[C:3](=[O:14])[O:4]2
Reactant: COc1cccc2oc(=O)c(C)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of 3-methyl-5-(methyloxy)-2H-chromen-2-one (Intermediate 111, 2.5 g) in dry dichloromethane (45 ml) cooled to 0° C. was added BBr3 (39.4 ml, 39.4 mmol). The reaction mixture was warmed to room temperature and stirred at room temperature overnight under nitrogen. The reaction was then cooled to 0° C. and quenched with ice. The obtained mixture was diluted with diethyl ether and the two phases obtained were separated through a separating funnel. The aqueous phase was back-extracted with diethyl ether. The collected organic phases were dried over sodium sulphate, filtered and evaporated under vacuum to give the title compound as a light brown solid (2.225 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[N:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2=[N:22][N:23]=[C:24]([C:25]3[CH:29]=[C:28]([CH3:30])[O:27][N:26]=3)[N:14]2[N:13]=1>>[CH3:30][C:28]1[O:27][N:26]=[C:25]([C:24]2[N:14]3[N:13]=[C:12]([O:1][CH2:2][C:3]4[N:8]=[N:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=4)[C:21]4[C:16]([C:15]3=[N:22][N:23]=2)=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:29]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Reactant: OCc1ccc(CO)nn1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(CO)nn4)nn23)no1
Yield: 12.7 %

Procedure:
(6-Hydroxymethylpyridazin-3-yl)methanol (J. Het. Chem., 1996, 33 (6), 2059-2061) (0.10 g, 0.71 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (0.22 g, 0.77 mmol) were coupled together and purified as in Example 1, step 4 to give {6-[3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazin-6-yloxymethyl]pyridazin-3-yl}methanol as a white solid (35 mg). 1H NMR (400 MHz, d6-DMSO) δ 2.58 (3H, s), 4.80 (2H, s), 5.65-5.75 (1H, br s), 5.92 (2H, s), 6.99 (1H, s), 7.81 (1H, d, J 8), 7.98 (1H, t, J 8), 8.07-8.15 (2H, m), 8.32 (1H, d, J 8), 8.58 (1H, d, J 8). m/z (ES+) 390 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18]C)=[O:17])[C:11]1=[O:20])[CH3:3]>O1CCCC1.CO.[OH-].[Na+].O>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[C:11]1=[O:20])[CH3:1]
Reactant: COC(=O)c1cccn(-c2ccccc2C(C)C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccccc1-n1cccc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
Methyl 2-oxo-2H-pyran-3-carboxylate (3.0 g, 19 mmol) was dissolved in a mixed solvent of tetrahydrofuran (40 mL) and N,N-dimethylformamide (10 mL), and 2-(1-methylethyl)aniline (2.7 mL, 19 mmol) was added. After stirring overnight at room temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.5 g, 23 mmol) and 4-(N,N-dimethylamino)pyridine (120 mg, 1.0 mmol) were added, and the mixture was further stirred overnight at room temperature. The reaction system was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→60/40) to give methyl 1-[2-(1-methylethyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (800 mg). Methyl 1-[2-(1-methylethyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (800 mg) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and methanol (5 mL), 1N aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 2 hr. The mixture was diluted with distilled water (20 mL) and washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid (7 mL) and extracted twice with ethyl acetate. The collected organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. A small amount of hexane/ethyl acetate was added to the residue, and the resulting precipitate was collected by filtration to give 1-[2-(1-methylethyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid (760 mg, 15%) as a white solid.
Reaction SMILES: C([C:5]1[C:6]([O:14][CH3:15])=[C:7]([NH2:13])[CH:8]=[C:9]([I:12])[C:10]=1[Cl:11])(C)(C)C.Br[CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:11][C:10]1[C:9]([I:12])=[CH:8][C:7]([NH:13][CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: COc1c(N)cc(I)c(Cl)c1C(C)(C)C
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Nc1cc(I)c(Cl)cc1OC
Temperature: 100 °C
Reaction time: 16 h
Yield: 42.9 %

Procedure:
A mixture of tert-butyl 4-chloro-5-iodo-2-methoxybenzenamine (2 g, 7.07 mmol), methyl 2-bromopropanoate (1.17 g, 7.07 mmol), K2CO3 (1.94 g, 14.14 mmol) and KI (0.235 g, 1.414 mmol) in DMF (25 mL) was stirred at 100° C. for 16 h. The mixture was allowed to cool to RT, quenched with aqueous NaHCO3 solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=1:20) to afford the desired product (1.12 g, 43% yield) as a yellow solid. ESI-MS m/z: 370.1[M+H]+.