Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1.O=[C:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]1.[BH3-]C#N.[Na+]>CO>[CH3:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([CH:13]3[CH2:14][CH2:15][N:16]([CH:30]4[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29]4)[CH2:17][CH2:18]3)=[N:7][C:6]=2[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Cc1nn(-c2ccccc2)c2nc(C3CCNCC3)[nH]c(=O)c12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nn(-c2ccccc2)c2nc(C3CCN(C4CCN(C(=O)OC(C)(C)C)C4)CC3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-methyl-1-phenyl-6-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrochloride (500 mg, 1.45 mmol, 1.00 equiv) in methanol (50 mL) at room temperature. To the resulting mixture was then added tert-butyl 3-oxopyrrolidine-1-carboxylate (804 mg, 4.35 mmol, 3.00 equiv), in portions at room temperature, followed by NaBH3CN (456 mg, 7.24 mmol, 5.00 equiv) at room temperature. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in water (50 mL). The resulting solution was extracted with ethyl acetate (3×50 mL), the organic layers combined and concentrated under vacuum to yield tert-butyl 3-(4-(3-methyl-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-1-yl)pyrrolidine-1-carboxylate as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:3][CH:2]=1.CCO.[CH2:24]([NH2:27])[CH2:25][NH2:26].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)=[N:27][CH:24]=[CH:25][N:26]=2)=[CH:3][CH:2]=1
Reactant: O=C(C(=O)c1cccc(C(F)(F)F)c1)c1ccncc1
Reactant: NCCN
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(-c2nccnc2-c2ccncc2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 4 %

Procedure:
Under Ar, a solution of 46 (2.3 g, 8.2 mmol) in abs. EtOH (100 mL) was treated with ethylene diamine (0.58 g, 9.6 mmol) and heated at 50° C. After 18 h, the solution was concentrated to dryness. The residue was partitioned between H2O and EtOAc (3×) and the organic extracts were dried, filtered and concentrated to dryness. The residue was treated with toluene (125 mL) and DDQ (3.8 g, 16.7 mmol) and then heated to 80° C. After 18 h, the reaction was concentrated to dryness. The residue was dry packed with silica gel (100 mL) and chromatographed on a Still column (80 mm). The product was eluted with EtOAc and the common fraction concentrated to dryness. The residue was treated with Et2O and ethanolic-HCl and concentrated to dryness. The residue was triturated from EtOAc and filtered to yield 100 mg of 47.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[C:6](/[Br:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([C@@H:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>C(Cl)(Cl)Cl>[CH3:16][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](/[Br:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][C@H:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:14]
Reactant: CCOC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, the product of Step A and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-bromo-3-oxo-3-ethoxy-propenyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =-70.5°±2° (c=0.7% in chloroform).
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]2[C@@H:6]([C@:7]([C:12]3[CH:13]=[C:14]([NH:20][C:21]([C:23]4[CH:32]=[CH:31][C:26]([C:27](=N)[O:28][CH3:29])=[CH:25][N:24]=4)=[O:22])[CH:15]=[C:16]([F:19])[C:17]=3[F:18])([CH:9]([F:11])[F:10])[N:8]=1)[CH2:5]2.Cl.C(=O)(O)[O-:35].[Na+]>[OH-].[Na+]>[NH2:1][C:2]1[O:3][C@@H:4]2[C@H:6]([C@@:7]([C:12]3[CH:13]=[C:14]([NH:20][C:21]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:28][CH3:29])=[O:35])=[CH:25][N:24]=4)=[O:22])[CH:15]=[C:16]([F:19])[C:17]=3[F:18])([CH:9]([F:11])[F:10])[N:8]=1)[CH2:5]2
Reactant: COC(=N)c1ccc(C(=O)Nc2cc(F)c(F)c([C@@]3(C(F)F)N=C(N)O[C@@H]4C[C@@H]43)c2)nc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1ccc(C(=O)Nc2cc(F)c(F)c([C@]3(C(F)F)N=C(N)O[C@H]4C[C@H]43)c2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.5 %

