Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25]
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccco1
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccco4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.080 mMol) furoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[C:5](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[C:29](Cl)=[N:28][CH:27]=[CH:26][N:25]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:16][O:15][C:4]1[CH:3]=[C:2]([S:1][C:29]2[C:24]([Cl:23])=[N:25][CH:26]=[CH:27][N:28]=2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: Clc1nccnc1Cl
Reactant: COC(=O)c1cc([N+](=O)[O-])c(S)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])c(Sc2nccnc2Cl)cc1OC
Yield: 33.3 %

Procedure:
To a solution of 6.45 g of methyl 4-mercapto-5-nitro-o-anisate in N,N-dimethylformamide (100 ml) were added 4.4 g of potassium carbonate and 4.75 g of 2,3-dichloropyrazine. Then the mixture was allowed to react at 80° C. for 2 hours. After adding ethyl acetate, the reaction mixture was washed with a saturated aqueous solution of sodium chloride and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 3.14 g of the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCN2C(=NCCC2)CC1>ClCCl.CCOC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([O:17][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(OCc3ccccc3)c(Br)cc21
Reaction time: 2 h
Yield: 86 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.075 g, 0.213 mmol) in dichloromethane (5 mL) was treated with benzyl bromide (0.072 g, 0.64 mmol), DBU (0.100 g, 0.64 mmol), and stirred 2 hours at 20 C. The product mixture was diluted with EtOAc (50 mL), washed with 5% aqueous HCl (20 mL), brine (20 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 0.081 g of a clear oil. MS calculated for C20H19BrF3NO2+H: 442, observed: 442.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([O:13][CH3:14])=[O:12])[N:2]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[CH3:25][Si](C)(C)N[Si](C)(C)C.[Na].CI>C1COCC1>[CH3:25][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1][N:2]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: COC(=O)C1Cc2ccccc2CN1C(=O)OCc1ccccc1
Agent: [Na]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)Cc2ccccc2CN1C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
Step-2: To a solution of 2-benzyl 3-methyl 3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (3 g, 9.23 mmol) in THF (30 mL) at −80° C. was added sodium hexamethyldisilazane (1M, 23.1 mL, 23.1 mmol) and stirred for 20 min. Methyl iodide (1.44 mL, 23.1 mmol) was added and the reaction was allowed to warm to −20° C. and stirred at −20° C. for 6 h. The reaction was quenched with water, neutralized with 2N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to afford 2-benzyl 3-methyl 3-methyl-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate. MS (ES+): m/z 340.20 [M+H]+
Reaction SMILES: Br[CH:2]1[C:6]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:5][CH2:4][CH2:3]1.[N+:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2([CH2:2][CH2:3][CH2:4][CH2:5]2)[C:7]1=[O:15].[N+:16]([C:19]1[CH:24]=[C:23]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:15])[C:6]23[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:22]=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=C1Nc2ccccc2C12CCCC2Br
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C1Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc2C12CCCC2
Product: O=C1Nc2ccccc2C12CCCC2
Temperature: 25 °C
Yield: 123.6 %

Procedure:
A solution of 5-bromo-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one (0.3 g, 1.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.07 g, 0.06 mmol) in dimethoxyethane (8 cm3) was stirred under N2 for 20 min. To this mixture was then added 3-nitrophenylboronic acid (0.23 g, 1.4 mmol) and sodium carbonate (0.36 g, 3.4 mmol) in water (3 cm3). The solution was brought to reflux for 3 h then cooled to RT, poured into water and extracted with EtOAc (×3). The combined organic extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate: hexane 1:3) to afford the title compound (0.21 g, 0.68 mmol, 62%) as a yellow solid: mp. 238-240 C.; 1H NMR (DMSO-d6) δ1.89-1.99 (m, 8H), 6.96 (d, J=8.1 Hz, 1H), 7.58 (dd, J=8.1, 1.8 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.71 (dd, J=8.0, 8.0 Hz, 1H), 8.13 (dd, J=7.0, 1.0 Hz, 2H), 8.4 (d, J=1.8 Hz, 1H), 10.42 ( br s, 1H); 13C NMR (dioxane-d8) δ26.31, 38.13 (t), 53.85 (s), 108.9, 121.15, 121,33, 126.23, 129.38, 132.11 (d), 132.6, 138.32, 141.84, 142.74, 149.14, 182.68 (s); MS (EI) m/z 308 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl.Cl[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)[CH:10]=3
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: ClCc1cccnc1
Agent: Cl
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCc4cccnc4)cc13)Sc1ccc(Br)cc1-2
Yield: 38.6 %

