Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][C:11](=[O:13])[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][C:18](=[O:31])[CH2:19][O:20][C:21]1[C:22]([N+:28]([O-:30])=[O:29])=[N:23][C:24](Br)=[CH:25][CH:26]=1)[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O1CCOCC1>[CH2:15]([O:17][C:18](=[O:31])[CH2:19][O:20][C:21]1[C:22]([N+:28]([O-:30])=[O:29])=[N:23][C:24]([N:10]2[CH2:9][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14])[CH2:12][C:11]2=[O:13])=[CH:25][CH:26]=1)[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC(=O)C1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(N2C[C@@H](NC(=O)OC(C)(C)C)CC2=O)nc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 6 h
Yield: 35.5 %

Procedure:
A mixture of [(3S)-5-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester (synthesized with reference to WO2004/22536; 505 mg, 2.52 mmol), [(6-bromo-2-nitropyridin-3-yl)oxy]acetic acid ethyl ester (synthesized with reference to WO2004/2992; 769 mg, 2.52 mmol), palladium acetate (56.6 mg, 0.252 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (157 mg, 0.252 mmol), potassium phosphate (1.74 g, 7.56 mmol) and 1,4-dioxane (25 ml) was stirred under a stream of nitrogen gas at 100° C. for 6 hours. After cooling, ethyl acetate was added to the reaction solution to remove the insoluble material by filtration. The obtained filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 380 mg (36%) of the title compound in the form of a light brown syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:28]([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[O:29])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCN=C=O
Solvent: Cc1ccccc1
Product: CCCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 56 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinazoline (100 mg) was dissolved in toluene (10 ml) with heat, n-butyl isocyanate (0.29 ml) was added, and the admixture was refluxed with heat for 40 minutes. After removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (5/1) to obtain 75 mg of the title compound (yield: 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH2:6].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.[Na+].S(O)(C)(=O)=O.OCC(CO)O.[OH-].[Na+]>O1CCOCC1>[CH3:10][C:9]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:6]=[CH:15][CH:14]=[CH:19]2
Reactant: COc1cc(N)ccc1C
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: OCC(O)CO
Solvent: C1COCCO1
Product: COc1cc2ncccc2cc1C
Temperature: 150 °C
Yield: 98.2 %

Procedure:
Using a minimal amount of dioxane, 3-methoxy-4-methylaniline (5.00 g, 36.5 mmol) was slowly added to a mixture of sodium m-nitrobenzenesulfonate (6.62 g, 29.4 mmol), MsOH (20 mL), and FeSO4.7H2O (0.39 g, 1.4 mmol) in a 100 mL round bottom flask heated to an internal temperature of 145-155° C. Glycerol (10.75 g, 116.8 mmol) was then added dropwise via addition funnel while keeping the internal temperature at 145-155° C. After addition, the reaction was stirred in a 150° C. oil bath until LCMS indicated completion (4-6 h). After being cooled to rt, ice (20 g) was added, then the solution was neutralized with 10 N NaOH (calculated to same eq of MsOH) at a speed to keep the internal temperature below 40° C. A thick suspension appeared after addition, and this was extracted with EtOAc (50 mL×3). The organic layer was filtered through a Celite pad to remove insoluble black particles and then purified by flash column chromatography on silica gel to give the desired product (5.0 g, 79%). MS (ES) m/z 174.1 (M+H+).
Reaction SMILES: I[C:2]1[N:14]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:5]2=[N:6][CH:7]=[C:8]3[CH:12]=[N:11][N:10]([CH3:13])[C:9]3=[C:4]2[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:31]=[C:30]2B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+].O>C(Cl)Cl.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.O1CCOCC1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:31]=[C:30]2[C:2]1[N:14]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=2)(=[O:17])=[O:16])[C:5]2=[N:6][CH:7]=[C:8]3[CH:12]=[N:11][N:10]([CH3:13])[C:9]3=[C:4]2[CH:3]=1
Reactant: COc1ccc2c(c1)c(B1OC(C)(C)C(C)(C)O1)cn2C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c4c(cnc32)cnn4C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2C(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 100.4 %

