Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH:23](=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[BH4-].[Na+]>>[CH2:23]([NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Reactant: CCCCCC=O
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCNCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Yield: 57.7 %

Procedure:
Using a method similar to Example 201, using 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide (intermediate 20, 148 mg, 0.500 mmol), hexanal (75 mg, 0.750 mmol), and NaBH4 (38 mg, 1.00 mmol) gives the title compound (110 mg) as a colorless glass. Mass spectrum (ion spray): m/z=382 (M+1); 1HNMR (CDCl3): 8.57 (s, 1H), 8.15 (d, 1H), 7.21-7.14 (m, 2H), 6.90 (m, 2H), 6.05 (br. s, 2H), 3.01)m, 1H), 2.90-2.79 (m, 2H), 2.69-2.55 (m, 3H), 2.50-2.42 (m, 1H), 1.84-1.64 (m, 4H), 1.49 (m, 2H), 1.29 (m, 6H), 0.89 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[CH:14]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([CH3:41])=[CH:33][CH:34]=[C:35]([C:38](O)=[O:39])[N+:36]=2[O-:37])=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH:21]1([C:19]([NH:18][C:16]2[N:17]=[C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:38]([C:35]5[N+:36]([O-:37])=[C:31]([C:28]6[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=6)[C:32]([CH3:41])=[CH:33][CH:34]=5)=[O:39])=[N:7][CH:6]=4)=[CH:14][N:13]3[CH:15]=2)=[O:20])[CH2:22][CH2:23]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cn1
Reactant: Cc1ccc(C(=O)O)[n+]([O-])c1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cn2)[n+]([O-])c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a solution of N-{6-[(6-aminopyridin-3-yl)oxy]imidazo[1,2-a]pyridin-2-yl}cyclopropanecarboxamide (100 mg, 0.323 mmol) and 6-(4-fluorophenyl)-5-methylpyridine-2-carboxylic acid 1-oxide (103.8 mg, 0.42 mmol) in N,N-dimethylformamide (1 mL) were added N,N-diisopropylethylamine (111 μL, 0.646 mmol) and HATU (160 mg, 0.42 mmol), and the mixture was stirred at room temperature for 4 hr. Ethyl acetate, tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (140 mg, 80%) as a slightly yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[N:11]=[C:10](SC)[C:9]=2[C:33]#[N:34])[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[N:11]=[C:10]([N:45]3[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]3)[C:9]=2[C:33]#[N:34])[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc2nc(Nc3ccc(Oc4ccncc4)cc3)nn2c(-c2cccc(Cl)c2)c1C#N
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2nc3nc(Nc4ccc(Oc5ccncc5)cc4)nn3c(-c3cccc(Cl)c3)c2C#N)CC1

Procedure:
7-(3-Chlorophenyl)-5-methylsulfanyl-2-[4-(pyridin-4-yloxy)phenylamino]-1,2,4-triazolo[1,5-a]pyrimidine-6-carbonitrile (50 mg, 0.10 mol) is heated at 100° C. for 18 h in 1-methylpiperazine (1 ml) in a closed vessel. Ethyl acetate (5 ml) is added to the cooled solution, and the precipitate which forms is filtered off, washed with diethyl ether and dried, giving 32 mg (0.06 mmol, 55%) of “136”, [M+H]+ 539.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=1.[C:17](OC)(OC)(OC)[CH3:18].CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO.C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:17]([CH3:18])[N:9]([C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:16])[N:15]=3)[C:3]=2[CH:4]=1
Reactant: Nc1ncnc(Nc2cc(Br)ccc2N)n1
Reactant: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2ccc(Br)cc2n1-c1ncnc(N)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
To a solution of 2-N-(2-amino-5-bromophenyl)-1,3,5-triazine-2,4-diamine (2.50 g, 8.89 mmol) in methanol (25 mL) and THF (100 mL) was added trimethyl orthoacetate (16.77 ml, 133.4 mmol) and TsOH (153.14 mg, 0.89 mmol). The reaction mixture was stirred at 70° C. for 1 hr then allowed to cool to RT overnight. Saturated aqueous sodium bicarbonate (30 mL) was introduced and the resulting precipitous solution filtered. The filtrate was extracted into DCM (3×100 mL extractions). The combined organic extracts were washed with brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. The orange/yellow solid residue was then triturated from a mixture of DCM and MeOH to give the title compound as a pale yellow powder (400 mg): 1H NMR (500 MHz, DMSO) delta 2.89 (3H, s), 7.46 (1H, dd, J=8.5, 1.9 Hz), 7.57 (1H, d, J=8.4 Hz), 8.02 (1 H, s), 8.10 (1H, s), 8.61 (1H, d, J=1.8 Hz), 8.64 (1H, s); LC-MS: m/z=+306.7 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]1[O:24][C:17]2([CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[O:16][CH2:15]1>C(Cl)CCl>[O:16]1[C:17]2([CH2:22][CH2:21][CH:20]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)[CH2:19][CH2:18]2)[O:24][CH2:14][CH2:15]1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: ClCCCl
Product: Fc1ccc(N2CCN(C3CCC4(CC3)OCCO4)CC2)cc1
Reaction time: 18 h

