Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=2)[NH:12][N:11]=1.[CH:20]([O-])=[O:21].[Na+]>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:20]=[O:21])[CH:17]=2)[NH:12][N:11]=1
Reactant: O=C[O-]
Reactant: Ic1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1
Temperature: 90 °C
Yield: 37 %

Procedure:
3-(1H-benzimidazol-2-yl)-5-iodo-1H-indazole (500 mg, 1.39 mmol) was dissolved in DMF (5 mL), then Pd(PPh3)2Cl2 (24 mg, 0.034 mmol) and sodium formate (142 mg, 2.1 mmol) were added. The reaction mixture was put under vacuum and recharged with CO three times, then heated up to 90° C. for 4 hr. The mixture was diluted with EtOAc, washed with brine, dried and concentrated. The crude product was purified by flash chromatography to afford 3-(1H-benzimidazol-2-yl)-1H-indazole-5-carboxaldehyde (135 mg, 37%) as yellow solid.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[CH3:13][C:14](O)=[O:15]>C([O-])(=O)C.[Na+]>[C:14]([NH:2][NH:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1)(=[O:15])[CH3:13]
Reactant: COC(=O)c1ccc(NN)cc1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(NNC(C)=O)cc1
Temperature: 80 °C
Yield: 115.7 %

Procedure:
5.5 g of methyl 4-hydrazinobenzoate are dissolved in 38.2 ml of AcOH containing 2.4 g of sodium acetate, and the mixture is heated at 80° C. for 18 hours. The mineral is filter-dried, then evaporation is performed and the product is taken up with a minimum of Et2O. The product is filter-dried so as to obtain 7.97 g of the expected compound.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([CH3:25])=[CH:23][S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[C:24]([CH3:25])=[CH:23][S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: Cc1csc2nc(-c3cnccn3)nc(Cl)c12
Product: Cc1csc2nc(-c3cnccn3)nc(NCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-benzylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CC(C)CC[O:5][C:6]1[C:11]2[C:12](=[O:21])[CH:13]=[C:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[O:15][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[CH:8][CH:7]=1.Br.C(=O)(O)[O-].[Na+].Cl>O>[OH:5][C:6]1[C:11]2[C:12](=[O:21])[CH:13]=[C:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[O:15][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[CH:8][CH:7]=1
Reactant: CCCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnn[nH]3)oc12
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: CCCc1ccc(O)c2c(=O)cc(-c3nnn[nH]3)oc12

Procedure:
A mixture of 5 parts of 5-[5-(3-methyl-n-butoxy)-8-n-propyl-4-oxo-4H-1 -benzopyran-2-yl]tetrazole in 130 parts by volume of 48% aqueous hydrobromic acid was refluxed for 3 hours, then cooled and water added. The resulting mixture was neutralised by the addition of solid sodium bicarbonate, then made slightly acidic by re-acidification with dilute hydrochloric acid and extracted with chloroform. The chloroform extract was washed with saturated brine and water, and was dried. Evaporation of the chloroform gave a solid which was purified by precipitation from aqueous ethanol to give 0.36 parts of 5-[5-hydroxy-8-n-propyl-4-oxo-4H-1-benzopyran-2-yl]tetrazole, m.p. 242.5°-245° C.
Reaction SMILES: [C:1](CC(O)CCN)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[OH:24])([O-:16])=[O:15]>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N+:14]([O-:16])=[O:15])=[C:18]([CH:19]=1)[O:24][CH:18]([CH2:19][CH3:20])[CH2:17][NH:14][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CC(C)(C)OC(=O)CC(O)CCN
Product: CCC(CNC(=O)OC(C)(C)C)Oc1cc(F)ccc1[N+](=O)[O-]

Procedure:
Prepared analogously to example I-1 using BOC-4-amino-2-butanol and 2-nitro-5-fluorophenol.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:22])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].CN(C)C.[C:27]([O:34][CH:35]([CH3:39])[C:36](Cl)=[O:37])(=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:36](=[O:37])[CH:35]([O:34][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:39])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CCCCCC(=O)OC(C)C(=O)Cl
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1O
Agent: CN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCC(=O)OC(C)C(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C