Procedure:
A flask was charged with 7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.80 g, 1.76 mmol, Preparation #1), tert-butyl 5-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (0.792 g, 2.12 mmol, prepared using H from tert-butyl 3-bromo-5-methoxy-1H-indole-1-carboxylate (SynChem) with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane), Cs2CO3 (1.44 g, 4.42 mmol), PdCl2(PPh3)2 (0.074 g, 0.106 mmol), water (2.6 mL) and 1,4-dioxane (8.0 mL). The mixture was heated to about 85° C. for about 2 h and then cooled to rt. The mixture was diluted with DCM (60 mL) and washed with water (30 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with a gradient of 0 to 20% EtOAc/DCM to afford tert-butyl 5-methoxy-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indole-1-carboxylate (1.01 g, 100%): LC/MS (Table 2, Method c) Rt=1.71 min; MS m/z 572 (M+H)+.
Reaction SMILES: [O-]CC.[Na+].[SH:5][CH2:6][CH2:7][OH:8].[CH:9]([CH:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:10]>C(O)C>[OH:8][CH2:7][CH2:6][S:5][CH:11]([CH:9]=[CH2:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCS
Reactant: C=CC(Cl)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CC(SCCO)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 408 g (6 moles) of sodium ethoxide in 3 l of absolute ethanol, cooled to 0° to 5° C., was added dropwise 476 g (6.1 moles) of 2-mercaptoethanol. Following addition, the solution was stirred for an additional hour at room temperature and then 915 g (6.0 moles) of vinylbenzyl chloride (60 percent m, 40 percent p) was added dropwise. After addition, the mixture was refluxed for 1 hour and was then cooled to room temperature. The sodium chloride was removed by filtration and the solvent was removed on a rotary evaporator to give the product as a yellow oil. The oil was distilled via a short path column to give 626.5 g (54 percent) of the desired product (b.p. 110° to 120° C. and 7 microns Hg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][N:19]=[C:20]([C:23]4[C:28]([CH2:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:31][CH3:32])[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:36]([CH2:40][CH2:41][CH3:42])[CH2:37][CH2:38][CH3:39].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][N:19]=[C:20]([C:23]4[C:28]([CH2:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:31][CH3:32])[CH:21]=3)[N:16]([CH:36]([CH2:40][CH2:41][CH3:42])[CH2:37][CH2:38][CH3:39])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(Br)CCC
Reactant: CCc1cccc(CC)c1-c1cc2c(C3=CCN(C(=O)OC(C)(C)C)CC3)c[nH]c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CCC)n1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2cc(-c3c(CC)cccc3CC)ncc21
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of the 4-[5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (120 mg, 0.30 mmol) in DMF (4 mL), NaH (60 wt % suspension in mineral oil, 36 mg, 0.89 mmol) is added followed by 4-bromoheptane (159 mg, 0.89 mmol). The mixture is stirred for 40 h at room temperature. The mixture is poured to water (10 mL), and the product is extracted with EtOAc. The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Chromatography of the residue affords 4-[5-(2,6-diethyl-phenyl)-1-(1-propyl-butyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as colorless oil.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][C:8]([CH3:12])([OH:11])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[CH3:12][C:8]1([OH:11])[C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=3)[C:3]=2[CH2:10][CH2:9]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC1(O)CCc2c(Br)cncc21
Product: CC1(O)CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 85 %

Procedure:
In analogy to the procedure described for the preparation of example 1 (rac)-4-bromo-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (intermediate A-13) was reacted with 4-(trifluoromethyl)phenylboronic acid to give the title compound as grey solid in 85% yield. MS: 294.1 (M+H+)
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].Br[CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][Br:25])[C:17]([O:19][CH3:20])=[O:18]>>[Br:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:16]([O:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(Br)CCCCBr
Reactant: O=[N+]([O-])c1cc2c(cc1O)CCCC2
Product: COC(=O)C(CCCCBr)Oc1cc2c(cc1[N+](=O)[O-])CCCC2

