Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:6]=[C:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:8]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10][C:9]=2[N:25]=1)(=O)=O.[C:37]1(S)[CH:42]=[CH:41]C=[CH:39][CH:38]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[C:1]1([S:2][C:5]2[N:6]=[C:7]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[C:8]3[CH2:14][CH2:13][N:12]([C:15]4[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:11][CH2:10][C:9]=3[N:25]=2)[CH:41]=[CH:42][CH:37]=[CH:38][CH:39]=1
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Reactant: Sc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(Nc2nc(Sc3ccccc3)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Temperature: 100 °C

Procedure:
To a microwave reaction vial were added [2-methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine (53 mg, 0.1 mmol), thiophenol (16 mg, 0.15 mmol), p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol), and DMF (0.4 mL). The vial was capped, and the mixture was heated via microwave irradiation at 100° C. for 10 min, filtered through a 0.45 μm filter, and the filtrate was purified by reversed phase HPLC (Phenomenex Gemini 30 mm×100 mm column, gradient of acetonitrile in 20 mM aqueous NH4OH). The title compound was obtained as a white solid (27 mg, 48%). MS (ESI): mass calcd. for C27H21F6N5S, 561.14; m/z found, 562 [M+H]+. 1H NMR (CDCl3): 8.38 (dd, J=4.7, 1.5 Hz, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H), 7.68-7.62 (m, 2H), 7.56-7.50 (m, 1H), 7.50-7.42 (m, 2H), 7.23 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 6.96 (dd, J=7.4, 4.6 Hz, 1H), 6.58 (bs, 1H), 3.66-3.55 (m, 4H), 3.23-3.17 (m, 2H), 2.96-2.90 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:15]=2[C:16]([OH:18])=O)=[C:11]([CH3:29])[CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][C:55]1[CH:67]=[CH:66][C:58]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[CH:57][CH:56]=1>CN(C=O)C>[F:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:15]=2[C:16]([NH:54][C:55]2[CH:67]=[CH:66][C:58]([C:59]([O:61][C:62]([CH3:63])([CH3:64])[CH3:65])=[O:60])=[CH:57][CH:56]=2)=[O:18])=[C:11]([CH3:29])[CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: Cc1cc(F)ccc1Oc1ccc(C(F)(F)F)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1Oc1ccc(C(F)(F)F)cc1C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
Triethylamine (177.4 ml, 1.27 mmol) was added to a solution of 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzoic acid (100 mg, 0.32 mmol), HATU (121 mg, 0.32 mmol) and tert-butyl 4-aminobenzoate (61.49 mg, 0.32 mmol) in DMF (1 mL) and the reaction was stirred at room temperature overnight. The reaction was filtered and purified by reverse phase LC-MS using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield tert-butyl 4-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)benzoate (43.8 mg, 28%). ESI-MS m/z calc. 489.16, found 490.3 (M+1)+; Retention time: 2.46 minutes (3 minutes run).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:21]([O:20][C:16](=[O:19])/[CH:17]=[CH:18]/[C:2]1[CH:3]=[C:4]([C:8]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)[CH3:22]
Reactant: CCOC(=O)C1(c2cccc(Br)c2)CC1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Product: CCOC(=O)/C=C/c1cccc(C2(C(=O)OCC)CC2)c1
Yield: 55.2 %

