Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[NH2:10][C:11]1[CH2:12][C:13]([C:29](OCC)=[O:30])=[CH:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[CH:18][C:16]=2[N:17]=1>C1(C)C=CC=CC=1.ClCCCl>[NH2:10][C:11]1[CH2:12][C:13]([C:29]([N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:4][CH2:3][O:2][CH3:1])=[O:30])=[CH:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]([F:28])([F:27])[C:23]([F:24])([F:25])[F:26])=[CH:18][C:16]=2[N:17]=1
Reactant: CCOC(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(N)C1
Reactant: COCCNCCOC
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: COCCN(CCOC)C(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(N)C1
Temperature: 75 °C

Procedure:
Trimethylaluminuni (0.34 mL of a 2.0 M solution in toluene) was added to bis(2-methoxyethyl)amine (92 mg, 0.69 mmol) in DCE (3 mL). After 10 minutes solid (1E,4E)-ethyl 2-amino-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylate (80 mg, 0.23 mmol) was added and the vessel was sealed and heated to 75° C. for 16-20 hours. Upon cooling the reaction was quenched with saturated Rochelle's salt (2 mL) and after 20 minutes the mixture was partitioned between CH2Cl2 (50 mL) and brine (50 mL). The phases were separated and the aqueous was extracted with CH2Cl2 (2×20 mL). The combined organics were dried and concentrated. The crude material was purified via preparative TLC (2, 0.5 mm plates, eluting with 5-10% MeOH/CH2Cl2 with 4-6 drops of NH4OH). 1H NMR (CDCl3) δ 2.81 (s, 2H), 3.36 (s, 6H), 3.55-3.74 (m, 8H), 6.98 (s, 1H), 7.20 (d, 1H), 7.40 (d, 1H), 7.39 (s, 1H).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.O=[C:12]1[CH2:18][CH:17]2[N:19](C(OC(C)(C)C)=O)[CH:14]([CH2:15][CH2:16]2)[CH2:13]1>Cl.C(O)(=O)C>[ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[NH:9][C:12]1[CH2:13][CH:14]3[NH:19][CH:17]([C:18]2=1)[CH2:16][CH2:15]3
Reactant: NNc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: Cl
Solvent: CC(=O)O
Product: Brc1cccc2c3c([nH]c12)CC1CCC3N1
Temperature: 22.5 °C
Reaction time: 20 h

Procedure:
A mixture of 2-bromophenylhydrazine hydrochloride (4.44 g, 19.81 mmol, Aldrich) and t-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (4.48 g, 19.89 mmol, Chem-Impex) in 1 M HCl/acetic acid was stirred at 20-25° C. for 20 hours, and then heated at 65-70° C. for 48 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue was heated to boiling in absolute ethanol (25 mL) and the suspension was stirred at room temperature for 2 hours, then filtered. The solid was washed with cold ethanol and dried under vacuum to provide the title compound: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.74-1.86 (m, 1H), 2.07 (t, J=9.7 Hz, 1H), 2.15-2.32 (m, 2H), 2.88 (d, J=17.4 Hz, 1H), 3.35-3.49 (m, 1H), 4.41 (s, 1H), 5.16 (d, J=4.4 Hz, 1H), 6.98 (t, J=7.7 Hz, 1H), 7.25-7.37 (m, 1H), 7.58 (d, J=7.9 Hz, 1H), 8.63-9.49 (m, 1H), 11.37 (s, 1H); MS (DCI/NH3) m/z 277/279 (M+H)+.
Reaction SMILES: N1(S([Br:8])=O)CCC1=O.[C:9]1(=[O:34])[N:13]([CH:14]2[C:27](=[O:28])[N:16]3[CH:17]([C:23]([O:25][CH3:26])=[O:24])[C:18](=[CH2:22])[CH2:19][S:20](=[O:21])[C@H:15]23)[C:12](=[O:29])[C:11]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:10]12>C(Cl)Cl>[CH3:19][C:18](=[CH2:22])[CH:17]([N:16]1[C:27](=[O:28])[CH:14]([N:13]2[C:12](=[O:29])[C:11]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:10]3[C:9]2=[O:34])[CH:15]1[S:20]([Br:8])=[O:21])[C:23]([O:25][CH3:26])=[O:24]
Reactant: O=C1CCN1S(=O)Br
Reactant: C=C1CS(=O)[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)OC
Solvent: ClCCl
Product: C=C(C)C(C(=O)OC)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1S(=O)Br

