Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][Si:35]([CH3:62])([CH3:61])[CH2:36][CH2:37][O:38][CH2:39][N:40]1[CH:44]=[CH:43][N:42]=[C:41]1[CH2:45][NH:46][CH2:47][C:48]1[N:49]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:50]=[CH:51][N:52]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>ClCCl.O>[C:2]1([CH2:1][O:8][C:9](=[O:10])[N:11]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([N:46]([CH2:47][C:48]3[N:49]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:50]=[CH:51][N:52]=3)[CH2:45][C:41]3[N:40]([CH2:39][O:38][CH2:37][CH2:36][Si:35]([CH3:61])([CH3:62])[CH3:34])[CH:44]=[CH:43][N:42]=3)=[O:30])=[CH:32][CH:33]=2)[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ccnc1CNCc1nccn1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCCN(Cc1ccc(C(=O)O)cc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCN(Cc1ccc(C(=O)N(Cc2nccn2COCC[Si](C)(C)C)Cc2nccn2COCC[Si](C)(C)C)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
To a solution of the compound 5 (137 mg) in dichloromethane (3 mL), the compound 2 (131 mg), 1-hydroxybenzotriazole (69 mg), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (86 mg) and diisopropylethylamine (105 μl) were added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was added by water and then extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→0:100→dichloromethane:methanol=10:1) to obtain the title compound (225 mg) having the following physical properties.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[N:6][CH:7]=1.N([O-])=O.[Na+].[Na+].[I-:20]>Cl.O>[I:20][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[N:6][CH:7]=1
Reactant: [I-]
Reactant: Nc1ccc(-n2ccccc2=O)nc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=c1ccccn1-c1ccc(I)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To a solution of 1-(5-aminopyridin-2-yl)pyridin-2(1H)-one (316 mg, 1.69 mmol) in concentrated HCl (8 mL) cooled in an ice bath, a solution of NaNO2 (117 mg, 1.69 mmol) in H2O (3 mL) was added dropwise. After 30 min of stirring, NaI (1.03 g, 6.87 mmol) in H2O (4 mL) was added. The mixture was stirred at 0° C. for 1 h. It was then allowed to warm up to room temperature and stirred at room temperature overnight. The mixture was extracted with EtOAc. The EtOAc solution was washed with 5% NaHCO3, then with Na2S2O3, dried over Na2SO4, and concentrated in vacuo to give 1-(5-iodopyridin-2-yl)pyridin-2(1H)-one (189 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([CH3:15])[C:7]=1[NH:8][C:9](=[O:14])[CH2:10][O:11][CH2:12][CH3:13].[CH3:17][N:18]=[C:19]=[O:20]>C1(CC#N)C=CC=CC=1.C(N(CC)CC)C>[CH3:17][NH:18][C:19](=[O:20])[O:16][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:14])[CH2:10][O:11][CH2:12][CH3:13])=[C:6]([CH3:15])[CH:5]=1
Reactant: CCOCC(=O)Nc1c(C)cc(O)cc1C
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: N#CCc1ccccc1
Product: CCOCC(=O)Nc1c(C)cc(OC(=O)NC)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3,5-Dimethyl-4-ethoxyacetamidophenol (1.1g., 0.0049 mole, m.p. 157°-59° C., prepared by reaction of ethoxyacetyl chloride with 3,5-dimethyl-4-aminophenol) was reacted with methyl isocyanate (0.3g., 0.0053 mole) using benzeneacetonitrile as solvent and triethylamine as a catalyst. The reaction mixture was stirred at ambient temperature for 31/2 hours, followed by warming at about 45° C. for 2 hours. Solvents were removed under reduced pressure, and the residual solid recrystallized from diethylether and benzene (m.p. 112.5°-115° C.).
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[C:1]([O:16][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCC
Reaction time: 24 h