Procedure:
Ethyl 1-(3-bromophenyl)cyclopropanecarboxylate (740 mg, 2.75 mmol) was dissolved in acetonitrile (20 mL) and the solution was treated with ethyl acrylate (3.90 mL, 35.7 mmol) and tri-o-tolyl phosphine (83.7 mg, 0.275 mmol). The reaction mixture was stirred at room temperature until all of the tri-o-tolyl phosphine had dissolved. Palladium acetate (30.9 mg, 0.137 mmol) was added in a single portion and the reaction mixture was stirred at reflux for 16 hr. Palladium acetate was added (10 mg) and the reaction mixture was stirred for another 4 h. The solvent was removed under reduced pressure and the crude material was purified via flash chromatography (pentane/ethyl acetate 95/5 to 92/8) to afford (E)-ethyl 1-(3-(3-ethoxy-3-oxoprop-1-en-1-yl)phenyl)cyclopropanecarboxylate (438 mg, 55%). 1H NMR (400 MHz, CDCl3) δ 1.09-1.19 (m, 5H), 1.31 (t, 3H), 1.56-1.63 (m, 2H), 4.03-4.11 (m, 2H), 4.23 (q, 2H), 6.40 (d, 1H), 7.20-7.36 (m, 2H), 7.36-7.42 (m, 1H), 7.44-7.51 (m, 1H), 7.66 (d, 1H).
Reaction SMILES: O[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Oc1nc2ccccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccccc2[nH]1
Yield: 57 %

Procedure:
According to the procedure D. Harrison, et al., J. Chem. Soc., 2930, 1963, a mixture of 2-hydroxybenzimidazole (40.0 g, 0.298 mol) and phosphoryl chloride (400 mL) was heated under reflux for 3 hours, cooled, and concentrated. The resulting slurry was poured onto ice and the solid (starting material) was removed by filtration. The filtrate was adjusted to pH 6 with 30% aqueous NH3 and the resulting white precipitate was collected by filtration and dried to give 26.1 g (57%) of product m.p. 184°-186° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1>[Ni].C(O)C.C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Raney nickel was added to a flask containing ethanol (20 mL). The catalyst was triturated with ethanol (3×20 mL) and the a suspension of ethyl 4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (4.0 g, 12.2 mmol) in ethanol (600 mL) and THF (200 mL) was added. The reaction was then placed under a hydrogen atmosphere (1 atm) and allowed to stir at rt overnight. The reaction was filtered through a pad of Celite® using a mixture of ethanol and THF (3:1) to rinse. The filtrate was concentrated in vacuo to afford the desired product (3.60 g, 96%). 1H-NMR (DMSO-d6) 8.05 (s, 1H), 8.04 (br s, 2H), 7.88 (s, 1H), 7.01 (d, J=8.0 Hz, 2H), 6.61 (d, J=8.0 Hz, 2H), 5.31 (br s, 2H), 4.07 (q, J=7.3 Hz, 2H), 1.12 (t, J=7.3 Hz, 3H); ES-MS m/z 298.2 (MH)+; HPLC RT (Method A) 1.64 min; TLC Rf=0.30 (Acetone/CH2Cl2 1:3).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13]C(C)([O-])C.[K+].IC>C1COCC1>[CH3:13][C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[O:1]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)C1CCCCC1=O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCCC1=O
Reaction time: 0.08 h

