Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4](=[S:21])[NH:3]1.[H-].[Na+].I[CH3:25]>O1CCCC1>[CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4]([S:21][CH3:25])=[N:3]1
Reactant: CI
Reactant: Cn1[nH]c(=S)n(-c2ccccc2Oc2ccccc2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nn(C)c(=O)n1-c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
A solution of 900 mg of crude 2-methyl-4-(2-phenoxyphenyl)-5-thioxo-1,2,4-triazolidin-3-one in 50 mL of tetrahydrofuran was treated with 150 mg of sodium hydride (60% oil dispersion). After 5 minutes, 0.5 mL of iodomethane was added, and the mixture was stirred at ambient temperature overnight. The solid was removed by filtration and the filtrate concentrated to an oil. The oil was partitioned between ether and 1N hydrochloric acid solution. The organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was triturated in hexane/n-butyl chloride to afford 530 mg (56%) of the title compound of Step C, m.p. 129°-130° C.
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[NH:58]1[CH2:63][CH2:62][CH:61]([NH:64][C:65]2[CH:70]=[CH:69][C:68]([S:71][C:72]([F:75])([F:74])[F:73])=[CH:67][CH:66]=2)[CH2:60][CH2:59]1>CN(C)C=O.ClCCl.O1CCCC1>[F:23][C:3]([F:2])([F:22])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][C:19]([N:58]3[CH2:63][CH2:62][CH:61]([NH:64][C:65]4[CH:66]=[CH:67][C:68]([S:71][C:72]([F:73])([F:75])[F:74])=[CH:69][CH:70]=4)[CH2:60][CH2:59]3)=[O:20])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Sc1ccc(NC2CCNCC2)cc1
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc(SC(F)(F)F)cc2)CC1
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (16 mg; 0.05 mmol, prepared in accordance with Example 3) diisopropylethyl amine (18 μL; 0.10 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution piperidin-4-yl-(4-trifluoromethylsulfanyl-phenyl)-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 47) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 105 minutes at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (10 mg; 0.02 mmol). The structure was confirmed using Protocol II-A. Calculated mass=575; observed mass=575; HPLC retention time=3.65 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=O)[C:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:19]([CH3:31])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[C:6]([OH:33])[CH:5]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:11]([C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[C:19]([CH3:31])[CH:18]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])[O:33][C:6]=2[CH:5]=1)=[O:34]
Reactant: CCC(CC)(C(=O)Nc1ccc(C(=O)OC)cc1O)c1ccc(OCc2ccccc2)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(OCc2ccccc2)c(C)c1)c1nc2ccc(C(=O)OC)cc2o1
Temperature: 160 °C
Yield: 72.6 %

Procedure:
A solution of 4-[2-(4-benzyloxy-3-methyl-phenyl)-2-ethyl-butyrylamino]-3-hydroxy-benzoic acid methyl ester (2.15 g, 4.66 mmol) in toluene (50 mL) is treated with TsOH—H2O (443 mg, 2.33 mmol). The reaction is heated to 160° C. for 60 m. The reaction mixture is cooled down, and toluene is removed under vacuum. The residue is purified by column chromatography (10% EtOAc/Hex) to give the title compound as an oil (1.50 g, 72%) MS (ES) m/e: 444.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)[OH:4].CC1(C)[NH:16][C:15](=[O:17])[C:14]2[CH:18]=[C:19]([O:22][CH2:23][CH2:24]Br)[CH:20]=[CH:21][C:13]=2[O:12]1.N>C(O)(C)C>[C:15]([C:14]1[CH:18]=[C:19]([CH:20]=[CH:21][C:13]=1[OH:12])[O:22][CH2:23][CH2:24][NH:1][CH2:2][CH:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)[OH:4])(=[O:17])[NH2:16]
Reactant: NCC(O)c1ccco1
Reactant: CC1(C)NC(=O)c2cc(OCCBr)ccc2O1
Agent: N
Solvent: CC(C)O
Product: NC(=O)c1cc(OCCNCC(O)c2ccco2)ccc1O
Reaction time: 1 h