Procedure:
In 15 ml of dichloromethane are dissolved 0.75 g of 16β-ethyl-17β-hydroxy-4-estren-3-one and 0.5 ml of trimethylamine, and 0.5 ml of 2-(n-hexanoyloxy)propionyl chloride is added to the solution. The mixture is refluxed for 2 hours. After cooling, the reaction mixture is poured into a mixture of 100 ml of ethyl acetate and 30 ml of saturated aqueous sodium hydrogen carbonate solution. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue dissolved in a small amount of diisopropyl ether. The solution is subjected to silica gel column chromatography. After serial passage of diisopropyl ether-n-hexane mixtures (2:8, 100 ml and 1:6, 300 ml), elution is carried out with 500 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.48 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[CH2:17]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([Cl:31])[C:22]=1[N+:32]([O-])=O)[CH:18]=[CH2:19]>ClCCl.O.CC[N+]1C=CC(C2C=C[N+](CC)=CC=2)=CC=1.[Br-].[Br-]>[CH2:17]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([Cl:31])[C:22]=1[NH2:32])[CH:18]=[CH2:19]
Reactant: C=CCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Agent: CC[n+]1ccc(-c2cc[n+](CC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: C=CCNc1c(N)c(Cl)nc2ccccc12
Yield: 64.6 %

Procedure:
An aqueous solution (200 mL) of potassium carbonate (55.3 g, 400 mmol) and sodium dithionate (62.7 g, 360 mmol) was added dropwise over 30 minutes to a mixture of N-allyl-2-chloro-3-nitroquinolin-4-amine (21.0 g, 79.9 mmol) and ethyl viologen dibromide (1.80 g, 4.80 mmol) in dichloromethane (320 mL) and water (40 mL) under a nitrogen atmosphere. The dark blue-green mixture was stirred rapidly and was heated at reflux overnight. The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were filtered through CELITE filter agent, dried over magnesium sulfate, filtered, and concentrated to a dark oil. The crude product was purified by suction filter chromatography (silica gel, gradient elution from 3:1 to 1:3 hexanes/ethyl acetate, then 4:1 dichloromethane/ethyl acetate) to afford pure product N4-allyl-2-chloroquinoline-3,4-diamine (12.06 g) along with some impure product (3.10 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:36])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:35])[NH:24][CH2:25][C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)=[CH:20][C:21]=1[Cl:22])=[O:16])[CH2:12][NH2:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[S:78]1[CH:82]=[CH:81][CH:80]=[C:79]1[C:83](O)=[O:84]>CN(C=O)C.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:36])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:35])[NH:24][CH2:25][C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)=[CH:20][C:21]=1[Cl:22])=[O:16])[CH2:12][NH:13][C:83]([C:79]1[S:78][CH:82]=[CH:81][CH:80]=1)=[O:84]
Reactant: O=C(O)c1cccs1
Reactant: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To a solution of (S)-3-Amino-2-({3-chloro-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester trifluoro-acetic acid salt (0.19 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.08 mL, 0.57 mmol), HBTU (0.108 g, 0.29 mmol), HOBt (0.031 g, 0.23 mmol), and 2-Thiophenecarboxylic acid (0.029 g, 0.23 mmol). The mixture was stirred at room temperature 2 h, treated with EtOAc (30 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column (0-100% EtOAc in hexane) to give 0.0487 g (47%) colorless oil. MS m/e 545.9 (M+H+).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([CH3:27])=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][C:18]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([CH3:27])=[CH:20][N:19]=2)=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(Nc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
To a mixture of 4-(benzyloxy)aniline hydrochloride (4.10 g) and 2-chloro-5-methyl-3-nitropyridine (3.0 g) in DMF (30 mL) was added TEA (7.27 mL) at room temperature, and the mixture was stirred at room temperature for 2 h. The mixture was heated to 60° C. After stirring at 60° C. overnight, K2CO3 (4.81 g) was added to the mixture. The mixture was heated to 100° C. and stirred at 100° C. overnight. The mixture was poured into water and the mixture was extracted with AcOEt. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, silica gel, eluted with 5%-30% AcOEt in hexane) to give N-[4-(benzyloxy)phenyl]-5-methyl-3-nitropyridin-2-amine (1.33 g) as a red solid.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([CH3:20])[CH:14]=1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[F:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:3])=[C:15]([CH3:20])[CH:14]=1
Reactant: COC(=O)c1cccoc1=O
Reactant: Cc1cc(F)ccc1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(-c2ccc(F)cc2C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.9 %

