Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH2:14]([O:16][C:17](=[O:29])[CH:18]([NH2:28])[CH:19]([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH3:15].N1C=CC=CC=1>C(Cl)Cl>[CH2:14]([O:16][C:17](=[O:29])[CH:18]([NH:28][S:10]([C:4]1[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=1)(=[O:12])=[O:11])[CH:19]([C:20]([F:23])([F:21])[F:22])[C:24]([F:26])([F:27])[F:25])[CH3:15]
Reactant: CCOC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cc(F)c(F)c(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(NS(=O)(=O)c1cc(F)c(F)c(F)c1)C(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 84.3 %

Procedure:
A solution of 3,4,5-trifluorobenzenesulfonyl chloride (0.348 mL, 2.50 mmol) in CH2Cl2 (5 mL) was added to a solution of 2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl ester (0.4 g, 1.67 mmol) prepared as described (J. Med Chem. 1981, 24, 1043-1047), and pyridine (0.27 mL, 3.34 mmol) in CH2Cl2 (5 mL) at 0° C. and allowed to warm to 25° C. for 19 h. The solution was washed with 1M HCl (1 mL), brine (1 mL), dried over Na2SO4 and concentrated. The crude solid was purified by Biotage Flash™ chromatography, eluting with EtOAc/hexanes (1:4), to give 4,4,4-trifluoro-2-(3,4,5-trifluoro-benzenesulfonylamino)-3-trifluoromethyl-butyric acid ethyl ester (0.63 g, 85%) as a white solid. Mass Spectrum (+ESI): 448 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].N[C@H:15](C1C=CC=CC=1)[CH2:16]C(O)=O.CC#N.O.CC#N>O>[C:1]([NH:4][C@H:5]([C:9]1[CH:8]=[CH:7][CH:6]=[CH:16][CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)NC1(CC(=O)O)CCCC1
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Solvent: O
Solvent: CC#N
Product: CC(=O)N[C@@H](CC(=O)O)c1ccccc1

Procedure:
The title compound is prepared analogously as described for (1-acetylamino-cyclopentyl)-acetic acid from (S)-3-amino-3-phenylpropionic acid. MS (LC-MS): [M+H]+=208.2. tR (HPLC, -Waters Symmetry C18 column, 10-95% CH3CN/H2O/3.5 min, 95% CH3CNIH2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 0.79 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>ClCCl>[CH2:40]([O:39][C:37](=[O:38])[NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1)[CH3:41]
Reactant: CCOC(=O)Cl
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCOc1ccc(NC(=O)c2cccc(OC)c2)cc1-c1ccnn1C
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
The N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (30.0 mg, 74.5 μmol) and triethylamine (31.1 μL, 3.0 eq) were taken up in 2 mL of dichloromethane and stirred for 15 mins. To this was added ethyl chloroformate (8.58 μL, 1.2 eq) and the reaction was stirred at room temperature for 18 hrs. The solvents were evaporated under a stream of nitrogen and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 52.4% yield. LCMS m/z (%)=439 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, J=7.07 Hz, 3 H), 3.44-3.51 (m, 2H), 3.85 (s, 3 H), 3.88 (s, 3 H), 3.94-4.21 (m, 5 H), 6.38 (d, J=2.53 Hz, 1 H), 7.03 (d, J=9.60 Hz, 1 H), 7.11 (dt, J=4.67, 2.27 Hz, 1 H), 7.36-7.46 (m, 3 H), 7.62-7.72 (m, 2 H), 7.83 (s, 1H)
Reaction SMILES: [Mg].II.BrC(Br)C.[CH:8]([C:11]1[CH:12]=[C:13](Br)[CH:14]=[CH:15][CH:16]=1)([CH3:10])[CH3:9].[C:18]1(=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH:8]([C:11]1[CH:12]=[C:13]([C:18]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:14]=[CH:15][CH:16]=1)([CH3:10])[CH3:9]
Reactant: O=C1CCCCC1
Reactant: CC(C)c1cccc(Br)c1
Agent: CC(Br)Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)c1cccc(C2(O)CCCCC2)c1
Temperature: 70 °C
Yield: 63.2 %

