Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C[O:10][C:11](=[O:26])[CH:12]([O:24][CH3:25])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22]Br)[CH:15]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:22][CH2:21][O:20][C:16]1[CH:15]=[C:14]([CH2:13][CH:12]([O:24][CH3:25])[C:11]([OH:26])=[O:10])[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C(Cc1cccc(OCCBr)c1)OC
Reactant: Oc1cccc(F)c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCOc2cccc(F)c2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-fluoro-phenol and 3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 351, Step 1) via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example-285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C18H19FO5 [M−H]−: 333.1.
Reaction SMILES: [CH:1]1([N:4]([CH:6]2[C:15]3[C:10](=[CH:11][C:12]([C:17]#[CH:18])=[C:13]([CH3:16])[CH:14]=3)[C:9]([CH3:20])([CH3:19])[CH2:8][CH2:7]2)[CH3:5])[CH2:3][CH2:2]1.[CH3:21][O:22][C:23](=[O:52])[C:24]([C:27]1[CH:32]=[CH:31][C:30](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:29][CH:28]=1)([CH3:26])[CH3:25].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:21][O:22][C:23](=[O:52])[C:24]([C:27]1[CH:28]=[CH:29][C:30]([C:18]#[C:17][C:12]2[C:13]([CH3:16])=[CH:14][C:15]3[CH:6]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:5])[CH2:7][CH2:8][C:9]([CH3:20])([CH3:19])[C:10]=3[CH:11]=2)=[CH:31][CH:32]=1)([CH3:26])[CH3:25]
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Reactant: C#Cc1cc2c(cc1C)C(N(C)C1CC1)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc3c(cc2C)C(N(C)C2CC2)CCC3(C)C)cc1

Procedure:
Following General Procedure B and using cyclopropyl-(6-ethynyl-4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methyl-amine (Intermediate 174, 0.1 g, 0.29 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.09 g, 0.29 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.11 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 1–2% ethyl acetate in hexane as the eluent, the title compound was obtained (0.035 g, 26%).
Reaction SMILES: [CH3:1][CH:2]1[CH:9]2[CH2:10][CH:5]([C:6]([CH3:11])=[CH:7][CH2:8]2)[CH:4]([OH:12])[CH2:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>O1CCCC1>[C:13]([O:12][CH:4]1[CH2:3][CH:2]([CH3:1])[CH:9]2[CH2:10][CH:5]1[C:6]([CH3:11])=[CH:7][CH2:8]2)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=CCC2CC1C(O)CC2C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OC1CC(C)C2CC=C(C)C1C2
Yield: 86.9 %

Procedure:
To a solution of 10 g (60.2 mmol) of 4,8-dimethylbicyclo[3.3.1]nona-7-en-2-ol [IA] in 40 ml of tetrahydrofuran were added 6.8 g (66.6 mmol) of acetic anhydride and 5.2 g (65.7 mmol) of pyridine and the resulting mixture was heated under reflux for 5 hours. After cooling, the tetrahydrofuran was distilled off, the residue was subjected to column chromatography and eluate with toluene gave 10.9 g of the title compound, which had a woody-like smell.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[F:9].CC1(C)C(C)(C)OB([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])O1>>[CH3:24][CH2:25][CH2:18][CH:19]([CH3:22])[CH3:20].[F:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[C:18]1[C:19]([C:20]#[N:21])=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Fc1cccc(F)c1Br
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Product: CCCC(C)C
Product: N#Cc1ccccc1-c1c(F)cccc1F
Yield: 153.7 %

Procedure:
2-Bromo-1,3-difluorobenzene (3.0 g, 15.5 mmol) was coupled to 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (4.63 g, 20.2 mmol) as described in Example 51. The resulting black solid was purified by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (10-15%). Trituration with isohexane (20 ml) gave 2′,6′-difluorobiphenyl-2-carbonitrile as a pale yellow solid (3.34 g, 100%): δH (360 MHz, CDCl3) 7.06 (2H, dd, J 8 and 7), 7.38-7.44 (1H, m), 7.47-7.56 (2H, m), 7.61-7.72 (1H, m), 7.82 (1H, dd, J 8 and 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:26])[C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[CH:21]=1)[C:5]([NH:7][CH2:8][CH2:9]Cl)=[O:6].N12CCCN=C1CCCCC2>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH2:9][CH2:8][N:7]=2)[CH:11]=[C:12]([Cl:26])[C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[CH:21]=1
Reactant: Cc1cc(CCCCCOc2c(Cl)cc(C(=O)NCCCl)cc2Cl)on1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1cc(CCCCCOc2c(Cl)cc(C3=NCCO3)cc2Cl)on1
Yield: 65.7 %

