Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:25])=[C:20](B(O)O)[CH:21]=1>CCCCCCC.CCOC(C)=O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:25])=[C:18]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:17]=1
Reactant: CC(C)(C)C(=O)Nc1cnccc1I
Reactant: Cc1ccc(Cl)cc1B(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccc(Cl)cc1-c1ccncc1NC(=O)C(C)(C)C

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-2,2-dimethyl-propionamide (CAS RN 113975-32-9) and 5-chloro-2-methylphenylboronic acid (CAS RN 148839-33-2) and using a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (99%). MS (ESI): m/z=303.126 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:23]([O:25]CC)=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].S(=O)(=O)(O)O.C(O)(=O)C>O>[F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)c(F)c2c1=O
Yield: 92.5 %

Procedure:
40.1 g of ethyl 5,6,7,8-tetrafluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate are added to a mixture of 28.5 ml of concentrated sulphuric acid, 250 ml of glacial acetic acid and 200 ml of water and the mixture is heated under reflux for 2 hours. The hot solution is poured onto ice and the precipitate is filtered off with suction, washed with water and dried. 34.5 g of the title compound of melting point 250°-252° C. are obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[C:4]([C:8]#[N:9])[N:5]([CH3:7])[CH:6]=1.[Si:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:3]([CH3:10])=[C:4]([C:8]#[N:9])[N:5]([CH3:7])[CH:6]=2)=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: Cc1c(Br)cn(C)c1C#N
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2)cn(C)c1C#N
Temperature: 100 °C

Procedure:
4-Bromo-1,3-dimethyl-1H-pyrrole-2-carbonitrile (2.03 g, 10.2 mmol) and 4-[(tert-butyldimethylsilyl)oxy]aniline (3.41 g, 15.3 mmol) are dissolved in toluene (40 mL). The solution is degassed with nitrogen for 10 minutes. Sodium tert-butylate (1.18 g, 12.2 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.17 g, 0.41 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.187 g, 0.2 mmol) are then added. The mixture is heated at 100° C. for 30 minutes and then cooled to ambient temperature. Water (50 mL) and Celite (6 g) are added. The suspension is filtered over Celite, and the filtrate is diluted with MTBE. The phases are separated and the aqueous phase is extracted with MTBE (2×50 mL). The combined organic phases are dried over Na2SO4 and filtered. The residue is purified by chromatography over silica gel using ethyl acetate and heptane as eluants followed by reverse-phase chromatography using methanol and water as eluants. The product obtained is lyophilised to provide the expected compound in the form of a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:5]=[C:6]([N+:9]([O-])=O)[C:7]=1[OH:8].O.S(S([O-])=O)([O-])=O.[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>O.C(O)C>[NH2:9][C:6]1[CH:5]=[C:4]([C:12]([F:15])([F:13])[F:14])[CH:3]=[C:2]([F:1])[C:7]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(F)c1O
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)cc(F)c1O
Reaction time: 0.5 h