Procedure:
For the synthesis of the protected acid side-chain 1-methyl-2-(tetrahydropyran-2′-yloxy)-cyclohexane carboxylic acid, ethyl 2-oxocyclohexane carboxylate (8.5 g, 50 mmol) was dissolved in dry THF at ambient temperature under N2. Potassium tert-butoxide (75 mmol) was added slowly and the reaction was stirred for 5 minutes. Iodomethane (100 mmol) was then added and the reaction was stirred at ambient temperature for 1 hour. The reaction solvent was removed under reduced pressure and the residue was partitioned between water and hexane. The organic layer was dried over sodium sulfate and reduced under reduced pressure to give racemic ethyl 1-methyl-2-oxo-cyclohexanecarboxylate as a colourless oil (8.11 g 88%); δH (400 MHz, CDCl3) 4.25-4.12 (2H, m, OCH2CH3), 2.55-2.40 (3H, m, CH2CO and one other cyclohexane peak), 2.05-1.95 (1H, m, cyclohexane), 1.77-1.57 (3H, m, cyclohexane), 1.50-1.40 (1H, m, cyclohexane), 1.28 (3H, s, CCH3) and 1.25 (1H, t, J 7, CH2CH3). Ethyl 1-methyl-2-oxo-cyclohexanecarboxylate (5.52 g, 30 mmol) was dissolved in ethanol (100 ml) at ambient temperature and sodium borohydride (1.14 g, 30 mmol) was added slowly. After 1 hour the reaction solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic extracts were dried over sodium sulphate and reduced to give ethyl 2-hydroxy-1-methylcyclohexanecarboxylate as a mixture of diastereoisomers (5.37 g 96%). This material was then protected and the ester hydrolysed as follows: Ethyl 2-hydroxy-1-methylcyclohexanecarboxylate (16.7 mmol) was dissolved in dichloromethane along with 3,4-dihydro-2H-pyran (17 mmol) and para-toluene-sulphonic acid (5 mg), and the reaction was stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure to give a residue to which was added ethanol (40 ml), water (10 ml) and potassium hydroxide (20 mmol). The mixture was heated at reflux overnight and allowed to cool. The reaction solvent was removed under reduced pressure and the residue was partioned between water and diethyl ether. The aqueous layer was acidified to pH 2 and then extracted with diethyl ether. This ether layer was dried over sodium sulphate and reduced in vacuo to give crude 1-methyl-2-(tetrahydropyran-2′-yloxy)-cyclohexane carboxylic acid (2.52 g) as a mixture of diastereoisomers. This material was used in the synthesis of (S)-3-(2′-hydroxy-1′-methylcyclohexanecarbonyl)amino-caprolactam above
Reaction SMILES: C([CH:3]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[C:4]([OH:6])=[O:5])C.[CH2:17]([CH:22]([N:29]1[C:37]2[C:32](=[CH:33][C:34](/[C:38](/[CH3:43])=[CH:39]/[C:40](O)=[O:41])=[CH:35][CH:36]=2)[CH:31]=[CH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:17]([CH:22]([N:29]1[C:37]2[C:32](=[CH:33][C:34](/[C:38](/[CH3:43])=[CH:39]/[C:40]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][CH2:3][C:4]([OH:6])=[O:5])=[O:41])=[CH:35][CH:36]=2)[CH:31]=[CH:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCC(CCOc1ccccc1N)C(=O)O
Reactant: CCCCCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Product: CCCCCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
1.01 g of compound 43 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.54 g of ethyl 4-(2-aminophenoxy)butyric acid and 1.30 g of 3-[1-(α-pentylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [F:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH2:12](I)[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)C>[CH2:12]([O:9][C:5]1[CH:6]=[C:7]([I:8])[C:2]([F:1])=[CH:3][C:4]=1[O:10][CH3:11])[CH3:13]
Reactant: CCI
Reactant: COc1cc(F)c(I)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cc(I)c(F)cc1OC
Temperature: 40 °C
Yield: 84.4 %

Procedure:
A mixture of 64C (580 mg, 2.16 mmol), ethyl iodide (0.23 mL, 2.92 mmol) and K2CO3 (598 mg, 4.32 mmol) in DMF (5.0 mL) was heated at 40° C. for 3.0 h. It was diluted with diethyl ether, washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude product was purified by silica gel chromatography (EtOAc:hexanes=1:5) to give 64D (540 mg, 85% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, J=7.03 Hz, 3H) 3.82 (s, 3H) 4.01 (q, J=7.03 Hz, 2H) 6.64 (d, J=9.23 Hz, 1H) 7.09 (d, J=6.15 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([O:11][CH3:12])[C:3]=1[O:13][CH2:14][O:15][CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[C:36](=[O:40])[O:35][CH2:34]3)O1>CN(C)C=O.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>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[C:36](=[O:40])[O:35][CH2:34]3)=[C:3]([O:13][CH2:14][O:15][CH3:16])[C:4]=1[O:11][CH3:12])[CH3:10]
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Reactant: CCOc1ccc(Br)c(OCOC)c1OC
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: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(OCOC)c1OC
Temperature: 85 °C
Yield: 40.2 %

