Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[O:7])=[CH:4][C:3]=1[Br:22].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][C:39]([O-:41])=[O:40].[Na+]>>[NH2:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:41][C:39](=[O:40])[CH2:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[NH:31][C:25]2[C:24]([Cl:23])=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:30])=[O:7])=[CH:4][C:3]=1[Br:22]
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: Nc1c(Br)cc(C(=O)OCCCCCl)cc1CN1CCCC1
Agent: [Na+]
Product: Nc1c(Br)cc(C(=O)OCCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc1CN1CCCC1

Procedure:
This compound was prepared from 4-(4-amino-3-bromo-5-pyrrolidinomethyl-benzoyloxy)-n-butyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9]([C:11]2[C:12](=[O:30])[N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[O:10])[CH:5]=[N:4]1)[CH3:2].C(N(CC)CC)C.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1.[Cl-].[NH4+]>C(#N)C>[CH2:1]([N:3]1[C:7]([O:8][S:44]([C:41]2[CH:42]=[CH:43][C:38]([CH3:48])=[CH:39][CH:40]=2)(=[O:46])=[O:45])=[C:6]([C:9]([C:11]2[C:12](=[O:30])[N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[O:10])[CH:5]=[N:4]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCn1ncc(C(=O)c2cnc(-c3ccccc3)n(Cc3ccccc3)c2=O)c1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1ncc(C(=O)c2cnc(-c3ccccc3)n(Cc3ccccc3)c2=O)c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 5-[(1-ethyl-5-hydroxy-1H-pyrazol-4-yl)carbonyl]-2-phenyl-3-(phenylmethyl)-4(3H)-pyrimidinone (i.e. the product from Example 3, Step B) (300 mg, 0.75 mmol) in acetonitrile (10 mL) was added triethylamine (116 mg, 1.12 mmol), followed by p-toluenesulfonyl chloride (171 mg, 0.90 mmol), and the reaction mixture was stirred at room temperature for 72 h. Saturated aqueous ammonium chloride solution was added to the mixture, and the aqueous layer was extracted with dichloromethane. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 50% ethyl acetate in hexanes to afford the title product, a compound of the present invention, as a white solid (160 mg).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:24])[C:15]=1[C:25]([F:28])([F:27])[F:26]>O>[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:8]([O-:11])=[O:9])[C:20]=2[CH3:24])[C:15]=1[C:25]([F:26])([F:28])[F:27]
Reactant: COc1ccc2c(C)cccc2c1C(F)(F)F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc2c(C)c([N+](=O)[O-])ccc2c1C(F)(F)F
Temperature: 5 °C
Yield: 41 %

Procedure:
To a cooled solution (3° to 4° C.) of acetic anhydride (640 mL) was added fuming nitric acid (90%, specific gravity=1.5, 160 mL) dropwise via an addition funnel at such a rate as to keep the internal temperature at or below 8° C. (~1 hour 20 minutes total addition time). After the internal temperature had again cooled to 3°-4° C., 2-methoxy-5-methyl-1-trifluoromethylnaphthalene (200 g, 0.833 mol) was added portion wise. The portions added were small enough such that the internal temperature did not rise above 10° C. and each portion was added when the temperature had cooled to 5° C. (addition time ~1 hour 15 minutes). After an additional 15 minutes the reaction mixture was added to water (3 L). The resulting amorphous solid was filtered, washed with water and the lumps broken up and dried in vacuo overnight. The dry solid (~225 g) was recrystallized from 95:5 ethanol:isopropanol (3 L). The resulting long yellow needles were filtered and washed with ethanol (2×50 mL) to provide the product (97.5 g, 41%), m.p. 141°-142° C. A small amount of the desired product was recrystallized from 4:1 petroleum ether:ethyl acetate.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:10]=[CH:11][C:12]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:31][CH2:30][C@H:29]([O:32][Si](C(C)(C)C)(C)C)[CH2:28][CH2:27]3)[CH:25]=2)=[C:13]2[CH:17]=[C:16](B(O)O)[O:15][C:14]=12)=O)(C)(C)C.Br[C:48]1[C:56]2[S:55][N:54]=[N:53][C:52]=2[CH:51]=[C:50]([C:57]#[N:58])[CH:49]=1>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][CH2:31]3)[CH:25]=2)=[C:13]2[CH:17]=[C:16]([C:48]3[C:56]4[S:55][N:54]=[N:53][C:52]=4[CH:51]=[C:50]([C:57]#[N:58])[CH:49]=3)[O:15][C:14]=12
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2cc(B(O)O)oc12
Reactant: N#Cc1cc(Br)c2snnc2c1
Product: N#Cc1cc(-c2cc3c(-c4cnn([C@H]5CC[C@H](O)CC5)c4)cnc(N)c3o2)c2snnc2c1

