Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:17])[CH3:16])[CH2:4][CH2:3]1.C([O:22][C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][N:27]=1)(C)(C)C.[OH-].[K+]>CCO.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:17])/[CH:16]=[CH:32]/[C:29]2[CH:30]=[CH:31][C:26](/[CH:25]=[CH:24]/[C:23]([OH:34])=[O:22])=[N:27][CH:28]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Reactant: CC(=O)c1ccccc1CN1CCN(C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(Cc2ccccc2C(=O)/C=C/c2ccc(/C=C/C(=O)O)nc2)CC1
Temperature: 4 °C
Reaction time: 8 h
Yield: 133.2 %

Procedure:
A mixture of 1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-ethanone (obtained as described in Preparation 11, 250 mg, 1.07 mmol), (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (described in Example 11 STEP A-D, 251 mg, 1.07 mmol) and 1.7 M KOH (0.633 ml) in EtOH (10 ml) was stirred at 4° C. overnight. The resulting solution was diluted with water and extracted with AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 95:5:0.2) and the resulting product was dissolved in DCM (10 ml) and TFA (2 ml) and stirred at room temperature for 4 h. The solvent was evaporated to give 558 mg of (E)-3-(5-{(E)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid as its tris-trifluoroacetate salt.
Reaction SMILES: [C:1]([NH:4][OH:5])(=[O:3])[CH3:2].Cl[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:17]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[C:20]([F:22])[CH:21]=2)=[CH:11][CH:10]=1)[CH3:8]>>[C:1]([NH:4][O:5][CH:7]([CH3:8])[C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)Cl)cc3)c2)CCOCC1
Reactant: CC(=O)NO
Product: COC1(c2cc(F)cc(Sc3ccc(C(C)ONC(C)=O)cc3)c2)CCOCC1
Temperature: 60 °C
Yield: 62 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reactants were heated to 60° C for 2 hours, acetohydroxamic acid was reacted with 4-{3-[4-(1-chloroethyl)phenylthio]-5-fluorophenyl}-4-methoxytetrahydropyran to give 4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-methylbenzyl acetohydroxamate as a gum in 62% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:6][C:5]2=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:6][C:5]2=[S:28]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=c1cc(-c2cccnc2)oc2ccc(F)cc12
Solvent: Cc1ccccc1
Product: Fc1ccc2oc(-c3cccnc3)cc(=S)c2c1
Yield: 138.5 %

Procedure:
A stirred mixture of 6-fluoro-2-pyridin-3-yl-chromen-4-one (128 mg, 0.53 mmol), Lawesson's reagent (129 mg, 0.32 mmol) and anhydrous toluene (3.5 mL) was refluxed under N2 for 0.5 hr. The solvent was removed under vacuum and the residue was purified by silica gel chromatography (EtOAc/MeOH/NEt3, 40/2/1) to give 6-fluoro-2-pyridin-3-yl-chromene-4-thione (114.0 mg, 83.6% yield) as a brown yellow solid which was used in next step without further purification. LC/MS: 258.1 (M+H); LC/Method A/5.94 min, 96.6% purity by area %.
Reaction SMILES: [CH2:1]([CH:3]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:6]=2[O:5][CH2:4]1)[CH3:2].[CH:16](=O)[CH3:17].[BH3-]C#N.[Na+]>>[CH2:1]([CH:3]1[N:8]([CH2:16][CH3:17])[C:7]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:6]=2[O:5][CH2:4]1)[CH3:2]
Reactant: CC=O
Reactant: CCC1COc2cc([N+](=O)[O-])ccc2N1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCC1COc2cc([N+](=O)[O-])ccc2N1CC
Yield: 75 %

