Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:9][O:10]C)[C:3]=1[O:15][CH3:16].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH:12]2[CH2:13][CH2:14]2)[CH:9]=[O:10])[C:3]=1[O:15][CH3:16]
Reactant: COC=C(c1nccc(Cl)c1OC)C1CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(Cl)ccnc1C(C=O)C1CC1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
4-chloro-2-(1-cyclopropyl-2-methoxyvinyl)-3-methoxy-pyridine (259 mg, 1.1 mmol) was dissolved in THF (10 ml) and cooled to 0° C. 4M sulfuric acid (2.7 ml, 10 mmol) was added and the reaction was performed at reduced pressure while heating at 50° C. for 2.5 h. The mixture was diluted in ice water (10 mL) and sodium bicarbonate added until neutralized. The mixture was washed with DCM (3×10 mL) and the organic phase dried, filtered and evaporated to dryness to obtain 2-(4-chloro-3-methoxy-pyridin-2-yl)-2-cyclopropyl-acetaldehyde as a yellow oil (233 mg) to be used without further purification.
Reaction SMILES: [F-].[Cs+].[CH3:3]OCCOCCOC.[CH3:12][O:13][C:14](=[O:24])[CH:15]([C:20]([F:23])([F:22])[F:21])[C:16]([O:18][CH3:19])=[O:17].CI>O>[CH3:3][C:15]([C:20]([F:22])([F:23])[F:21])([C:16]([O:18][CH3:19])=[O:17])[C:14]([O:13][CH3:12])=[O:24]
Reactant: COC(=O)C(C(=O)OC)C(F)(F)F
Reactant: COCCOCCOC
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CI
Product: COC(=O)C(C)(C(=O)OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of dried CsF (9.11 g, 60 mmol), diglyme (41 ml), dimethyl(trifluoromethyl)malonate (4 g, 20 mmol), and methyl iodide (3.12 g, 22 mmol) was stirred overnight at room temperature. The reaction mixture was poured into water and the resultant oily layer and the ether-extract from the aqueous layer were combined and washed with water to remove diglyme. After drying over MgSO4, the ether was evaporated and the residue was subjected to distillation, giving dimethyl methyl(trifluoromethyl)malonate (2.56 g, 60%), b.p. 63°-65° C./10 mmHg. This product showed the following analytical properties: 19F NMR: δ--7.5 (s, CF3); 1H NMR: δ 3.81 (s, 6H, CO2CH3), 1.66 (s, CH3).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:16][C:3]1([CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:27][CH2:28]2)[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(CCCc3ccccc3)CC1)O2
Yield: 42 %

Procedure:
Using 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 4-(3-phenylpropyl)piperidine, the procedure of Example 1 was otherwise repeated to provide the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([O:35][C:36]1[CH:37]=[C:38](O)[CH:39]=[CH:40][CH:41]=1)[CH:33]=[CH2:34].[CH3:43][O:44][C:45]1[CH:46]=[C:47]([CH:52]=[CH:53][C:54]=1[O:55][CH3:56])[CH:48]=[CH:49][CH2:50][OH:51]>C1COCC1.C(OCC)C>[CH2:32]([O:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=1[O:51][CH2:50][CH:49]=[CH:48][C:47]1[CH:52]=[CH:53][C:54]([O:55][CH3:56])=[C:45]([O:44][CH3:43])[CH:46]=1)[CH:33]=[CH2:34]
Reactant: C=CCOc1cccc(O)c1
Reactant: COc1ccc(C=CCO)cc1OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOc1ccccc1OCC=Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl azodicarboxylate (26.1 g, 0.15 mol) and triphenyl phosphine (39.3 g, 0.15 mol) were added to a solution of 3-allyloxyphenol (15 g, 0.1 mol) and 3,4-dimethoxycinnamyl alcohol (19.4 g, 0.1 mol) in THF (100 ml). The mixture was stirred at room temperature overnight, and ethyl ether was added. The precipitate was filtered off, and the filtrate was evaporated to a residue, which was purified by HPLC using hexane-ethyl acetate (4:1 v/v) as a liquid phase. 3,4-Dimethoxycinnamyl allyloxyphenyl ether was isolated as a crystalline mass (7.4 g, 23%), m.p. 60°-60.5° C.; NMR (CDCl3): δ3.93, 3.94 (s, s, 2 OCH3), 4.57 (d, t, J=5.5, 1.5, 1.5 Hz, CH2CH=CH2), 4.71 (d, d, J=6.0, 1.5 Hz, CH=CHCH2), 5.28-5.50 (m, CH2CH=CH2), 6.10 (m, CH2CH=CH2 ), 6.26-6.40 (m, CH=CHCH2), 6.56-7.28 (m, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]1[N:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1)[CH2:6][CH2:5]2.[NH2:19][C:20]1[C:21]([CH3:29])=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH2:25])=[O:24].C(N(C(C)C)C(C)C)C.CC(O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]1[N:13]=[CH:14][N:15]=[C:16]([NH:19][C:20]3[C:21]([CH3:29])=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([NH2:25])=[O:24])[N:17]=1)[CH2:6][CH2:5]2
Reactant: Clc1ncnc(N2CCc3cc(Br)ccc3C2)n1
Reactant: Cc1c(N)cccc1C(N)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Nc2ncnc(N3CCc4cc(Br)ccc4C3)n2)cccc1C(N)=O
Temperature: 95 °C
Yield: 25.1 %