Procedure:
The title compound was prepared from {7-[bis(tert-butoxycarbonyl)amino]-4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-2-yl}boronic acid and 7-bromo-1,2,3-benzothiadiazole-5-carbonitrile by a procedure analogous to Example 368. MS (ESI): 458.14 [M+H]+; HPLC tR=0.79 min (TOF: polar—2 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[NH:19]1[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[CH:20]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:19]2[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[CH:20]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: N#Cc1c[nH]cn1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(-n2cnc(C#N)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 8.8 %

Procedure:
A solution of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (3.2 g, 11.98 mmol), 1H-imidazole-4-carbonitrile (2.017 g, 14.37 mmol) and ethyl-diisopropyl-amine (8.4 ml, 47.9 mmol) in 10 ml of dioxane is heated to reflux for 24 hours. The solution is allowed to cool to room temperature and evaporated. The residue is chromatographed on silica gel using gradients of dichloromethane and methanol to give 0.36 g (1.05 mmol, 8.8%) of amorphous 5-(4-cyano-imidazol-1-yl)-2-nitro-4-trifluoromethyl-benzoic acid methyl ester, ES-MS: m/z 341 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH:5]=[N:6][OH:7].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2([CH2:25][CH:24](B(O)O)[CH2:23][CH2:22][CH2:21]2)[C:13]1=[O:29]>>[F:11][C:3]1[C:2]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[NH:12][C:13](=[O:29])[C:14]23[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[N:6][OH:7]
Reactant: O=C1Nc2ccccc2C12CCCC(B(O)O)C2
Reactant: ON=Cc1cccc(Br)c1F
Product: O=C1Nc2ccc(-c3cccc(C=NO)c3F)cc2C12CCCCC2

Procedure:
The title compound was prepared from 3-bromo-2-fluorobenzaldoxime (0.40 g, 1.83 mmol) and (spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid as described in example 18, to afford the product (0.094 g, 0.27 mmol, 15% yield) as a white solid: mp. 213-217° C.; 1H NMR (CDCl3) δ 10.95 (s, 1H), 9.65 (s, 1H), 8.41 (s, 1H), 7.76 (t, 1H, J=7.1 Hz), 7.59 (s, 1H), 7.43-7.33 (m, 3H), 7.19 (t, 1H, J=7.7 Hz), 6.98 (d, 1H, J=8 Hz) and 1.91-1.60 (m, 10H); MS ((+) ESI) m/z=339 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)=[O:32])[C:27](O)=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)=[O:32])[C:27]([NH:1][CH:2]([C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CC(N)c1cc(Cl)cc(Cl)c1
Reactant: O=C(NC(COCc1ccccc1)C(=O)O)OCCNc1ccccn1
Product: CCOC(=O)CC(NC(=O)C(COCc1ccccc1)NC(=O)OCCNc1ccccn1)c1cc(Cl)cc(Cl)c1