Procedure:
To a solution of 1.0 g 3,5-dichloro-N-(2-chloroethyl)-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}benzamide in 75 ml methylene dichloride was added 0.92 g 1,8-diazabicyclo[5.4.0]undec-7-ene, and the mixture was heated at reflux for about 16 hrs. The reaction mixture was concentrated in vacuo and the residue partitioned between 150 ml ethyl acetate and 50 ml water. The organic layer was separated, washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 1:1 ethyl acetate:hexane. The eluted material was isolated, dissolved in ether and crystallized upon seeding to give 0.60 g (66%) of 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole, light yellow solid, m.p. 39°-40° C., identical with the compound of Example 105, as confirmed by thin layer chromatography.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[CH:8]=1.[N:22]12[CH2:32]CCN=C1CCCCC2.[ClH:33]>CS(C)=O>[Cl:33][C:8]1[N:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:6]=[C:5]([C:32]#[N:22])[C:4]=1[C:3]#[CH:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cl
Reactant: FC(F)(F)c1cc(Cl)c(-n2cc(C=C(Br)Br)cn2)c(Cl)c1
Solvent: CS(C)=O
Product: C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Cl

Procedure:
To a stirred solution of 5-chloro-3-cyano-)-4-(2,2-dibromoethenyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (2.12 g) in dimethylsulphoxide (8 ml) at 15° C. was added dropwise a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.21 ml) in dimethylsulphoxide (7.9 ml). After two hours the reaction mixture was neutralism with 0.5N hydrochloric acid and partitioned between water and dichloromethane. The aqueous layer was thrice extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. The aqueous layer was thrice extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with hexane dichloromethane (1:1). Combination and evaporation of suitable fractions followed by recrystallisation from hexane gave the title compound as a light pink solid, m.p. 109.1-109.9° C.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1C(OC)=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[OH-:22].[K+].Cl.[CH3:25][OH:26]>>[CH2:1]([O:11][C:12]1[CH:13]=[CH:18][C:19]([C:25]([OH:26])=[O:22])=[CH:20][CH:21]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: COC(=O)c1ccccc1OC/C=C(\C)CCC=C(C)C
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of methyl geranyloxybenzoate (13.00 g) in methanol (50 ml) was added an aqueous solution (10 ml) of potassium hydroxide (3.90 g), After being stirred at room temperature for one night, the mixture was refluxed with heating for 1 hour. Concentrated hydrochloric acid was added to the reaction solution so as to acidified. Then, the resulting solution was extracted with chloroform. The extract was dried over sodium sulfate anhydride and then the solvent was evaporated under a vacuum. The residue was recrystallized from an n-hexane/ethyl acetate mixed solution, thereby yielding 9.77 g (71%) of the aimed compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:29])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH2:27][CH3:28])[N:6]=2.[CH3:30][S:31]([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1([CH3:43])[CH3:42])(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:42][C:37]1([CH3:43])[N:36]([CH2:35][CH2:34][S:31]([CH3:30])(=[O:32])=[O:33])[CH2:41][CH2:40][N:39]([CH2:2][C:3]2[N:4]([CH3:29])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH2:27][CH3:28])[N:6]=3)[CH2:38]1
Reactant: CC1(C)CNCCN1CCS(C)(=O)=O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCl)n(C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CCS(C)(=O)=O)C(C)(C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.8 %

