Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].C1N2CN3CN(C2)C[N:13]1C3.Cl>C1(C)C=CC=CC=1.C(O)C>[NH2:13][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: NCC(=O)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
To a stirred solution of 2-bromo-1-(4-bromophenyl)ethanone (130 g 0.478 mol) in toluene (2500 mL) was added hexamethylenetetramine (65.6 g 0.478 mol). The mixture was stirred at 40° C. for 16 hrs. The resulting solid was filtered off and washed with toluene and ether to give a white solid. To a stirred suspension of this white solid in ethanol (800 mL) was added concentrated hydrochloride acid (300 mL). The mixture was stirred at ambient temperature for 20 hrs. The solid was collected by filtration and washed with ethanol and water and dried in vacuo to give 2-amino-1-(4-bromophenyl)ethanone (4) (95 g, yield: 92%) as a white solid, which was used without purification for the next step. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.58 (s, br, 2H), 7.96 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 4.48-4.52 (m, 2H). ES LC-MS m/z=214, 216 (M+H)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[C:11]3[C:28]([O:30]CC)=[O:29])=[CH:4][C:3]=2[O:2]1.C1OC2C=CC(C3(O)C4C(=CC=CC=4)C(C4C=CC5OCOC=5C=4)=C3C(OCC)=O)=CC=2O1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([OH:30])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
Ethyl (RS)-1,3-Di-(3,4-methylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1-hydroxyindene-2-carboxylate (0.29 g, 0.65 mmol) in CH2Cl2 (3 ml) at 0° C. under an argon atmosphere was added triethylsilane (91 mg, 0.78 mmol), followed by boron trifluoride etherate (0.3 ml, 2.4 mmol). The reaction mixture was stirred for 10 min, at which time was added ice-cold 1M HCl, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was placed on a small pad of silica gel, eluting with CH2Cl2 to provide the title compound (257 mg, 92%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].C([O:27][P:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C.C(#N)C>CCOC(C)=O>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[P:28](=[O:27])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Reactant: CCOP(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccc2ccccc2c1

Procedure:
1-(trimethylsilyl)naphthalen-2-yl trifluoromethanesulfonate (25 mg, 0.071 mmol), Cesium Fluoride (60 mg, 0.395 mmol), Ethoxydiphenylphosphane (68 mg, 0.287 mmol), Acetonitrile (1 ml): Reaction Time: 16 h; Rf: 0.4 (1:3 EtOAc:Pet Ether); Thick oil; 19.5 mg, 83%; 1H NMR (400 MHz, CDCl3, TMS) δ 8.28 (d, J=13.8 Hz, 1H), 7.95-7.84 (m, 3H), 7.79-7.40 (m, 13H); 13C NMR (100 MHz, CDCl3, TMS) δ 134.7 (d, J=2.3 Hz), 134.0 (d, J=9.3 Hz), 133.0, 132.3, 132.1 (d, J=10.0 Hz), 132.0 (d, J=1.5 Hz), 131.3 (d, J=243.5 Hz), 128.9, 128.5 (d, J=12.3 Hz), 128.4, 128.2, 127.4 (d, J=87.9 Hz), 126.8 (d, J=10.8 Hz); 31P NMR (162 MHz, CDCl3) δ 29.3; HRMS-ESI (m/z) calcd (C22H17OP+H)+: 329.1090. found: 329.1086; Known compound, Lit. Y. -L. Zhao, G. -J. Wu, Y. Li, L. -X. Gao, F.-S. Han, Chem. Eur. J. 2012, 18, 9622.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([Br:9])=[C:4]([Cl:8])[N:3]=1
Reactant: Nc1cncc(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Nc1cnc(Br)c(Cl)n1
Yield: 18.6 %

Procedure:
A solution of 2-amino-6-chloropyrazine (5.0 g) and N-bromosuccinimide (13.9 g) in chloroform (200 ml) was heated under reflux for 2 hours. Insoluble material was removed by filtration and the filtrate was concentrated by evaporation. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane, to give 2-amino-5-bromo-6-chloropyrazine (1.5 g); m.p. 120°-122° C.; mass spectrum (+ve CI): 208 (M+H)+.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.[CH2:14]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH2:23][CH3:24])[C:17]=1[C:25](=[O:37])[C:26]([NH:28][N:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH3:15].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O.NN.O>[CH2:14]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH2:23][CH3:24])[C:17]=1[C:25](=[O:37])[C:26]([N:28]([CH3:1])[N:29]=[CH:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:27])[CH3:15]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: NN
