Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[NH:39][CH:38]=[CH:37]4)[N:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[N:39]([C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:12])=[CH:4][C:3]([O:2][CH3:1])=[O:13])[CH:38]=[CH:37]4)[N:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: COC(=O)C#Cc1ccccc1Cl
Product: COC(=O)C=C(c1ccccc1Cl)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 43 %

Procedure:
The title compound was synthesized from (2-chloro-phenyl)-propynoic acid methyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 43% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.54–7.30 (m, 6H), 7.18 (m, 1H), 6.95 (m, 1H), 6.83 (m, 1H), 6.68–6.50 (m, 2H), 6.35 (s, 0.33H), 5.95 (s, 0.67H), 4.39 (m, 2H), 3.78 (m, 2H), 3.64 (s, 3H), 3.22 (m, 2H), 2.73 (m, 2H), 1.92 (m, 2H), 1.52 (s, 9H). Mass Spectrum (LCMS, ESI) calculated for C28H27ClN3O3 488.2 (M-Boc+H); found 488.4.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[N:4]=1.[CH:11]([O:14][CH2:15][CH2:16][OH:17])([CH3:13])[CH3:12]>>[Br:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:17][CH2:16][CH2:15][O:14][CH:11]([CH3:13])[CH3:12])[N:4]=1
Reactant: BrCc1cccc(CBr)n1
Reactant: CC(C)OCCO
Product: CC(C)OCCOCc1cccc(CBr)n1
Yield: 28 %

Procedure:
Prepared from 2,6-bis(bromomethyl)pyridine and 2-(isopropyloxy)ethanol by the alkylation method described for the final step of Example 32 to give the title compound (28%); NMR δH (400 MHz, CDCl3) 7.69 (1H, t, J 7.5 Hz), 7.43 (1H, d, J 7.5 Hz), 7.33 (1H, d, J 7.5 Hz), 4.69 (2H, s), 4.53 (2H, s), 3.73-3.69 (2H, m), 3.68-3.58 (3H, m), 1.18 (6H, d, J 6.0 Hz); (M+H)+288, 290.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]#[N:15].[H][H]>[Co].C(CN)O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][NH2:15]
Reactant: Cc1oc(-c2ccccc2)nc1CC#N
Reactant: [H][H]
Agent: [Co]
Solvent: NCCO
Product: Cc1oc(-c2ccccc2)nc1CCN
Yield: 102.3 %

Procedure:
This example was run in an analogous manner as example 5 but using 6.00 g (30 mmol) of (5-Methyl-2-phenyl-oxazol-4-yl)-acetonitrile in the presence of 0.60 g of wet Raney Cobalt catalyst (Johnson Matthey 8B0022, wet, ca. 50 weight %) in the presence of 40 μL of ethanolamine as modifier in a 185 mL autoclave at 70° C. under 9 bar of hydrogen pressure for 1.5 h. Removal of the catalyst by filtration, evaporation of the solvents and drying (50° C./10 mbar/2 h) afforded 6.21 g of 2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamine with a purity of 90.3% (HPLC area %).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]3/[C:14](=[CH:23]/[C:24]#[N:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-:32].[Na+].O>C(O)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]3/[C:14](=[CH:23]/[C:24]([NH2:25])=[O:32])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [OH-]
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(N)=O
Temperature: 70 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (404 mg, 1.00 mmol) obtained in Example 1 was dissolved in ethanol (8 mL), 2 mol/L aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at 70° C. for 2 days. Water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with 2 mol/L aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was filtered to give the title compound (compound 3) (279 mg, 66%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1c[nH]c2ccccc12
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1cc(C(=O)c2cccc([N+](=O)[O-])c2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A mixture of 3-(3-nitrobenzoyl)indole (2.09 g), ethyl 4-bromobutyrate (1.614 g) and potassium carbonate (3.118 g) in N,N-dimethylformamide (20 ml) was stirred at 25° C. overnight. The reaction mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to give ethyl 4-[3-(3-nitrobenzoyl)indol-1-yl]butyrate (2.71 g) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.S(O[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:30]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[N:35]1([C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:27][N:1]2[CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: c1ccc2c(c1)COc1ccccc1N2C[C@H]1CCCN1
Reactant: CS(=O)(=O)OCCc1cccc(N2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: c1cc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc(N2CCCC2)c1
Temperature: 90 °C