Procedure:
To 1.2 g (50 mmol) of magnesium turnings in 15 mL of dry THF is added a small crystal of iodine followed by 40 μL of dibromoethane. This mixture is placed in a water bath at 50° C. and 3-isopropylbromobenzene (5.0 g, 25 mmol) in 15 mL of dry tetrahydrofuran (THF) is added dropwise over 20 min, while the bath temperature is raised to 70° C. The mixture is stirred and refluxed for 40 additional min. The solution is cooled in an ice-water bath and cyclohexanone (2.0 mL, 19 mmol) in 10 mL of dry THF is added dropwise over 15 min. The ice bath is removed and the mixture is allowed to warm to ambient temperature over 1 h. The solution is decanted into aqueous saturated NH4Cl, and combined with an ether wash of the residual magnesium turnings. The organic phase is washed twice more with aqueous NH4Cl, dried over anhydrous Na2SO4, filtered and concentrated. Chromatography on silica gel, eluting with 10% ethyl acetate in heptane, affords 2.7 g (12 mmol, 60%) of compound 1 as an oil: 1H NMR (CDCl3) δ 7.39 (m, 1H), 7.3 (m, 2H), 7.12 (m, 1H), 2.92 (m, 1H), 1.84-1.54 (m, 10H), 1.26 (d, J=7 Hz, 6 H).
Reaction SMILES: C([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([NH:22][CH:23]1[CH2:26][N:25]([S:27]([O-:30])(=[O:29])=[O:28])[C:24]1=[O:31])=[O:21])(OCC1C=CC=CC=1)=O.[Na+:32].C(O)(=O)C>CO.[H][H].[Pd]>[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([NH:22][CH:23]1[CH2:26][N:25]([S:27]([O-:30])(=[O:28])=[O:29])[C:24]1=[O:31])=[O:21].[Na+:32]
Reactant: O=C(Cc1ccccc1CNC(=O)OCc1ccccc1)NC1CN(S(=O)(=O)[O-])C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NCc1ccccc1CC(=O)NC1CN(S(=O)(=O)[O-])C1=O
Yield: 77.9 %

Procedure:
In 35 ml of 30% methanol is dissolved 0.30 g of the above sodium 3-[2-(2-carbobenzoxyaminomethylphenyl)acetamido]-2-oxoazetidine-1-sulfonate, followed by addition of 0.68 ml of 6% acetic acid and 76 mg of palladium black. The mixture is stirred in hydrogen gas streams at room temperature for 90 minutes. The catalyst is filtered off and the filtrate is purified on an Amberlite XAD-II column. The above procedure provides 0.167 g of sodium 3-[2-(2-aminomethylphenyl)acetamido]-2-oxoazetidine-1-sulfonate.acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[N:16][CH:17]=2)=[O:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:46][CH2:45][CH2:44][C:43]3=[O:47])=[N:40][CH:41]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:47]=[C:43]1[CH2:44][CH2:45][CH2:46][N:42]1[C:39]1[N:40]=[CH:41][C:36]([C:2]2[CH:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)=[N:16][CH:17]=3)=[O:9])=[CH:4][CH:3]=2)=[CH:37][CH:38]=1
Reactant: CC1(C)OB(c2ccc(N3CCCC3=O)nc2)OC1(C)C
Reactant: O=C(NCc1ccc(-c2ccnc(C(F)(F)F)c2)nc1)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCc1ccc(-c2ccnc(C(F)(F)F)c2)nc1)c1ccc(-c2ccc(N3CCCC3=O)nc2)cn1
Temperature: 96 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-N-((2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)picolinamide 72-1 (22 mg, 0.05 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidin-2-one 72-2 (29 mg, 0.1 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) and K3PO4 (21 mg, 0.1 mmol) in dioxane (0.5 mL) and water (0.1 mL) was stirred at 96° C. under argon overnight. After cooling to room temperature, the mixture was filtered through celite (washed with ethyl acetate) and the filtrate was redistributed between ethyl acetate and water. The organic phase was dried over Na2SO4 and concentrated with rotavap. The residue was subjected to preparative reverse phase HPLC separation to give 6′-(2-oxopyrrolidin-1-yl)-N-((2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)-[3,3′-bipyridine]-6-carboxamide 72 as a solid. MS m/z 519.2 (M+1). 1H NMR 400 MHz (CDCl3) δ 8.83 (d, 1H), 8.79 (d, 1H), 8.76 (dd, 1H), 8.62 (dd, 1H), 8.57 (dd, 1H), 8.52 (t, 1H), 8.34-8.29 (m, 2H), 8.10-8.02 (m, 2H), 7.96-7.88 (m, 2H), 7.84 (d, 1H), 4.79 (d, 2H), 4.16 (t, 2H), 2.71 (t, 2H), 2.18 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.O[C:23]1[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:25]([CH3:35])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)=[CH:9]/[CH2:10][O:11][C:23]2[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:25]([CH3:35])[CH:24]=2)=[CH:4][CH:3]=1
Reactant: OC/C=C(/c1ccc(Br)cc1)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)COc1ccc(O)cc1C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Br)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 0 °C