Procedure:
In a manner similar to that of Reference Example 5, 5,6,7,8-tetrahydro-3-nitro-2-naphthol was allowed to react with methyl 2,6-dibromohexanoate to give methyl 6-bromo-2-(5,6,7,8-tetrahydro-3-nitro-2-naphthyloxy)hexanoate as an oily product, which was then allowed to react, in a manner similar to that of Reference Example 8, with 1-(4-fluorophenyl)piperadine to obtain methyl 6-[4-(4-fluorophenyl)-1-piperazinyl]-2-(5,6,7,8-tetrahydro-3-nitro-2-naphthyloxy) hexanoate as an oily product. The overall yield was 79.4%.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:14]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH3:14])=[O:9])=[CH:11][CH:12]=1
Reactant: CO
Reactant: O=C(O)COc1ccc(O)cc1
Agent: Cl
Product: COC(=O)COc1ccc(O)cc1
Reaction time: 8 h

Procedure:
A solution of 4-hydroxyphenoxyacetic acid (33.6 g) in methanol was treated with hydrogen chloride gas and left to stand at ambient temperature overnight. The solvent was removed in vacuo and the residue taken up in ethyl acetate. This solution was washed sequentially with saturated sodium hydrogen carbonate solution (2×100 ml) and brine (100 ml), then dried (MgSO4) and the solvent evaporated to give methyl 4-hydroxyphenoxyacetate as a colourless crystalline mass, m.p. 112°-114° C.; NMR: 3.8 (s, 3H, CH3), 4.55 (s, 2H, CH2), 6.75 (s, 4H, phenyl-H) 6.8-7.8 (broad s, 1H, OH); m/e 200 (M+NH4)+.
Reaction SMILES: [N+](C1C=CC=CC=1C1CCNC1)([O-])=O.BrC1C=C(OC)C=CC=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[N+:43]([O-])=O)[CH2:33]2)[CH:29]=[CH:30][CH:31]=1>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[NH2:43])[CH2:33]2)[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cccc(N2CCC(c3ccccc3[N+](=O)[O-])C2)c1
Agent: COc1cccc(Br)c1
Agent: O=[N+]([O-])c1ccccc1C1CCNC1
Product: COc1cccc(N2CCC(c3ccccc3N)C2)c1
Yield: 99.3 %

Procedure:
Synthesized from 1-bromo-2-nitrobenzene according to an analogous synthetic method to Preparation Example 103, 1-benzyl-3-(2-nitrophenyl)pyrrolidine (1.0 g) was used according to an analogous synthetic method to Preparation Example 104 to provide 3-(2-nitrophenyl)pyrrolidine (184 mg). Synthesized from 3-(2-nitrophenyl)pyrrolidine and 3-bromoanisole according to an analogous synthetic method to Example 116 described below, 1-(3-methoxyphenyl)-3-(2-nitrophenyl)pyrrolidine (141 mg) was used according to an analogous synthetic method to Example 22 to provide the title compound (126 mg).
Reaction SMILES: Cl.[CH2:2]([O:9][C@H:10]([CH3:25])[C@@H:11]([CH3:24])[O:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15](Cl)[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:42])(=[N:35][C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[O:34])=[CH:29][CH:28]=1>O1CCOCC1.C(#N)C.C(OCC)(=O)C>[CH2:2]([O:9][C@H:10]([CH3:25])[C@H:11]([O:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([S:33]([CH3:42])(=[N:35][C:36](=[O:41])[C:37]([F:40])([F:38])[F:39])=[O:34])=[CH:31][CH:32]=2)[N:14]=1)[CH3:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1C(F)(F)F
Reactant: CS(=O)(=NC(=O)C(F)(F)F)c1ccc(N)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Nc2ccc(S(C)(=O)=NC(=O)C(F)(F)F)cc2)ncc1C(F)(F)F
Temperature: 80 °C
Reaction time: 6 h
Yield: 76.8 %