Procedure:
The azetidinone sulfinyl bromide from above was dissolved in 20 ml. of methylene chloride; 0.6 ml. of stannic chloride was added to the solution. After 45 minutes at room temperature the reaction mixture was washed with water and brine, dried over anhydrous MgSO4, and evaporated in vacuo to dryness to provide 1.15 g. of methyl 7-phthalimido-3-methylenecepham-4-carboxylate-1-oxide (a mixture of R- and S-sulfoxide isomers). For the predominant isomer: nmr (CDCl3) δ3.64, 4.20 (ABq, 2, J=13.0 Hz, C2 --H), 3.84 (s, 3, COOCH3), 4.90 (d, 1, J=4.0 Hz, β-lactam H), 5.3-5.7 (m, 3), 5.97 (d, 1, J=4.0 Hz, β-lactam H), and 7.84 (bs, 4, ArH).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]([CH3:28])[C:15]=1[CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][N:19]=1>O.C1COCC1>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]([CH3:28])[C:15]=1[CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)nnn2C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of lithium hydroxide monohydrate (23 mg, 0.56 mmol) in water (0.8 mL) was added dropwise to a suspension of methyl 6-((4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinate (95 mg, 0.28 mmol) in THF (0.8 mL). The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (68 mg, 75%) as a white solid. MS: m/e=327.1 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][CH2:8][N:9]2[C:14](=[O:15])[CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2]>C(O)(=O)C.C(Cl)Cl.[Pt](=O)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:10]2[CH2:11][O:12][CH2:13][C:14](=[O:15])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C2COCC(=O)N2CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1CCN2C(=O)COCC12
Reaction time: 18 h
Yield: 102.2 %

Procedure:
A solution of 68 (1.056 g, 5.0 mmol) in 25 ml of acetic acid is hydrogenated over 1.056 g of platinum dioxide at RT and normal pressure for 18 hours. The black suspension is diluted with 20 ml of DCM and filtered through a pad of celite. The filtrate is evaporated to give 1.09 g of a yellow oil which is purified by chromatography (Silica gel 60, 0.063-0.2 mesh, ethyl acetate/ethanol 9:1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([C:14]1[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=1)([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:20][N:17]1[CH2:16][C:15]2[C:4]3[C:3](=[CH:2][CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=3)[C:11]([CH3:13])([CH3:12])[C:14]=2[CH:19]=[CH:18]1
Reactant: CN1CC=C(C(C)(C)c2ccc([N+](=O)[O-])cc2Br)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C=CC2=C(C1)c1cc([N+](=O)[O-])ccc1C2(C)C
Temperature: 80 °C

Procedure:
4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-1,2,3,6-tetrahydro-pyridine (9 g), Pd(OAc)2 (900 mg), and DIEA (15 mL) was dissolved in DMF (300 mL), and heated to 80° C. overnight. Solvents were removed in vacuo. The residue was partitioned between CH2Cl2/NaHCO3(sat, aq.). The CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified via flash chromatography on silica to give the desired compound. (MS: M+H=257)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[C:18]([CH2:19]Br)=[C:17]([F:21])[C:16]([F:22])=[C:15]([F:23])[C:14]=1[F:24]>>[F:12][C:13]1[C:18]([CH2:19][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[C:17]([F:21])[C:16]([F:22])=[C:15]([F:23])[C:14]=1[F:24]
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: O=C(O)c1cc(NCc2c(F)c(F)c(F)c(F)c2F)ccc1O
Yield: 59.8 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and pentafluorobenzyl bromide (1.02 g, 3.92 mmole), 650 mg (60% yield) of 5-(pentafluorobenzyl)aminosalicylic acid was obtained as a white solid.: mp>190° C. (decompose).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([CH2:18][CH2:19][C:20]([F:21])([F:22])[F:23])[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:24])=[CH:5][N:6]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2c(CCC(F)(F)F)noc2C)nc1
Product: Cc1onc(CCC(F)(F)F)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 10 %

Procedure:
As described for example 1e, 6-[5-methyl-3-(3,3,3-trifluoro-propyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (215 mg, 0.62 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (26 mg, 10%) which was obtained as a white solid after purification by chromatography (silica, 0 to 60% ethyl acetate in heptane) and trituration with ethyl acetate and hexane. MS: m/e=414.3 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[NH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.N1C=CC=CC=1>C(Cl)Cl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([NH:14][C@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
To a stirred solution 4-nitrophenyl chloroformate (26.0 mg, 0.13 mmol) in anhydrous CH2Cl2 was added a solution of (S)-tert-butyl 3-aminopiperidine-1-carboxylate (27.0 mg, 0.13 mmol) and pyridine (7 μL) in CH2Cl2 (0.5 mL). The mixture was stirred for 30 min. LC-MS showed complete conversion. This intermediate was used as a solution for the next step.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].[OH-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[C:17](OC([O-])=O)(=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>O.O1CCOCC1>[C:19]([O:18][C:17]([NH:1][CH:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: N[C@@H](CCO)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CCO)C(=O)O
Reaction time: 0.08 h