Procedure:
The above allyl alcohol (0.77 g, 2.16 mmol), methyl (4-hydroxy-2-methylphenoxy)acetate (0.47 g, 2.37 mmol) and triphenylphosphine (0.68 g, 2.59 mmol) were dissolved in a mixture of anhydrous toluene (10 mL) and tetrahydrofuran (3 mL). The mixture was degassed, cooled to 0° C. and a degassed solution of diisopropyl azodicarboxylate (0.525 g, 2.60 mmol) in anhydrous tetrahydrofuran (3 mL) was added dropwise under nitrogen. The reaction mixture was stirred at ambient temperature over night. The solvents were evaporated in vacuo and the residue was submitted to column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 95: 5-90:10) affording methyl (E)-[4-[3-(4-bromophenyl)-3-[4-trifluoromethyl phenyl]allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[ClH:4].[Cl:5][CH2:6][CH2:7][CH:8]1[CH2:12][N:11]([CH2:13][CH3:14])[C:10](=[NH:15])[N:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[ClH:5].[ClH:4].[CH2:13]([N:11]1[CH2:12][CH:8]([CH2:7][CH2:6][N:2]([CH3:3])[CH3:1])[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]1[NH2:15])[CH3:14]
Reactant: CNC
Reactant: CCN1CC(CCCl)N(c2ccccc2)C1=N
Agent: Cl
Solvent: CCO
Product: CCN1CC(CCN(C)C)N(c2ccccc2)C1N

Procedure:
To a 9.4 g (0.21 mole) of dimethylamine in 200 ml ethanol was added 20 g (0.0695 mole) of 4-(2-chloroethyl)-1-ethyl-2-imino-3-phenylimidazolidine hydrochloride and the solution heated at 100° C. in a steel bomb for 18 hours. The contents were concentrated on the rotary evaporator and the resulting residue partitioned between chloroform and dilute NaOH. The chloroform solution was concentrated and the residue dissolved in isobutyl methyl ketone which was acidified with ethereal HCl. The resulting crystals were recrystallized from isopropanol-isobutyl methyl ketone. Yield 7.8 g (37.8%); m.p. 252°-254° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[C:6]([O:12][CH3:13])[CH:5]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:15]=[N+:16]=[N-:17])=[C:6]([O:12][CH3:13])[CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])c(OC)c1
Yield: 96.8 %

Procedure:
A solution of 4-(bromomethyl)-3-methoxybenzoic acid methyl ester (8 g; 31 mmol) and NaN3 (2 g; 31 mmol) in DMF (90 mL) was stirred overnight at room temperature. The volatiles were removed under vacuum and the crude product was dissolved in EtOAc (50 mL). The solution was washed with water (2×50 mL) and dried. The volatiles were evaporated to provide 4-(azidomethyl)-3-methoxybenzoic acid methyl ester (6.68 g; 30 mmol). Yield 97%.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH2:18]O.[Br:20]CCCC1N=C(C2C=CC=CC=2)OC=1C>>[Br:20][CH2:18][C:17]#[C:16][CH2:15][CH2:14][CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:2]=1[CH3:1]
Reactant: Cc1oc(-c2ccccc2)nc1CCCC#CCO
Reactant: Cc1oc(-c2ccccc2)nc1CCCBr
Product: Cc1oc(-c2ccccc2)nc1CCCC#CCBr
Yield: 80 %

Procedure:
Alcohol 1-8 (1.2 g, 4.7 mmol) was treated in a manner similar to the preparation of bromide 1-5. Chromatography with 10% EtOAc/Hexanes gave the product 1-9 as a colorless oil (1.7 g) in 80% yield. NMR CDCl3 (δ): 7.97 (2H, m); 7.40 (3H, m); 3.93 (2H, s); 2.60 (2H, m); 2.34 (3H, s); 2.28 (2H, m); 1.89 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][C:14]([CH3:17])([CH3:16])[C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>CN(C=O)C>[N:26]1[CH:27]=[CH:28][C:23]([CH:21]([OH:20])[CH2:22][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][C:14]([CH3:17])([CH3:16])[C:5]2=3)=[CH:24][CH:25]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3(C)C
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)C(C)(C)CN(C)C1
Reaction time: 4 h
Yield: 58.7 %