Procedure:
The product from (e) (4.1 g) in water (50 ml) was stirred vigorously while sodium dithionite hydrate (10 g) was added in portions. The mixture was stirred for 30 minutes and then ethanol (25 ml) and further sodium dithionite (5 g) were added. The mixture was stirred for another 15 minutes and then diluted to 400 ml, acidified (HCl) and extracted with dichloromethane (4×200 ml). The dichloromethane extract was dried (MgSO4) and evaporated to give a yellow oil which crystallised on cooling. This was identified as 3-amino-5-fluoro-4-hydroxybenzotrifluoride (2.9 g).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[C:19]([C:24]4[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[C:28]=4[CH3:29])[CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[C:32]([O:34]CC)=[O:33])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br.Br[CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[C:19]([C:24]4[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[C:28]=4[CH3:29])[CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[C:16]=2[C:32]([OH:34])=[O:33])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1cccnc1
Reactant: CCOC(=O)c1[nH]c2c(-c3c(C)nn(C)c3C)cccc2c1CCCOc1cccc2ccccc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nn(C)c(C)c1-c1cccc2c(CCCOc3cccc4ccccc34)c(C(=O)O)n(Cc3cccnc3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 580A (90 mg), 3-(bromomethyl)pyridine hydrobromide (47.3 mg) and cesium carbonate (183 mg) in N,N-dimethylformamide (3.5 ml) was stirred at room temperature overnight. The insoluble material was filtered off and the filtrate was concentrated. The residue was suspended in tetrahydrofuran-methanol, and 10% NaOH was added. The resulting mixture was stirred at room temperature overnight and concentrated. The residue was dissolved in a mixture of DMSO and methanol. The solution was purified by reverse phase HPLC (mobile phase: 10%-100% acetonitrile in 0.1% TFA aqueous solution during 60 minutes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=5.22 Hz, 1 H), 8.23-8.28 (m, 1 H), 7.85-7.90 (m, 1 H), 7.80-7.85 (m, 2 H), 7.49-7.57 (m, 3 H), 7.45-7.49 (m, 1 H), 7.38-7.43 (m, 1 H), 7.19 (d, J=7.67 Hz, 1 H), 7.10-7.15 (m, 1 H), 6.92 (t, J=7.67 Hz, 2 H), 5.65 (d, J=17.49 Hz, 1 H), 5.44 (d, J=17.80 Hz, 1 H), 4.26 (t, J=5.98 Hz, 2 H), 3.62 (s, 3 H), 3.35-3.49 (m, 2 H), 2.24-2.32 (m, 2 H), 1.67 (s, 3 H), 1.59 (s, 3 H).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.OS(O)(=O)=O.[CH3:19][CH2:20]O>>[CH2:19]([O:12][C:1](=[O:13])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1)[CH3:20]
Reactant: COc1cc(CC(=O)O)ccc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(O)c(OC)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of homovanillic acid (5 g, 27.4 mmol) and H2SO4 (96%, 1.46 mL, 27.4 mmol) in EtOH (100 mL) was stirred for 1 h at 85° C., allowed to cool to RT and concentrated. The residue was diluted in H2O and extracted with DCM. The organic phase was washed with H2O, dried (Na2SO4), filtered and concentrated to afford 5.8 g of the title compounds as a yellow oil. LC-MS: m/z 211.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=1[N+:19]([O-])=O)#[N:2].ClCCl.N>CO>[C:1]([C:3]1[C:8]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=1[NH2:19])#[N:2]
Reactant: COc1cc([N+](=O)[O-])c(C#N)c(OC2CCCC2)c1OC
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N)c(C#N)c(OC2CCCC2)c1OC

Procedure:
The subtitle compound was prepared from 2-cyano-3-cyclopentyloxy-4,5-dimethoxynitrobenzene following the procedure described in Example 10(f) and was obtained as a cream coloured solid (66%). Rf 0.79 (dichloromethane:methanol:0.880 aqueous ammonia, 92:7:1, v/v). 1H-NMR (CDCl3): Γ=1.57 (2H, m), 1.70 (2H, m), 1.90 (4H, m), 3.68 (3H, s), 3.82 (3H, s), 5.10 (1H, m), 5.98 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]2[C:45]=1[CH3:46]>O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[O:11][C:10]([CH3:21])([CH3:22])[C:9](=[O:23])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:36][C:37]3[N:38]=[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]4[C:45]=3[CH3:46])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Reactant: Cc1c(CCl)nc2ccccn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4nc5ccccn5c4C)cc3)C(=O)C(C)(C)O2)cc1
Yield: 1925.1 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (0.1 g, 0.32 mmol) was added to a mixture of cesium carbonate (0.52 g, 1.62 mmol) and DMF (20 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl)-3-methylimidazo[1,2-a]pyridine (87 mg, 0.48 mmol) was added. The mixture was heated at for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((3-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (2.8 g, 77%,) as an off-white solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.25 (d, 1H), 7.45 (d, 3H), 7.25 (t, 1H), 7.15-6.95 (Ar, 7H), 5.2 (s, 2H), 3.85 (s, 3H), 2.45 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=455.3. HPLC: (96.3%, Condition-A).
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.[C:25]1(C2C=CC=CC=2)[CH:30]=[CH:29][C:28]([C:31]2[N:32]=[C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]3[C:40]=2[CH2:41]Cl)=[CH:27][CH:26]=1.[NH:49]1[CH:53]=[CH:52][N:51]=[N:50]1>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]2[N:34]([C:40]([CH2:41][N:49]3[CH:53]=[CH:52][N:51]=[N:50]3)=[C:31]([C:28]3[CH:27]=[CH:26][CH:25]=[CH:30][CH:29]=3)[N:32]=2)[CH:35]=1
Reactant: ClCc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(Cl)cn12
Reactant: c1c[nH]nn1
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: Clc1ccc2nc(-c3ccccc3)c(Cn3ccnn3)n2c1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 2-(biphenyl-4-yl)-6-chloro-3-(chloromethyl)imidazo[1,2-a]pyridine hydrochloride and 1H-1,2,3-triazole. (m, 3H), 7.62 (dd, J=0.7, 9.5 Hz, 1H), 7.52 (m, 2H), 7.46 (m, 2H), 7.26 (m, 1H), 5.99 (s, 2H) ppm.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:17])[CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([NH:22][CH2:23][CH2:24][NH2:25])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:8](=[O:17])[CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:25][CH2:24][CH2:23][NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCCCC1)C(Br)c1ccccc1
Reactant: CC(C)(C)NCCN
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)NCCNC(C(=O)NC1CCCCC1)c1ccccc1
Yield: 38.8 %