Procedure:
A stirring solution of 1-bromo-4-ethoxy-3-methoxy-2-(methoxymethoxy)benzene (200 mg, 0.722 mmol) in dimethylformamide (5 mL) was purged with argon for 1 h, to this cesium carbonate (700 mg, 2.166 mmol), Pd(PPh3)4 (41 mg, 0.036 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one (280 mg, 1.08 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded 5-(4-Ethoxy-3-methoxy-2-(methoxymethoxy)phenyl)isobenzofuran-1(3H)-one as a solid (100 mg, 40%).
Reaction SMILES: BrCC1C=C(C=CC=1)C(OC)=O.Cl[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][Cl:22])[CH:16]=1.BrCC1C=C(C=CC=1)C=O.[CH2:33]([N:35](CC1C=C(C=CC=1)C(OC)=O)[CH2:36]/[CH:37]=[CH:38]/[C:39]#[C:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH3:34]>>[CH2:33]([N:35]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][Cl:22])[CH:16]=1)[CH2:36]/[CH:37]=[CH:38]/[C:39]#[C:40][C:41]([CH3:42])([CH3:44])[CH3:43])[CH3:34]
Reactant: ClCc1cccc(CCl)c1
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(C(=O)OC)c1
Agent: COC(=O)c1cccc(CBr)c1
Agent: O=Cc1cccc(CBr)c1
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(CCl)c1

Procedure:
When the same reactions as in Referential Example 4 are carried out using methyl 3-bromomethylbenzoate [synthesized by brominating methyl m-toluate with N-bromosuccinimide] or α,α'-dichloro-m-xylene instead of the starting 3-bromomethylbenzaldehyde, methyl (E)-3-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl)benzoate or (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-chloromethylbenzylamine is obtained.
Reaction SMILES: [CH3:1][OH:2].C(N(CC)CC)C.Cl[Si:11]([CH2:19][Cl:20])([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[Cl:20][CH2:19][Si:11]([O:2][CH3:1])([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[Si](Cl)(CCl)c1ccccc1
Reactant: CO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CO[Si](C)(CCl)c1ccccc1
Yield: 79.7 %

Procedure:
A solution of 1.6 ml (1.3 g, 0.040 mol) of methanol and 3.0 ml (2.2 g, 0.022 mol) of triethylamine in 100 ml of ether was stirred while a solution of 4.1 g (0.020 mol) of chloro(chloromethyl)methyl(phenyl)silane in 10 ml of ether was added dropwise. The resulting slurry was refluxed for 2 hours, cooled, washed with water, 0.1N aqueous HCl, saturated aqueous NaHCO3, water, and brine, dried over magnesium sulfate, and evaporated to leave 3.2 g of a pale yellow liquid. Distillation provided 1.7 g (42%) of the title compound as a colorless liquid: bp 46°-49° (0.05 mm); nD22 1.5207; nmr (CDCl3): 0.5 (3H, s), 3.0 (2H, s), 3.5 (3H, s) and 7.3-7.8 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)NC(=O)c1ccc(Cl)nc1

Procedure:
The product was prepared from 6-chloro-nicotinic acid (1.0 g), carbonyldiimidazole (0.8 g) and isopropylamine (0.6 ml) using the method of example 115 step (i). Yield 0.75 g.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][C:11]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[CH2:12].CCN(CC)CC>C(Cl)(Cl)Cl>[CH2:1]([NH:8][CH2:12][C:11]([O:13][S:14]([C:17]([F:20])([F:18])[F:19])(=[O:16])=[O:15])=[CH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CBr)OS(=O)(=O)C(F)(F)F
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=C(CNCc1ccccc1)OS(=O)(=O)C(F)(F)F
Yield: 55 %