Procedure:
To a solution of homoserine bromohydrate (2 g ; 16.78 mmol.) in H2O (20 ml), addition was made in succession of a 1 M NaOH solution (16.78 ml) and cesium carbonate (3.01 g; 9.23 mmol.). After stirring for 5 minutes, the solution was cooled in an ice/water bath. Dioxane (60 ml) and t-butyl pyrocarbonate were then added. The reaction mixture was kept under stirring in an ice-cold water bath for 1 hour and thereafter at room temperature for 5 hours. The solvent was subsequently evaporated under vacuum and the dry residue was directly used in the next step.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[C:15]([O:21][CH2:22][N:23]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][C:28]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:29][C:30]=2O)[N:25]=[CH:24]1)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>ClCCl>[CH2:36]([O:35][C:28]1[CH:27]=[C:26]2[C:31]([C:32](=[O:33])[N:23]([CH2:22][O:21][C:15](=[O:20])[C:16]([CH3:17])([CH3:18])[CH3:19])[CH:24]=[N:25]2)=[C:30]([O:1][CH2:2][C@H:3]2[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:29]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)C(=O)OCn1cnc2cc(OCc3ccccc3)cc(O)c2c1=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(OCc2ccccc2)cc2ncn(COC(=O)C(C)(C)C)c(=O)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.70 g, 8.6 mmol) was added to a solution of [7-(benzyloxy)-5-hydroxy-4-oxoquinazolin-3(4H)-yl]methyl pivalate (see WO01/094341, 3.0 g, 7.8 mmol) and PS-triphenylphosphine (1.5 mmol/g, 7.2 g, 4.2 mmol) in dichloromethane (120 ml). The reaction mixture was cooled to 0° C. and then a solution of di-tert-butylazodicarboxylate (2.1 g, 9.3 mmol) in dichloromethane (15 ml) was added dropwise over 30 minutes. The mixture was allowed to warn to room temperature and then stirred for 2 hours. The mixture was evaporated under reduced pressure and the residue was purified by silica gel chromatography eluting with a 0 to 10% mixture methanol in dichloromethane to give tert-butyl (2R)-2-{[(7-(benzyloxy)-3-{[(2,2-dimethylpropanoyl)oxy]methyl}-4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate (1.58 g, 36% yield):
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:17])([O-])=O.[CH3:26]O>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:17]
Reactant: CO
Reactant: O=C(NCC1CCNCC1)Nc1cc(-c2cccs2)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: CN1CCC(CNC(=O)Nc2cc(-c3cccs3)ccc2N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 1-(2-nitro-5-(thiophen-2-yl)phenyl)-3-(piperidin-4-ylmethyl)urea (0.045 g, 0.12 mmol, 1.0 equiv.) in methanol was added Pd/C (0.02 g, 0.02 mmol, 0.16 equiv.). The reaction mixture was stirred at room temperature under H2 balloon pressure for 1 h. The reaction was filtered through celite and concentrated under reduced pressure. The crude solid was washed with ether to obtain of pure 1-(2-Amino-5-(thiophen-2-yl)phenyl)-3-((1-methylpiperidin-4-yl)methyl)urea (0.03 g, 67% yield). ESI+ MS: m/z 345 ([M]+). 1H NMR (500 MHz, d6-DMSO): δ 7.66 (d, J=1.5 Hz, 1H), 7.56 (s, 1H), 7.33 (d, J=5.0 Hz, 1H), 7.17 (d, J=3.0 Hz, 1H), 7.10 (dd, J=3.5 Hz, 1H), 7.03 (t, J=4.0 Hz, 1H), 6.71 (d, J=7.5 Hz, 1H), 6.27 (t, J=5.5 Hz, 1H), 4.88 (bs, 2H), 2.98 (t, J=5.5 Hz, 2H), 2.77 (d, J=11.0 Hz, 2H), 2.16 (s, 3H), 1.85 (m, 2H), 1.63 (d, J=4.5 Hz, 2H), 1.36-1.33 (m, 1H), 1.20-1.13 (m, 3H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[C:16]([C:18]3[N:19]([CH3:30])[N:20]=[N:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:15]=[CH:14]2)=[CH:9][CH:8]=1>O.C1COCC1.CO>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[N:21]=[N:20][N:19]([CH3:30])[C:18]=2[C:16]2[N:15]=[CH:14][N:13]([C:10]3[CH:9]=[CH:8][C:7]([C:6]([OH:31])=[O:5])=[CH:12][CH:11]=3)[CH:17]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)nnn3C)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A solution of lithium hydroxide monohydrate (85 mg, 2.01 mmol) in water (2.5 mL) was added dropwise to a suspension of 4-{4-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-imidazol-1-yl}-benzoic acid methyl ester (380 mg, 1.01 mmol) in THF (2.5 mL) and methanol (0.5 mL). The reaction mixture was then stirred at room temperature for 1 h and was then evaporated and the residue dissolved in water, acidified with HCl (1 N), and the resulting precipitate filtered off to afford the title product (315 mg, 86%) as a white solid. MS: m/e=362.3 [M−H]−.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH:8]([CH3:11])[CH2:9][CH3:10].C(N(CC)CC)C>ClCCl.O>[CH3:1][S:2]([O:6][CH:7]([C:12]1[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=1)[CH:8]([CH3:11])[CH2:9][CH3:10])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C)C(O)c1ccc(C#N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(C)C(OS(C)(=O)=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 122 %