Procedure:
A mixture of N-cyclohexyl-α-bromophenylacetamide (2.37 g), N-tert-butylethylenediamine (2.00 g), triethylamine (1.12 ml) and toluene (30 ml) was refluxed for 18 hours. The reaction mixture was concentrated and the residue was purified by means of alumina column chromatography (developing solvent, ethyl acetate) and then distilled under reduced pressure to obtain 1.03 g (38.9%) of title compound as a colorless oily product.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C=O)C>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[C:5]3[CH:12]=[CH:13][C:2]([CH3:1])=[CH:3][C:4]=3[C:9](=[O:10])[O:8][C:7]2=[O:11])=[CH:19][CH:18]=1
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(=O)oc(=O)n2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A solution of Compound 11 (5 g, 28 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 1.24 g, 31 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat 4-fluorobenzyl bromide (3.81 mL, 31 mmol) was added, and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 6.3 g (79%) of white solids. M.P. 153° C. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 5.24 (s, 2H), 7.14–7.17 (m, 3H), 7.44 (m, 2H), 7.54 (dd, J=1.7, 8.2 Hz, 1H), 7.83 (d, J=1.2 Hz, 1H). Anal. (C16H12FNO3) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>C(COC)OC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Solvent: COCCOC
Product: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Yield: 94 %

Procedure:
A mixture of 4-chlorobenzeneboronic acid (19.4 g, 1 equiv), 4-bromobenzaldehyde (22.9 g, 1 equiv), palladium(H) acetate (1.4 g, 0.05 equiv) aqueous sodium carbonate (30.3 g in 144 ml solution, 2 equiv) and dimethoxyethane (500 ml) was stirred at reflux under argon for 2.5 h, then evaporated to low volume and diluted with dichloromethane: Workup continued as in (a) above to give identical material (25.2 g, 94%). 1H-NMR (CDCl3) δ 10.05 (1H, s), 7.96 (2H, d), 7.73 (2H, d), 7.57 (2H, d), 7.46 (2H, d); MS (AP+) found (M+1)=217, C13H935ClO requires 216.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.Cl.[CH2:12]([NH:19][NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[CH2:12]([N:19]1[C:6]([NH2:7])=[C:5]2[C:4]([CH:3]=[C:2]([Br:1])[CH:9]=[CH:8]2)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNCc1ccccc1
Reactant: N#Cc1ccc(Br)cc1F
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c2ccc(Br)cc2nn1Cc1ccccc1
Temperature: 140 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
To a dried flask charged with 4-bromo-2-fluorobenzonitrile (5.0 g, 22.5 mmol) in n-butanol (60 mL) was added a solution of benzylhydrazine hydrochloride (17.56 g, 90 mmol, 4.0 eq) and diisopropylethylamine (32.1 mL, 184.48 mmol, 8.2 eq). The reaction mixture was stirred at 140° C. under N2 for 3 days. The mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified using an ISCO® instrument (gradient 5 to 60% EtOH/DCM) and the product containing fractions were concentrated to give 3.4 g (50%) of the title compound as beige solid. 1H NMR (300 MHz, CD2Cl2) δ 7.63 (dd, 1H), 7.37 to 7.30 (m, 4H), 7.20 to 7.16 (m, 2H), 6.94 (dd, 1H), 5.44 (s, 2H), 4.02 (broad s, 2H); ES-MS m/z 302.3/304.3 [M+H]+, RT (min) 2.34.
Reaction SMILES: C([O:5][C:6](=[O:23])[CH2:7][N:8]([C:16]([C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:16]([N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][C:6]([OH:23])=[O:5])=[O:17]
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccc1)C(=O)c1ccc[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN(Cc1ccccc1)C(=O)c1ccc[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution containing 2.85 (9.01 mmol) of (Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl ester in 50 mL of anhydrous dichloromethane cooled to 0° C. was added 25 mL of TFA dropwise. After 90 minutes an additional 25 mL of TFA was added and allowed to stir for 30 minutes. The mixture was evaporated in vacuo to afford 2.19 g of (Pyrole-2-carbonyl)-N-(benzyl)glycine as a tan solid. FAB MS [M+H] m/z; Calcd. 259, Found 259.
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(C(F)(F)C(F)C(F)(F)F)CC)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>C(OCC)C>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:13])=[CH:32][CH:31]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: CCN(CC)C(F)(F)C(F)C(F)(F)F
Solvent: CCOCC
Product: COc1ccc(NC(=O)C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C