Procedure:
Methyl 6-((3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)carbamoyl)nicotinimidate (0.050 g, 0.111 mmol) was dissolved in hydrochloric acid (2N, 5 mL, 10.00 mmol) and stirred at room temperature. After 15 minutes, the reaction mixture was neutralized with 1 N sodium hydroxide (10 mL). A solution of aqueous saturated sodium bicarbonate (5 mL) was added and the mixture stirred for 10 minutes. The suspension was filtered and the solid was washed with water (10 mL). The solid was further purified by silica gel chromatography [10-90% (2% NH4OH in 3:1 ethyl acetate: ethanol) in hexane] to give the title compound (0.0298 g, 0.066 mmol, 59.5% yield). MS m/z=452.9 [M+H]+. 1H NMR (CHLOROFORM-d) Shift: 9.75 (s, 1H), 9.04 (dd, J=2.0, 0.7 Hz, 1H), 8.48 (dd, J=8.0, 2.0 Hz, 1H), 8.26 (dd, J=8.1, 0.7 Hz, 1H), 7.99 (ddd, J=11.7, 7.0, 2.8 Hz, 1H), 7.22-7.28 (m, 1H), 6.23 (td, J=55.8, 0.9 Hz, 1H), 5.17 (br. s., 2H), 4.01 (s, 3H), 3.92 (td, J=6.8, 2.6 Hz, 1H), 1.80-1.92 (m, 1H), 1.40-1.49 (m, 1H), 0.90-1.03 (m, 1H)
Reaction SMILES: [CH2:1]([O:8]/[N:9]=[C:10]1\[CH2:11][CH2:12][C:13]2[C:18]\1=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]1[C:24]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[N:25][N:26]([CH3:28])[CH:27]=1>C(#N)C.O>[CH2:1]([O:8][N:9]=[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:23]3[C:24]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[N:25][N:26]([CH3:28])[CH:27]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc(Br)c(-c2ccncc2)n1
Reactant: OB(O)c1ccc2c(c1)CC/C2=N\OCc1ccccc1
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2ccc3c(c2)CCC3=NOCc2ccccc2)c(-c2ccncc2)n1
Yield: 75.4 %

Procedure:
To (E)-1-(benzyloxyimino)-2,3-dihydro-1H-inden-5-ylboronic acid (3.00 g; Example 2, Step 4) in 32 mL acetonitrile and 8.0 mL water was added 4-(4-bromo-1-methyl-1H-pyrazol-3-yl)pyridine (2.00 g; Example 3, Step 3). The solution was deoxygenated by bubbling nitrogen through the solution for 10 min. To the resulting mixture was added 5.62 g potassium carbonate, 10 mL N,N-dimethylformamide, and 290 mg tetrakis(triphenyphosphine)palladium(0). The mixture was then refluxed for 8 hours (over the course of this time a small portion of catalyst was added twice). The cooled reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. The filtrate was washed with water, brine, dried over sodium sulfate, filtered, and evaporated under vacuum to yield 5.1 g crude product as an oil. The crude material was purified by chromatography, eluting with ethyl acetate to afford 2.50 g (80% yield) product as a light yellow foam. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 395.2 by positive ESI.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[C:6](Cl)[N:5]=1)[CH3:2].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:5]=1)[CH3:2]
Reactant: CCN(CC)c1nc(Cl)cc(N2CCNCC2)n1
Reactant: C1CCNC1
Product: CCN(CC)c1nc(N2CCCC2)cc(N2CCNCC2)n1