Procedure:
To a solution of 8-chloromethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (107 mg, 0.26 mmol) and 1-(2-methanesulfonylethyl)-2,2-dimethylpiperazine (68 mg, 0.31 mmol) in DMF (3 mL) was added K2CO3 (106 mg, 0.77 mmol). The resulting mixture was allowed to stir at room temperature for 16 h. The reaction mixture was dissolved in EtOAc, washed with H2O (×4) then dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) and (Si—PCC, MeOH:DCM 0-5%). The resulting residue was further purified by reverse phase HPLC (Phenomenex Luna C18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 5:95) to afford 310 as a white solid (40 mg, 26%). LCMS (Method G): RT 6.68 min, [M+H]+ 596.3. 1H NMR (CDCl3, 400 MHz): δ 8.04-7.99 (m, 1 H); 7.77-7.72 (m, 1 H); 7.28-7.23 (m, 2 H); 4.35 (m, 4 H); 3.87 (m, 7 H); 3.69 (s, 2 H); 3.36 (q, J=7.5 Hz, 2 H); 3.11-3.03 (m, 5 H); 2.92 (m, 2 H); 2.62 (m 2 H); 2.51 (m, 2 H); 2.37-2.22 (m, 2 H); 1.45 (t, J=7.5 Hz, 3 H) and 1.09 (s, 6 H)
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Br:25][C:26]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:27]=1[NH2:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Br:25][C:26]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1
Reactant: Cc1ccc(N)c(Br)c1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCn1c(Nc2ccc(C)cc2Br)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 130 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 1.50 g, 4.04 mmol), 2-bromo-4-methylaniline (1.0 mL, 8.08 mmol), p-toluenesulfonic acid monohydrate (822.2 mg, 4.32 mmol) and xylene (5.0 mL) was stirred at 130° C. for 12 hr. After cooling, the reaction mixture was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as an oil (1.42 g, 2.73 mmol, 68%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[CH3:7][N:8]([CH3:11])C=O.[CH3:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)[N:16]=[CH:15][C:14]=1[C:28]([OH:30])=O>ClCCl>[OH:5][CH:1]1[CH2:2][CH2:23][C:22]([C:11]2[N:8]=[CH:7][C:15]([NH:16][C:28]([C:14]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][N:19]=4)[C:13]=3[CH3:12])=[O:30])=[CH:14][C:13]=2[CH3:12])=[CH:21][CH2:20]1
Reactant: CN(C)C=O
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.20 ml) and N,N-dimethylformamide (catalytic amounts) were added at room temperature to a solution of 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid (175 mg) described in Reference Example 8 in dichloromethane (10 ml) and stirred at room temperature for two hours. The solvent and an excess amount of oxalyl chloride were evaporated, and toluene (10 ml) was added to the resulted reaction mixture. Next, a solution of 4-(5-amino-3-methylpyridin-2-yl)cyclohex-3-en-1-ol (120 mg) described in Reference Example 111 in pyridine (10 ml) was added under ice-cooling, and the mixture was stirred at room temperature overnight. After the reaction, 1N aqueous solution of sodium hydroxide was added under ice-cooling and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with a silica gel column chromatography (chloroform/methanol), washed with ethanol, the resulting solid was filtered and dried at 60° C. in vacuo to give the titled compound (146 mg) as a white solid.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:12]=[N:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)C>C(O)(=O)C>[C:1]1([N:7]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)=[N:13][CH:12]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-c2ncnn2-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of 5.4 g. of phenylhydrazine in 70 ml. of 30% aqueous acetic acid is added 10.0 g. of N-(dimethylaminomethylene)-p-nitrobenzamide. The reaction mixture is stirred at 90° C. for one hour and then cooled. The solid is collected and recrystallized from ethanol giving 9.1 g. of the desired product as colorless crystals, mp. 130°-132° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.O.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)NCCc1ccsc1
Agent: C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccsc2C1
Temperature: 25 °C