Procedure:
A mixture of 7.0 g of α-(aminomethyl)-2-furan-methanol and 7.5 g of 2,3-dihydro-2,2-dimethyl-6-(2-bromoethoxy)-4H-1,3-benzoxazin-4-one is melted and the melt is stirred for 1 hour in a bath at about 110°. 50 ml of isopropanol and 2 ml of concentrated ammonia solution are added to the reaction mixture whilst this is still warm, the mixture is boiled for 5 minutes and filtered and the filtrate is allowed to cool. After working up, α-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl]-2-furanmethanol with a melting point of 169°-171° is obtained.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[CH2:13]([NH:20][C@H:21](C(O)=O)[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:13]([N:20]1[CH:21]([CH3:22])[CH2:3][CH:2]2[CH:11]1[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](NCc1ccccc1)C(=O)O
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC(C)N(Cc3ccccc3)C2C1

Procedure:
42.8 g (0.25 mol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate are heated under reflux overnight with 44.8 g (0.25 mol) of N-benzylalanine in 750 ml of toluene. The mixture is concentrated and the residue is distilled twice.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:38])([CH2:35][CH2:36][CH3:37])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:34])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])=[CH:20][C:19]([CH2:32][CH3:33])=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:38])([CH2:35][CH2:36][CH3:37])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:34])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])=[CH:20][C:19]([CH2:32][CH3:33])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(CC)cc12)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(CC)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.7 %

Procedure:
A solution of 19 mg (0.033 mmol, 95% purity) of rac-{1-[({7-[(2,6-difluorobenzyl)oxy]-5-ethyl-2-methylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 169A) in 1 ml of dichloromethane was admixed with 0.15 ml of trifluoroacetic acid. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the remaining residue was purified by preparative HPLC chromatography (Method 21), which gave 4.5 mg (15% yield) of product.
Reaction SMILES: OC([C@@]1(O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](NC(C)=O)[C@@H](O)C1)[O:5][CH2:6][C@H:7]1[O:24][C@@H:11]([O:12][C@@H:13]2[C@@H:19]([CH2:20][OH:21])[O:18][CH:16]([OH:17])[C@H:15]([NH2:22])[C@H:14]2[OH:23])[C@H:10]([OH:25])[C@@H:9]([OH:26])[C@H:8]1[OH:27])=O.C(O)[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O.CC(N[C@H]1C([C@H](O)[C@H](O)CO)O[C@](OP(OC[C@H]2O[C@@H](N3C(=O)N=C(N)C=C3)[C@H](O)[C@@H]2O)([O-])=O)(C(O)=O)C[C@@H]1O)=O.[Na+]>>[O:12]([C@@H:13]1[C@@H:19]([CH2:20][OH:21])[O:18][CH:16]([OH:17])[C@H:15]([NH2:22])[C@H:14]1[OH:23])[C@@H:11]1[O:24][C@H:7]([CH2:6][OH:5])[C@H:8]([OH:27])[C@H:9]([OH:26])[C@H:10]1[OH:25]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@@](OC[C@H]2O[C@@H](O[C@H]3[C@H](O)[C@@H](N)C(O)O[C@@H]3CO)[C@H](O)[C@@H](O)[C@H]2O)(C(=O)O)C[C@@H]1O
Agent: CC(=O)N[C@H]1C([C@H](O)[C@H](O)CO)O[C@](OP(=O)([O-])OC[C@H]2O[C@@H](n3ccc(N)nc3=O)[C@H](O)[C@@H]2O)(C(=O)O)C[C@@H]1O
Agent: OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O
Agent: [Na+]
Product: N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O