Procedure:
34.3 g myristic acid and 32.2 g myristyl alcohol were heated up to 95° C. and 4 g ground immobilised esterase as prepared in Example 13 were added. Samples of the reaction mixture were withdrawn after 1, 2, 4, 8 and 24 h for conversion determination by acid value titration. The initial activity in myristyl myristate synthesis was determined by the help of the mathematical means from example 1.2. After 24 h the reaction was stopped and the enzyme was recovered by mixing the ester with 200 g warm acetone, filtering and washing the residual enzyme with 40 g warm acetone twice. After drying the enzyme in an exsiccator over night under 20 mbar vacuum and ambient temperature, the recovered enzyme was used again in myristyl myristate synthesis in the same manner as described above and was shown to maintain its activity following the above described procedure. The procedure was repeated 10 times. The enzyme was stable throughout the entire test, in the last cycle a relative activity of approx. 95% was found which is within the detection limits. The results are shown in Table 14.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].Cl[C:19]1[S:20][C:21]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=2[N:23]=1.Cl.O1CCOCC1>CCO>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:19]3[S:20][C:21]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:15][CH:16]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: CCOC(=O)c1cc(-c2ccc(N)cc2)no1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1
Temperature: 60 °C
Yield: 57.2 %

Procedure:
A mixture of the compound of step 2 (3.0 g; 12.9 mmol) and 2-chloro-6-fluoro benzothiazole (2.67 g; 14.2 mmol) in EtOH (60 ml) was heated at 60° C. to get a clear solution. To the hot solution 4N HCl in dioxane (1.6 ml; 6.45 mmol) was added and the resulting reaction mixture was refluxed for 20 hours. The reaction mixture was cooled to room temperature and the solid was filtered, and washed with EtOH (2×10 ml). The solid was dried under vacuum to yield 2.83 g (57.2%) of the title compound. Mass (ES−) 382 (M−1); IR (KBr): 3410 (br), 2710 (br), 1729, 1719, 1630, 1598; 1H NMR (DMSO-d6): δ 1.36 (t, 3H), 4.41 (q, 2H), 7.20 (m, 1H), 7.67 (m, 1H), 7.78 (m, 1H), 7.81 (s, 1H), 7.87-7.99 (m, 4H), 10.92 (br, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[C:6]=1[CH3:17])[CH3:2].CO[CH:21]([N:24]([CH3:26])[CH3:25])OC>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[C:6]=1[CH:17]=[CH:21][N:24]([CH3:26])[CH3:25])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C=CN(C)C
Temperature: 100 °C
Yield: 26.1 %

Procedure:
A mixture of 2-methyl-3,5-dinitro-benzoic acid ethyl ester (35 g, 0.14 mol) and dimethoxymethyl-dimethyl-amine (32 g, 0.27 mol) in DMF (200 mL) was heated at 100° C. for 5 h. The mixture was poured into ice-water. The precipitate was collected via filtration and washed with water to give 2-(2-dimethylamino-vinyl)-3,5-dinitro-benzoic acid ethyl ester (11.3 g, 48%).
Reaction SMILES: C([O:5][C:6](=[O:26])[CH:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])[CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(C)(C)C>C1COCC1.CO.O>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH:7]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[C:6]([OH:26])=[O:5])=[C:19]([F:25])[CH:20]=1
Reactant: CC(C)(C)OC(=O)NCC(Cc1ccc(Br)cc1F)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC(Cc1ccc(Br)cc1F)C(=O)O
Yield: 88.3 %

Procedure:
2-(4-Bromo-2-fluoro-benzyl)-3-tert-butoxycarbonylamino-propionic acid tert-butyl ester (1.30 g, 3.01 mmol) was dissolved in THF (12 mL) and MeOH (12 mL). A solution of LiOH monohydrate (0.50 g, 12.0 mmol) in H2O (12 mL) was added. The mixture was heated at reflux overnight. After cooling, the solvents were evaporated in vacuo. The residue was dissolved in water and extracted with ether (2x). The aqueous phase was acidified with 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated to give 2-(4-Bromo-2-fluoro-benzyl)-3-tert-butoxycarbonylamino-propionic acid (1.00 g, 88%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ 7.26 (m, 2H), 7.19 (m, 1H), 3.27 (m, 2H), 2.86 (m, 3H), 1.43 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1ccc2cc[nH]c2c1
Solvent: C1CCNC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cc(Br)ccc23)CC1
Yield: 46.9 %