Procedure:
This compound was prepared by General Method 3 (EXAMPLE 1) from 3-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 42) (200 mg, 0.96 mmol), acetaldehyde (424 mg, 9.6 mmol) and NaBH3CN (293 mg, 4.6 mmol) to afford 170 mg (75%) of (±)-3,4-diethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine, a yellow solid. Data for (±)-3,4-diethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine: Rf 0.80 (3:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 7.80 (dd, 1H, J=8.9, 2.6), 7.66 (d, 1H, J=2.6), 6.55 (d, 1H, J=9.2), 4.07 (dd, ABX, 1H, J=10.7, 2.5), 3.96 (dd, ABX, 1H, J=10.7, 2.6), 3.60 (m, 1H), 3.55-3.35 (m, 2H), 1.29 (d, 3H, J=6.6), 1.24 (t, 3H, J=7.0).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[CH:22]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([N:13]2[CH2:14][CH2:15][N:16]([CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:17][CH2:18]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Clc1ccc(C(Cl)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1ccc(C(c2ccccc2)N2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1

Procedure:
A solution of 4-(4-chlorobenzhydryl)piperazine 1 (2 mmols) and chloro-(4-chlorophenyl)phenylmethane 21 (Aldrich, 2 mmols) in methylene chloride (10 mL) and Et3N (0.3 mL) is stirred under an inert atmosphere. The solution is warmed and the course of the reaction is followed by TLC. When the reaction is complete, dil. aq. Na2CO3 is added to the solution, shaken, and the layers are separated. The aqueous layer is extracted with additional CH2Cl2, the combined organic extracts are washed with half-saturated brine, dried (Na2SO4), filtered and concentrated under reduced pressure giving the crude product. The desired compound 1,4-bis-(4-chlorobenzhydryl)piperazine 22 is obtained by purification of the crude product with the use of HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[CH:4][N:3]=1.C(N(CC)CC)C.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19](Cl)=[O:20]>ClCCl>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:19](=[O:20])[C:18]2[C:17]([F:16])=[CH:25][CH:24]=[CH:23][C:22]=2[F:26])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cnc(Br)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cnc(Br)cn1)c1c(F)cccc1F
Temperature: 25 °C

Procedure:
To a stirred solution of 2-bromo-5-amino-pyrazine (24 mmol), triethyl amine (TEA) (5 mL) in dry dichloromethane (DCM) (50 mL) at 00° C. was added 2,6-difluoro-benzoyl chloride (3.0 mL, 24 mmol) dropwise. The mixture was allowed to warm to room temperature over 2 h before it was washed with water (2×100 mL) and dried. Removal of solvents gave N-(5-bromo-pyrazin-2-yl)-2,6-difluorobenzamide (b) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[N:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cnccc21
Product: CC1c2ccncc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Yield: 54 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-methyl-1,2,3,4-tetrahydro-[2,6]naphthyridine to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O)[C@H:23]1[O:25][CH2:24]1>CC(C)=O>[CH2:22]([C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][C:12]=1[OH:15])[C@@H:23]1[O:25][CH2:24]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Oc1ccc(OCc2ccccc2)cc1C[C@H]1CO1

