Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2I.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([Sn](C)(C)C)[N:34]=[C:33]([N:41]2[CH2:46][CH2:45][CH:44]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:43][CH2:42]2)[N:32]=1>CN(C=O)C.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.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2[C:35]1[CH:36]=[C:31]([O:30][CH3:29])[N:32]=[C:33]([N:41]2[CH2:46][CH2:45][CH:44]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:52])([CH3:51])[CH3:53])[CH2:43][CH2:42]2)[N:34]=1
Reactant: COc1cc([Sn](C)(C)C)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4c(F)cccc4F)ccc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4c(F)cccc4F)cc23)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 90 °C
Yield: 43.5 %

Procedure:
To a solution of 5-(2,6-difluorophenyl)-3-iodo-1-tosyl-1H-indole (0.107 g, 0.2 mmol) and tert-butyl (1-(4-methoxy-6-(trimethylstannyl)pyrimidin-2-yl)piperidin-4-yl)carbamate (0.1 g, 0.2 mmol) in DMF (2 mL) was added Pd(PPh3)4 (23 mg, 0.02 mmol) and CuI (42 mg, 0.22 mmol) and argon gas was bubbled for 15 min. The reaction was heated at 90° C. for 1 h then quenched with water. The suspension was extracted with EtOAc and the organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified with basic alumina chromatography (eluting with 50% EtOAc in petroleum ether) to give tert-butyl (1-(4-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)piperidin-4-yl)carbamate (60 mg, 41%). MS (ESI, pos. ion) m/z: 690.2 (M+1); 1H-NMR (DMSO-d6, 300 MHz): δ ppm 8.71 (s, 1H), 8.61 (s, 1H), 8.10-8.20 (m, 3H), 7.42-7.52 (m, 4H), 7.20-7.25 (m, 3H), 6.76 (m, 1H), 4.56 (d, J=12.9 Hz, 2H), 3.87 (s, 3H), 3.32 (d, J=9 Hz, 3H), 3.03 (m, 2H) 2.33 (s, 3H), 1.74 (d, J=12.9 Hz, 2H), 1.3 (s, 9H).
Reaction SMILES: C(O[C:4](=[O:17])[C:5](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16])[C:6]#[N:7])C.[CH2:18]([NH2:20])[CH3:19].O.C(N(CC)CC)C>CO>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][N:8]=[C:5]([C:6]#[N:7])[C:4]([NH:20][CH2:18][CH3:19])=[O:17]
Reactant: CCOC(=O)C(C#N)=NNc1ccccc1Br
Reactant: CCN
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCNC(=O)C(C#N)=NNc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [(2-bromophenyl)-hydrazono]-cyanoacetic acid ethyl ester (1.0 g, 3.4 mmol) in methanol (14 mL) was added 70% ethyl amine in water (16 mL, 20.2 mmol) followed by triethyl amine (468 uL, 3.6 mmol). The reaction was stirred at room temperature overnight, concentrated and dried under high vacuum. The material was routinely used crude. Purification on silica gel using a gradient of 10to 50% ethyl acetate in hexanes afforded the title compound as a yellow solid. 1H NMR (300.132 MHz, CDCl3) δ 14.33 (s, 1H), 7.67 (dd, J=8.3, 1.4 Hz, 1H), 7.53 (dd, J=8.1, 1.3 Hz, 1H), 7.34 (tq, J=7.8, 0.6 Hz, 1H), 7.01 (td, J=7.7, 1.6 Hz, 1H), 3.45 (dq, J=5.9, 7.2 Hz, 2H), 1.26 (t, J=7.3 Hz, 3H). HPLC 4.66 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH3:12])=[C:5]2[CH2:13][CH3:14].[C:15](Cl)(Cl)=[O:16].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:16])=[CH:10][CH:9]=2)[C:5]([CH2:13][CH3:14])=[C:6]1[CH3:12]
Reactant: Nc1ccccn1
Reactant: CCc1c(C)n(C)c2ccc(N)cc12
Reactant: O=C(Cl)Cl
Product: CCc1c(C)n(C)c2ccc(NC(=O)Nc3ccccn3)cc12