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a 50 mL volume three-necked flask, 7.6 mg of hydrazine hydrate, 2.3 ml of toluene, 629 mg of potassium carbonate and 574 mg of dimethyl sulfate were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 5° C. and 1.6 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(phenylmethylidene)hydrazine ((40-a)-(14)-6) solved in 2.3 g of toluene was added thereto. The reaction mixture was stirred at 5° C. for 31.5 hours. 5 mL of water was added and the resultant was neutralized to pH 7 with 20 wt % of sulfuric acid. The organic layer was removed and the aqueous layer was extracted with toluene two times. The organic layers were combined and concentrated under reduced pressure to give 1.22 g of a mixture (22:1 (GC area %)) of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(phenylmethylidene)hydrazine ((40-b)-(15)-5) and methyl 2-(2,6-diethyl-4-methylphenyl)-2-oxo-N-(phenylmethylidene)ethanehydrazonate (x-1).
Reaction SMILES: [Li]CCCC.CCCCCC.[O:12]1[CH2:17][CH2:16][O:15][C:14]2=[CH:18][S:19][CH:20]=[C:13]12.CN(C)CCN(C)C.[CH2:29]([Sn:33](Cl)([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32]>O1CCCC1>[CH2:38]([Sn:33]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:34][CH2:35][CH2:36][CH3:37])[C:18]1[S:19][CH:20]=[C:13]2[C:14]=1[O:15][CH2:16][CH2:17][O:12]2)[CH2:39][CH2:40][CH3:41]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1scc2c1OCCO2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1scc2c1OCCO2
Temperature: 35 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
1.5M n-BuLi in hexane (53 mL, 80 mmol) was added in small portions to a solution of 2,3-dihydrothieno[3,4-b][1,4]dioxine (10.00 g, 80 mmol) and tetramethylethylenediamine (12.0 mL, 80 mmol) in tetrahydrofuran (100 mL) stirred under argon and cooled in a dry ice/acetone bath. The reaction mixture was heated to 35° C., stirred at this temperature for 1 hour, and then cooled in a dry ice/acetone bath. Tributylstannyl chloride (20.3 mL), 75 mmol was then added, the mixture was allowed to warm up, and it was left at room temperature for 16 hours. The volatiles were removed under reduced pressure. The residue was diluted with toluene (100 mL) and chromatographed using a column filled with silica gel (500 mL) washed with 2% triethylamine in hexane (500 mL) to give tributyl(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)stannane (12.17 g, 40%) of high purity. 1H NMR (400 MHz, CDCl3): δ 6.57 (s, 1H, thiophene), 4.15 (m, 4H, OCH2CH2O), 1.53 (m, 6H, Bu), 1.32 (quintet, J=7.3 Hz, 6H, Bu), 1.09 (m, 6H, Bu), 0.88 (t, J=7.3 Hz, 9H, Bu).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.[O:53]1[C:57]([C:58](Cl)=[O:59])=[CH:56][CH:55]=[N:54]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:58]([C:57]2[O:53][N:54]=[CH:55][CH:56]=2)=[O:59])[CH2:25]1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1ccno1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CN(C(=O)c2ccno2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 68 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and isoxazole-5-carbonyl chloride as the starting materials in 68% yield. LCMS for C26H24ClN8O3 (M+H)+: m/z=531.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[S:19][C:18]([C:20](O)=[O:21])=[C:17]([CH3:23])[CH:16]=2)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[S:19][C:18]([C:20]([NH:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:21])=[C:17]([CH3:23])[CH:16]=2)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Product: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cccnc1