Procedure:
A solution of 1.753 g (7.711 mmol) of N-tert-butoxycarbonyl-2-(3-thienyl)ethylamine, 0.46 g (15.4 mmol) of powdered paraformaldehyde and 73 mg (0.39 mmol) of p-toluenesulfonic acid monohydrate in 150 ml of toluene was refluxed under dehydrating conditions for 0.5 hours in a Dean-Stark trap. The reaction mixture was cooled to room temperature and diluted with ethyl acetate, after which it was washed with aqueous sodium hydrogen carbonate; the organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1 to 9/1) to yield the desired product.
Reaction SMILES: ClC1C=C(/C=C/C(N2CCC(=O)NCC2)=O)C=CC=1Cl.Cl.Cl.[N:23]1([CH2:29][CH2:30][CH2:31][N:32]2[C:38](=[O:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[Cl:40][C:41]1[CH:51]=[CH:50][C:44](/[CH:45]=[CH:46]/[C:47](O)=[O:48])=[CH:43][C:42]=1[F:52]>CCOC(C)=O>[Cl:40][C:41]1[CH:51]=[CH:50][C:44](/[CH:45]=[CH:46]/[C:47]([N:35]2[CH2:36][CH2:37][C:38](=[O:39])[N:32]([CH2:31][CH2:30][CH2:29][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:33][CH2:34]2)=[O:48])=[CH:43][C:42]=1[F:52]
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Reactant: O=C(O)/C=C/c1ccc(Cl)c(F)c1
Agent: Cl
Agent: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1ccc(Cl)c(F)c1)N1CCC(=O)N(CCCN2CCCCC2)CC1

Procedure:
In analogy to the procedure described in intermediate 1A, 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B) and (E)-4-chloro-3-fluorocinnamic acid gave after work up with EtOAc (×3)/saturated NaHCO3 and precipitation (n-pentane) the title compound as off-white solid. MS: 422.2 (MH+, Cl).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[C:20]([CH2:21][CH3:22])=[N:19][C:18]([C:23](=[O:25])[NH2:24])=[C:17]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH:38]=4)=[CH:29][CH:28]=3)[N:16]=2)[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:15]1[N:16]=[C:17]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH:38]=3)=[CH:29][CH:28]=2)[C:18]([C:23]([NH2:24])=[O:25])=[N:19][C:20]=1[CH2:21][CH3:22]
Reactant: CCc1nc(C(N)=O)c(Oc2ccc(C3=CCN(C)CC3)cc2)nc1Oc1cccc(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc(C(N)=O)c(Oc2ccc(C3=CCN(C)CC3)cc2)nc1Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To a mixture of tert-butyl[3-({5-carbamoyl-3-ethyl-6-[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]pyrazin-2-yl}oxy)phenyl]carbamate (150 mg) and dichloromethane (3 mL) was added trifluoroacetic acid (421 μL), followed by stirring at room temperature for 2 hours. The mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and then the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 type, eluent; chloroform:methanol=1:0-95:5) to obtain 5-(3-aminophenoxy)-6-ethyl-3-[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]pyrazine-2-carboxamide (56 mg) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:11]O>C(O)(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:11]
Reactant: OO
Reactant: FC(F)(F)c1ccccn1
Solvent: CC(=O)O
Product: [O-][n+]1ccccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 2-trifluoromethyl pyridine (5 g, 34 mmol) in acetic acid (25 mL) is added 33% of aqueous H2O2 (20 mL) at room temperature. The reaction mixture is allowed to stir for 12 h at 70° C. After complete consumption of starting material the reaction mixture is concentrated under reduced pressure. The residue is dissolved in chloroform (250 mL) and pH is adjusted to 7 with K2CO3 (20 g approx). Resulting solid is filtered through glass sintered funnel and washed with chloroform. Filtrate is concentrated under reduced pressure to give 2-trifluoromethyl-pyridine 1-oxide as syrupy liquid (4.3 g).
Reaction SMILES: C[Si](C)(C)[O:3][CH2:4][CH2:5][O:6][CH2:7]I.[CH:11]([N+:18]([O-:20])=[O:19])([N+:15]([O-:17])=[O:16])[N+:12]([O-:14])=[O:13].C([N+]([O-])=O)([N+]([O-])=O)[N+]([O-])=O.C(Cl)Cl.CN(C)C=O>C(Cl)Cl>[OH:3][CH2:4][CH2:5][O:6][CH2:7][C:11]([N+:18]([O-:20])=[O:19])([N+:15]([O-:17])=[O:16])[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Reactant: C[Si](C)(C)OCCOCI
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])C(COCCO)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The iodomethyl 2-(trimethylsilyloxy)ethyl ether solution prepared in example 2 was kept in a dry ice-acetone bath and a dry solution of nitroform (76 g; 0.5 moles) in 375 ml of methylene chloride was added over 20 minutes through an addition funnel. [See Example 5 for the preparation of the nitroform solution]. After the addition of the nitroform-methylene chloride solution was complete, dry dimethylformamide (100 ml) was added and after five minutes the reaction solution was removed from the dry ice-acetone bath and allowed to warm to near 0° C. (takes about 45 minutes). The solution was then cooled in an ice bath for 15 minutes before it was poured into 600 ml of ice water. The lower organic layer was separated after which the aqueous phase was extracted with 3×25 ml of methylene chloride. The combined organic extracts were dried over sodium sulfate and then allowed to stand in a hood in a current of air to remove volatiles. The residue (approximately 150 g but depends on the amount of dimethylformamide lost) contains mainly 2,2,2-trinitroethyl 2-hydroxyethyl ether1 and dimethylformamide along with much smaller amounts of two byproducts2 (A and B). The crude ether was added to 46 ml of concentrated hydrochloric acid and the mixture was stirred well at 60°-65° C. for 1 hour. After cooling to room temperature, 30 ml of methylene chloride was added and the organic layer was separated and washed with 3×30 ml of water. The combined water extracts (90 ml) were back extracted with methylene chloride (30 ml) and the combined organic extracts were dried over sodium sulfate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.Cl.[NH2:12][OH:13].C(N(CC)CC)C>CO>[NH2:1][C:2]1[C:3](/[C:9](=[N:12]\[OH:13])/[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: N#Cc1nc(Br)cnc1N
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N/C(=N/O)c1nc(Br)cnc1N
Temperature: 0 °C
Reaction time: 48 h
Yield: 98.4 %