Procedure:
The title compound was prepared from the aminoindole (D1), phosgene and 2-aminopyridine using a procedure similar to that described for Example 1, the product being isolated as the free base, m.p. 120°-123° C.
Reaction SMILES: [CH:1]([OH:6])(O)[CH2:2][CH2:3][CH3:4].Cl[CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(Cl)(=[O:20])C.S(=O)(=O)(O)O>C(Cl)Cl.C(N(CC)CC)C>[CH2:10]([O:9][CH2:8][O:20][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCC(O)O
Reactant: CC(=O)Cl
Reactant: CCCCCCCCOCCl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCOCOCCCCO

Procedure:
The precursor, C8H17OCH2OC4H8OH was prepared by monoalkylation of butane diol with octyl chloromethyl ether. The precursor was first acetylated with acetyl chloride in methylene chloride containing triethylamine and then fluorinated, and a portion of the crude perfluorinated product was hydrolyzed by treatment with aqueous sulfuric acid and then distilled to yield the carboxylic acid C8F17OCF2OC3F6CO2H, having a boiling range 100°-106° C. at 1.1 torr. Differential scanning calorimetry revealed the acid had a Tg of -97.0° C. and several crystalline exotherms of -77.4, -61.5 and -37.7° C. and a broad melting point at -9.0° C.
Reaction SMILES: [C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)/[C:27]([O-:29])=O)[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].CS(Cl)(=O)=O.[NH2:57][C@@H:58]1[C:89](=[O:90])[N:60]2[C:61]([C:73]([O:75][CH:76]([C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=3)[C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=3)=[O:74])=[C:62](/[CH:65]=[C:66]3\[CH:67]=[C:68]([CH3:72])[C:69](=[O:71])[O:70]\3)[CH2:63][S:64][C@H:59]12.N1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH3:72][C:68]1[C:69](=[O:71])[O:70]/[C:66](=[CH:65]/[C:62]2[CH2:63][S:64][C@@H:59]3[C@H:58]([NH:57][C:27](=[O:29])/[C:26](=[N:30]\[O:31][C:32]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)/[C:24]4[N:25]=[C:21]([NH:20][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)[S:22][CH:23]=4)[C:89](=[O:90])[N:60]3[C:61]=2[C:73]([O:75][CH:76]([C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)[C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)=[O:74])/[CH:67]=1
Reactant: CC1=C/C(=C\C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](N)[C@H]3SC2)OC1=O
Reactant: O=C([O-])/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1=C/C(=C\C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)OC1=O
Temperature: -15 °C
Yield: 39.4 %

Procedure:
Sodium 2-(2-triphenylmethylaminothiazol-4-yl)2-Z-triphenylmethoxyiminoacetate (0.832 g), in dry DMF (2 mls) was cooled to ca -50° C. under argon and treated with methanesulphonyl chloride (0.093 mls). The solution was allowed to warm to -15° C. over 30mins and then treated with a solution of diphenylmethyl 7β-amino-3-(E-2,5-dihydro-3-methyl-2-oxofuran-5-ylidenemethyl)ceph-3-em-4-carboxylate (0.474 g) and pyridine (0.096 mls) in DMF (3 mls). The reaction was allowed to warm to room temperature over 1h., diluted with ethyl acetate and washed with water (3×), brine and dried. After removal of solvent, flash chromatography on silica gel eluting with 30, 40% ethyl acetate/hexane, gave the title compound as a foam, (0.444 g, 39%), νmax (CH2Cl2) 3375, 1780 (shoulder), 1760, 1720, 1680 and 1500cm-1 ; δH (CDCl3) 1.88 (3H,s), 3.37 (2H,ABq, J17.6Hz), 5.14 (1H,d,J5.1Hz), 6.10 (1H,dd,J5.1,8.8Hz), 6.44 (1H,s), 6.48 (1H,s) 6.77 (1H,br.s, exch.), 6.98 (1H,s), 7.00 (1H,s) and 7.2-7.4 (40H,m); [mass spectrum: +ve ion (NOBA) MH+, 1128].
Reaction SMILES: Cl.[NH2:2][OH:3].O.[OH-].[Na+].[CH3:7][N:8]([CH3:18])[C:9]1[CH:14]=[C:13]([C:15](=O)[CH3:16])[CH:12]=[CH:11][N:10]=1>CO>[CH3:7][N:8]([CH3:18])[C:9]1[CH:14]=[C:13]([C:15](=[N:2][OH:3])[CH3:16])[CH:12]=[CH:11][N:10]=1
Reactant: CC(=O)c1ccnc(N(C)C)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NO)c1ccnc(N(C)C)c1
Reaction time: 0.08 h