Procedure:
2,4,4,8-Tetramethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 gm, 4.385 mmol) was dissolved in DMF (8 mL) and sodium hydride (0.526 g, 13.15 mmol) was added portionwise under nitrogen. 4-Oxiranyl-pyridine (0.9 g, 7.45 mmol) was diluted in DMF (2 mL) and added dropwise at RT and stirred for 4 h. After consumption of starting material (by monitoring TLC & LCMS), the reaction mixture was poured in to ice water, product was precipitated and filtered, and the residue was washed with water & hexane, dried under reduced pressure and crystallized in EtOH (10 mL) and diethyl ether (50 mL) to obtain 900 mg of 1-pyridin-4-yl-2-(2,4,4,8-tetramethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.62 (d, 2H), 7.37 (d, 2H), 7.31 (d, 1H), 7.19 (s, 1H), 7.01 (d, 1H), 5.22 (t, 1H), 4.32 (d, 1H), 3.6 (d, 1H), 3.48 (d, 1H), 2.65 b (s, 1H), 2.44 (s, 3H), 1.47 (s, 3H), 1.28 (s, 3H). Separation by chiral HPLC provides enantiomers 71a and 71b.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(O)=O.C([O-])(=O)C.[Cu+2:20].C([O-])(=O)C>CO>[Cu:20].[C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)c1ccc(C(=O)O)cc1
Solvent: O=CO
Solvent: CO
Product: [Cu]

Procedure:
0.41 g of terephthalic acid was dissolved under heating in a mixture solvent of 250 cm3 of methanol and 15 cm3 of formic acid. After this solution was cooled to the normal temperature, into this solution, a further solution in which 0.50 g of copper acetate was dissolved in 40 cm3 of methanol was dripped and then this was kept still for a few days. Thereafter, the precipitation product was suction-filtered and dried for 110° C./4 hours, whereby 0.38 g of terephthalic acid copper was obtained.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[NH2:7][C:8]1[C:13]2=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)=[O:27])=[CH:21][CH:20]=3)[C:15]([CH:17]=O)=[CH:16][N:12]2[N:11]=[CH:10][N:9]=1.O>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:7][C:8]1[C:13]2=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)=[O:27])=[CH:21][CH:20]=3)[C:15]([CH:17]=[CH2:1])=[CH:16][N:12]2[N:11]=[CH:10][N:9]=1
Reactant: Nc1ncnn2cc(C=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (1.0 g, 9.06 mmol) was suspended in 1,4-dioxane (20 mL) and treated with methyltriphenylphosphonium bromide (3.2 g, 9.06 mmol). The mixture was allowed to stir at rt for 30 min. A yellow suspension formed then Intermediate AF (1-[4-(4-amino-6-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-3-[4-(trifluoromethyl)-pyridin-2-yl]urea) (2.0 g, 4.53 mmol) in 1,4-dioxane (10 mL) was slowly added and the reaction was stirred at rt for 4 hr. The reaction was slowly poured into vigorously stirring water. The mixture was allowed to stir for 1 hr. The solid was filtered and rinsed with water and MeOH. A light brown solid was isolated (1.2 g, 60%). 1H-NMR (DMSO-d6) δ 9.90 (s, 1H), 9.77 (s, 1H), 8.53 (d, J=5.2 Hz, 1H), 8.06-8.05 (m, 2H), 7.84 (s, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.36 (d, J=5.4 Hz, 1H), 7.31 (d, J=8.5 Hz, 2H), 6.39 (dd, J1=11.3, J2=17.6 Hz, 1H), 5.63 (dd, J1=1.7, J2=17.5 Hz, 1H), 5.12 (dd, J1=1.5, J2=11.1 Hz, 2H). MS [M+H]+=440.0; LCMS RT=2.88.
Reaction SMILES: C(N(CC)CC)C.C(Cl)(Cl)[Cl:9].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1NC(=O)CC1C=CC(OC2C=CC(O[C@H]3CC[C@@H](N)CC3)=CC=2)=CC=1>>[C:14]([Cl:9])(=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccccc1NC(=O)Cc1ccc(Oc2ccc(O[C@H]3CC[C@@H](N)CC3)cc2)cc1
Reactant: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cl)c1ccccc1
Yield: 149.1 %