Procedure:
Sources of Starting Materials as illustrated in FIG. 10, SCHEME B: α,β-Unsaturated amides with exocyclic double bonds: Reaction conditions: (a) TfOH, CHCl3, RT; (b) BnNH2, CHCl3, reflux; (c) 10 mol % Pd(PPh3)4, Bu3N, CO (1 atm), CH3CN, 65° C. Typical experimental procedure for the preparation of 700—described for the case in which n=1, X=Br, and R=Bn: Triflic acid (2.32 mL, 26.23 mmol) was added dropwise under N2 over 10 min to a stirred solution of propargyl bromide (2.0 mL, 26.23 mmol) in CHCl3 (30 mL) at 0° C. The ice bath was removed and the dark solution was stirred at RT for 60 min, followed by the addition of pyridine (5 mL). The solution was washed with water (50 mL) and dil. hydrochloric acid (2×50 mL). The organic phase was dried and the solvent evaporated. The residue was purified by Kugelrohr distillation to yield 1-bromo-2-[(trifluoromethanesulfonyl]oxylprop-2-ene as a colorless liquid. A solution of benzylamine (81 mL, 0.74 mmol) in CHCl3 (4 mL) was added dropwise to a mixture of 1-bromo-2-[(trifluoromethanesulfonyl)oxy]prop-2-ene (0.37 mmol) and Et3N (0.1 mL, 0.74 mmol) in CHCl3 (4 mL) at 1° C. The solution was then heated at reflux for 15 h. The mixture was washed with water (10 mL), the organic extracts were dried and the solvent was evaporated. The residue was purified by flash chromatography (hexanes-EtOAc, 9:1) to yield N-benzyl-2-[(trifluoromethanesulfonyl)oxy]-2-propenylamine as a pale yellow solid. Yield: 55%. Next, for the case in which n=1 and R=Bn: Carbon monoxide was bubbled through a solution of N-benzyl-2-[(trifluoromethanesulfonyl)oxy]-2-propenylamine (0.36 mmol), Pd(PPh3)4 (0.041 g, 0.036 mmol), tri-n-butylamine (0.17 mL, 0.72 mmol) in acetonitrile (15 mL) for 25 min. The reaction was then heated to 65° C. for 5 h. The solution was then allowed to cool to room temperature upon which ether (15 mL) was added and the solution filtered through a pad of kenite. The pad was subsequently thoroughly rinsed with ether (3×10 mL). The solvent was then removed in vaccuo and the residue taken up in dichloromethane. Flash chromatography (hexanes:ethyl acetate; 19:1) twice yielded 1-benzyl-3-methyleneazetidinone as a white amorphous solid. Yield: 73%.
Reaction SMILES: [CH3:1][C:2]([NH2:12])([CH3:11])[CH2:3][CH2:4][NH:5][CH2:6][C:7]([F:10])([F:9])[F:8].[C:13](ON1C(=O)CCC1=O)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C1COCC1>[CH3:11][C:2]([NH:12][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH2:3][CH2:4][NH:5][CH2:6][C:7]([F:8])([F:9])[F:10])[CH3:1]
Reactant: CC(C)(N)CCNCC(F)(F)F
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CC(C)(CCNCC(F)(F)F)NC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 68.4 %