Procedure:
To 3.1 g. (45 mmoles) of hydroxylamine hyrochloride in 25 ml. of water and 22.5 ml. of 2 N sodium hydroxide solution was added 4.31 g. (26 mmoles) of 1-(2-dimethylamino-4-pyridyl)-1-ethanone, and the mixture was heated to boiling. After 5 minutes, methanol was added until the mixture became homogeneous. Heating was continued until a precipitate started to appear, and the mixture was then cooled. The solids were filtered, washed with water and dried. Recrystallization from toluene gave 4.03 g. (86%) of product, m.p. 145°-148° C.
Reaction SMILES: CC([N:5](C(O)=O)[NH:6][C:7](=[O:25])[CH:8]=[CH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=1)(C)C.Cl>C(O)C>[CH3:19][C:16]([C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:13]=1[OH:20])[CH:9]=[CH:8][C:7]([NH:6][NH2:5])=[O:25])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1cc(C=CC(=O)NN(C(=O)O)C(C)(C)C)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(C=CC(=O)NN)cc(C(C)(C)C)c1O
Yield: 93.9 %

Procedure:
1,1-Dimethylethyl 2-[3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl]hydrazinecarboxylic acid (4.3 g, 0.011 mole) in absolute ethanol (20 ml) is treated with aqueous 2M HCl (11.0 ml, 0.022 mole). The resulting mixture is heated on a steam-bath for one hour. The mixture is stripped of volatiles under reduced pressure and the residue partitioned between ether and water. The layers are separated and the aqueous phase is treated with saturated aqueous NaHCO3 until basic. The product is extracted out with a mixture of 1:1 ethyl acetate/ether. The organic extract is washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration provides a solid which is triturated in hot hexane and filtered to yield 3.0 g (3.2 g theor., 94%) of 3,5-bis(1,1-dimethylethyl)-4-hydroxycinnamic acid hydrazide, mp 166° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH3:17])(=O)=O.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][C:29]([NH2:32])([CH3:31])[CH3:30].N1C2C(=CC=CC=2)C(CC(N)(C)C)=C1>>[ClH:18].[NH:24]1[C:25]2[C:21](=[CH:20][CH:19]=[CH:27][CH:26]=2)[C:22]([CH2:28][C:29]([NH:32][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH3:17])([CH3:30])[CH3:31])=[CH:23]1
Reactant: CCOc1ccccc1OCCOS(C)(=O)=O
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Agent: CC(C)(N)Cc1c[nH]c2ccccc12
Product: CCOc1ccccc1OCCNC(C)(C)Cc1c[nH]c2ccccc12
Product: Cl

Procedure:
Proceeding as in Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-(2-ethyloxyphenoxy)ethyl methanesulfonate and [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2-(1H-indol-3-yl)-1,1-dimethylethyl]amine, gave [2-(1H-indol-3-yl)-1,1-dimethylethyl][2-(2-ethyloxy-phenoxy)ethyl]amine hydrochloride, m.p. 184°-186° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:34])=[C:4]([S:9]([NH:12][C:13]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:14]=2[CH2:15][NH:16]C(=O)OC(C)(C)C)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:16][CH2:15][C:14]1[C:24]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:25][CH:26]=[CH:27][C:13]=1[NH:12][S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:34])(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)NCc1c(NS(=O)(=O)c2cc(Cl)cc(Cl)c2O)cccc1N1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1c(NS(=O)(=O)c2cc(Cl)cc(Cl)c2O)cccc1N1CCCCC1
Reaction time: 8 h