Procedure:
Analogously to Example 2, ethyl 3-amino-3-(3,5-dichlorophenyl)propionate is reacted with 3-benzyloxy-2-[2-(pyridin-2-ylamino)ethoxycarbonylamino]-propionic acid and purified by chromatography, giving ethyl 3-{3-benzyloxy-2-[2-(pyridin-2-ylamino)ethoxycarbonylamino]propanoylamino}3-(3,5-dichlorophenyl)propionate, RT 1.712 min, FAB-MS (M+H)+ 604.
Reaction SMILES: Br[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:18])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[N:3]=1.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29](B1OC(C)(C)C(C)(C)O1)=[CH:28][CH:27]=2.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([C:2]1[C:11]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[CH3:18])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=3)[N:3]=1)=[CH:28][CH:27]=2
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Reactant: COC(=O)c1ccc2nc(Br)c(N3CCCC[C@@H]3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
To a solution of (S)-methyl 2-bromo-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate (200 mg, 0.55 mmol) in ethylene glycol dimethyl ether (7 ml) was added 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (141 mg, 0.55 mmol), sodium carbonate (116 mg, 1.09 mmol), water (2 mL), and Pd(PPh3)4 (32 mg, 0.03 mmol). The resulting solution was stirred for 3 h at 90° C. and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (2% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(2-methyl-1H-indol-5-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate as a light yellow solid (142.1 mg, 62%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Mn]([O-])(=O)(=O)=[O:13].[K+].[OH-].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]([OH:13])=[O:8]
Reactant: COc1ccc(F)cc1C=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(F)cc1C(=O)O
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a solution of 5-fluoro-2-methoxybenzaldehyde (1 g) in acetone (4 mL) was added a solution of potassium permanganate (1.54 g) in water (16 mL), and the mixture was heated for reflux for 4 hours. The reaction mixture was cooled to room temperature. To the mixture was added 2 mol/L aqueous sodium hydroxide solution (5.2 mL), and the insoluble material was removed by filtration. The filtrate was washed with ethyl acetate. The aqueous layer was acidified by addition of 2 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate twice. The extracts were combined and washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate) to give 5-fluoro-2-methoxybenzoic acid (0.66 g). This material was dissolved in N,N-dimethylformamide (15 mL). To the solution were added potassium carbonate (0.63 g) and iodomethane (0.26 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give methyl 5-fluoro-2-methoxybenzoate (0.7 g). This material was dissolved in tetrahydrofuran (10 mL). To the solution was added methylmagnesium iodide (3.0 mol/L diethyl ether solution, 3.82 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (0.65 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH2:7][C:8]([OH:15])([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11].N1([CH:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:25][C:26](=[O:28])[O-:27])C=CC=N1>CC#N>[C:32]([O:31][C:30]([NH:29][C:24](=[N:25][C:26](=[O:28])[O:27][C:3]([CH3:4])([CH3:18])[CH3:2])[NH:1][CH2:2][C:3]1[CH:18]=[CH:17][CH:16]=[C:5]([CH2:6][CH2:7][C:8]([OH:15])([CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH3:14])[CH:4]=1)=[O:36])([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC(NC(=O)[O-])n1cccn1
Reactant: CCCC(O)(CCC)CCc1cccc(CN)c1
Solvent: CC#N
Product: CCCC(O)(CCC)CCc1cccc(CNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1

Procedure:
Reaction of 4-(3-(aminomethyl)phenethyl)heptan-4-ol with tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate in CH3CN gives tert-butyl (tert-butoxycarbonylamino)(3-(3-hydroxy-3-propylhexyl)benzylamino)methylenecarbamate.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Br[C:6]([CH3:17])([CH3:16])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:8]>C(=S)=S>[F:15][C:12]1[CH:11]=[C:10]2[C:9](=[CH:14][CH:13]=1)[C:7](=[O:8])[CH:6]([CH3:17])[CH2:16]2
Reactant: CC(C)(Br)C(=O)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1Cc2cc(F)ccc2C1=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a slurry of 120.2 g. (0.90 mole) of anhydrous aluminum chloride in 54 ml. of carbon disulfide is added 122.6 g. (0.50 mole) of 2-bromo-4'-fluoro-2-methylpropiophenone at 15° to 20°C over 1 hour. The mixture is warmed to 50°C over 1 hour, stirred at 50°C for 3 hours and quenched in ice. The product is extracted into toluene. The toluene layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.
Reaction SMILES: [OH:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5].[C:22](N1C=CN(C)C1)(=[O:24])[CH3:23].O>C(Cl)Cl>[C:22]([O:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5])(=[O:24])[CH3:23]
Reactant: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)N(C)O)c([N+](=O)[O-])c1
Reactant: CC(=O)N1C=CN(C)C1
Solvent: O
Solvent: ClCCl
Product: CC(=O)ON(C)C(=O)C(C)Nc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]
Yield: 63.3 %