Procedure:
A stirred solution of 6-bromoindole (390 mg, 2.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (438 mg, 2.2 mmol), and pyrrolidine (0.42 mL, 5.0 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (354 mg, 47%).
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][C:24]([CH3:53])([CH3:52])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49][CH:50]=[CH2:51])[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27].I[C:55]1[CH:60]=[CH:59][C:58]([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[C:57]([CH3:68])[CH:56]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:53][C:24]([CH3:52])([CH3:23])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49]/[CH:50]=[CH:51]/[C:55]1[CH:60]=[CH:59][C:58]([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[C:57]([CH3:68])[CH:56]=1)[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27]
Reactant: Cc1cc(I)ccc1Oc1ccccc1
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(/C=C/C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c2ccccc2)C(C)(C)C)ccc1Oc1ccccc1
Yield: 81.6 %

Procedure:
A mixture of palladium acetate (20 mg, 0.08 mmol) and tri-(2-methylphenyl)phosphine (50 mg, 0.16 mmol) was added to a stirred solution of tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)hex-5-enoate (Preparation 2)(578 mg, 1.23 mmol), 1-iodo-3-methyl-4-phenoxybenzene (Preparation 11)(384 mg, 1.35 mmol), and triethylamine (300 μL, 2.14 mmol) in anhydrous acetonitrile (3 mL) under nitrogen. The mixture was purged with nitrogen, then heated at reflux for 24 h. After being cooled, the mixture was poured into ethyl acetate (100 mL) and washed with saturated aqueous sodium chloride (2×50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with hexane:ethyl acetate=9:1 and then 4:1) to give mainly tert-butyl (3R,5E)-3-({[(1S)-2,2-dimethyl-1-({ [(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-(3-methyl-4-phenoxyphenyl)hex-5-enoate as an orange foam (615 mg). 1H nmr suggested that two alkene isomers, the (5Z) and (4E), together with the alkene starting material (10%) were also present. The mixture of alkenes was taken onto the next step (see b, below).
Reaction SMILES: [O:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]>C(O)(=O)C.CCOC(C)=O.[Fe]>[O:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cn1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(N)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A 100 mL round-bottom flask was charged with the iron powder (5.6 g, 10 mmol) in acetic acid (30 mL) and heated to 80° C. (oil bath) under N2. To this mixture was added slowly the above 2-isopropoxyl-5-nitropyridine (4.6 g, 25.2 mmol) in acetic acid (30 mL) via dropping funnel and the reaction stirred at 80° C. for another 30 min after the addition. After cooling the reaction mixture, it was diluted with EtOAc, filtered through celite, and the solvent evaporated in vacuo. The residue was dissolved in EtOAc and washed with NaHCO3 (sat.), brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified through automated normal-phase chromatography to afford 2-isopropoxyl-5-aminopyridine (3.8 g, 99%) which was used directly for the next step: 1H NMR (400 MHz, CDCl3) δ 7.64 (d, 1H), 7.00 (dt, 1H), 6.52 (d, 1H), 5.10 (sep, 1H), 1.30 (d, 6H); MS (ES) (M++H) expect 153.1, found 153.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]4[O:25][C:26](=[O:29])[CH2:27][N:28]=4)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:34][CH2:35][CH:36]1[CH2:38][CH2:37]1>CN(C)C=O.O>[CH:36]1([CH2:35][NH:34][C:26](=[O:29])[CH2:27][NH:28][C:24]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([C:11]3[CH2:10][C:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)([C:30]([F:31])([F:33])[F:32])[O:13][N:12]=3)=[CH:15][CH:16]=2)=[O:25])[CH2:38][CH2:37]1
Reactant: O=C1CN=C(c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c3ccccc23)O1
Reactant: NCC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12)NCC1CC1
Temperature: 150 °C

Procedure:
A mixture of 2-[4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]-5(4H)-oxazolone (i.e. the title product of Step A) (50 mg) and (aminomethyl)cyclopropane (0.1 mL) in N,N-dimethylformamide (1 mL) was irradiated with microwave radiation to maintain a temperature around 150° C. for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate (3:2 to 3:7) as eluent to afford the title compound, a compound of the present invention, as a pale yellow solid (47 mg, 82% yield).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]([O:14][CH3:15])[O:12][CH3:13])=[N:10][C:5]2=[N:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][C:26]=1[C:40]1[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=1>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>[CH3:13][O:12][CH:11]([O:14][CH3:15])[C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[C:26]([C:40]4[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:27]=3)=[CH:3][N:4]=[C:5]2[N:10]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: COC(OC)c1ccn2c(Br)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(OC)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1
Temperature: 80 °C