Procedure:
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (3 g, 19.5 mmol) in N,N-dimethylformamide, (18 mL) was added 4-fluoro-2-methylaniline (2.44 g, 19.5 mmol), and the mixture was stirred at room temperature for 3 hr. 4-Dimethylaminopyridine (119 mg, 0.974 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.48 g, 23.4 mmol) were added to the reaction mixture, and the mixture was further stirred at room temperature for 16 hr. 2N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1), and the obtained solid was washed with hexane/ethyl acetate (=1/1) and collected by filtration to give the title compound (0.40 g, 8%) as a yellow solid.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH:30][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
A mixture of 4-phenoxybenzoic acid (0.136 g, 0.634 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.146 g; 0.635 mmol), HATU (0.265 g; 0.698 mmol) and N,N-diisopropylethyldiamine (0.273 mL; 1.59 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.070 g (28%) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:7]=[CH:8][C:9]=1Cl)([O-:3])=[O:2].[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:28]1[CH:29]=[CH:30][S:26][CH:27]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(-c2nc3cc(-c4ccccc4)ccc3o2)ccc1Cl
Reactant: OB(O)c1ccsc1
Product: O=[N+]([O-])c1cc(-c2nc3cc(-c4ccccc4)ccc3o2)ccc1-c1ccsc1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-chlorophenyl)-5-phenylbenzoxazole (177 mg, 0.51 mmol) and thiophene-3-boronic acid (97 mg, 0.76 mmol) the subtitle compound was obtained (150 mg, 74%). 1H NMR (DMSO) δ 8.67(d, 1H), 8.48(dd, 1H), 8.12(d, 1H), 7.91(m, 2H), 7.83(m, 1H), 7.79–7.77(m, 4H), 7.51(m, 2H), 7.40(t, 1H), 7.22(dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH2:16][CH3:17])[CH:10]([CH3:15])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[OH:18].CO.O.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@H:9]([CH2:16][CH3:17])[C@H:10]([CH3:15])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[OH:18]
Reactant: CCC1C(c2ccc(N)c(O)c2)=NNC(=O)C1C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC[C@H]1C(c2ccc(N)c(O)c2)=NNC(=O)[C@H]1C

Procedure:
1.10 g (4.45 mmol) 6-(4-amino-3-hydroxy-phenyl)-5-ethyl-4-methyl-4,5-dihydro-2H-pyridazin-3-one are separated by RP (xBridge, MeOH/H2O/TFA).
Reaction SMILES: [CH2:1]([C:9]1[C:14]([CH:15]=[CH:16][C:17]([O:19]C)=[O:18])=[CH:13][CH:12]=[C:11]([C:21]([F:24])([F:23])[F:22])[N:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([C:9]1[C:14]([CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=[C:11]([C:21]([F:23])([F:22])[F:24])[N:10]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C=Cc1ccc(C(F)(F)F)nc1CCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=Cc1ccc(C(F)(F)F)nc1CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a suspension of compound 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid, methyl ester (1.46 g, 4.35 mmol) in THF (3 ml) was added a solution of 1 N-LiOH (6.0 ml), and the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H2O and then washed with EtOAc, acidified with 1N HCl to pH 1˜2. The solution was extracted three times with methylene chloride and then dried over anhyd. MgSO4 and concentrated in vacuo to give 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (1.37 g, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]=[C:18]=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([OH:24])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: O=C=NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 24 h

Procedure:
A solution of 3.2 g (12.3 mmol) of (1-benzyloxycarbonylpiperidin-4-yl)isocyanate from Step A in 25 mL of DMF was slowly added to a suspension of CuCl3 in 25 mL of DMF and 12 mL of t-butanol. The reaction was stirred for 24 h and then diluted with water and extracted twice with 1:1 ether:ethyl acetate. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 20% ethyl acetate in hexanes to afford 685 mg of title compound.
Reaction SMILES: CO[CH:3]1[O:8][CH:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH:6]([CH3:18])[CH:5]=[C:4]1[CH3:19].B(F)(F)F.CCOCC.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:18][CH:6]1[CH:5]=[C:4]([CH3:19])[CH2:3][O:8][CH:7]1[C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: COC1OC(c2c([N+](=O)[O-])cnn2C)C(C)C=C1C
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: ClCCl
Product: CC1=CC(C)C(c2c([N+](=O)[O-])cnn2C)OC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(6-methoxy-3,5-dimethyl-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-pyrazole (100 mg, 0.38 mmol) in DCM (1 mL) cooled to −78° C. was added boron trifluoride diethyl etherate (0.14 mL, 1.13 mmol) and triethylsilane (0.36 mL), 2.68 mmol). After stirring at −78° C. for 1 hr, the reaction mixture was allowed to warm to room temperature and stirred for 18 hr. Saturated aqueous NaHCO3 (5 mL) and DCM (5 mL) were added and the organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave 5-(3,5-dimethyl-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-pyrazole as a yellow oil. The reaction was repeated to provide more material. To a solution of 5-(3,5-dimethyl-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-pyrazole (305 mg, 1.29 mmol) in DCM (6.5 mL) cooled to 0° C. was added m-CPBA (70-75%, 382 mg, 1.54 mmol) and the mixture was stirred at 0° C. for 90 min. More m-CPBA (70-75%, 191 mg, 0.774 mmol) was added and the mixture was slowly warmed to room temperature over 6 hr. The mixture was filtered through Celite® washing with DCM (15 mL) and the filtrate washed with saturated aqueous NaHCO3 (2×10 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave 5-(2,6-dimethyl-4,7-dioxabicyclo[4.1.0]heptan-3-yl)-1-methyl-4-nitro-pyrazole as a single diastereomer as an off-white solid (189 mg, 53% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 5.32-5.28 (m, 1H), 4.15-4.08 (m, 1H), 4.06 (s, 3H), 3.78 (d, J=12.9 Hz, 1H), 3.30 (d, J=5.6 Hz, 1H), 2.71-2.61 (m, 1H), 1.38 (s, 3H), 0.92 (d, J=7.0 Hz, 3H).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[CH:8]=1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:20]([CH2:6][C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:16]([O:18][CH3:19])=[O:17])=[N+:21]=[N-:22]
Reactant: COC(=O)c1cc(COS(C)(=O)=O)cc([N+](=O)[O-])c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(CN=[N+]=[N-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.2 %