Procedure:
Synthesis of NeuAcα2-6Galβ1-4GlcNH2 βSEt. Galβ1-4GlcNH2 βSEt is prepared as described above and used directly or after isolation as acceptor for a β-D-galactoside α2-6-sialyltransferase (e.g. EC 2.4.99.1) reaction with a suitable glycosyl donor such as CMP-NeuAc.
Reaction SMILES: [CH3:1][SH:2].[OH-].[K+].Cl[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1>CN(C)C=O.C(O)C>[CH3:1][S:2][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CS
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CSc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
28.3 g of methylmercaptan are dissolved in 500 ml of dimethylformamide at 0° C., under nitrogen. 37.4 g of potassium hydroxide, dissolved in 150 ml of ethanol, are then added dropwise at -10° C., after which 94.5 g of 4-chloronitrobenzene are added. The reaction mixture is warmed to 100° C. and stirred at this temperature for 8 hours. It is then stirred into 5 kg of ice water. The precipitate is filtered off with suction, washed, dried and recrystallised from methanol. Yield: 86.2 g of yellow crystals of melting point 71°-73.5° C.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][CH2:7][O:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[CH:4][N:3]=[N:2]1.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[NH:1]1[C:5]([CH2:6][CH2:7][O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)COCCc1cnn[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COCCc1cnn[nH]1

Procedure:
Stir a mixture of tert-butyl 2-[2-(1H-triazol-5-yl)ethoxy]acetate (14.15 g; 62.26 mmol) and trifluoroacetic acid (70.75 mL, 935.69 mmol) in dichloromethane (70.75 mL) for 2 hours at room temperature. Concentrate the reaction mixture under reduced pressure to provide the title compound containing additional trifluoroacetic acid (20.22 g, >100%) as a brown solid. MS (m/z): 172.05 (M+1).
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=1)=O)(C)(C)C>O1CCOCC1.CCOC(C)=O>[CH3:23][CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH2:10][NH2:9])=[CH:16][CH:15]=1)[CH2:18][C:19]([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(CC(C)(C)C)c1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(CC(C)(C)C)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
Add 4N hydrogen chloride in dioxane (10 mL) to a stirred solution of N-(tert-butoxycarbonyl)-4-(1,3,3-trimethyl-butyl)-benzylamine (225 mg, 0.74 mmol) in EtOAc (15 mL) and stir the mixture at ambient temperature overnight. Concentrate in vacuo and wash the solid with diethyl ether. Suspend the solid in dichloromethane and saturated aqueous NaHCO3 and stir until both phases are clear (15 min). Extract the aqueous phase twice with dichloromethane. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to give the title compound as an oil (0.136 g, 90%) that was used without any further purification. MS (ES+) m/z: 206 (M+H)+.
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:8]=[C:9]([CH3:12])[CH2:10][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[C:13]([C:17]1[CH:34]=[CH:33][C:20]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)=O)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].Cl>C(OCC)C.C(COC)OC>[C:3]([C:7]1[CH:8]=[C:9]([CH3:12])[C:10](=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:25][CH:24]=2)[C:20]2[CH:33]=[CH:34][C:17]([C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:18][CH:19]=2)[CH:11]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1ccc(C(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CC1=CC(C(C)(C)C)=CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: COCCOC
Product: CC1=CC(C(C)(C)C)=CC1=C(c1ccc(C(C)(C)C)cc1)c1ccc(C(C)(C)C)cc1