Procedure:
According to Example 34, the compound (300 mg) produced in Example 37 was reacted with 3-chloromethylpyridine hydrochloride (142 mg) to obtain the title compound (140 mg; 46%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20]C)=[O:19])[CH:8]=[C:7]2Cl)(=[O:3])[CH3:2].[CH2:23]([NH2:25])[CH3:24].O>C(O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=[C:7]2[NH:25][CH2:23][CH3:24])(=[O:3])[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Reactant: CCN
Solvent: CCO
Solvent: O
Product: CCCc1c(O)c(C(C)=O)cc2c(NCC)cc(C(=O)O)nc12

Procedure:
Methyl 6-acetyl-4-chloro-7-hydroxy-8-propylquinoline-2-carboxylate (8.9 g; 27.7258 mmole) and ethylamine in ethanol (33% w/w; 24 ml) was heated at 100° C. under pressure (autoclaved) for 28 hours. The mixture was cooled, treated with water and concentrated, followed by extraction with chloroform. The organic extract was washed with water, dried and evaporated to give a red solid (8.1 g; 81%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][N:5]([CH3:22])[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1)=[O:7].[CH3:23]I.O>C1COCC1>[CH3:3][O:4][N:5]([CH3:22])[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH3:23])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:9]1)=[O:7]
Reactant: CI
Reactant: CON(C)C(=O)C1CCCC(NC(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)C1CCCC(N(C)C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a suspension of NaH (60%, 340 mg, 8.38 mmol) in THF (10 mL) was added dropwise a solution of tert-butyl 3-{[methoxy(methyl)amino]carbonyl}cyclo-hexylcarbamate (2.00 g, 6.98 mmol) in THF (10 mL) followed by methyl iodide (1.09 g, 7.68 mmol). The mixture was stirred at 60° C. for 0.5 hr. After cooled to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/1) to give tert-butyl N-[3-(N-methoxy-N-methyl-carbamoyl)cyclohexyl]-N-methylcarbamate as a colorless oil (1.94 g, yield; 93%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C(O)C.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>[CH3:10][O:9][C:7]([C:5]1[S:6][C:2]([C:19]2[N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH:22]=[CH:21][CH:20]=2)=[CH:3][CH:4]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: COC(=O)c1ccc(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cccn2C(=O)OC(C)(C)C)s1
Temperature: 60 °C

Procedure:
A mixture of methyl 5-bromothiophene-2-carboxylate (4 g), 1-(tert-butoxycarbonyl)pyrrole-2-boronic acid (3.8 g), dichlorobis (triphenylphosphine)palladium(II) (1.2 g) and 2M sodium carbonate solution (18 mL) in DME/water/ethanol (7/3/2, 200 mL) was heated at 60° C. for 4 hours, cooled and partitioned between ethyl acetate and brine. The extract was washed with water and concentrated, and the concentrate was flash chromatographed on silica gel with 5-40% ethyl acetate in hexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[CH3:7].C(Cl)(=O)C(Cl)=O.N1C=C[CH:20]=[CH:19][CH:18]=1.C(O)(C)C>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH:19]([CH3:20])[CH3:18])=[O:9])[S:5][C:6]=1[CH3:7]
Reactant: c1ccncc1
Reactant: Cc1sc(C(=O)O)cc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1sc(C(=O)OC(C)C)cc1Br
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
A solution of 5 g (22.6 mmol) of 4-bromo-5-methylthiophene-2-carboxylic acid was dissolved in dry dichloromethane (200 mL) and reacted with oxalyl chloride (2 mL, 22.6 mmol) and dimethylformamide (100 μL) stirring on an ice bath for 30 min and then at room temperature for 2.5 h. The solvents were removed in vacuo and the residue was passed through silica gel, eluting off with hexanes:ethyl acetate 7/3 (v:v), ethyl acetate, and dichloromethane. The solvents were removed in vacuo and the resulting oil dissolved in dry dichloromethane (100 mL). This solution was reacted with dry pyridine (9 mL, 113 mmol) and dry isopropanol (40 mL, 522 mmol) for 88 h. The solvents were removed in vacuo and the residue partitioned between sodium bicarbonate (150 mL) and dichloromethane (75 mL). The aqueous layers were extracted with dichloromethane (2×20 mL), and the combined organic layers were washed with sodium bicarbonate (30 mL), brine (30 mL), and dried over anhydrous sodium sulfate. The solvents were removed in vacuo. The residue was purified by column chromatography eluting with hexanes:ethyl acetate 9/1 (v:v) to give isopropyl 4-bromo-5-methylthiophene-2-carboxylate (1.91 g, 32%) as a pale yellow oil. 1H-NMR NMR (DMSO-d6; 300 MHz) δ7.66 (s, 1H), 5.07 (septet, 1H, J=6.2 Hz), 2.42 (s, 3H), 1.29 (d, 6H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C9H11O2SBr 264.2 (M+H), found 264.8.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH2:17]=[O:18].C(#N)C.Cl[CH:23]([F:25])[F:24]>[OH-].[K+]>[F:24][CH:23]([F:25])[O:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[CH2:17][OH:18]
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Reactant: FC(F)Cl
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: OCc1c(C(F)(F)F)nn(-c2ccccc2)c1OC(F)F
Temperature: 25 °C
Yield: 84.9 %