Procedure:
A mixture of 11.5 gm of 1-(4-fluoro-phenyl)-piperazine 10.0 gm of 1,4-cyclohexanedione mono-ethylene ketal (available from Aldrich) and 27.2 gm NaB(OAc)3 in 250 ml dichloroethylene was kept for 18 hours at ambient temperature. The solvents were removed and the residue partitioned between ethyl acetate (200 ml) and 2N NaOH (200 ml). The ethyl acetate layer is washed with 2×20 ml water and dried over Na2SO4. The crude 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-(4-fluoro-phenyl)-piperazine (20.1 gm of a solid) obtained after removing the solvents had a melting point of 116-118° C. A sample of this material (C18H25FN2O2) showed an elemental analysis of C, 67.24%, H, 8.22%. N, 8.98%.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[I:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.C1C2C(=CC=CC=2)C=CC=1C(O)=O>>[I:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])=[O:9])=[CH:13][CH:12]=1
Reactant: Nc1ccc(I)cc1
Reactant: Cc1ccsc1C(=O)O
Agent: O=C(O)c1ccc2ccccc2c1
Product: Cc1ccsc1C(=O)Nc1ccc(I)cc1

Procedure:
This compound was synthesized by the same procedure as for Example 15, except 3-methyl-2-thiophenecarboxylic acid and 4-iodoaniline were used instead of 2-napthoic acid and 4-iodoaniline. M+1=344.2, mp 141˜142° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[N:7]([CH3:14])[C:6](=[O:15])[C:5]12[CH2:17][CH2:16]1>CO.Cl.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([CH3:14])[C:6](=[O:15])[C:5]12[CH2:16][CH2:17]1
Reactant: CN1C(=O)C2(CC2)c2cc(N)c([N+](=O)[O-])cc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1C(=O)C2(CC2)c2cc(N)c(N)cc21

Procedure:
Analogously to general procedure (II) the compound is prepared from 5′-amino-1′-methyl-6′-nitro-spiro[cyclopropane-1,3′-indoline]-2′-one (50 mg) in MeOH (10 ml) and hydrochloric acid (1 ml) using Pd/C (15.0 mg) as catalyst (3 h; 1 bar). After an aqueous work-up the compound is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[S:10][C:3]=12.CN(C=O)C.Cl[CH:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[CH2:24]([O:23][C:21]([C:20]1[S:13][C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[N:12][C:26]=1[CH3:28])=[O:22])[CH3:25]
Reactant: NC(=S)c1cc2nccc(Cl)c2s1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-c2cc3nccc(Cl)c3s2)nc1C
Temperature: 80 °C
Yield: 53.8 %