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 1.58 g of powdery potassium hydroxide (28.2 mmol) and 100 ml of dehydrated dimethoxy ethane were added in a nitrogen atmosphere. To the suspension, 2.31 g of 3-tert-butyl-1-methyl-cyclopentadiene (17.0 mmol) was gradually added dropwise at room temperature and stirred under reflux for 1 hr. Thereafter, a solution prepared by dissolving 5.25 g of 4,4′-di-tert-butyl-benzophenone (17.8 mmol) to 40 ml of dehydrated dimethoxyethane was gradually added dropwise and stirred under reflux for 2 days. To the resulting reaction mixture, 50 ml of a hydrochloric acid aqueous solution (1N) was gradually added dropwise in an ice bath and stirred at room temperature for some time. Diethyl ether was added to the mixed solution to separate an organic phase. The organic phase was washed with a saturated sodium bicarbonate aqueous solution, water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a reddish-brown solid. The solid was purified with a column chromatography using 240 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure, and thereby the aimed compound was obtained in an amount of 2.10 g (5.09 mmol) as a reddish-orange solid (yield: 30%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[N:12]=2)=[CH:7][CH:6]=1.N1(C(N2C=CN=C2)=O)C=CN=C1.[C:43]([CH2:45][C:46](O)=[O:47])#[N:44]>ClCCl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:46](=[O:47])[CH2:45][C:43]#[N:44])[CH2:22]3)[N:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]4[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=4[F:1])=[CH:10][CH:9]=3)[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3F)cc1)nn2[C@@H]1CCCNC1
Reactant: N#CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-[4-(2-fluorophenoxy)-phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.25 mmol, 1.00 equiv) in dichloromethane (10 mL), 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (60 mg, 0.37 mmol, 1.50 equiv), and 2-cyanoacetic acid (110 m/z, 1.29 mmol, 5.23 equiv). The resulting solution was stirred for 60 min at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 0.06 g (51%) of 3-[(3R)-3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[C:20]([C:28]4[CH:29]=[C:30]([NH:34]C(=O)C(F)(F)F)[CH:31]=[CH:32][CH:33]=4)=[N:21][N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=34)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.[Li+].[OH-]>>[NH2:34][C:30]1[CH:29]=[C:28]([C:20]2[C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:41])[CH3:1])[CH:7]=4)[N:18]=3)=[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]3[N:21]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)C(F)(F)F)c4)nn4ccccc34)n2)c1
Agent: [Li+]
Agent: [OH-]
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1

Procedure:
The compound was prepared from N-[3-(3-{2-[(3-{[2-(dimethylamino)ethyl]oxy}-phenyl)amino]-4-pyrimidinyl}pyrazolo[1,5-a]pyridin-2-yl)phenyl]-2,2,2-trifluoroacetamide and LiOH using the hydrolysis conditions described in Example 36, Step G to generate the desired product in quantitative yield. 1H NMR (400 MHz, d6-DMSO): δ 9.51 (s, 1H), 8.80 (d, J=7.1 Hz, 1H), 8.56 (d, J=8.8 Hz, 1H), 8.24 (d, J=5.3 Hz, 1H), 7.54 (s, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.08-7.18 (m, 3H), 6.80 (s, 1H), 6.68 (t, J=7.9 Hz, 2H), 6.51-6.55 (m, 2H), 5.24 (s, 2H), 3.99 (t, J=5.8 Hz, 2H), 2.59 (t, J=5.9 Hz, 2H), 2.18 (s, 6H). ES-LC/MS m/z=466 [M+H]+.
Reaction SMILES: CC1(C)OB([C:7]2[CH:8]=[N:9][N:10](C(OC(C)(C)C)=O)[CH:11]=2)OC1(C)C.Br[C:23]1[C:24]([O:38][CH:39]2[CH2:42][CH2:41][CH2:40]2)=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]([O:35][CH3:36])=[O:34])[C@@H:28]([CH3:37])[CH2:27][CH2:26]2.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:39]1([O:38][C:24]2[C:23]([C:7]3[CH:11]=[N:10][NH:9][CH:8]=3)=[CH:32][CH:31]=[C:30]3[C:25]=2[CH2:26][CH2:27][C@H:28]([CH3:37])[N:29]3[C:33]([O:35][CH3:36])=[O:34])[CH2:40][CH2:41][CH2:42]1
Reactant: COC(=O)N1c2ccc(Br)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N1c2ccc(-c3cn[nH]c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A 100-mL round-bottom flask was charged with tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (250 mg, 0.85 mmol), (S)-methyl 6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (317 mg, 0.89 mmol), sodium carbonate (150 mg, 1.42 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (58 mg, 0.18 mmol), 1,4-dioxane (10 mL), and water (2 mL). The resulting mixture stirred overnight at 100° C. in an oil bath. After cooling to room temperature, the reaction mixture was poured into 10 mL of water and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 5:1, ethyl acetate/petroleum ether) to afford (S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (200 mg, 52%) as yellow oil. MS (ESI, pos. ion) m/z 342 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[N:10][NH:11][C:12]2=S)=[CH:7][CH:6]=1.O.[NH2:22][NH2:23]>>[OH:1][CH:2]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[N:10][N:11]=[C:12]2[NH:22][NH2:23])=[CH:7][CH:6]=1
Reactant: CC(C)NCC(O)COc1ccc2cn[nH]c(=S)c2c1
Reactant: NN
Solvent: O
Product: CC(C)NCC(O)COc1ccc2cnnc(NN)c2c1