Yield: 39 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 5-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 39% yield: mp 165-167° C.; 1H NMR (300 MHz, CDCl3) δ 8.61 (d, J=1.5 Hz, 1H), 8.54 (dd, J=4.7, 1.5 Hz, 1H), 7.71 (dt, J=7.8, 1.5 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.43-7.27 (m, 6H), 6.85 (s, 1H), 6.30 (t, J=5.8 Hz, 1H), 6.15 (dd, J=7.8, 2.7 Hz, 1H), 6.06 (d, J=2.7 Hz, 1H), 5.04 (s, 2H), 4.61 (d, J=5.8 Hz, 2H), 2.54 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.2, 162.6, 160.9, 138.8, 137.5, 135.4, 135.0, 128.5, 128.2, 128.0, 126.9, 120.5, 102.6, 97.3, 70.0, 15.5; MS (ES+) m/z 432.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:8][OH:9])[CH2:5][CH:4]1[CH:6]=[CH2:7].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH2:19]>N1C=CC=CC=1.C1CCCCC1.CCOC(C)=O>[C:10]([O:1][CH2:2][C:3]1([CH2:8][O:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][CH:4]1[CH:6]=[CH2:7])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CC1CC1(CO)CO
Reactant: O
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCCCC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CC1CC1(COC(=O)c1ccccc1)COC(=O)c1ccccc1
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of 5.5 g (43 mmoles) of 1,1-bis(hydroxymethyl)-2-vinylcyclopropane in 40 ml of pyridine was cooled to 0° and 18.5 g (130 mmoles; 15.2 ml) of benzoyl chloride was added dropwise over 15 minutes. The mixture was stirred at 22° for 2 hours. TLC in cyclohexane-EtOAc (4:1) indicated that the reaction was complete. The reaction mixture was treated with 8 ml of water and stirred at 22° for 20 hours. It was concentrated to a residual oil and redissolved in 150 ml of EtOAc and washed with 50 ml of water, three 50-ml portions of 2N HCl, four 50 ml portions of saturated NaHCO3, dried (MgSO4), filtered and concentrated to give 11 g (75%) of the title compound, Rf cyclohexane-ethyl acetate (4:1) 0.7.
Reaction SMILES: Cl[C:2]1[CH:25]=[N:24][C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH:3]=1.[Na].[CH3:27][OH:28]>C(Cl)Cl>[CH3:27][O:28][C:2]1[CH:25]=[N:24][C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: Cc1ccc(-c2nc3cc(Cl)cnc3nc2-c2ccc(C)cc2)cc1
Reactant: CO
Agent: [Na]
Solvent: ClCCl
Product: COc1cnc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2c1
Temperature: 25 °C

Procedure:
A mixture comprising 7-chloro-2,3-dip-tolylpyrido[2,3-b]pyrazine (836 mg, 2.417 mmol) in dry MeOH (10 ml) and DCM (5 ml) bubbled through with nitrogen was treated portionwise with sodium (278 mg, 12.09 mmol). The resulting mixture was heated at reflux overnight. A further portion of sodium (278 mg, 12.09 mmol) was added and refluxing continued overnight. After cooling to RT, the solvent was removed in vacuo and the resulting residue was added to water. The mixture was extracted with DCM (×3) and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica eluting with 10-40% EtOAc/iso-hexane afforded the title compound;
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:34][CH2:35][OH:36]>C(O)C.C(Cl)Cl>[OH:36][CH2:35][CH2:34][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCNCC4)cc23)cn1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(CCO)CC4)cc23)cn1
Temperature: 80 °C
Reaction time: 13 h

Procedure:
4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid piperidin-4-ylamide (181), 150 mg, 0.43 mmol) is dissolved in 3 ml of ethanol under argon. After addition of sodium carbonate (182 mg, 1.7 mmol) and 2-bromo-ethanol (61 ul, 0.85 mmol), the reaction mixture is stirred at 80° C. for 13 h. The mixture is diluted with methylene chloride, filtrated and the filtrate is evaporated. Evaporation under reduced pressure gave 128 mg of crude product, which is further purified by Flash-chromatography (dichloro methane/methanol/25% ammonia (90:9:1). Yield: 90 mg (53%). MS (ESI): 395.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.[F:19][C:20]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=1[CH2:22]Br>O1CCCC1>[CH3:10][O:9][C:6]1[C@@H:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:31])[F:30])=[CH:27][C:20]=2[F:19])[N:8]=[C:3]([O:2][CH3:1])[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=1
Reactant: Fc1cc(C(F)(F)F)ccc1CBr
Reactant: COC1=N[C@@H](C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](Cc2ccc(C(F)(F)F)cc2F)C(OC)=N[C@H]1C(C)C