Procedure:
22.8 g (0.10 mole) of the 5-hydroxy-1-phenyl-3-trifluoromethylpyrazole synthesized in Reference Example 2 was dissolved in 35.0 g (0.15 mole) of a 24% aqueous potassium hydroxide solution. To the solution being stirred at room temperature was dropwise added 9.7 g (0.12 mole) of a 37% formalin solution, followed by stirring at the same temperature for 1 hour. Then, there were added 70.0 g (0.3 mole) of a 24% aqueous potassium hydroxide solution and 100 ml of acetonitrile. Therein was blown 17.3 g (0.20 mole) of chlorodifluoromethane at room temperature in 2 hours, followed by stirring at room temperature for 2 hours to give rise to a reaction. After the reaction, the organic layer which appeared by phase separation, was concentrated under reduced pressure to obtain 28.0 g (purity: 93.6%, yield: 84.9%) of a crude solution of title compound. The crude solution was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain a title compound as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](Cl)=[O:10])[CH:5]=[CH:6][CH:7]=1>CCCCCCC.C(OCC)(=O)C>[CH2:9]([O:10][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH:8]=[CH2:4]
Reactant: O=C(Cl)Cc1cccc(Br)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C=CCOC(=O)Cc1cccc(Br)c1

Procedure:
The title compound was prepared in an analogous manner as described for intermediate B3A from (3-bromo-phenyl)-acetyl chloride (intermediate B2B) (12.1 g, ca. 50 mmol). The compound was obtained after silica gel column chromatography with n-heptane/ethyl acetate as a light yellow liquid (7.934 g, 62%). MS (ISP): m/z=272.1 [(M+NH4)+] and 274.1 [(M+2+NH4)+]
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:34]=[CH:33][C:9]([CH:10]([C:23]([OH:32])([CH2:28][C:29]([CH3:31])=[CH2:30])[C:24]([F:27])([F:26])[F:25])[NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[N:15][C:16]([CH3:22])=[N:17]3)=[C:8]([O:35][CH3:36])[CH:7]=1>CCCCCC.C(OCC)(=O)C>[F:5][C:6]1[CH:34]=[CH:33][C:9]([CH:10]([C:23]([OH:32])([CH:28]=[C:29]([CH3:30])[CH3:31])[C:24]([F:26])([F:25])[F:27])[NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[N:15][C:16]([CH3:22])=[N:17]3)=[C:8]([O:35][CH3:36])[CH:7]=1
Reactant: C=C(C)CC(O)(C(Nc1cccc2nc(C)ncc12)c1ccc(F)cc1OC)C(F)(F)F
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1C(Nc1cccc2nc(C)ncc12)C(O)(C=C(C)C)C(F)(F)F

Procedure:
Analogously to Example 6, 340 mg (1.1 mmol) of 4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 211 mg (1.32 mmol) of 5-amino-2-methylquinazoline (described in Example 6) are reacted with 0.46 ml (2.2 mmol) of titanium tetraethylate to form imine. After analogous rearrangement with boron tribromide and subsequent chromatography on silica gel with hexane-ethyl acetate (0-50%), 156 mg of a mixture that consists of 2-{4-fluoro-alpha-[(2-methylquinazolin-5-yl)amino]-2-methoxybenzyl}-1,1,1-trifluoro-4-methylpent-4-en-2-ol and 2-{4-fluoro-alpha-[(2-methylquinazolin-5-yl)amino]-2-methoxybenzyl}-1,1,1-trifluoro-4-methylpent-3-en-2-ol is obtained. The separation is carried out by means of preparative thin-layer chromatography on silica gel (dichloromethane/2-propanol 5%) and yields 51 mg of the main component and 9 mg of the minor component.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:13][N:14]([CH3:16])[CH:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Br[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:16][N:14]1[CH:15]=[C:3]2[C:4]([N:5]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]2=[O:1])=[N:13]1
Reactant: CCOC(=O)c1cnc2nn(C)cc2c1O
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCC(C)C)c2nn(C)cc2c1=O