Procedure:
A mixture of 4-benzyloxyphenol (2.0 g, 10 mMol) and potassium carbonate (4.14 g, 30 mMol) in acetone (50 ml) was heated under reflux for 15 mins. (S)-Glycidyl-3-nitrobenzenesulphonate (2.23 g, 10 mMol) was added and the reaction mixture was heated under reflux for 18 hours. After cooling, the reaction mixture was filtered and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic fractions were combined, washed with water and brine, dried and evaporated to give the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:27])[N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:12][C:11]=2[S:10][C:9]=1[NH:35]C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:27])[N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:35])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1c(NC(=O)OCc2ccccc2)sc2c1CC(CN1Cc3ccccc3C1=O)N(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1Cc3ccccc3C1=O)N(C(=O)OC(C)(C)C)C2
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a solution of the above 2-benzyloxycarbonylamino-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (9 mg, 0.014 mmol) in methanol (2 ml) was added 10% Pd/C (4 mg). The mixture was stirred under hydrogen (1 atm.) for 3 hours and then filtered. The filtrate was evaporated in vacuo affording 6 mg (93%) of 2-amino-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.C([O-])(=O)C.[NH4+].[BH3-]C#[N:20].[Na+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH2:20])[CH2:6][CH2:5]2
Reactant: [BH3-]C#N
Reactant: O=C1CCCc2cc(F)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: NC1CCc2cc(F)ccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Over a solution of 6-fluorotetralone (6-fluoro-3,4-dihydro-1 H-naphthalen-2-one; 1 equivalent) and ammonium acetate (5 equivalents) in a 2:1 mixture of MeOH:THF (0.24 M), was carefully added NaCNBH3 (2 eq), and the reaction mixture was stirred at room temperature for 2 hours. Concentrated HCl was added at 0° C. until the pH was less than 2, and the MeOH was removed in vacuo. The residue was taken up in water and extracted with CHCl3 (2×). The aqueous solution was basified with solid KOH and extracted with CHCl3 (3×). The combined extracts were dried (MgSO4) and evaporated in vacuo to give the titled compound.
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][C:18](N)=[N:19][CH:20]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].[O:22]=[N+]=O>OS(O)(=O)=O>[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][C:18]([OH:22])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: O=[N+]=O
Reactant: CS(=O)(=O)c1ccc(-c2cnc(N)cn2)cc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
NaNO2 (0.20 g, 2.76 mmol) was added in portions to concentrated H2SO4 (1.4 mL) at 0° C. The mixture was heated at 50° C. until all of the NaNO2 had dissolved and the mixture was again cooled to 0° C. A solution of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinamine (0.51 g, 2.05 mmol) in concentrated H2SO4 (4.2 mL) was added dropwise to the nitronium solution. The ice bath was removed, and the mixture was warmed to ambient temperature and stirred for 15 min, then heated to 45° C. for 30 min. The mixture was cooled to ambient temperature and poured into ice water. The pH was adjusted to about 4 with 4N NaOH and the solid was collected, washed with water, and air dried to give 0.415 g (81%) of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 12.77 (bs, 1H), 8.30-8.05 (m, 4H), 7.92 (d, 2H, J=8.6 Hz), 3.21 (s, 3H); LRMS (ESI), m/z 251 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:25]=[C:26]([NH:30][C:31]([N:35]([CH3:37])[CH3:36])=[N:32][C:33]#[N:34])[CH:27]=[C:28]([CH3:29])[C:5]=2[N:4]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:25]=[C:26]([NH:30][C:31]([N:35]([CH3:37])[CH3:36])=[N:32][C:33]#[N:34])[CH:27]=[C:28]([CH3:29])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(NC(=NC#N)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nc2c(C)cc(NC(=NC#N)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1d from methyl 4'-[[2-ethyl-4-methyl-6-(2-cyano-3,3-dimethyl-guanidino)-1H-benzimidazol -1-yl]-methyl]-biphenyl-2-carboxylate and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]=1[CH2:25]Cl)[CH2:2][CH2:3][CH3:4].[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K].O>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]=1[CH2:25][N:31]1[C:27](=[O:37])[C:28]2[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30]1=[O:32])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2ccc(OCC)cc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC(C)(C)C)c(=O)c2ccc(OCC)cc12
Yield: 97.8 %