Procedure:
(R)-5,11-dihydro-5-(2-pyrrolidylmethyl)dibenzo[b,e][1,4]oxazepine (240 mg, 0.85 mmol, prepared by a method disclosed in International Patent No. 9912925A1), 3-pyrrolidinophenethyl mesylate (253 mg, 0.94 mmol), sodium carbonate (106 mg, 1.0 mmol) and sodium iodide (10 mg, 0.07 mmol) were added to acetonitrile (20 ml), and they were heated at 90° C. under reflux for 6.5 hours. The solvent was evaporated under reduced pressure, and the residue was distributed into ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (15:1) and then with hexane and ethyl acetate (2:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(3-pyrrolidinophenethyl)pyrrolidin-2-ylmethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oily substance (208 mg, 54%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.P(Cl)(Cl)([Cl:30])=O>O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:30])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1O
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Temperature: 100 °C

Procedure:
A 2-liter round bottom flask was charged with 7-(benzyloxy)-3-nitroquinolin-4-ol (100.0 g, 0.3 mol) and N,N-dimethylformamide (DMF) (650 mL). Phosphorous oxychloride (62.1 g, 37.7 mL, 1.2 equivalents (eq)) was slowly added dropwise. The resulting mixture was heated at 100° C. for 10 minutes, and then allowed to cool to 39° C. The reaction mixture was poured over ice (3 L). A brown precipitate formed. The mixture was diluted with water (1 L) and stirred to break up the precipitate. The precipitate was collected by vacuum filtration. The filter cake was washed with water (2 L) and air-dried on vacuum filter for 1 hour. The solid was dissolved in dichloromethane and placed in a separatory funnel. The water was removed, and the dichloromethane solution was dried over magnesium sulfate. The solution was then filtered through filter agent to provide a solution of 7-(benzyloxy)-4-chloro-3-nitroquinoline in dichloromethane (approximately 1700 mL).
Reaction SMILES: C[Sn]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])(C)C.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=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>[Br:15][C:16]1[N:17]=[C:18]([C:5]2[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=2[CH3:10])[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=S)c1cc([Sn](C)(C)C)c(C)s1
Reactant: Brc1cccc(Br)n1
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: COC(=S)c1cc(-c2cccc(Br)n2)c(C)s1
Temperature: 120 °C
Yield: 42.4 %

Procedure:
Methyl 4-(1,1-dimethyl-1-stannaethyl)-5-methylthiothiophene-2-carboxylate (195 mg, 0.56 mmol) as prepared in previous step, and 2,6-dibromopyridine (398 mg, 1.7 mmol) were taken in anhydrous DMF (2 mL). To this mixture tetrakistriphenylphosphine-palladium (20 mg) was added and heated at 120° C. for 24 h. DMF was removed under vacuum and the residue was purified by preparative silica gel thin-layer chromatography to give 78 mg (41%) of methyl 4-(6-bromo(2-pyridyl))-5-methylthiothiophene-2-carboxylate as a solid. 1H-NMR (CDCl3; 300 MHz) δ2.60 (S, 3H), 3.78 (s, 3H), 7.19 (S, 1H), 7.47 (dd, J=1.09 and 7.67 Hz, 1H)), 7.58 (t, J=7.70, 1H), 7.65 (dd, J=1.12 and 7.43 Hz, 1H).
Reaction SMILES: [CH2:1]([CH:11]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70]CCCC)[CH2:12][N:13]=[C:14]([C:16]1[C:25]2[C:24]([C:26]([OH:28])=[O:27])=[C:23]([Br:29])[C:22]([Br:30])=[C:21]([C:31]([OH:33])=[O:32])[C:20]=2[C:19]([C:34](=[N:36][CH2:37][CH:38]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]CC)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]CCCCCC)[OH:35])=[C:18]([Br:61])[C:17]=1[Br:62])[OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CCCC.C(C(CCCCCCCC)CN)CCCCC>>[CH2:39]([CH:38]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:37][N:36]=[C:34]([C:19]1[C:20]2[C:21]([C:31]([OH:33])=[O:32])=[C:22]([Br:30])[C:23]([Br:29])=[C:24]([C:26]([OH:28])=[O:27])[C:25]=2[C:16]([C:14](=[N:13][CH2:12][CH:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[OH:15])=[C:17]([Br:62])[C:18]=1[Br:61])[OH:35])[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)CN=C(O)c1c(Br)c(Br)c(C(O)=NCC(CCCCCCCCCC)CCCCCCCCCCCC)c2c(C(=O)O)c(Br)c(Br)c(C(=O)O)c12
Agent: CCCCCCCCC(CN)CCCCCC
Product: CCCCCCCCC(CCCCCC)CN=C(O)c1c(Br)c(Br)c(C(O)=NCC(CCCCCC)CCCCCCCC)c2c(C(=O)O)c(Br)c(Br)c(C(=O)O)c12
Yield: 18 %