Procedure:
To a vial charged with 6-bromo-2-(4-chloro-1,3,5-triazin-2-yl)-1,2,3,4-tetrahydroisoquinoline (163 mg, 499 μmol) and 3-amino-2-methylbenzamide (75 mg, 499 μmol) was added N-ethyl-N-isopropylpropan-2-amine (174 μl, 999 μmol) and propan-2-ol (1665 μl, 499 μmol). The vial was sealed and heated to 95° C. overnight. The product was purified by reverse phase liquid chromatography using TFA as a modifier. Fractions containing the product were combined and neutralized with saturated NaHCO3 (35 mL). The product was extracted with DCM (3×30 mL). The organics were separated, dried over Na2SO4, and filtered to afford 3-(4-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-1,3,5-triazin-2-ylamino)-2-methylbenzamide (55 mg, 25%) as a white solid upon drying.
Reaction SMILES: [CH2:1]([CH:3]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:14])[CH3:2].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].[S]>N1C=CC=CC=1>[CH2:1]([CH:3]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[O:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=1)[CH3:2]
Reactant: Nc1ccccc1O
Reactant: CCCCC(CC)Cn1c(C)nc2ccccc21
Agent: [S]
Solvent: c1ccncc1
Product: CCCCC(CC)Cn1c(-c2nc3ccccc3o2)nc2ccccc21
Temperature: 25 °C

Procedure:
24.4 g (0.1 mol) of 1-(2-ethylhexyl)-2-methylbenzimidazole (prepared by heating N-2-ethylhexyl-o-phenylenediamine in acetic acid/hydrochloric acid), 10.9 g (0.1 mol) of o-aminophenol and 9.6 g (0.3 mol) of sulfur in 100 ml of pyridine are heated under reflux for 18 hours. After cooling to room temperature, the crude product is precipitated by addition of water. Multiple recrystallization from n-hexane with addition of active charcoal gives 5.7 g (16% of theory) of product, which according to melting point, HPLC and UV determination is identical to the compound obtained in Example 7.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].[NH4+].[Cl-].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:6]2[NH:16][N:15]=[N:14][N:7]=2)=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C#N)cc(C)c1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nnn[nH]2)cc(C)c1Br
Temperature: 100 °C

Procedure:
To a solution of 4-bromo-3,5-dimethylbenzonitrile (1 g) in N,N-dimethylformamide (10 mL) is added NH4Cl (770 mg) and NaN3 (800 mg) and the mixture is heated to 100° C. for 12 hours. After cooling to room temperature the mixture is diluted with water. The formed precipitate is filtered off, washed with water and dried to give the title compound. Yield: 650 mg; Mass spectrum (ESI+): m/z=253 [M+H]+.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][C:11]=1[Cl:23])([O:3]CC)=O.[CH2:24]([NH2:27])[CH2:25][NH2:26]>>[NH2:26][CH2:25][CH2:24][NH:27][C:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][C:11]=1[Cl:23])=[O:3]
Reactant: NCCN
Reactant: CCOC(=O)CCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Product: NCCNC(=O)CCCOc1ccc(C2=NNC(=O)CC2)cc1Cl

Procedure:
A solution of 4.5 g (13.3 mol) of 6-[4-carboethoxypropyloxy-3-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone (prepared as described in Example 23) in 12.0 g 199 mmol) of ethylenediamine is heated at 95° C. under N2 for 12 hrs. Volatiles are removed under vacuum and the residue recrystallized from EtOAc-methanol to give 3.65 g of 6-{4-[2-aminoethylcarbamoylpropyloxy]-3-chlorophenyl}-4,5-dihydro-3(2H)-pyridazinone as a white powder. Yield, 78%.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:8]([Cl:14])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=O)C>Cl>[NH2:4][C:5]1[CH:6]=[C:7]([C:15]([F:18])([F:16])[F:17])[C:8]([Cl:14])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Product: Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Yield: 77.9 %