Procedure:
A solution of 2-diethylamino-4-piperazino-6-chloro-pyrimidine (4.10 g) in pyrrolidine (4.10 g) is heated for 12 hr at 100°, then concentrated. The concentrate is partitioned between aqueous sodium bicarbonate and methylene chloride. The phases are separated, the organic phase is dried and concentrated to give 2-diethylamino4-piperazino-6-pyrrolidino-pyrimidine. A solution of this amine (4.01 g), 21-bromo-17α-hydroxypregna-4,9(11)-diene-3,20-dione (5.41 g), and potassium carbonate (1.75 g) are stirred in acetonitrile (200 ml) for 19 hr. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated. The concentrate is chromatographed on silica gel (methylene chloride to 4% methanol/methylene chloride) to give the free base corresponding to the title compound. An ethyl acetate solution of this compound is converted to the hydrochloride salt with ether/hydrochloric acid to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)(=[O:24])=[O:23]
Reactant: N#Cc1ccc(COCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCc1ccc(C#N)cc1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 93.8 %

Procedure:
4-[(2-Hydroxyethoxy)methyl]benzonitrile (5.5 g, 30.5 mmol; see step (i) above) was dissolved in DCM (61 mL) and cooled to −10° C. Triethylamine (5 mL, 36.5 mmol) and methanesulfonyl chloride (3.84 g, 33.5 mmol) were added and the resulting mixture was stirred at below −5° C. for 1.5 h and then at RT overnight. Dichloromethane (200 mL) was added and the mixture was washed with water (2×100 mL) and then dried over Na2SO4. Evaporation of solvents gave 7.3 g (94%) of the title compound, which was used without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1.[Br:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](F)=[CH:14][CH:13]=1>>[Br:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([O:10][CH:9]2[CH2:8][NH:7][CH2:6][C:5]3[S:1][CH:2]=[CH:3][C:4]2=3)=[CH:14][CH:13]=1
Reactant: OC1CNCc2sccc21
Reactant: Fc1ccc(Br)c2ccccc12
Product: Brc1ccc(OC2CNCc3sccc32)c2ccccc12

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 5) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 1-bromo-4-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [C:1]1([SH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>>[Cl:14][C:15]1[CH:20]=[C:19]([S:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Sc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Sc2cccc3ccccc23)ccn1
Yield: 89.2 %