Reaction time: 0.33 h

Procedure:
To a solution of 3.32 g (18 mmol) of commercially available (2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine in 100 mL of tetrahydrofuran at −70° C. was added 12 mL (19 mmol) of a 1.6M solution of butyllithium in hexanes. After stirring at this temperature for 20 min, 5 g (19.5 mmol) of 2-fluoro-4-trifluoromethylbenzyl bromide in 20 mL of tetrahydrofuran was added and stirring was continued for 3 h before warming the reaction to ambient temperature. The reaction was quenched with water, concentrated in vacuo, and extracted with ethyl acetate. The combined organic phase was washed with brine, dried, and concentrated in vacuo. Purification by flash chromatography (silica gel, 0–5% ethyl acetate in hexanes) afforded the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:32]=[CH:33]/[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]2([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])OCC[O:41]2)[C@@:22]([OH:31])([CH3:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].O.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:32]=[CH:33]/[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](=[O:41])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C@@:22]([OH:31])([CH3:30])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@](C)(O)C(=O)OC(C)(C)C)C(=O)OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@](C)(O)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
(2S,3S,E)-tert-Butyl 3-((S)-3-(4-(but-2-ynyloxy)phenyl)-1-methoxy-1-oxopropan-2-ylcarbamoyl)-11-(2-heptyl-1,3-dioxolan-2-yl)-2-hydroxy-2-methylundec-4-enoate (540 mg, 0.756 mmol) was dissolved in dichloromethane (3.5 mL), and water (0.35 mL) was added. Trifluoroacetic acid (10 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated. The residue was then purified by diol column chromatography (n-hexane/acetone) to obtain the target compound as pale yellow oil at a yield of 91%.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.[CH2:52]([NH2:55])[CH2:53][NH2:54]>CN(C)C=O.CO.C(Cl)(Cl)Cl>[NH2:54][CH2:53][CH2:52][NH:55][C:22](=[O:23])[CH2:21][O:20][C:19]1[CH:25]=[CH:26][C:16]([CH2:15][CH:14]([C:9]2[NH:8][C:7]3[N:6]([CH2:28][CH2:29][CH3:30])[C:5](=[O:31])[N:4]([CH2:1][CH2:2][CH3:3])[C:12](=[O:13])[C:11]=3[N:10]=2)[CH3:27])=[CH:17][CH:18]=1
Reactant: NCCN
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)NCCN)cc3)[nH]c2n(CCC)c1=O
Reaction time: 1 h

Procedure:
Dissolve 2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenoxy]acetic acid (800 mg, 1.87 mmol) in dimethylformamide (20 mL) and treat with N-hydroxysuccinimide (215 mg, 1.87 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (751 mg, 3.92 mmol). Stir for 1 hour and add to a stirring solution of ethylenediamine (20 mL of a 10% solution in methanol). Stir for 1 hour and dilute with chloroform (600 mL). Separate the organic phase, wash with 5% sodium carbonate (200 mL), then brine (300 mL). Dry (MgSO4) and evaporate the solvent in vacuo. Purify by radial chromatography (5→10% methanol/chloroform with 1% ammonium hydroxide) and recrystallize (10% isopropanol/hexane) to give the title compound (364 mg); mp 143-44° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][CH3:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.C=C1O[C:20](=[O:21])[CH2:19]1>C1(C)C=CC=CC=1.O>[CH3:8][N:7]([CH2:6][C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:20](=[O:21])[CH3:19]
Reactant: C=C1CC(=O)O1
Reactant: CNCc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N(C)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolved in toluene was 3.1 g (0.02 mole) of 4-chloro-N-methyl-benzylamine, followed by an addition of a catalytic amount of pyridine and a further dropwise addition of 1.8 g (0.022 mole) of diketene at room temperature. After stirring the reaction mixture at room temperature for 3 hours, it was poured in water and then extracted with toluene. Subsequent to purification, N-methyl-N-(4-chlorobenzyl)acetamide was obtained in an oily form.