Procedure:
A mixture of 3-acetamido-6-chloro-4-nitrobenzotrifluoride (780 mg, 2.76 mmol) in concentrated HCl (3 mL) was refluxed overnight and it was extracted by ethyl acetate (2×3 mL). The extract was dried over Mg2SO4 and evaporated to give 517 mg (78%) of 3-amino-6-chloro-4-nitrobenzotrifluoride. 1H NMR (CDCl3): δ6.205 (s, 2H); 7.206 (s, 1H); 8.263 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[N:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:13]=[C:12]([CH3:26])[C:11]=2[C:10](=O)[CH2:9]1.[C:28]([NH:31][NH2:32])([NH2:30])=[NH:29].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[N:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:13]=[C:12]([CH3:26])[C:11]=2[C:10](=[N:32][NH:31][C:28]([NH2:30])=[NH:29])[CH2:9]1
Reactant: Cc1nn(CCCc2ccccc2)c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1nn(CCCc2ccccc2)c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 175.4 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-1-(3-phenylpropyl)-4,5,6,7-tetrahydroindazol-4-one (0.11 g), aminoguanidine hydrochloride (0.048 g), concentrated hydrochloric acid (0.073 ml), water (0.073 ml) and ethanol (10 ml) was refluxed for 8 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-1-(3-phenylpropyl)-4,5,6,7-tetrahydroindazole hydrochloride (Compound 153) (0.12 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C([Li])CCC.[N:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[CH:36]=1)=[C:33]=[S:34]>O1CCCC1>[C:37]1([CH3:41])[CH:38]=[CH:39][CH:40]=[C:35]([NH:32][C:33]([N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)[C:22](=[O:24])[CH3:23])=[S:34])[CH:36]=1
Reactant: CC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1cccc(N=C=S)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)N(C(=S)Nc1cccc(C)c1)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To N-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetamide in tetrahydrofuran (1.1 mL) cooled to −78° C. was added n-butyllithium (2.5 M, 0.13 mL). The reaction was stirred for 1 hour. 1-Isothiocyanato-3-methylbenzene was added and the solution was slowly warmed to 0° C. over 1 hour. The mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified via radial chromatography using a 97:3 chloroform/methanol mixture as eluent providing the title compound as a tan solid (0.062 g, 55%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=1)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O=[Pt]=O.CO>[CH:2]1([CH2:1][CH:8]2[CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:15][CH2:16][NH:17]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccnc(Cc2ccccc2)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(CC2CCCCC2)C1
Reaction time: 72 h

Procedure:
Methyl 2-benzylisonicotinate (1.29 g, 5.67 mmol) and PtO2 (0.13 g, 0.57 mmol) were added to acetic acid (50 mL). The reaction mixture was hydrogenated in a Büchi hydrogentor at 8 bar at room temperature for 3 days. Methanol (100 mL) was added and the catalyst filtered off. The solvent was evaporated. The crude product was partitioned between Na2CO3 (aq) and ethyl acetate. The organic phase was isolated, dried over Na2SO4, filtered through Celite® and the solvent was evaporated. 1H NMR (600 MHz, cdcl3) δ 0.78-0.91 (m, 2H), 1.04-1.27 (m, 5H), 1.27-1.38 (m, 1H), 1.48 (ddd, 2H), 1.63 (dd, 5H), 1.80-1.93 (m, 2H), 2.36 (tt, 1H), 2.51-2.57 (m, 1H), 2.61 (td, 1H), 3.11 (ddd, 1H), 3.64 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:9]=2)[N:4]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:11]1[C:10]2[C:5](=[CH:6][C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:25])([F:1])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:12]=1
Reactant: COC(=O)c1ccc2c(O)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Yield: 86 %