Procedure:
Using the method of Example 3, Step A, naphthalen-1-thiol (909 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to afford 2-chloro-4-(naphthalen-1-ylthio)pyridine (1.53 g, 95% yield) as an oil. 1H NMR (CDCl3) δ 8.22 (d, 1H), 8.03-8.05 (m, 2H), 7.89-7.96 (m, 2H), 7.54-7.59 (m, 3H), 6.82 (s, 1H), 6.72 (d, 1H).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:36]=[CH:35][C:9]([CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[N:17]=[C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[S:19][CH:20]=3)[C:13]([C:29](N(OC)C)=[O:30])=[N:12]2)=[CH:8][CH:7]=1>C1COCC1.CCOC(C)=O.Cl>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[N:17]=[C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[S:19][CH:20]=3)[C:13]([C:29](=[O:30])[CH3:1])=[N:12]2)=[CH:35][CH:36]=1
Reactant: C[Mg]Br
Reactant: COc1ccc(Cn2cc(-c3csc(Oc4cccc(C)n4)n3)c(C(=O)N(C)OC)n2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(-c3csc(Oc4cccc(C)n4)n3)c(C(C)=O)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
According to Scheme 5, Step 5: Methylmagnesium bromide 3 M (148 μmol, 49 μL) was added dropwise at room temperature to a solution of 1-(4-methoxybenzyl)-N-methoxy-N-methyl-4-(2-(6-methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazole-3-carboxamide (99 μmol, 46 mg) in THF (0.5 mL) and the reaction mixture was stirred for 1 hour at room temperature. The reaction was diluted with EtOAc and with an aqueous solution of HCl 1M. The aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4, was filtered and was concentrated to yield 1-(1-(4-methoxybenzyl)-4-(2-(6-methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazol-3-yl)ethanone (0.10 mmol, 42 mg, 100%) as a beige solid. The mixture was used without further purification.
Reaction SMILES: C1(C)C=CC=CC=1.[OH:8][N:9]=[C:10]1[CH2:18][C@@H:17]2[C@@H:12]([CH2:13][CH:14]=[CH:15][CH2:16]2)[CH2:11]1.[H-].[Na+].Cl[CH2:22][CH2:23][CH2:24][C:25]#[N:26]>O>[C:25]([CH2:24][CH2:23][CH2:22][O:8][N:9]=[C:10]1[CH2:11][C@@H:12]2[C@@H:17]([CH2:16][CH:15]=[CH:14][CH2:13]2)[CH2:18]1)#[N:26]
Reactant: N#CCCCCl
Reactant: ON=C1C[C@H]2CC=CC[C@H]2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CCCCON=C1C[C@H]2CC=CC[C@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a toluene solution (20 ml) of 8-hydroxyimino-cis-bicyclo[4,3,0]nona-3-ene (1 g), was added sodium hydride (50% mineral oil dispersion, 330 mg), and the mixture was stirred for 0.5 hr at room temperature. After addition of γ-chlorobutyronitrile (5 g) to the mixture, stirring was continued for 2 hr. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over Na2SO4 and concentrated to give an oil. This material was chromatographed on silica gel to give 8-(3'-cyanopropoxy)imino-cis-bicyclo[4,3,0]nona-3-ene as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:18][CH:19]4[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: NC1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 180 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
To a solution of 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (200 mg, 0.757 mmol) and 4-aminocyclohexanone (290 mg, 2.56 mmol) in NMP (1.0 mL) was added NaHCO3 (118 mg, 1.52 mmol), the mixture was stirred at 180° C. for 60 mins under microwave irridation. The mixture was purified by flash chromatograph to give 4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanone (40 mg, 0.117 mmol, 16%) as a pale yellow solid.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=1[NH2:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][C:16]=1[CH:25]1[CH2:29][CH2:28][N:27]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26]1>N1C=CC=CC=1>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=1[NH:6][S:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[C:16]([CH:25]2[CH2:29][CH2:28][N:27]([C:30](=[O:35])[C:31]([F:34])([F:32])[F:33])[CH2:26]2)[CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(OC(F)F)c(N)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C1CCN(C(=O)C(F)(F)F)C1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cc(C)ccc2OC(F)F)cc1C1CCN(C(=O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
0.093 g of 2-(difluoromethoxy)-5-methylaniline (0,538 mmol, purchased at Fluorochem) were dissolved in 10 mL of pyridin. 0.2 g of 4-methoxy-3-(1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)benzene-1-sulfonyl chloride (0.538 mmol) were slowly added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was evaporated and several times co-destilled with toluene. The oily brown residue was dissolved in dichloromethane and washed with a 5% aqueous ammonium chloride solution. After washing with saturated aqueous sodium chloride solution, the organic layer was dried over sodium sulphate, filtered, and the solvent evaporated. The crude product was purified via silica gel chromatography using a 40 g Redisep-column with dichloromethane/methanol 0-20% to yield 0.096 g of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[O:13]=[C:11]1[NH:6][C@@H:5]([C:4]([O:3][CH3:2])=[O:9])[CH2:7][O:8]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](N)CO
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H]1COC(=O)N1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a suspension of D-serine methyl ester hydrochloride (25.0 g, 160.7 mmol) in tetrahydrofuran (150 mL), a solution of triphosgene (47.68 g, 160.7 mmol) in tetrahydrofuran (100 mL) was added at 0° C. and the mixture was stirred at 80° C. for 2 hours. The volatiles were evaporated under vacuum and the residue was subjected to flash column silica gel chromatography using 5% methanol in chloroform. Yield: 17.5 g (75%). 1H NMR (400 MHz, DMSO-d6) δ: 3.69 (s, 3H), 4.32-4.33 (m, 1H), 4.32-4.33 (m, 2H), 8.22 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Cl[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:21][C:20]([F:23])([F:22])[C:16]1[N:15]=[C:14]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1CCCc2cc(Oc3cccc(C(F)(F)F)n3)ccc21
Temperature: 120 °C
Yield: 61.3 %