Procedure:
3 g of N-hydroxy-N-methyl-2-(4-methyl-2,6-dinitrophenylamino)propanamide and 0.82 g of N-acetyl-N'-methylimidazole were added to a stirred suspension in 0.8 g of methylene chloride for 3 hours. The resulting mixture was poured into water. The methylene chloride layer was washed, dried over MgSO4, and evaporated to give a yellow residue which was recrystallized from ethanol to yield 1.4 g (41% yield) of product; m.p. 137-138° C., (d,1) isomer form.
Reaction SMILES: [CH:1]1([CH:11]2[CH2:13][CH2:12]2)[CH2:3][CH:2]1[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[NH2:10].C(=O)([O-])[O-].[K+].[K+].[F:20][CH:21]([F:32])[C:22]1[C:26]([C:27](Cl)=[O:28])=[C:25]([F:30])[N:24]([CH3:31])[N:23]=1>C(#N)C>[CH:1]1([CH:11]2[CH2:13][CH2:12]2)[CH2:3][CH:2]1[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[NH:10][C:27]([C:26]1[C:22]([CH:21]([F:32])[F:20])=[N:23][N:24]([CH3:31])[C:25]=1[F:30])=[O:28]
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Reactant: NC1CCCCC1C1CC1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1nc(C(F)F)c(C(=O)NC2CCCCC2C2CC2C2CC2)c1F
Temperature: 25 °C
Yield: 41.2 %

Procedure:
To a mixture of 0.489 g (2.73 mmol) 2-[1,1′-bi(cyclopropyl)-2-yl]cyclohexanamine and 0.565 g (4.09 mmol) potassiumcarbonate in 30 ml Acetonitrile was added 0.638 g (3.00 mmol) 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride and stirred at ambient temperature over night. At the end of the reaction the reaction mixture was extracted with ethylacetate and water. The organic layer was dried with natriumsulfate and the solvent was removed by vacuum. The crude product was purified by column chromathography (Solvent: Cyclohexane/ethylacetate gradient). Finally 0.40 g (33%) of N-{2-[1,1′-bi(cyclopropyl)-2-yl]cyclohexyl}-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide with a purity of 87% LC-MS was isolated. logP (acid) of 4.02.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([CH3:19])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH:32]=[CH2:33])[CH2:27][CH2:26]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(#N)C>[CH3:19][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([C:6]1[CH:7]=[C:2]([CH:33]=[CH:32][C:31]([N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[O:34])[CH:3]=[CH:4][C:5]=1[O:20][CH2:21][CH2:22][CH3:23])[NH:17][C:16]2=[O:18]
Reactant: C=CC(=O)N1CCN(C)CC1
Reactant: CCCOc1ccc(Br)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccc(C=CC(=O)N2CCN(C)CC2)cc1-c1nc2c(C)cccc2c(=O)[nH]1