Procedure:
1-Adamantanecarboxylic acid (10.8 g, 0.06 mole) was dissolved in N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine (13.4 g, 0.06 mole) as described in example 1. After the reaction mixture cooled to room temperature, a solution of p-anisidine (18.5 g, 0. 15 mole) in ethyl ether (minimum amount) was added and the reaction mixture was stirred for about an hour. The ethyl ether was removed at the rotary evaporator and the N-p-methoxyphenyl-1-adamantanecarboxamide was isolated as described in example 1 to give 15.8 g, 92%; mp 186-187° C. The analytical sample was recrystallized from cyclohexane and sublimed. Anal. Calcd. for C18H23NO2: C, 75.80; H, 8.07; N, 4.91. Found: C, 75.69; H, 8.17; N, 4.92.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][NH:14][CH3:15].CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[O:33]=[C:34]1[NH:43][C:42]2[N:41]=[CH:40][C:39](/[CH:44]=[CH:45]/[C:46]([OH:48])=O)=[CH:38][C:37]=2[CH2:36][CH2:35]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][N:14]([CH3:15])[C:46](=[O:48])/[CH:45]=[CH:44]/[C:39]1[CH:40]=[N:41][C:42]2[NH:43][C:34](=[O:33])[CH2:35][CH2:36][C:37]=2[CH:38]=1
Reactant: CNCc1c(OC)ccc2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: COc1ccc2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 71 %

Procedure:
According to the procedure of Example 1 (a), except substituting (2-methoxy-naphthalen-1-ylmethyl)methylamine for the methyl-(1-propyl-naphthalen-2ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.403 g, 71%) was prepared as an orange-brown solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.37 (s, 1H), 8.08-7.81 (m, 4H), 7.70-7.11 (m, 5H), 5.22-5.09 (m, 2H), 3.98-3.90 (m, 3H), 2.91-2.87 (m, 5H), 2.63-2.49 (m, 2H); MS (ESI) m/e 402 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]=O.C(O)(=O)C.[C-:15]#[N:16].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:15]#[N:16]
Reactant: [C-]#N
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#CCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5.25 parts of (2,6-dichlorophenyl)methanone, 4.08 parts of intermediate 8 and 105 parts of acetic acid was stirred for 2 hours at room temperature. There were added 1.96 parts of potassium cyanide and stirring was continued for 20 hours. The reaction mixture was poured into water and the product was extracted with dichloromethane. The extract was washed with NaOH (10%) and water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /hexane 80:20). The eluent of the desired fraction was evaporated and the residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 4.28 parts (49.3%) of (±)-α-[2-acetyl-5-ethylphenyl)amino]-2,6-dichlorobenzeneacetonitrile; mp. 111.3° C. (interm. 9).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]2[C:9]([Sn](CCCC)(CCCC)CCCC)=[CH:10][CH:11]=[CH:12][C:7]2=[CH:6][N:5]=1)[CH3:2].Br[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[Cs+]>O1CCOCC1.C(OCC)C>[CH2:1]([S:3][C:4]1[N:8]2[C:9]([C:35]3[C:36]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:32]=[CH:33][CH:34]=3)=[CH:10][CH:11]=[CH:12][C:7]2=[CH:6][N:5]=1)[CH3:2]
Reactant: Brc1cccc2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc2cnc(SCC)n12
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCSc1ncc2cccc(-c3cccc4ccccc34)n12
Temperature: 100 °C

Procedure:
To a solution of the title C compound, 3-ethylsulfanyl-5-tributylstannyl-imidazo-[1,5-a]pyridine (550 mg, 1.18 mmol) in 1,4-dioxane (8 mL), 1-bromonaphthalene (0.18 mL, 1.29 mmol) is added followed by tris(dibenzylidineacetone)dipalladium(0) (38 mg, 0.041 mmol), tri-t-butylphosphine (80 μL, 0.329 mmol) and cesium fluoride (396 mg, 2.6 mmol). The suspension is heated at 100° C. under nitrogen in a sealed tube for two days. The mixture is cooled, diluted with ethyl ether and filtered through a short silica plug. The solvent is evaporated under reduced pressure, and the residue is purified by flash column chromatography on silica using 10% ethyl acetate in hexanes to yield 3-ethylsulfanyl-5-naphthalen-1-yl-imidazo[1,5-a]pyridine as an amber oil: 1H-NMR (CDCl3) δ 8.01 (dd, J=7.5, 1.8, 1H), 7.93 (d, J=8.1, 1H), 7.61 (s, 1H), 7.58-7.47 (m, 4H), 7.41-7.32 (m, 2H), 6.78 (dd, J=9.0, 6.6, 1H), 6.51 (dd, J=6.6, 1.2, 1H), 2.66 (q, J=7.2, 2H), 0.86 (t, J=7.2, 3H), MS (M+1)+ 305.