Procedure:
A mixture of 3-bromo-7-dimethoxymethylimidazo[1,2-α]pyrimidine (1.36 g, 5 mmol), potassium phosphate (2.12 g, 10 mmol), 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (2.42 g, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (230 mg, 0.2 mmol) in N,N-dimethylformamide (15 ml) was heated at 80° C. for 14 h. The reaction was cooled and partitioned between ethyl acetate and water. The organics were washed with water, brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to afford crude 5′-(7-dimethoxymethylimidazo[1,2-α]pyrimidin-3-yl)-2′-fluorobiphenyl-2-carbonitrile. The residue was suspended in 1,4-dioxane (30 ml) then treated with 3N hydrochloric acid (30 ml) and this mixture was heated at 60° C. for 14 h. The reaction was cooled and partitioned between dichloromethane and water. The organics were washed with water, brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with dichloromethane (+1% triethylamine) on a gradient of methanol (1-4%) gave a solid. Trituration with ether afforded 2′-fluoro-5′-(7-formylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as a yellow powder (1.2 g, 70% over 2 steps): δH (400 MHz, DMSO) 7.48 (1H, d, J 7), 7.65-7.72 (2H, m), 7.75-7.80 (1H, m), 7.87 (1H, ddd, J 8, 8 and 1), 7.95-7.99 (2H, m), 8.02-8.05 (1H, m), 8.40 (1H, s), 9.27 (1H, dd, J 7 and 1), 9.96 (1H, s); m/z (ES+) 343 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([S:18](=[O:25])(=[O:24])[NH:19][CH2:20][CH2:21][O:22][CH3:23])=[C:13]2[N:12]=[CH:11][C:10]=1[C:26]([O:28]CC)=O.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([S:18]([NH:19][CH2:20][CH2:21][O:22][CH3:23])(=[O:24])=[O:25])=[C:13]2[N:12]=[CH:11][C:10]=1[C:26]([N:41]1[CH2:42][CH2:43][CH:38]([C:35]2[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=2)[CH2:39][CH2:40]1)=[O:28]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NCCOC)cnn2c1Nc1ccccc1Cl
Product: COCCNS(=O)(=O)c1cnn2c(Nc3ccccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 16.6 %

Procedure:
Using ethyl 7-(2-chlorophenylamino)-3-[N-(2-methoxyethyl)sulfamoyl]pyrazolo[1,5-a]pyrimidine-6-carboxylate (0.459 g, 1.008 mmol) obtained in step 1 and 4-(4-fluorophenyl)piperidine (0.158 g, 0.881 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.086 g, 15%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:23])=[C:14]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:15]=2)[CH:5]=[CH:4][N:3]=1.[I-].[NH2:25][N+:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:23])=[C:14]([NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH:15]=3)=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(C#Cc2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Reactant: N[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Reaction time: 3 h
Yield: 55.6 %

Procedure:
To a solution of N-{5-[(2-chloro-4-pyrimidinyl)ethynyl]-2-methylphenyl}-2,2,2-trifluoroacetamide (2.7 g, 8 mmol) in DMF (50 mL) was added N-aminopyridinium iodide (3.6 g, 16 mmol) and K2CO3 (3.3 g, 24 mmol). After 3 h, the reaction was diluted with water and extracted with DCM. The combined organic solutions were dried over MgSO4 and concentrated onto silica gel. The crude material was purified by column chromatography. Fractions containing product were concentrated and the solid triturated with DCM and hexanes to give 1.92 g of the desired product (56%). 1H NMR (400 MHz, d6-DMSO) δ 11.07 (s, 1H), 8.89 (d, J=6.8 Hz, 1H), 8.45 (d, J=6.8 Hz, 1H), 8.40 (d, J=8.8 Hz, 1H), 7.65-7.61 (m, 1H), 7.55 (s, 1H), 7.52-7.49 (m, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.22-7.19 (m, 1H), 7.08 (d, J=5.6 Hz, 1H), 2.27 (s, 3H) ppm.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[N:6]=[C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[CH3:17])[N:4]=1.[I-].[Na+].[Si](Cl)(C)(C)C.S(=O)(=O)(O)[O-].[Na+]>C(#N)C.O>[CH3:17][C@H:12]1[CH2:13][O:14][CH2:15][CH2:16][N:11]1[C:5]1[N:4]=[C:3]([OH:2])[CH:8]=[C:7]([OH:9])[N:6]=1
Reactant: COc1cc(OC)nc(N2CCOC[C@@H]2C)n1
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)([O-])O
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: C[C@H]1COCCN1c1nc(O)cc(O)n1
Temperature: 25 °C
Yield: 68.6 %