Procedure:
A mixture of methyl 2-(difluoro(4-fluorophenyl)methyl)-4-hydroxyquinazoline-7-carboxylate (1.1 g, 3.2 mmol) and phosphorus oxychloride (15 mL) was heated at reflux overnight. The mixture was concentrated under reduced pressure, and then toluene (20 mL) was added and evaporated under reduced pressure (2×). The residue in DCM was filtered through a pad of silica gel eluting with DCM. The filtrate was concentrated under reduced pressure to afford methyl 4-chloro-2-(difluoro(4-fluorophenyl)methyl)quinazoline-7-carboxylate (1 g, 86%). 1H NMR (300 MHz, DMSO-d6) δ 3.98 (s, 3H), 7.37 (t, 2H), 7.75 (t, 2H), 8.39 (d, 1H), 8.49 (s, 1H), 8.64 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]2[CH3:25])=[CH:4][CH:3]=1.[N:27]([C:30]1[C:31]([CH3:36])=[N:32][O:33][C:34]=1[CH3:35])=[C:28]=[O:29]>ClCCl>[CH3:36][C:31]1[C:30]([NH:27][C:28]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:26])[CH2:9][N:10]3[C:14](=[O:15])[C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]3[CH3:25])=[CH:6][CH:7]=2)=[O:29])=[C:34]([CH3:35])[O:33][N:32]=1
Reactant: Cc1noc(C)c1N=C=O
Reactant: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc(N)cc2)C1=O
Solvent: ClCCl
Product: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc(NC(=O)Nc3c(C)noc3C)cc2)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.3 %

Procedure:
A mixture of (+/−)-3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5-phenyl-5-propyl-3,5-dihydro-imidazol-4-one (88 mg, 0.25 mmol) and 4-isocyanato-3,5-dimethyl-isoxazole (35 mg, 0.25 mmol) in 3 mL dichloromethane is stirred at room temperature for 18 hours. Subsequently the solvent is evaporated and the residue is dissolved in acetonitrile, the solution filtrated and subjected to preparative HPLC purification (method 3) to yield (+/−)-1-(3,5-dimethyl-isoxazol-4-yl)-3-{4-[2-(2-methyl-5-oxo-4-phenyl-4-propyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-urea (43 mg, 35%), LC/MS at 254 nm; [M+H] 488; Rt 2.648 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[CH:28]=[CH:27][NH:26][N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:29]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[C:28]([I:29])=[CH:27][NH:26][N:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1cc(-c2cc[nH]n2)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: ClCCl
Product: Clc1cc(-c2n[nH]cc2I)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a mixture of 3-(2,4-bis-benzyloxy-5-chloro-phenyl)-1H-pyrazole (4.06 g 10.05 mmol) in DCM (50 ml) was added N-iodosuccinimide (2.35 g, 10.45 mmol) in bulk. The mixture was stirred at room temperature for two hours and then partitioned between water and DCM. The organics were washed with saturated sodium thiosulphate solution then water and dried in vacuo to give a yellow crystalline mass, which was triturated from ethyl acetate by the gradual addition, whilst stirring, of hexanes to give 3-(2,4-bis-benzyloxy-5-chloro-phenyl)-4-iodo-1H-pyrazole (5.21 g, 97%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:17])/[CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1.[C:18]1([CH:24]2[CH2:30][CH2:29][C:28](=O)[O:27][C:25]2=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[C:18]1([CH:24]([CH2:30][CH2:29][C:28]2[O:1][N:2]=[C:3]([CH2:4][CH2:5][CH2:6][C:7]3[CH:16]=[CH:15][C:14]4[CH2:13][CH2:12][CH2:11][NH:10][C:9]=4[N:8]=3)[N:17]=2)[C:25]([OH:27])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N/C(CCCc1ccc2c(n1)NCCC2)=N\O
Reactant: O=C1CCC(c2ccccc2)C(=O)O1
Solvent: C1COCCO1
Product: O=C(O)C(CCc1nc(CCCc2ccc3c(n2)NCCC3)no1)c1ccccc1
Temperature: 100 °C

Procedure:
A stirred mixture of (1Z)-N′-hydroxy-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanimidamide (100 mg, WO 99/30709), 2-phenylglutaric anhydride (80 mg, Aldrich) and 1,4-dioxane (2 mL, Aldrich) was heated to 100° C. for 16 hrs. The resulting solution was purified by HPLC to provide the title compound as a gum. 1H (CD3OD) δ 1.93 (2H, p); 2.12 (2H, m); 2.18-2.37 (2H, comp. band); 2.42-2.55 (1H, comp. band); 2.74-2.90 (7H, comp. band); 3.48 (2H, t); 3.66/4.38 (1H, t); 6.60/6.62 (1H, d); 7.23-7.39 (5H, comp. band); 7.51/7.55 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5](I)[N:4]=1.[Cu](C#N)[C:13]#[N:14]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([C:13]#[N:14])[N:4]=1
Reactant: N#C[Cu]C#N
Reactant: COc1ccc(I)nc1OC
Solvent: CN(C)C=O
Product: COc1ccc(C#N)nc1OC
Temperature: 150 °C