Procedure:
3-amino-6-bromo-pyrazine-2-carbonitrile (4.5958 g, 23.09 mmol) was dissolved in MeOH (91.92 mL), cooled to 0° C. and treated with hydroxylamine hydrochloride (1.605 g, 23.09 mmol) and triethylamine (2.336 g, 3.218 mL, 23.09 mmol). The reaction was allowed to warm to ambient temperature, stirred for 48 hours and then evaporated to dryness. Methanol (a minimum amount) was added, the mixture sonicated, filtered and washed with MeOH to give the product as a brown solid 5.27 g, 98% Yield). 1H NMR (400.0 MHz, DMSO) d 5.88 (s, 2H), 7.64 (br s, 2H), 8.14 (s, 1H) and 10.38 (s, 1H) ppm; MS (ES+) 233.75
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([OH:20])[CH2:19][NH:18][CH2:17]3)=[CH:12][C:11]=2[O:21][CH3:22])=[CH:6][CH:5]=1)[CH3:3].CCN=C=NCCCN(C)C.Cl.[CH:37]1[CH:38]=[CH:39][C:40]2[N:45](O)N=N[C:41]=2[CH:42]=1.CN(C=[O:51])C>O.C(N(CC)CC)C>[CH2:2]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([OH:20])[CH2:19][N:18]([C:41]([C:40]4[CH:39]=[CH:38][CH:37]=[CH:42][N:45]=4)=[O:51])[CH2:17]3)=[CH:12][C:11]=2[O:21][CH3:22])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CN(C)C=O
Reactant: CCc1ccc(COc2ccc(C3(O)CNC3)cc2OC)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1ccc(COc2ccc(C3(O)CN(C(=O)c4ccccn4)C3)cc2OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74 %

Procedure:
To a solution of 3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]-azetidin-3-ol hydrochloride (0.50 g) prepared in (3), 2-pyridinecalboxylic acid (0.070 g), WSC.HCl (0.12 g) and HOBt.H2O (0.092 g) in DMF (3.0 mL) was added triethylamine (0.070 mL). The reaction mixture was stirred at RT for 15 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure. A mixed solvent of chloroform/hexane was added the residue. The precipitated solid was collected on a filter and dried to give the title compound (0.15 g, 74%).