Procedure:
Add methanesulfonyl chloride (540 mg, 4.72 mmol) to a solution of 4-(1-hydroxy-2-methyl-butyl)-benzonitrile (800 mg, 4.23 mmol) and triethylamine (0.88 mL, 6.35 mmol) in dichloromethane (10 mL) at 0° C. Warm the mixture to room temperature and stir for 1 h. Dilute the mixture with water and dichloromethane. Extract the aqueous layer with dichloromethane. Wash the combined organic extracts with water. Dry the organic solution over Na2SO4, filter and concentrate in vacuo to provide the desired intermediate as a clear oil (1.38 g) that was used without further purification. MS (APCI) m/z: 268 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]([CH3:18])[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[O:19]([C:21]#N)[K]>CCCCCC>[CH3:18][N:4]1[C:3]2[NH:2][C:21](=[O:19])[C:17]3[C:12]([C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: Cn1c(N)c(-c2ccccc2)c2ccccc21
Reactant: N#CO[K]
Agent: Cl
Solvent: CCCCCC
Product: Cn1c2ccccc2c2c3ccccc3c(=O)[nH]c21
Yield: 20.1 %

Procedure:
The same product as in the foregoing example is prepared by heating to 270°-280° C. for 15 minutes 2.59 g (0.01 mole) of 2-amino-1-methyl-3-phenylindole hydrochloride and 3.24 g (0.04 mole) of KOCN in 25 ml of vaseline oil. The reaction mass is taken up with hexane and the insoluble parts, collected by filtration under vacuum, are washed with water in order to remove inorganic salts and crystallized from dimethylformamide, yielding 0.5 g of the pure desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1Cl)[C:7]([NH2:9])=[O:8])([O-:3])=[O:2].[CH2:14]([NH2:16])[CH3:15]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:16][CH2:14][CH3:15])[C:7]([NH2:9])=[O:8])([O-:3])=[O:2]
Reactant: CCN
Reactant: NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CCNc1ccc(C(N)=O)cc1[N+](=O)[O-]

Procedure:
II (160 g - 0.8 mole) was added portionwise with stirring at 60° C to 720 g of 50 % by weight aqueous ethylamine. The mixture was cooled, the precipitate was collected and crystallized from the monomethyl ether of ethylene glycol (5 ml per gram of dried product).
Reaction SMILES: [CH3:1][C:2]([C:11]1[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([CH:17]=1)[OH:16])([CH3:10])[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:19]([CH:22]1[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][C:23]1=O)(=O)[CH3:20]>>[OH:18][C:13]1[C:14]2[CH:19]([CH3:20])[C:22]3[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][C:23]=3[O:16][C:15]=2[CH:17]=[C:11]([C:2]([CH3:1])([CH3:10])[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:12]=1
Reactant: CC(=O)C1CCC(C)CC1=O
Reactant: CCCCCC(C)C(C)(C)c1cc(O)cc(O)c1
Product: CCCCCC(C)C(C)(C)c1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C

Procedure:
Reaction of 5-(1,1,2-trimethylheptyl)resorcinol with 2-acetyl-5-methylcyclohexanone as described in Example 1 gives the title compound.
Reaction SMILES: Br.[CH2:2]([C:6]1[CH:24]=[CH:23][C:9]([CH2:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21]C)=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]>>[CH2:2]([C:6]1[CH:24]=[CH:23][C:9]([CH2:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(Cc2nccc3cc(OC)ccc23)cc1
Agent: Br
Product: CCCCc1ccc(Cc2nccc3cc(O)ccc23)cc1
Yield: 94.6 %