Procedure:
To a solution of 47 (75 mg) in dichloromethane (5 mL) was added TFA (0.5 mL). The solution was stirred overnight. Followed by usual workup. The title compound was obtained as an off-white solid (35 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].Br[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([F:9])[C:7]=1[O:8][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(F)c(OCc2ccc3ccccc3c2)c(F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
Ethyl 3,5-difluoro-4-hydroxybenzenepropanoate (200 mg, 0.87 mmol) was dissolved in DMF (10 mL). 2-(Bromomethyl)naphthalene (212 mg, 0.96 mmol) and potassium carbonate (132 mg, 0.96 mmol) were added thereto, and then the mixture was stirred at 80° C. for 4 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 80:20) to give the title compound (298 mg, yield 93%).
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)#[N:2].[C:12]([O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:12]([O:16][C:17]([C:18]1[CH:23]=[CH:22][C:21]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:11]=[C:3]2[C:1]#[N:2])=[CH:20][CH:19]=1)=[O:25])([CH3:15])([CH3:13])[CH3:14]
Reactant: N#Cc1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-n2c(C#N)cc3ccccc32)cc1
Temperature: 110 °C
Yield: 55 %

Procedure:
A mixture of 3.0 g (0.02 mol) of 2-cyanoindole, 4.2 g (0.02 mol) of tert-butyl-4-fluorobenzoate, and 5.5 g (0.04 mol) of potassium carbonate in 30 ml dimethyl sulfoxide was heated at 110° C. for 48 hours. The reaction was poured onto ice-water and extracted twice with ethyl acetate. The organic extracts were combined, washed with water and dried over magnesium sulfate. Evaporation yielded a dark oil which was flash chromatographed on silica gel, eluting with ethyl acetate-hexane 1:9 to give 3.6 g (0.011 mol) of 1-[4-(tertbutoxycarbonyl)phenyl]-2-cyanoindole as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1.[CH3:21]N(C(OC)OC)C.Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[O:32].CO>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:30]([C:31]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[O:32])=[CH:21][N:20]=2)[CH:19]=1
Reactant: Nc1ccc(N2CCCC2c2cc(F)ccc2F)cn1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)cc1)c1cnc2ccc(N3CCCC3c3cc(F)ccc3F)cn12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To stirred solution of 5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyridin-2-amine (0.3 g, 1.0 mmol) (from Int-15) in dry toluene (3 ml, 10 v) was added DMF-DMA (0.14 g, 1.2 mmol) under N2 atm and stirred for 2 h at 120° C., after completion of starting material; cooled it to 10° C. then added 2-bromo-1-(4-fluorophenyl)ethanone (0.3 g, 1.4 mmol) drop wise and methanol (1 ml) was added under N2 atm then stirred for 16 h at 120° C. Reaction mixture was cooled to room temperature and solvent was removed under vacuum and residue was dissolved in DCM (100 ml), washed with water, brine and dried over Na2SO4 and concentrated under vacuum to get crude product. Crude was purified by column chromatography using 60-120 mesh silica gel product eluted with 30-40% ethyl acetate/Hexane to afford (6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridin-3-yl)(4-fluorophenyl)methanone as a off white solid (0.02 g, 4.3% Yield), MS (ESI): m/z 423.1 (M+H). 1H NMR (300 MHz, CDCl3) δ 9.08 (1H, s), 8.04 (1H, s), 7.89-7.84 (2H, m), 7.59-7.56 (1H, d J=9 Hz), 7.23-7.17 (2H, m), 7.09-7.08 (1H, m), 6.96-6.92 (2H, m), 6.81 (1H, bs), 5.07-5.04 (1H, d J=9 Hz), 3.85-3.75 (1H, m), 3.49-3.47 (1H, m), 2.54-2.46 (1H, m), 2.14-2.08 (3H, m) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1Br)=[O:5])[CH3:2].[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].N(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1[C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1C#C[Si](C)(C)C
Temperature: 25 °C