Procedure:
A stirred mixture of 2-(5-bromo-2-n-propoxy-phenyl)-8-methylquinazolin-4(3H)-one (Preparation 11; 0.5 g, 0.0013 mol), 1-methyl-4-propenoylpiperazine (Makromol. Chem., 1984, 185, 1525; 0.24 g, 0.0015 mol), palladium diacetate (0.175 g, 0.00077 mol), tri-o-tolylphosphine (0.30 g, 0.001 mol), triethylamine (1 ml) and acetonitrile (25 ml) was heated under reflux under a nitrogen atmosphere for 4 days. The cool mixture was filtered and the filtrate evaporated to dryness under vacuum. The residue was suspended in saturated aqueous sodium carbonate solution (25 ml), the resulting solution extracted with dichloromethane (50 ml) and the organic extract washed with brine (2×30 ml) dried (Na2SO4) and evaporated under vacuum. Chromatography of the residue on silica gel (10 g), using a methanol in dichloromethane elution gradient (0-4%), gave the title compound which crystallized from hexane-ethyl acetate as a pale pink solid (0.072 g, 12%), m.p. 184-185° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8](Cl)=[O:9])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[S:3]1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[S:23]C(=O)N(CC(Cl)=O)[C:20]=2[CH:29]=1>>[O:1]=[C:2]1[N:6]([CH2:7][C:8](=[O:9])[S:23][C:19]2[CH:20]=[CH:29][CH:16]=[CH:17][CH:18]=2)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[S:3]1
Reactant: O=C(Cl)Cn1c(=O)sc2ccc(Cl)cc21
Reactant: O=C(Cl)Cn1c(=O)sc2ccccc21
Product: O=C(Cn1c(=O)sc2ccccc21)Sc1ccccc1

Procedure:
The procedure of Example 3 was followed utilizing 2-oxo-3-benzothiazolineacetyl chloride in lieu of 5-chloro-2-oxo-3-benzothiazolineacetyl chloride.
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].[C:6]1([S:12]([O:14][Na])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>CN(C=O)C>[C:6]1([S:12]([CH2:2][C:3]([NH2:5])=[O:4])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(O[Na])c1ccccc1
Reactant: NC(=O)CBr
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of α-bromoacetamide IV in anhydrous DMF, is added PhSO2Na at 0° C. The reaction mixture is stirred for 1 hour at room temperature and is then poured into water. The organic layer is washed with brine, dried over Na2SO4, and evaporated. The residue is purified by silica gel column chromatography to give α-phenylsulfonylacetamide III.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9](=[O:19])[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:20]([O:22]C)=O)[CH:4]=1)[CH3:2].CN(C)C=O.[H-].[Na+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>C(OCC)(=O)C>[CH2:1]([C:3]1[S:7][C:6]2[N:8]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([C:39]4[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=4)=[CH:37][CH:38]=3)[C:9](=[O:19])[C:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:20]([OH:22])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCc1cc(C(=O)OC)c(NC(=O)CCCc2ccccc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(O)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
To a mixture of methyl 5-ethyl-2-[(4-phenylbutanoyl)amino]thiophene-3-carboxylate (15 g) and N,N-dimethylformamide (150 mL) was added 60% sodium hydride (2.17 g), and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added 4′-(bromomethyl)biphenyl-2-carbonitrile (14.8 g), and the mixture was further stirred for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. After purification by silica gel column chromatography, the obtained residue was dissolved in tetrahydrofuran (200 mL), potassium tert-butoxide (5.3 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was extracted with saturated aqueous ammonium chloride solution and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless oil (4.89 g, 22%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:22])=[CH:7][N:8]3[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:12]=[C:9]32)=[CH:4][CH:3]=1.[CH3:23][CH:24]([CH:28]([CH3:31])[CH2:29][CH3:30])[C:25](Cl)=[O:26]>N1C=CC=CC=1>[CH3:23][CH:24]([CH:28]([CH3:31])[CH2:29][CH3:30])[C:25]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:22])=[CH:7][N:8]3[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:12]=[C:9]32)=[CH:4][CH:3]=1)=[O:26]
Reactant: CCC(C)C(C)C(=O)Cl
Reactant: CCOC(=O)c1cnc2c3cc(N)ccc3c(C)cn2c1=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc2c3cc(NC(=O)C(C)C(C)CC)ccc3c(C)cn2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of ethyl 10-amino-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (1.5 g) in pyridine (110 ml) was added 2,3-dimethylpentanoyl chloride (1.4 g) under ice cooling. After stirring for 2 hours at ambient temperature, the reaction mixture was concentrated in vacuo. The residue in chloroform (100 ml) was washed with water, a cold 1N hydrochloric acid and water in turn and dried over magnesium sulfate. After removal of the solvent, the residue was chromatographed on a silica gel column using chloroform as an eluent to give ethyl 10-(2,3-dimethylpentanoylamino)-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (1.94 g).