Procedure:
22.1 g. of 4-hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester (0.1 mol.), 17 g. of 1-bromo-3-methylbutane and 21 g. of potassium carbonate are heated together with stirring in 100 ml. of dimethylformamide at 100° for 12 hours. The mixture is filtered hot, evaporated to dryness and the residue recrystallized from ethyl acetate to obtain 4,7-dihydro-2-methyl-7-(3-methylbutyl)-4-oxo-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester, yield (63%); m.p. 105°-106°.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][Si:11]([CH3:27])([CH3:26])[CH2:12][CH2:13][O:14][CH2:15][N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C:17]1=[O:25].Br[CH2:29][C:30]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:31]=1[C:32](Cl)=[O:33]>C1COCC1>[N+:39]([C:36]1[CH:35]=[C:31]2[C:30]([CH2:29][C:18]3([C:32]2=[O:33])[C:19]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:16]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:27])([CH3:26])[CH3:10])[C:17]3=[O:25])=[CH:38][CH:37]=1)([O-:41])=[O:40]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1CBr
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2=O)c2cccnc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N,N-Diisopropylethylamine (3.64 mL, 22 mmol) is added to a stirred solution of 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (prepared according to the procedures described in WO2008/020902) (2.64 g, 10 mmol) in THF (75 mL) at ambient temperature. To the stirred mixture is added dropwise a solution of 2-(bromomethyl)-5-nitrobenzoyl chloride (3.06 g, 11 mmol) [Pifferi et al. (1966) Tetrahedron 22, 2107] in THF (75 mL) and the mixture is then stirred at ambient temperature for 18 h. The mixture is then partitioned between EtOAc and saturated aqueous NaHCO3. The layers are separated and the aqueous layer further extracted with EtOAc. The combined organic extracts are washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient elution with hexanes-EtOAc) to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:23])[CH:3]=1.[CH3:24][C:25]1([CH3:31])[O:29][C:28](=[O:30])[N:27]=[CH:26]1>>[F:23][C:4]1[CH:3]=[C:2]([N:27]2[CH2:26][C:25]([CH3:31])([CH3:24])[O:29][C:28]2=[O:30])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: CC1(C)C=NC(=O)O1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3F)CC2)nc1
Yield: 54.2 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2-fluorophenyl)[4-(5-methylpyridin-2-yl)piperazin-1-yl]methanone (567 mg) described in Preparation Example 184 and 5,5-dimethyloxazolin-2-one (207 mg) described in Preparation Example 43, the title compound (335 mg) was obtained.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[C:13]([CH3:26])[CH:12]=2)[CH2:6]1)=O.[CH3:27][NH2:28]>C(O)C>[CH3:27][NH:28][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[C:13]([CH3:26])[CH:12]=2)[CH2:6]1)=[O:2]
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)c(C)c2)C1
Reactant: CN
Solvent: CCO
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)c(C)c2)C1

Procedure:
In analogy to the aminolysis described in Example 1e), the (RS)-1-[(4-(3-fluoro-benzyloxy)-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester is treated in a sealed tube with methylamine in ethanol at 60° C. for 18 h to yield the (RS)-1-[(4-(3-fluoro-benzyloxy)-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl amide as a light yellow solid; MS: m/e=357 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:38]=[CH:37][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([NH:31][CH2:32][C:33]([O:35]C)=[O:34])=[O:30])[S:27][CH:28]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].C1COCC1.CO.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])[S:27][CH:28]=3)[CH:19]=2)=[CH:37][CH:38]=1)=[O:11]
Reactant: COC(=O)CNC(=O)c1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4csc(C(=O)NCC(=O)O)c4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl {[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}acetate (60 mg, 0.11 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) was added 1 ml of 1M NaOH (1.0 mmol) solution. The mixture was stirred at room temperature for 1 hour and poured into 100 ml of water. 2M HCl was added until pH=3. The resulting precipitates were filtered, washed with water, and dried in vacuo to give {[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}acetic acid as white solid. Yield: 50 mg, 86%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][CH:13]=[N:14][NH:15][CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([N+]([O-])=O)[CH2:29][CH:30]2[O:34][CH2:33][CH2:32][O:31]2)=[CH:23][CH:22]=1>C1COCC1>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][C:13]1[C:28]([CH2:29][CH:30]2[O:34][CH2:33][CH2:32][O:31]2)=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[N:15]([CH:16]([CH3:17])[CH3:18])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C(=Cc1ccc(F)cc1)CC1OCCO1
Reactant: CC(C)NN=CCCNC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)n1nc(CCNC(=O)OCc2ccccc2)c(CC2OCCO2)c1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of [3-(isopropyl-hydrazono)-propyl]-carbamic acid benzyl ester (60.0 mg, 0.228 mmol) and 2-[3-(4-fluoro-phenyl)-2-nitro-allyl]-[1,3]dioxolane (54.0 mg, 0.213 mmol) in THF (2 mL) was stirred at rt for 3 days. The mixture was treated with additional [3-(isopropyl-hydrazono)-propyl]-carbamic acid benzyl ester (1.4 equiv.) and was stirred at 60° C. for 18 h. Additional [3-(isopropyl-hydrazono)-propyl]-carbamic acid benzyl ester (2.1 equiv.) was added, and the mixture was stirred at 60° C. for 18 h. The mixture was concentrated to oil and the residue was purified by FCC to give the title compound.