Procedure:
0.97 ml of 4N solution of hydrogen chloride in dioxane was added to 1.40 g (3.88 mmol) of 4-((1R,2R)-2-benzyloxy-1-methyl-propoxy)-2-chloro-5-trifluoromethyl-pyrimidine and 1.20 g (4.51 mmol) (RS)-S-(4-aminophenyl)-S-methyl-N-(trifluoroacetyl)sulfoximide in 19.0 ml acetonitrile and was then stirred for 6 hours at 80° C. After cooling, the mixture was diluted with ethyl acetate and washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated by evaporation. The residue is obtained was purified chromatographically (hexane/ethyl acetate 1:1). 1.76 g (2.98 mmol, yield: 77%) of the product was obtained.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27](=[N:31][O:32][CH3:33])[C:28]([NH2:30])=O)=[CH:17][CH:16]=1.N1C=CC=CC=1>CCOCC>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27](=[N:31][O:32][CH3:33])[C:28]#[N:30])=[CH:34][CH:35]=1
Reactant: CON=C(C(N)=O)c1ccccc1COc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CON=C(C#N)c1ccccc1COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Trifluoroacetic anhydride (3.15 g, 15 mmol) was added to a mixture of 2-(4-chlorophenoxymethyl)-α-methoxyiminophenylacetamide (1.19 g, 6 mmol) and pyridine (12 ml) under ice-cooling over 20 minutes, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, ether (150 ml) was added, and the mixture was washed with 1N hydrochloric acid (150 ml), water (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(4-chlorophenoxymethyl)-α-methoxyiminophenylacetonitrile (1.57 g, 87.0%) as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH2:29](O)C.C(O)(=O)C.C(N)=N.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:10]4=[N:11][C:12]([NH:19][C@H:20]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=5)[CH3:21])=[CH:13][CH:14]=[C:15]4[N:16]=[CH:29]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCO
Reactant: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cn1
Agent: [Pd]
Agent: N=CN
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ccc2ncn(-c3cc(C4CC4)[nH]n3)c2n1)c1ccc(F)cn1
Temperature: 25 °C

Procedure:
N2-(5-cyclopropyl-1H-pyrazol-3-yl)-N6-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-3-nitropyridine-2,6-diamine (Intermediate 10, 0.4 g) was dissolved into ethanol (20 mL) with Pd—C (60 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 95° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.16 g of the title compound. MS (electrospray): 364 (M+1) for C19H18FN7. 1H NMR (300 MHz, CD3OD) δ ppm 8.45 (s, 1H) 8.30 (s, 1H) 7.70 (d, 1H) 7.50 (d, 1H) 6.70 (d, 1H) 6.20 (s, 1H) 5.10 (dd, 1H) 2.00 (m, 1H) 1.55 (d, 3H) 1.00 (m, 2H) 0.80 (m, 2H).
Reaction SMILES: [OH-].[K+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])CC(C)=O.CCCCCCCCC[C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1>C(Cl)Cl>[C:3]([C:25]1([CH3:26])[C:24](=[O:27])[CH:23]1[CH:22]=[CH2:21])([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CC1C(=O)C1(C)C(=O)OCC
Yield: 74 %