Procedure:
To a mixture of 2-bromo-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1.00 equivalent), trimethylsilylacetylene (1.20 equivalents) and iPr2NH (2.00 equivalents) in THF is added CuI (0.10 equivalents) followed by Pd(PPh3)2Cl2 (0.10 equivalents). After stirring the reaction mixture at reflux for 16 hours, it is cooled to room temperature and diluted with ethyl acetate. The organic layer is washed with saturated NH4Cl solution and brine, dried (MgSO4) and concentrated under reduced pressure. The desired product is obtained by flash column chromatography as necessary.
Reaction SMILES: [OH:1][C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:23]([F:26])([F:25])[F:24])([OH:22])[C:18]([F:21])([F:20])[F:19])[CH:12]=1)([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:22][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]([C:3]([F:6])([F:5])[F:4])([O:1][S:35]([CH3:34])(=[O:37])=[O:36])[C:7]([F:10])([F:9])[F:8])[CH:12]=1)([C:18]([F:19])([F:20])[F:21])[C:23]([F:24])([F:25])[F:26])(=[O:37])=[O:36]
Reactant: OC(c1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(c1cccc(C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F)c1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
4.1 g (10 mmol) of 1,3-bis-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoroethyl)-benzene were dissolved in 50 ml of methylene chloride, and 2.5 g (25 mmol) of triethylamine were added. 3.64 g (25 mmol) of methanesulfonyl chloride were then added dropwise. The mixture was stirred for 8 hours at room temperature, separated off from the precipitated salt and evaporated down. 5.6 g of 1,3-bis-(1-methanesulfonyloxy-1-trifluoromethyl-2,2,2-trifluoro-ethyl)-benzene were obtained (colorless crystals, m.p.: 125° C. [from diisopropyl diether]).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]([O:10][CH2:11][CH2:12][OH:13])(=[O:9])C=C.O1CC[CH2:16][CH2:15]1>>[OH:13][CH2:12][CH2:11][O:10][C:6]([CH:2]1[CH2:1][CH:5]2[CH2:4][CH:3]1[CH:15]=[CH:16]2)=[O:9]
Reactant: C1=CCC=C1
Reactant: C1CCOC1
Reactant: C=CC(=O)OCCO
Product: O=C(OCCO)C1CC2C=CC1C2
Temperature: -30 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
About 66 g of cyclopentadiene is dissolved in about 500 g of tetrahydrofuran (THF). To the resulting mixture was added 130 g of 2-hydroxyethyl acrylate, and the reaction mixture was stirred at −30° C. for 10 hours. The solvent was removed by distillation through a rotary distiller. The title compound was obtained by distillation under reduced pressure (yield: 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][CH3:10])[CH:3]=1.O.[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]#[N:13])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COc1cc(Cl)ccc1C#N
Temperature: 25 °C
Yield: 90 %

Procedure:
A mixture of Example 59A (2.68 g, 10 mmol), Zn(CN)2 (0.654 g, 5.5 mmol), and Pd(PPh3)4 (0.577 g, 0.5 mmol) in DMF (15 mL) was stirred at 90° C. for 6 hours and cooled to room temperature. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate several times. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 9:1 hexanes/ethyl acetate to provide 1.34 g (90%) of the desired product. MS (DCI) m/e 168 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J=8.1 Hz, 1H), 6.97-7.03 (m, 2H).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH3:15])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([CH:57]([C:62]2[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=2)[CH2:58][CH2:59][CH2:60][NH2:61])=[CH:53][CH:52]=1>CN(C=O)C.C(OCC)C>[F:50][C:51]1[CH:56]=[CH:55][C:54]([CH:57]([C:62]2[CH:63]=[CH:64][C:65]([F:68])=[CH:66][CH:67]=2)[CH2:58][CH2:59][CH2:60][NH:61][C:12]([C@@H:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH3:15])=[O:14])=[CH:53][CH:52]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)N1CCCCCC1)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 65.6 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-propanoic acid (0.300 g, 1.40 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.732 mL, 4.20 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.531 g, 1.40 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.412 g, 1.40 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 40 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (70% EtOAc in hexanes) to afford 0.42 g (65%) of the pure titled compound as a white foam: mp 29-49° C. APCI-MS m/z 458.3 (MH+).