Procedure:
A solution of 4-butoxy-6-ethoxy-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (0.38 g, 1 mmol) and potassium phthalimide (0.28 g, 1.5 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-{(4-butoxy-6-ethoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione (0.48 g, 98.0%) as an amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:29]1[CH2:30][CH2:31][N:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:27][CH2:28]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: c1cnc(N2CCNCC2)nc1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ncccn2)CC1
Yield: 90 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-pyrimidyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 3.71 (s, 4H), 3.99 (s, 3H), 4.15 (s, 4H), 6.55 (s, 1H), 7.27-7.43 (m, 2H), 7.66 (s, 1H), 7.80 (s, 1H), 8.35 (s, 2H).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)[CH3:2].[C:19]1([SiH2]C2C=CC=CC=2)C=CC=C[CH:20]=1>O1CCCC1.C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Rh]>[CH2:1]([N:4]([CH2:5][C@H:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:19][CH3:20])[CH3:2]
Reactant: c1ccc([SiH2]c2ccccc2)cc1
Reactant: CC(=O)NC[C@H]1COCCN1C(=O)OC(C)(C)C
Agent: [Rh]
Agent: C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)C[C@H]1COCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-tert-butyl 3-((N-ethylacetamido)methyl)morpholine-4-carboxylate (INTERMEDIATE 86A, Step 2, 0.04 g, 0.14 mmol) and diphenylsilane (0.052 ml, 0.28 mmol) in tetrahydrofuran (1.345 ml) at rt was added carbonyltris(triphenylphosphine)rhodium(I)hydride (6.42 mg, 6.98 mol). After a brief surge of gas evolution, the now yellow reaction was stirred for 30 min and then quenched with 1N aqueous hydrogen chloride. The mixture was extracted with ether, and the aqueous layer was basified with 50% aqueous sodium hydroxide. The aqueous layer was the extracted with ethyl acetate (×4), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford (S)-tert-butyl 3-((diethylamino)methyl)morpholine-4-carboxylate (0.038 g, yield: almost quantitative) (INTERMEDIATE 86A, Step 3).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:10]([S:17][CH2:18][C:19](N)=[NH:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:19]([CH2:18][S:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:20]=1
Reactant: N#Cc1nccnc1N
Reactant: N=C(N)CSCc1ccccc1
Solvent: CCO
Product: Nc1nc(CSCc2ccccc2)nc2nccnc12

Procedure:
A suspension of 2.3 g (0.019 mole) of 3-amino-2-pyrazinecarbonitrile and 5.2 g (0.029 mole) of 2-(benzylthio)acetamidine [prepared according to J. M. McManus, J. Heterocycl. Chem. 1968, 5, 137] in 150 ml of absolute ethanol is refluxed for 2 hours. After cooling, the solution obtained is concentrated to dryness under reduced pressure. The residue is washed with isopropyl ether and dried under reduced pressure. An amorphous solid is obtained, and is used in the next step without further purification. Yld: 5.4 g (quantitative).
Reaction SMILES: O[CH2:2][CH:3]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][CH2:2][CH:3]([C:4]([O:6][CH3:7])=[O:5])[N:8]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)C(CO)NC(=O)c1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1COC(c2ccc(C(F)(F)F)cc2)=N1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 3-hydroxy-2-{[4-(trifluoromethyl)phenyl]-carbonylamino}propanoate (2.57 g, 8.83 mmol) in tetrahydrofuran (30 ml) was added triphenylphosphine (2.55 g, 9.71 mmol). The mixture was cooled to 0° C., and diisopropylazodicarboxylate (1.91 ml, 9.71 mmol) was added slowly. The mixture was stirred at room temperature for 2 days. Solvent was removed from the filtrate under reduced pressure, and the residue was purified by column chromatography, to yield methyl 2-[4-(trifluoromethyl)phenyl]-1,3-oxazoline-4-carboxylate, a compound of formula (14).
Reaction SMILES: [Cl:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH:10]=[CH:11]\[CH2:12][CH3:13].Br[CH2:15][CH2:16][CH2:17]Cl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH:13]=[CH:15]\[CH2:16][CH3:17]
Reactant: ClCCCBr
Reactant: CC/C=C/C=C\CC/C=C\CCCl
Product: CC/C=C/C=C\CC/C=C\CCCCCCl

Procedure:
The (Z,Z,E)-1-chloro-3,7,9-dodecatriene (2) is converted into a corresponding Grignard reagent and then the Grignard reagent is reacted with 1-bromo-3-chloropropane to obtain (Z,Z,E)-1-chloro-6,10,12-pentadecatriene (3).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:8]=1.[Na+].[I-].[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:21]([O:20][P:19]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:8]=1)([O:23][CH2:24][CH3:25])=[O:26])[CH3:22]
Reactant: CCOC(=O)c1cn2cc(CCl)ccc2n1
Reactant: CCOP(OCC)OCC
Agent: [I-]
Agent: [Na+]
Product: CCOC(=O)c1cn2cc(CP(=O)(OCC)OCC)ccc2n1
Yield: 42.6 %