Procedure:
To a solution of 2,3-dimethoxy-6-iodopyridine (4-4, 24.0 g, 91 mmol) in DMF (181 mL) was added copper cyanide (9.73 g, 109 mmol) and heated to 150° C. for 20 minutes in a microwave reactor. The mixture was partitioned between saturated sodium carbonate and EtOAc three times. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 40% EtOAc in hexanes) to yield the desired product (4-5) as an off-white crystalline powder. ESI+MS [M+H]+ C8H8N2O2: 165.0 found, 165.1 required.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=1)([O-:3])=[O:2].C(O[C:18]1(O[Si](C)(C)C)[CH2:20][CH2:19]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:18]1([N:12]2[CH2:13][CH2:14][CH:9]([N:7]3[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]3)[CH2:10][CH2:11]2)[CH2:20][CH2:19]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=[N+]([O-])c1cnn(C2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnn(C2CCN(C3CC3)CC2)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A mixture of 4-(4-nitro-1H-pyrazol-1-yl)piperidine (100 mg), (1-ethoxycyclopropoxy) trimethylsilane (267 mg), acetic acid (292 μL), Molecular Sieve 3 A (100 mg), and sodium cyanoborohydride (96 mg), and methanol (3 mL) was stirred at 65° C. for 8 hours. After leaving to be cooled, the insoluble matter was separated by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=100:0-95:5) to obtain 1-cyclopropyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine (110 mg) as a colorless solid.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[C@@H:3]([C:8]([O:10]C)=[O:9])[N:2]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CO.[OH-].[Li+]>C1COCC1>[C:15]([O:14][C:12]([N:2]1[C@H:3]([C:8]([OH:10])=[O:9])[C@H:4]2[CH2:7][C@@H:1]1[CH2:6][CH2:5]2)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)[C@@H]1[C@@H]2CC[C@@H](C2)N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@H]2CC[C@H](C2)[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of (1S,3S,4R)-2-tert-butyl 3-methyl 2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.67 g, 6.54 mmol) in THF:MeOH (41 mL:13 mL) was added aqueous Lithium hydroxide (1M, 8.2 mL, 8.2 mmol) and the reaction was allowed to stir at room temperature overnight. Upon completion, the reaction was concentrated in vacuo, diluted with ethyl acetate and washed with 1N HCl. The aqueous layer was back extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give (1S,3S,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.36 g, 86%). 1H NMR (400 MHz, Methanol-d4) δ 6.43 (s, 1H), 5.84 (s, 1H), 5.74 (d, 1H), 4.34 (s, 1H), 3.36-3.18 (m, 3H), 3.17-3.06 (m, 3H), 3.02 (s, 3H), 2.97 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[CH:12]([CH2:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1.[C:18](OC(=O)C)(=[O:20])[CH3:19].C(N(CC)CC)C>ClCCl>[C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)(=[O:20])[CH3:19]
Reactant: OCCCCCCN1CCCC2CC=CC=C21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCCCCCN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 233.4 g (1 mole) of N-hydroxyhexyltetrahydroquinoline and 153.1 g (1.5 moles) of acetic anhydride in dichloromethane are added 151.8 g (1.5 moles) of triethylamine and 8.5 g (1 mole %) of 4-N,N-dimethylaminopyridine, and the reaction is stirred at room temperature for 3 hours. The product solution is washed with cold 2N HCl followed by saturated sodium bicarbonate, and the organic layer is filtered through cotton and evaporated.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[CH3:23][O:24][C:25]([C:27]1(OC)[CH2:31][CH2:30][CH:29](OC)O1)=[O:26]>C(O)(=O)C>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([N+:20]([O-:22])=[O:21])=[C:2]([N:1]4[CH:29]=[CH:30][CH:31]=[C:27]4[C:25]([O:24][CH3:23])=[O:26])[CH:11]=3)[NH:6][C:7](=[O:19])[C:8]2=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)C1(OC)CCC(OC)O1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c(=O)n2C1CCCCC1
Solvent: CC(=O)O
Product: COC(=O)c1cccn1-c1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c(=O)n2C1CCCCC1
Temperature: 0 °C
Yield: 78.6 %

Procedure:
4.5 g (14.8 mmol) of 7-amino-1-cyclohexyl-6-nitro-2,3(1H,4H)-quinoxalinedione (product 37b) and 3.5 g (14.8 mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran in 75 ml of acetic acid were refluxed for 2 h. The mixture was poured into ice-water, and the precipitate was filtered off with suction to yield 4.8 g (78%) of the product. Melting point 293° C. (decomposition).