Procedure:
19.5 g (85.6 mmol) of 7-chloro-thieno[3,2-b]pyridine-2-carbothioic acid amide was added to 160 mL of a 1:1 DMF:THF solution mixture and cooled to 0° C. To this solution was slowly added 17.7 mL (128 mmol) of ethyl 2-chloroacetoacetate. After addition, the reaction was heated to 80° C. for sixteen hours. The reaction was cooled to room temperature and extracted with dichloromethane and water. The organic layer was separated and dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography to afford 2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (15.6 g) in 54% yield. C14H11ClN2O2S2: APCI m/z 339.1/341.0 (pos.); 1H NMR (CDCl3): δ 8.68 (d, 1H , J=5.4 Hz), 8.24 (s, 1H), 7.51 (d, 1H, J=5.4 Hz), 4.36 (q, 2H, J=7.1 Hz), 2.77 (s, 3H), 1.38 (t, 3H, J=7.1 Hz) ppm.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])[C:10](Cl)=[N:9][C:8]=2[N:7]=[C:6]1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[C:2]#[C:3][CH3:4].[C-:38]#[N:39].[Na+]>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])[C:10]([C:38]#[N:39])=[N:9][C:8]=2[N:7]=[C:6]1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[C:2]#[C:3][CH3:4]
Reactant: [C-]#N
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(Cc3ccccc3C#N)c(=O)c21
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(C#N)n(Cc3ccccc3C#N)c(=O)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
A mixture consisting of 8 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-1-(2-cyanobenzyl)-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate obtained in Example 96(a), 10 mg of sodium cyanide and 0.3 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water and then with saturated brine. The organic layer was concentrated. The residue was purified by thin layer chromatography (50% ethyl acetate/hexane) to give 6.1 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.F[B-](F)(F)F.[CH:24]1([C:30]2NC=C[N+]=2C2CCCCC2)[CH2:29]CCC[CH2:25]1.C([Mg]Cl)(C)(C)C.[NH4+].[Cl-]>C1COCC1.Cl[Ni]Cl>[C:24]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12)([CH3:30])([CH3:29])[CH3:25]
Reactant: O=C1C=C2c3cccc(Br)c3CCN2C(=O)CN1
Reactant: c1c[n+](C2CCCCC2)c(C2CCCCC2)[nH]1
Agent: Cl[Ni]Cl
Agent: CC(C)(C)[Mg]Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Temperature: -20 °C
Yield: 50 %

Procedure:
125-1. A mixture of 9-bromo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (2.0 g, 6.51 mmol), NiCl2*2H2O (0.43 g, 2.60 mmol) and dicyclohexylimidazolium tetrafluoroborate (0.83 g, 2.60 mmol) in THF (80 mL) was cooled to −20° C. and then treated with a 1M solution of tBuMgCl (39.0 mL, 39.0 mmol) dropwise. The mixture was allowed to slowly warm to RT, then poured onto a saturated aq. solution of NH4Cl and extracted with AcOEt. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 95:5) afforded the title compound (370 mg). UPLC-MS: MS 285.2 (M+H+); UPLC rt 0.91 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O1CCCCC1O[CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(Cl)Cl>[Br:20][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: BrBr
Reactant: CCCCC/C=C\CCCOC1CCCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCC/C=C\CCCBr
Temperature: 0 °C
Yield: 90 %