Procedure:
A reactor was charged with 358 μl (1.7 eq, 179 μmol) of 0.5M triethylamine-chloroform solution containing 420 μl (105 μmol, 50 mg) of 2-(2-(4-(4-(cis-4-aminocyclohexyloxy)phenoxy)phenyl)acetylamino)benzoic acid methyl ester (0.25M-CHCl3) obtained by the Example 17, benzoyl chloride (1.5 eq, 22 mg) was added thereto and the mixture was stirred for 2.5 hours. After completing the reaction, 139 mg (157.5 μmol) of an aminomethylated polystyrene resin (product of Novabiochem) was added to the system and stirred for 12 hours. The solution was put on a Silica cartridge (product of Waters) and developed with a hexane/ethyl acetate mixture (1/2) and the obtained solution was distilled to remove the solvent.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[C:11]([O:15][C:16](=[O:34])[CH2:17][N:18]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH2:33])[N:27]=1)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl>[C:11]([O:15][C:16](=[O:34])[CH2:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])[N:27]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CN)n1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2cccnc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of 3-pyridylsulfonyl chloride (640 mg, 3.60 mmol) in methylene chloride (14 ml) were added tert-butyl[(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetate (1.20 g, 3.56 mmol) obtained in Reference Example 12-(c) and triethylamine (2.24 ml, 16.2 mmol), followed by stirring at room temperature for 1 hour. After completion of the reaction, a 5% aqueous potassium hydrogensulfate solution was added to the reaction solution, followed by extraction with chloroform. The separated organic layer was washed sequentially with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:1→1:2 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.45 g) as a colorless oil. (Yield: 85%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](/[CH:28]=[CH:29]/[C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.Cl.C(Cl)(=O)C>CO>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](/[CH:28]=[CH:29]/[C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)c(/C=C/c2cnn(C)c2)nn3C2CCCCO2)c1Cl
Agent: Cl
Solvent: CO
Solvent: CC(=O)Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(/C=C/c4cnn(C)c4)c3cn2)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-[(E)-2-(1-methyl-1H-pyrazol-4-yl)vinyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine was dissolved in methanol (0.8 mL). To the solution was added HCl solution previously prepared from acetyl chloride (0.5 mL) and methanol (0.5 mL). The mixture was stirred at r.t. for 2 h. The solvent was removed. The residue was dissolved in methanol, and purified by RP-HPLC (pH=10) to afford the desired product (4.9 mg). LCMS (M+H)+=430.1.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:20])[NH:12][C:13]4[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[H-].[Na+].[CH3:23]I>COCCOCCOC>[CH3:19][C:17]1[CH:18]=[C:13]2[N:12]([CH3:23])[C:11](=[O:20])[C:10]3[CH:9]=[N:8][C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=4[C:15]=3[N:14]2[N:16]=1
Reactant: CI
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3cc(C)nn3c12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCn1ncc2c1ncc1c(=O)n(C)c3cc(C)nn3c12
Reaction time: 10 h

Procedure:
2.7 g. of 8-ethyl-2-methyl-4-H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one (0.01 mol.) are added to a suspension of 0.03 g. of sodium hydride in 50 ml. of diethylene glycol dimethyl ether at reflux temperature. The temperature is maintained for one hour and then lowered to 120°. 2.8 g. of methyl iodide are added and heating is continued for 10 hours. The precipitated sodium iodide is filtered off, the solution evaporated to dryness and the residue recrystallized from ethyl-acetate, yield 1.9 g. (68%); m.p. 206°-207°.
Reaction SMILES: C([Li])CCC.[CH:6]1([NH:9][C:10]([C:12]2[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[O:15][CH:16]=2)=[O:11])[CH2:8][CH2:7]1.[C:20](=[O:22])=[O:21]>CCCCCC.O1CCCC1>[CH:6]1([NH:9][C:10]([C:12]2[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[O:15][C:16]=2[C:20]([OH:22])=[O:21])=[O:11])[CH2:7][CH2:8]1
Reactant: CC(C)c1nc(C(=O)NC2CC2)co1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)c1nc(C(=O)NC2CC2)c(C(=O)O)o1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
0.12 mol of n-butyllithium (80.0 ml of a 1.5 molar solution in hexane) was added dropwise to a solution of 10.4 g (0.054 mol) of 2-(1-methylethyl)-oxazole-4 carboxylic acid cyclopropylamide in 250 ml of tetrahydrofuran under a nitrogen atmosphere of -70° C. and stirring was carried out for 30 minutes at this temperature. Thereafter, the reaction mixture was poured onto 500 g of solid CO2 and was left to stand overnight. The mixture was evaporated down, the residue was taken up in 200 ml of water and 30 ml of 10% strength NaOH, the solution was extracted twice with diethyl ether and the aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and the solvent was stripped off under reduced pressure. 10.4 g (81%) of 4-cyclopropylaminocarbonyl-2-(1-methylethyl)-oxazole-5-carboxylic acid were obtained as a white powder of melting point 109°-112° C.