Procedure:
3-Carbomethoxy-5-nitrobenzyl methanesulfonate (300.0 g, 1.04 mol) and sodium azide (81.0 g, 1.25 mol) were suspended in DMF (1700 ml) and stirred at room temperature for 5 hours. The reaction was diluted with ethyl acetate (2000 ml), washed with 1000 ml portions of H2O (2×) and saturated NaCl (1×), dried (MgSO4), and concentrated under reduced pressure. The resulting amber syrup was dried under vacuum at 40° C. to yield the title compound as a tan solid (226.5 g, 92%). 1H NMR (CDCl3): 8.60 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 4.52 (s, 2H), 3.88 (s, 3H); MP=44°-46° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1.Cl.[CH3:28][NH:29][CH3:30].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[C:21]([C:24]([N:29]([CH3:30])[CH3:28])=[O:25])[CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1
Reactant: O=C(O)c1ccc2c(c1)CCCN(c1cc(Cl)c3cc(Cl)ccc3n1)C2
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc2c(c1)CCCN(c1cc(Cl)c3cc(Cl)ccc3n1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
The mixture of 2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxylic acid (135 mg, 0.35 mmol), dimethylamine hydrochloride (34.2 mg, 0.42 mmol), triethylamine (105 mg, 1.05 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (159 mg, 0.42 mmol) and 5 mL of dichloromethane was stirred at room temperature overnight under nitrogen. The reaction was diluted with ethyl acetate (20 mL), washed with water and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography to give 133 mg of product as a white solid. (yield was 92%). MS obsd. (ESI+) [(M+H)+] 414.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([NH:13][CH2:14][CH2:15][NH:16][CH2:17][C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=1)[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](=O)(ON1C(=O)CCC1=O)[O:29]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCCl.ClC(Cl)C>[C:1]([O:5][C:6]([C@@H:8]([N:13]1[CH2:14][CH2:15][N:16]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=2)[C:28]1=[O:29])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: COC(=O)c1cccc(CNCCN[C@@H](C(=O)OC(C)(C)C)C(C)(C)C)n1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Yield: 86.3 %

Procedure:
A solution of the product of Example 50-3 (92 g, 243 mmol), disuccinimidyl carbonate (78 g, 304 mmol), and triethylamine (41 mL, 294 mmol) in 1,2-dichloroethane (1.8 L) was stirred at room temperature for 16 hours. The mixture was diluted with dichloroethane (200 mL), washed with saturated NaHCO3 (2×500 mL), and brine (200 mL), dried over MgSO4, filtered and concentrated. The residue was triturated with hexane (550 mL) and ethyl acetate (50 mL) at room temperature for two hours to give the title compound as a white solid (85 gm, 98% yield). 1H NMR (CDCl3): δ ppm 1.10 (s, 9 H), 1.48 (s, 9 H), 3.34 (m, 2 H), 3.62 (m, 1 H), 3.88 (m, 1 H), 4.00 (s, 3 H), 4.42 (s, 1 H), 4.64 (s, 2 H), 7.52 (d, 1 H), 7.81 (t, 1 H), 8.03 (d, 1 H).