Procedure:
By the method of Example 6, the product from Example 11 (2.66 g, 11.1 mmol) was treated with NaI (1.67 g, 11.1 mmol) and triethyl phosphite (2.03 g, 12.2 mmol). Workup produced 1.61 g (43%) of title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2.[OH:15][C@:16]1([C:23]2[CH:24]=[C:25]([SH:28])[S:26][CH:27]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1>>[F:1][C:2]1[CH:3]=[C:4]([S:28][C:25]2[S:26][CH:27]=[C:23]([C@@:16]3([OH:15])[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]3)[CH:24]=2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: C[C@H]1C[C@@](O)(c2csc(S)c2)CCO1
Reactant: CN1C(=O)CCc2cc(I)cc(F)c21
Product: C[C@H]1C[C@@](O)(c2csc(Sc3cc(F)c4c(c3)CCC(=O)N4C)c2)CCO1
Yield: 40 %

Procedure:
Using an analogous procedure to that described in Example 5, 8-fluoro-6-iodo-1-methyl-1,2,3,4-tetrahydroquinolin-2-one with (2S,4R)-4-hydroxy-4-(2-mercaptothien-4-yl)-2-methyltetrahydropyran to give (2S,4R)-4-[2-(8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thien-4-yl]-4-hydroxy-2-methyltetrahydropyran in 40% yield as a foam;
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH:7]2[CH2:9][CH2:8]2)[C:3]=1[CH3:10].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:7]1([C:4]2[C:3]([CH3:10])=[C:2]([NH:1][S:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:19])=[O:18])[O:6][N:5]=2)[CH2:9][CH2:8]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1c(C2CC2)noc1N
Product: Cc1c(C2CC2)noc1NS(=O)(=O)c1ccccc1
Yield: 62 %

Procedure:
This compound was prepared as described in Example 42 from 5-amino-3-cyclopropyl-4-methylisoxazole and benzenesulfonyl chloride in 62% yield. The crude product was preparative HPLC to give a viscous colorless oil.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11](C)[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18](Cl)=[CH:17][C:16]=2[CH3:23])[C:8]=1[N+:24]([O-])=O)[CH2:4][CH3:5])[CH3:2].[CH2:27](O)C>[Pd]>[CH3:23][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[O:14][C:9]1[C:8]([NH2:24])=[C:7]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:12]([CH3:27])=[CH:11][N:10]=1
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1[N+](=O)[O-]
Reactant: CCO
Agent: [Pd]
Product: CCC(CC)Nc1c(C)cnc(Oc2c(C)cccc2C)c1N

Procedure:
A mixture of (1-ethyl-propyl)-[6-methyl-3-nitro-2-(4 chloro-2,6-dimethyl-phenoxy)-pyridin-4-yl]-amine (800 mg, 2.12 mmol) and 160 mg of 10% Pd IC in 150 ml of ethanol was hydrogenated at 50 psi overnight. The mixture was filtered through Celite™ and the filtrate was concentrated to dryness to give a purple glass form (810 mg) which was purified through silica gel column chromatography using 1:1 chloroform:hexane as eluent to give the Ute compound as tan crystals (360 mg), mp 98-100° C. 1H NMR (CDCl3) δ 7.05 (m, 3H), 6.11 (s, 1H), 4.00 (brs, 1H), 3.28 (m, 1H), 3.09 (brs, 2H), 2.14 (s, 9H), 1.451.75 (m, 4H), 0.98 (t, 6H) ppm. The corresponding HCl salt was prepared as white solid, mp 158-162° C., 1H NMR(D2O) δ 7.27 (s, 3H), 6.67 (s, 1H), 3.65 (m, 1H), 2.27 (s, 3H), 2.16 (s, 6H), 1.45-1.80 (m, 4H), 0.93 (t, 6H) ppm.