Procedure:
A 47% hydrobromic acid solution was added to the compound of Example B146 (82 mg), and the mixture was stirred under reflux for 19 hours. The mixture was concentrated under reduced pressure, water was added, and the resulting mixture was neutralized with sodium carbonate to precipitate crystals. The obtained crystals were collected by filtration, washed with water, and then dried to give the title compound (74 mg).
Reaction SMILES: C(N(CCC)CCC)CC.I[CH2:12][CH2:13][C:14]([F:28])([F:27])[C:15]([F:26])([F:25])[O:16][C:17]([F:24])([F:23])[C:18]([F:22])([F:21])[C:19]#[N:20]>COCCOCCOC>[F:21][C:18]([F:22])([C:17]([F:23])([F:24])[O:16][C:15]([F:25])([F:26])[C:14]([F:27])([F:28])[CH:13]=[CH2:12])[C:19]#[N:20]
Reactant: N#CC(F)(F)C(F)(F)OC(F)(F)C(F)(F)CCI
Agent: CCCN(CCC)CCC
Solvent: COCCOCCOC
Product: C=CC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C#N
Temperature: 145 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
In a flask fitted with a thermometer, a magnetic stirring bar, and a still head were placed 4.5 g of tri-n-propylamine, 9.1 g of 8-iodo-2,2,3,3,5,5,6,6-octafluoro-4-oxaoctanenitrile, and 6 ml of 2-methoxyethyl ether. The flask and contents were heated rapidly to 145° C. and then stirred at 130°-145° C. for 31/2 hours during which a colorless distillate was collected. Further distillate was obtained by reducing the pressure to 24 mm. The distillate was fractionally distilled to give 2,2,3,3,5,5,6,6-octafluoro-4-oxa-7-octenenitrile (4.14 g, 67.1% yield), b.p. 84° C. The 1H-NMR spectrum showed a multiple line pattern between 5.2 and 5.6 ppm; the 19F-NMR spectrum contained three lines: at -89.1 ppm for CF2 groups surrounding 0, -113.0 ppm for CF2 adjacent to CN, and -120.4 ppm for CF2 adjacent to CH=CH2 group (integral ratios 2:1:1).
Reaction SMILES: Cl.[N:2]1([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([CH:20]4[CH2:24][CH2:23][CH2:22][N:21]4C(OC(C)(C)C)=O)[CH:19]=2)[O:16][C:15]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:14][C:13]3=[O:38])=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1>C(Cl)Cl>[N:2]1([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([CH:20]4[CH2:24][CH2:23][CH2:22][NH:21]4)[CH:19]=2)[O:16][C:15]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[CH:14][C:13]3=[O:38])=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc(C(=O)N2CCOCC2)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Cl
Solvent: ClCCl
Product: O=C(c1cc(C2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
Yield: 62.2 %

Procedure:
HCl 4M (9.74 mL, 39 mmol) was added to a stirred solution of tert-butyl 2-(6-(morpholine-4-carbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate (2 g, 3.89 mmol) dissolved in DCM (15 mL) at r.t and stirred over the week-end. After concentration, DCM (15 mL) and MeOH (15 mL) were added, followed by a solution of 10% methanolic ammonia (7 N) in DCM (10 mL). The crude product was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 0 to 10% methanol in DCM. The solvent was evaporated to dryness to give a solid and dried under vacuum to give 6-(morpholine-4-carbonyl)-2-morpholino-8-(pyrrolidin-2-yl)-4H-chromen-4-one (1.0 g, 62%) as a beige solid. Mass Spectrum: m/z [M+H]+=414.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:10]1[C:19]2[C:14](=[C:15]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[O:13][C:12](=[O:28])[CH:11]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10]1[C:19]2[C:14](=[C:15]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[O:13][C:12](=[O:28])[CH:11]=1
Reactant: Nc1ccccc1Cl
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Product: COc1ccc2c(Nc3ccccc3Cl)cc(=O)oc2c1OC1CCCC1

Procedure:
The title compound was prepared from 2-chloroaniline and 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one following the procedure outlined in Example 16. 1H NMR (400 MHz, DMSO-d6): δ 9.28 (s, 1H), 7.93 (d, 1H), 7.66 (d, 1H), 7.51-7.40 (m, 3H), 7.15 (d, 1H), 4.83 (m, 1H), 4.50 (s, 1H), 3.90 (s, 3H), 1.90-1.45 (m, 8H); MS (ESI): 385.9.