Procedure:
7-(2-Hydroxy-3-isopropylaminopropoxy)-1(2H)-phthalazinethione was reacted with hydrazine hydrate in a similar manner to that described in Example 1(viii) to give 7-(2-hydroxy-3-isopropylaminopropoxy)-1-hydrazinophthalazine which was isolated as its hydrochloride m.p. 249°-253° (decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.CCCCCCCCCC.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCCCCCC
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 56 %

Procedure:
To a mixture of 306 mg (purity: 98.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 825 mg (5.51 mmol) of 2-cyclopropyl-6-methylphenol were added decane (2.76 g) and 327 mg (5.55 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 282 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 56%) and 4.3 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.9%) were obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30](=[O:39])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38])([CH3:28])([CH3:27])[CH3:26].[CH3:40][O:41][C:42]([C:44]1[CH:45]=[CH:46][C:47]([C:50](O)=[O:51])=[N:48][CH:49]=1)=[O:43].CN1CCOCC1>CN(C=O)C.O>[C:25]([O:29][C:30]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][C:50]([C:47]1[CH:46]=[CH:45][C:44]([C:42]([O:41][CH3:40])=[O:43])=[CH:49][N:48]=1)=[O:51])=[O:39])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)nc1
Yield: 79 %

Procedure:
HATU (21 g, 55 mmol) was added to a solution of 2-aminophenylcarbamic acid t-butyl ester (Reference Compound No. 1-1, 10 g, 50 mmol), 5-methoxycarbonylpyridine-2-carboxylic acid (10 g, 55 mmol), and N-methylmorpholine (11 mL, 100 mmol) in DMF (100 mL), and then the reaction mixture was stirred at room temperature for 20 hours. Water (300 mL) was added thereto, and then the whole was extracted with ethyl acetate (300 mL) three times. The organic layer was washed with brine (200 mL), and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the obtained solid was collected by filtration to give 15 g of the title reference compound as a pale brown solid. (Yield 79%)
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][NH:6][C:7](=[O:31])[C@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:9][C:10](=[O:23])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C.C(OCC)(=O)C.C(Cl)(Cl)Cl.CO>C(O)(=O)C>[C:19]([O:18][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:10]([NH:9][C@H:8]([C:7]([NH:6][CH2:5][C:4]([OH:32])=[O:3])=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Yield: 89.8 %

Procedure:
N-t-butoxycarbonyl-prolyl-phenylalanyl-glycine was synthesized from N-t-butoxycarbonyl-prolyl-phenylalanyl-glycine ethyl ester in the same manner as described in Example 1 in yield of 89.8%. Crystals obtained by recrystallization from ethyl acetate and petroleum ether had a melting point of 98°-100° C. and Rf=0.67 (TLC, chloroform: methanol: acetic acid=95:5:3 by volume).