Reaction SMILES: [N:1]1([C:6]([C:8]2[C:9]([CH3:16])=[C:10]([CH:14]=O)[NH:11][C:12]=2[CH3:13])=[O:7])[CH:5]=[CH:4][N:3]=[CH:2]1.NCCN1C[CH2:24][O:23][CH2:22][CH2:21]1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])[CH2:30]2>C1COCC1>[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])/[C:30]/2=[CH:14]\[C:10]1[NH:11][C:12]([CH3:13])=[C:8]([C:6]([NH:1][CH2:5][CH2:4][N:3]2[CH2:21][CH2:22][O:23][CH2:24][CH2:2]2)=[O:7])[C:9]=1[CH3:16]
Reactant: NCCN1CCOCC1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)n1ccnc1
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCOC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCN1CCOCC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (5.0 g, 23.0 mmol), 4-(2-aminoethyl)morpholine (4.5 g, 34.6 mmol), 5-fluorooxindole (3.47 g, 23.0 mmol), and THF (80 ml) were mixed and heated to 65° C. After stirring for 24 h at 65° C., the mixture was cooled to room temperature and filtered. The cake was washed with 40 ml THF and dried overnight at 50° C. under house vacuum. 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-N-(2-morpholin-4-ylethyl)-1H-pyrrole-3-carboxamide (8.28 g) was obtained in 87% yield.
Reaction SMILES: [Li].C1C2C(=CC=CC=2)C=CC=1.[Cl-].[Zn+2:13].[Cl-].[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>C1COCC1>[Br-:15].[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Zn+:13])#[N:19]
Reactant: N#Cc1ccccc1Br
Reactant: [Zn+2]
Agent: [Cl-]
Agent: [Li]
Solvent: c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: N#Cc1ccccc1[Zn+]
Product: [Br-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Preparation of 2,2′-dicyanobiphenyl by nickel catalyzed reaction of 2-cyanophenylzinc bromide with 2-chlorobenzonitrile: Activated zinc was prepared and reacted with 2-bromobenzonitrile to provide 2-cyanophenylzinc bromide, as follows: A mixture of 0.208 g (30.0 mmol) lithium wire and 3.91 g (30.5 mmol) naphthalene in 15 mL of THF was stirred at room temperature for 4 h. To the resultant dark green solution was then added a solution of 2.04 g (15.0 mmol) zinc chloride in 15 mL of THF. After stirring the mixture for 10 minutes, 0.91 g (5.0 mmol) 2-bromobenzonitrile was added and the reaction mixture refluxed for 8 h. The resultant mixture was then filtered through a small pad of celite under nitrogen to provide a clear, dark solution of 2-cyanophenylzinc bromide.
Reaction SMILES: [C:1]([NH:6][C:7]1[S:18][C:10]2[CH2:11][N:12]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:14][C:9]=2[C:8]=1[C:19]([O:21]CC)=O)([O:3]CC)=O.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:39][CH3:40])[CH2:29][CH2:28]1>>[OH:3][C:1]1[N:24]([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[CH2:31][CH2:32]2)[C:19](=[O:21])[C:8]2[C:9]3[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][C:10]=3[S:18][C:7]=2[N:6]=1
Reactant: CCOC(=O)Nc1sc2c(c1C(=O)OCC)CCN(C(C)=O)C2
Reactant: COc1ccccc1N1CCN(CCN)CC1
Product: COc1ccccc1N1CCN(CCn2c(O)nc3sc4c(c3c2=O)CCN(C(C)=O)C4)CC1

Procedure:
2.5 g (7.3 mmol) of 2-carboethoxyamino-3-carboethoxy-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 1.7 g (7.3 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine were heated at 180° C. for 2 h under nitrogen and with the melt being thoroughly stirred. After cooling, the crude product was purified by column chromatography (silica gel, eluent methylene chloride/methanol 95/5). 0.7 g (20%) of product having a m.p. of 135-137° C. was isolated.