Procedure:
(3S)-4-(4,6-Dimethoxypyrimidin-2-yl)-3-methylmorpholine (6.3 g, 26.3 mmol) was dissolved in acetonitrile (88 mL). Argon was bubbled into the solution and sodium iodide (11.8 g, 79.0 mmol) and TMS-Cl (10.3 mL, 79.0 mmol) were added. The reaction was heated under reflux for 2 h, and then allowed to cool to room temperature. Water (50 mL) and sodium bisulfate (2.74 g, 26.3 mmol) was added. Acetonitrile was removed by rotary evaporation and the resulting slurry was filtered. The precipitate was suspended in ethanol and concentrated to dryness by rotary evaporation to give the title compound (3.81 g, 68%). 1H NMR (400 MHz, DMSO-d6) δ 10.61 (br s, 2 H), 4.80 (br s, 1 H), 4.40 (d, J=5.9 Hz, 1 H), 3.98 (d, J=12.7 Hz, 1 H), 3.85 (dd, J=11.3, 3.5 Hz, 1 H), 3.68-3.62 (m, 1 H), 3.56-3.50 (m, 1 H), 3.38 (td, J=11.8, 3.0 Hz, 1 H), 3.16-3.04 (m, 1 H), 1.16 (d, J=6.7 Hz, 3 H).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([C:11]([OH:13])=[O:12])([F:10])([F:9])[F:8]>>[CH:1]1([O:13][C:11](=[O:12])[C:7]([F:10])([F:9])[F:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCCC1
Reactant: O=C(O)C(F)(F)F
Product: O=C(OC1CCCCC1)C(F)(F)F
Yield: 17 %

Procedure:
Activation of cyclohexane was also investigated in two experiments. Under anhydrous conditions, slow addition of Cu(I) dissolved in CF3CO2H to a solution of Cu(II) dissolved in CF3CO2H/C6H12 in air and gave a 17% yield of cyclohexyltrifluoroacetate. A 19.2% yield of this ester was obtained when solid Cu2O was stirred in the Cu(II) solution under a 100% O2 atmosphere. The yields are comparable even under widely varying conditions. Also, the yields are higher than for methane activation, probably due primarily to easier activation of a secondary hydrogen atom, aided by a higher solution concentration of cyclohexane (0.4M compared to about 0.01M).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]2[CH:14]=[C:15]3[CH2:20][CH2:19][CH2:18][C:16]3=[CH:17][C:12]=2[O:11][C:10](=[O:21])[C:9]=1[C:22]([O:24]CC)=[O:23].Cl.C(O)(=O)C>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]2[CH:14]=[C:15]3[CH2:20][CH2:19][CH2:18][C:16]3=[CH:17][C:12]=2[O:11][C:10](=[O:21])[C:9]=1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1c(-c2ccccc2C)c2cc3c(cc2oc1=O)CCC3
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccccc1-c1c(C(=O)O)c(=O)oc2cc3c(cc12)CCC3

Procedure:
A mixture of ethyl 4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]benzopyran-3-carboxylate (5.0 g), concentrated hydrochloric acid (13 ml) and acetic acid (25 ml) was refluxed for 12 hours. To this reaction mixture was added water, whereupon 4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]benzopyran-3-carboxylic acid was obtained as crystals (4.5 g, 97.8%). Recrystallization from acetone-hexane gave colorless prisms, mp 213°-214° C.