Procedure:
To a solution of 6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (5.0 g, 30.8 mmol) and 2-chloro-6-(trifluoromethyl)pyridine (5.87 g, 32.3 mmol) in ACN (100 mL) was added potassium carbonate (6.39 g, 46.2 mmol), and the reaction was heated at 120° C. in a sealed vessel overnight. The reaction was cooled, diluted with water (100 mL), and extracted with EtOAc (100 mL×3). Organics were dried (Na2SO4), and concentrated. Purification by silica gel chromatography (10-80% EtOAc/hexanes) gave 5.8 g (61%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 2.13-2.20 (2H, m), 2.67 (2H, t, J=6.2 Hz), 2.97 (2H, t, J=6.0 Hz), 7.07-7.14 (2H, m), 7.45 (1H, d, J=7.4 Hz), 7.89 (1H, t, J=8.0 Hz), 8.09 (1H, d, J=8.3 Hz). [M+H] calc'd for C16H12F3NO2, 308; found 308.
Reaction SMILES: [CH:1]([N:4]([CH:22]([CH3:24])[CH3:23])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:18]([O:20][CH3:21])=[O:19])[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:26][NH:27][C:28]([NH2:30])=[O:29]>>[CH:1]([N:4]([CH:22]([CH3:24])[CH3:23])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:18]([O:20][CH3:21])=[O:19])/[C:10](=[N:26]/[NH:27][C:28]([NH2:30])=[O:29])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: NNC(N)=O
Reactant: COC(=O)c1cccc2c1N(CCN(C(C)C)C(C)C)C(=O)C2=O
Agent: Cl
Product: COC(=O)c1cccc2c1N(CCN(C(C)C)C(C)C)C(=O)/C2=N\NC(N)=O
Yield: 28.1 %

Procedure:
By using methyl 1-(2-diisopropylaminoethyl)-7-isatincarboxylate and semicarbazide hydrochloride, a method analogous to that described in Example 6 was carried out, and the reaction product was purified with silica gel column chromatography (eluent: chloroform/ethanol=20/1) and then recrystallized from chloroform-hexane to obtain (Z)-1-(2-diisopropylaminoethyl)-7-methoxycarbonylisatin 3-semicarbazone having a melting point of 192°-195° C. (yield: 28.1%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH2:10])[CH2:5][CH2:6][NH2:7].[C:11]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[NH2:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH2:10])[CH2:5][CH2:6][NH:7][CH:11]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NCCN(CCN)CCN
Reactant: O=C1CCCCCCCCCCCCCC1
Product: NCCN(CCN)CCNC1CCCCCCCCCCCCCC1

Procedure:
Following the general procedure of Example 33, but starting with tris-(2-aminoethyl)amine and cyclopentadecanone, the title compound is produced; IR (liquid film) 3361, 3287, 2928, 2857, 2810, 1460, 1350, 1282, 116, 1043, 893, 843, 711. (PLA2)
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6](/[C:10](=[N:16]/[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)/[C:11]([O:13]CC)=[O:12])[CH:7]=[CH:8][CH:9]=1.CO.Cl>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6](/[C:10](=[N:16]/[O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:30][C:31]=3[CH3:32])=[CH:23][CH:24]=2)/[C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2cccc(Br)c2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl Z-2-(3-bromopbenyl)-2-[4(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (430 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at 40° C. for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-2-(3-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetic acid (370 mg, yield 91%) as colorless crystals. m.p. 181-182° C. (decomposition)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][NH2:14]>C1COCC1>[CH3:13][NH:14][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CN
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CNc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
4-Fluoro-3-nitrobenzonitrile (0.25 g, 1.5 mmol) was cautiously added to a solution of methylamine (2.0 M, 5.0 mL) in THF. The mixture was stirred at room temperature for 8 h, concentrated under reduced pressure, and chromatographed (silica gel, DCM) to give the title product (0.18 g, 68%) as a yellow solid. 1H-NMR (CDCl3): δ 8.52 (1H, d), 8.41 (1H, br s), 7.64 (1H, dd), 6.92 (1H, d), 3.10 (3H, d).