Procedure:
The same synthetic method for compound 22 was used except using 2-hexyldecyl amine instead of 2-decyltetradecyl amine, and the yield was 18% (calculated based on TBNDA as a starting material).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.F[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:8]([O:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:5][CH2:6]1
Reactant: Fc1ccccn1
Reactant: N[C@H]1CC[C@H](Oc2nccnc2C2CCOCC2)CC1
Product: c1ccc(N[C@H]2CC[C@H](Oc3nccnc3C3CCOCC3)CC2)nc1
Temperature: 160 °C
Reaction time: 72 h

Procedure:
trans-4-(3-(Tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexanamine (0.053 g, 0.19 mmol) and 2-fluoropyridine (0.033 mL, 0.38 mmol) were mixed in a microwave tube. The tube was sealed, and the mixture was stirred neat at 160° C. for 3 d. The crude mixture was purified via silica gel column chromatography to give N-(trans-4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexyl)pyridin-2-amine as a brown solid. [M+1] 355.2. IC50 (uM): 2.665.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@@:8](O)([CH3:23])[CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]2([CH3:23])[CH2:9][N@:10]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[CH:7]=1
Reactant: C[C@@](O)(CNS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F
Agent: CC1(c2cc(Br)ccc2F)C[N@@]1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(c2cc(Br)ccc2F)C[N@]1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-[(S)-2-(5-bromo-2-fluoro-phenyl)-2-hydroxy-propyl]-2-nitro-benzenesulfon-amide (20.8 g, 48 mmol) in CH2Cl2 (400 ml) was added PPh3 (19.2 g, 72.4 mmol) at 0-5° C. and diethyl azodicarboxylate (11.6 ml, 72.4 mmol). The reaction mixture was stirred for 24 h at 25° C. and concentrated. The title compound was obtained after chromatographic purification over silica gel (hexane-EtOAc 20:1 to 2:1) as yellow crystals: TLC (toluene-EtOAc 3:1): Rf=0.69; HPLC RtH5=1.308 min; 1H NMR (360 MHz, CDCl3): δ 8.31 (m, 1H), 7.28 (m, 3H), 7.60 (dd, 1H), 7.42 (m, 1H), 6.91 (dd, 1H), 3.24 (s, 1H), 2.81 (s, 1H), 2.06 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[OH:15])[CH:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:3]=1.Br[CH2:25][CH:26]=[CH2:27]>>[CH2:27]([O:15][C:9]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:5]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Cl)ccc2O)n1
Product: C=CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(Cl)cc2)nc(N)n1
Yield: 80 %

Procedure:
Following the method described in Example 165, 2-[2-amino-6-(4-chloro-phenylamino)-pyrimidin-4-yl]-4-chloro-phenol and 3-bromo-propene provided the title compound (80% yield) 1H NMR (DMSO-d6) δ 4.68 (d, 2H, CH2), 5.25-5.28 (m, 1H, Ar), 5.36-5.41 (m, 1H, Ar), 6.03-6.08 (m, 1H, Ar), 6.36 (s, 2H, NH2), 6.70 (s, 1H, Ar), 7.14 (d, 1H, J=8.9 Hz, Ar), 7.31 (d, 2H, J=8.9 Hz, Ar), 7.40 (dd, 1H, J—2.8 Hz, J=8.8 Hz, Ar), 7.78 (d, 2H, J=8.9 Hz, Ar), 7.85 (d, 1H, J=2.8 Hz, Ar), 9.32 (s, 1H, NH).
Reaction SMILES: [F:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH3:20])=[CH:15][CH:14]=1)([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[NH2:23][OH:24].C(O)C>N1C=CC=CC=1>[F:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[N:23][OH:24])[CH3:20])=[CH:15][CH:14]=1)([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc(C(F)(F)C(F)(F)c2ccccc2)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1ccc(C(F)(F)C(F)(F)c2ccccc2)cc1