Procedure:
To a reactor containing 5.6 g potassium hydroxide and 60 mls. methylene dichloride were added 6.5 g ethyl acetoacetate and 1.33 g ethoxylated (9 E.O.) nonylphenol. The mixture was agitated and 10.7 g 1,4-dibromobutene-2 slowly added while maintaining the temperature at 30°-35° C. The reaction was continued with stirring at 30° C. for one hour after which time 74% yield 1-carboethoxy-1-methylketo-2-vinylcyclopropane was obtained. Similar results are obtained when the reaction is repeated using 1,4-dichlorobutene-2 and 1,4-diacetoxybutene-2.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[N:25][CH:24]=[CH:23][N:22]=1)CCC>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cnccn2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.5 g, 2.02 mmol), 2-(tributylstannyl)-pyrazine (0.818 g, 2.22 mmol), palladium tetrakistriphenylphosphine (0.233 g, 0.20 mmol) in toluene (4 mL) to give 4-chloro-5,7-difluoro-3-methyl-2-(pyrazin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=292.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH3:13][O:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:9]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[O:8][CH2:17][CH2:16][CH2:15][O:14][CH3:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: COCCCBr
Reactant: CC(C)(C)c1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COCCCOc1cc(Br)ccc1C(C)(C)C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of 2.60 g of 5-bromo-2-tert-butyl-phenol, 4.34 g of 3-methoxypropyl bromide and 5.55 g of caesium carbonate in 40 ml of acetone is stirred at 60° C. overnight. After cooling to room temperature, the mixture is filtered and the crude product obtained after concentration of the filtrate is purified by means of FC (80 g of silica gel, hexane/ethyl acetate=98:2). The title compound is obtained in the form of an oil: Rf (hexane/ethyl acetate=9:1)=0.56.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[O:20]([CH2:19][CH2:18][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([O:9][CH3:10])=[O:8])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCOc1ccccc1
Reactant: COC(=O)[C@H]1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCCCN1CCOc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Dissolve methyl (R)-piperidine-2-carboxylate (5.00 g, 34.9 mmol) in DMF (87 mL) and treat with K2CO3 (14.48 g, 104.8 mmol) and β-bromophenetole (7.16 g, 34.9 mmol). Stir the mixture overnight at 100° C. Cool the mixture to room temperature and add EtOAc (250 mL). Wash the organic phase with water (4×100 mL) and saturated aqueous NaCl (100 mL). Dry the organic phase over K2CO3, filter to remove the solids, and concentrate the filtrate under reduced pressure to furnish a yellow oil. Subject this crude material to flash chromatography on silica gel eluting with a gradient of 20% to 100% EtOAc/hexanes. Concentrate the fractions containing the desired product under reduced pressure to furnish the title compound as a colorless oil in ca. 90% purity by 1H NMR analysis (6.50 g, 64% yield). Mass spectrum (m/z) 264 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 7.27 (dd, J=8.5, 7.3 Hz, 2H), 6.93 (t, J=7.3 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 4.10 (app t, J=6.1 Hz, 2H), 3.72 (s, 3H), 3.29 (dd, J=8.4, 4.0 Hz, 1H), 3.14 (app dt, J=11.3, 6.4 Hz, 1H), 2.95 (app dt, J=13.7, 6.1 Hz, 1H), 2.89 (app dt, J=13.7, 6.1 Hz, 1H), 2.42 (ddd, J=11.6, 7.9, 3.7 Hz, 1H), 1.90-1.82 (m, 1H), 1.79 (app td, J=8.9, 3.8 Hz, 1H), 1.67-1.59 (m, 3H), 1.39 (app td, J=8.8, 4.0 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[C:15]1([CH2:14][CH2:13][CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4](=[O:21])[C:3]([OH:22])=[O:2])=[CH:10][CH:9]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C(=O)c1ccc(OCCCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCCc2ccccc2)cc1
Yield: 72.6 %

Procedure:
A mixture of 4-[(3-phenylpropyl)oxy]-alpha-oxobenzeneacetic acid methyl ester (0.65 g) in methanol and 0.5N sodium hydroxide (8 mL) was treated as in Example 19. Extraction provided 0.6 g which solidified and was crystallized from benzene-hexane to give 0.45 g of colorless 4-[(3-phenylpropyl)oxy]-alpha-oxobenzeneacetic acid, mp 58°-59° C.