Procedure:
Crude 3-methyl-N1-(2,2,2-trifluoroethyl)butane-1,3-diamine (3.86 g, 21.0 mmol) was dissolved into THF (200 mL) and cooled in an ice bath. A THF (50 mL) solution of CbzOSu (5.22 g, 1 equiv, 21.0 mmol) was added to the reaction dropwise over 5 min. The reaction was left to stand in an ice chest for 16 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (150 mL) and water (50 mL). The layers were separated and the organic layer washed with 1 M sodium carbonate (2×50 mL), 1 M HCl (50 mL) and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil (6.15 g). The crude oil was purified on an ISCO purification system with gradient elution from 0-6% methanol in DCM. The desired fractions were collected and concentrated to give a pale yellow oil (4.57 g, yield: 68.5%). 1H NMR (CDCl3, 400 MHz): δ 1.33 (s, 6H), 1.75-1.83 (t, J=7.2, 2H), 2.74-2.85 (t, J=7.2, 2H) 3.10-3.18 (q, J=9.4, 2H), 5.04 (s, 2H), 7.27-7.38 (m, 5H). LRMS (ESI+) for C15H21F3N2O2 (318.2); Found: 319 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OCC3C=CC=CC=3)=O)=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.[CH2:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36](=[O:52])[C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH:30]=1)[CH3:28]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][C:10]=2[C:40]2[CH:41]=[CH:42][C:37]([C:36]([NH:35][C:31]3[CH:30]=[C:29]([CH2:27][CH3:28])[CH:34]=[CH:33][N:32]=3)=[O:52])=[CH:38][CH:39]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Reactant: CCc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Product: CCc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCN4)n4ccnc(N)c34)cc2)c1
Yield: 89 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and N-(4-ethylpyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (intermediate 12) to afford the title compound (133.8 mg, 89%).
Reaction SMILES: [CH3:1][N:2]1[C:7](SC)=[N:6][C:5]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:4][C:3]1=[O:16].Cl.[NH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)CCO>[CH3:1][N:2]1[C:7]([NH:18][CH2:19][C:20](=[O:21])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:6][C:5]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:4][C:3]1=[O:16]
Reactant: NCC(=O)c1ccccc1
Reactant: CSc1nc(-c2ccncc2)nc(=O)n1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCO
Product: Cn1c(NCC(=O)c2ccccc2)nc(-c2ccncc2)nc1=O
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.12 g (0.51 mmol) of 1-Methyl-6-methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one in 1 mL of 3-methyl-1-butanol was added 0.088 g (0.51 mmol) of 2-Amino-1-phenyl-ethanone hydrochloride (commercially available). To the resulting mixture was added 7.1 mg (0.051 mmol) of potassium carbonate. The resulting mixture was stirred at 120° C. for 1 h. Then, 7.1 mg (0.051 mmol) of potassium carbonate were added each hour during 2 h.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH:3]([OH:6])[C:4]#[CH:5].[H-].[Na+].[CH2:10](Br)[CH:11]=[CH2:12]>CN(C=O)C.CCOCC>[CH2:12]([O:6][CH:3]([CH:2]([CH3:7])[CH3:1])[C:4]#[CH:5])[CH:11]=[CH2:10]
Reactant: C#CC(O)C(C)C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CC(OCC=C)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
A solution of 4-methylpent-1-yn-3-ol (2.00 g, 20.38 mmol) in DMF (30 ml) was cooled (0° C. ice bath) and treated with 60% NaH (0.992 g, 24.80 mmol). The reaction was stirred for 20 min, then warmed to room temperature and stirred for 1 hr. To this was added allyl bromide (5.3 ml, 61.2 mmol) over 5 min. The reaction was stirred over the weekend. The reaction was diluted with Et2O (100 mL), washed with water (4×25 mL), brine (25 mL), dried (MgSO4), filtered and concentrated to give the product, 3-(allyloxy)-4-methylpent-1-yne (2.401 g, 13.03 mmol, 63.9% yield) as a pale yellow mobile oil. 1H NMR consistent with expected product; contains approx 4:1 product/SM. Used as-is without further purification. 1H NMR (CDCl3) δ: 5.86-5.99 (m, 1H), 5.32 (dq, J=17.2, 1.7 Hz, 1H), 5.16-5.25 (m, 1H), 4.28 (ddt, J=12.7, 5.0, 1.6 Hz, 1H), 4.19 (td, J=5.7, 2.1 Hz, 1H), 3.98 (ddt, J=12.7, 6.3, 1.3 Hz, 1H), 3.87 (dd, J=5.8, 2.0 Hz, 1H), 2.41 (d, J=2.0 Hz, 1H), 1.92-2.03 (m, 1H), 0.98-1.06 (m, 8H).