Procedure:
A solution of 1.1 g. (0.00372 mole) of 4'-(α,α,β,β-tetrafluorophenethyl)-acetophenone, 0.7 g. (0.0071 mole) of hydroxylamine hydrochloride, 8.5 ml. of absolute ethanol, and 1.5 ml. of dry pyridine is heated to refluxing for 6 hours. Solvents are evaporated under reduced pressure and the residual solid is triturated with water. The crystalline product, m.p. 137°-139°C., is collected and recrystallized from hexane to obtain white needles, m.p. 139°-141°C. Recrystallization from hexane affords the analytical sample, m.p. 140°-141°C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23](=[O:24])[CH:22]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)[CH3:27]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A mixture of tert-butyl 4-oxopiperidine-1-carboxylate 165a (10.0 g, 50.2 mmol) and ethyl 2-(triphenylphosphoranylidene)acetate (26.2 g, 75.3 mmol) in toluene (200 mL) was stirred at 100° C. for 1 h. See FIG. 6. The mixture was concentrated and purified by column chromatography on silica gel (petroleum ether:ethyl acetate=10:1) to afford tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate 165b (12.6 g, 93%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 5.72 (s, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.52-3.45 (m, 4H), 2.94 (t, J=5.6 Hz, 2H), 2.28 (t, J=5.6 Hz, 2H), 1.48 (s, 9H), 1.29 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[Br:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH2:15][N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:18][CH:19]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1cccnc1
Solvent: CC#N
Product: O=c1c(Br)cc(-c2ccccn2)cn1C1=CCCN(Cc2ccccc2)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
718 mg of 3-bromo-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 40 ml of acetonitrile. 383 mg of benzyl bromide was added thereto, followed by stirring at 70° C. overnight. Further, 383 mg of benzyl bromide was added thereto, followed by stirring at 70° C. for 2 nights. After cooling to room temperature, the mixture was evaporated. The residue was dissolved in 30 ml of methanol, followed by cooling to 0° C. under stirring. 265 mg of sodium borohydride was added thereto, followed by stirring overnight under heating from 0° C. to room temperature. Water was added thereto, the solvent was evaporated, and then the residue was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 550 mg of 3-bromo-5-(2-pyridyl)-1-(1-benzyl-1,2,3,6-tetrahydropyridin-5-yl)-1,2-dihydropyridin-2-one. 270 mg of the product was dissolved in 20 ml of dimethylformamide. 179 mg of 2-(2-cyanophenyl)-1,3,2-dioxaborinate, 313 mg of cesium carbonate and 15 mg of tetrakistriphenylphosphine palladium were added thereto, followed by stirring at 120° C. for 1 hour. After cooling to room temperature, water was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 174 mg of the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[C:19]([O:21][CH3:22])=[O:20])[C:3]1=[O:23].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[C:15]([N:13]([CH3:14])[C@H:10]1[CH2:9][C@@H:8]([C:19]([O:21][CH3:22])=[O:20])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=3)[C:3]2=[O:23])[CH2:12][CH2:11]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Yield: 38 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butyl(methyl) amino)-cyclohexanecarboxylate (58 mg, 0.18 mmol), 3-(trifluoromethyl)benzoic acid (42 mg, 0.22 mol), EDCI (30 mg, 0.21 mmol), HOBT (30 mg, 0.21 mmol), and Et3N (21 mg 0.21 mmol) in CH2Cl2 was stirred overnight at room temperature. The solution was washed with water and brine, concentrated in vacuo and the residue chromatographed on silica gel (3%-5%-10% (NH4OH/MeOH)/CH2Cl2) to give 34 mg of the title product, (1R,2S,5R)-methyl 5-(tert-butyl(methyl)amino)-2-((S)-2-oxo-3-(3-(trifluoromethyl)-benzamido)pyrrolidin-1-yl)cyclohexanecarboxylate, as a white solid. MS found: (M+H)+=498.40.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[C:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH:21]=1>[Pt](=O)=O.CCOC(C)=O.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=CC(C)(C)CC(C)(C)C2)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2CC(C)(C)CC(C)(C)C2)c1
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A screw-cap pressure tube was charged with 69.31B (0.22 g, 0.55 mmol), 1:1 EtOAc/MeOH (10 mL), and platinum(IV) oxide (0.025 g, 0.11 mmol). The tube was purged three times with H2 at 50 psi and sealed, and the contents were stirred overnight. The mixture was diluted with EtOAc, filtered through silica gel (EtOAc), and concentrated. The crude product was purified by silica gel flash chromatography (0-8% EtOAc/hexane) to afford 69.32A (0.13 g, 59% yield) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][O:4][C:5]1[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1.[CH2:25](OC1OC(C(O)=O)=CC=1)CCCCCCCCC/C=C\CC>>[CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][O:4][C:5]1[O:9][C:8]([C:10]([CH3:25])=[O:12])=[CH:7][CH:6]=1
Reactant: CC/C=C\CCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: CCCCCCCCCCCCC(C)COc1ccc(C(=O)O)o1
Product: CCCCCCCCCCCCC(C)COc1ccc(C(C)=O)o1

Procedure:
In the procedure of Example 4(B) 5-(2-methyltetradecyloxy)-2-furancarboxylic acid was substituted for cis-5-(11-tetradecenyloxy)-2-furancarboxylic acid to yield methyl 5-(2-methyltetradecyloxy)-2-furyl ketone, M.P. 45°-47° C.