Procedure:
To an ice-cool solution of triphenylphosphine (0.72 g, 2.74 mmol) and bromine (0.41 g, 2.6 mmol) in CH2Cl2, a solution of (4Z)-1-(tetrahydropyran-2-yloxy)-4-decene (16) (0.41 g, 1.71 mmol), prepared according to Example 16, in methylene chloride was added dropwise. Isolation and purification by conventional means afforded the product 17 in 90% yield (0.33 g). 1H NMR (200 MHz ) δ: 5.42 (dtt, J=11.0, 7.0, 7.0, 1.0, 1.0 Hz, 2H, CH=CH-4, 5); 3.41 (t, J=6.6, 6.6 Hz, 2H CH2 -1, 2.20 (dt, J=7.0, 7.0 Hz, 2H, CH2 -3); 2.04 (dr, J=6.5, 6.5 Hz, 2H, CH2 -6); 1.91 (tt, J=6.5, 6.5, 6.5 Hz, 2H, CH2 -2); 1.30 (m, 6H, CH2 -7, 8, 9); 0.89 (t, J=7.0 Hz, CH3). MS [EI, m/z(%)] 220 (M+ -8), 218 (M+, 8), 164 (12), 162 (12), 150 (23), 148 (23), 135 (8), 109 (12), 97 (44), 95 (14), 83 (55), 82 (14), 81 (37), 79 (15), 70 (21), 69 (100), 67 (39), 56 (29), 55 (93), 54 (20), 43 (21), 42 (20), 41 (92), 39 (30). IR (CCl4, cm-1) 3008 (cis CH=CH), 1246 (RCH2CH2Br), 649, 566 (C--Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][CH:15]=[CH:14][C:13]=3[C:12]([CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1C(=O)N(Br)C(=[O:22])C1.OP([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:18]=[O:22])=[C:13]3[C:17]=2[O:16][CH:15]=[CH:14]3)=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2ccc(C)c3ccoc23)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2ccc(C=O)c3ccoc23)cc1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a solution of 7-(4-methoxyphenyl)-4-methylbenzofuran (1.27 g, 5.34 mmol) in carbon tetrachloride (150 ml) was added NBS (1.05 g, 5.87 mmol) and AIBN (50 mg). The solution was brought to reflux for 2 h, cooled to room temperature, and the solids were filtered off. The solution was then concentrated and anhydrous CH3CN (50 ml) was added. Then potassium benzeneselenite (Syper, Ludwik; Mlochowski, Jacek Synthesis 1984, 9, 747–752) (1.33 g, 5.87 mmol), and K2HPO4 (0.93 g, 5.34 mmol) were added and the reaction was heated to reflux for 1 h after which it was allowed to cool to room temperature. The solution was then passed through a silica plug and the plug was washed with 30% EtOAc/hexanes after which the CH3CN was stripped off under hi vacuum. Chromatography (100% CH2Cl2) removed the Ph2Se2 by-product to afford 1.0 g (75%) of product as a white solid: mp 143–144° C.; 1H NMR (300 MHz, DMSO-d6): δ 3.85 (3H, s), 7.15 (2H, d, J=8.7 Hz), 7.57 (1H, d, J=2.1 Hz), 7.75 (1H, d, J=7.8 Hz), 7.96 (3H, appt), 8.33 (1H, d, J=2.1 Hz), 8.04 (1H, d, J=2.2 Hz); MS (ESI) m/z 253 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1B(O)O>COCCOC.C(=O)(O)[O-].[Na+].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>[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:21]1[S:22][C:13]2[C:14](=[N:15][CH:16]=[C:17]([C:18]#[N:19])[C:12]=2[NH:11][C:3]2[CH:4]=[C:5]([O:9][CH3:10])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:20]=1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: OB(O)c1cc2ccccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4cc5ccccc5o4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 32.7 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (500 mg, 1.05 mmol), 2-benzofuranboronic acid (340 mg, 2.10 mmol) and 65 mg of tetrakis(triphenylphosphine)palladium(0) in 70 mL of ethylene glycol dimethyl ether and 40 mL of saturated aqueous sodium bicarbonate is heated at reflux for 2.5 hours. An additional 50 mg of tetrakis(triphenylphosphine)palladium(0) is added and the reaction is heated at reflux for 1 hour. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 2:1 hexane:ethyl acetate. The fractions containing product are combined and concentrated in vacuo. The residue is washed with diethyl ether to provide 160 mg of 2-(1-benzofuran-2-yl)-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 281-282° C.; 1H NMR (DMSO-d6) δ 3.87 (s, 3H), 7.29-7.45 (m, 3H), 7.61 (s, 1H), 7.69-7.73 (m, 2H), 7.81 (s, 1H), 8.02 (s, 1H), 8.65 (s, 1H), 9.82 (s, 1H); MS 464.2, 465.9 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[C:30](O)(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(O)C>[C:30]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCCCCO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCO
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution containing tert.-butyl 22-hydroxydocosanoate (34) (2.17 g, 5.26 mmol) and linoleic acid (1.45 g, 5.26 mmol) in dry ethanol free chloroform (50 ml) at room temperature under nitrogen was treated with dimethylaminopyridine (0.064 g, 0.524 mmol) and dicyclohexylcarbodiimide (1.19 g, 5.78 mmol), and the resulting solution was stirred for three hours at room temperature, after which time tlc indicated that the reaction is complete. The mixture was filtered and the filtrate washed with 5% acetic acid, then water, then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica (30 g). Elution with petrol followed by 5% ether in petrol gave the title compound (35) as a white wax (2.18 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.O.Cl.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1
Reactant: O=C1CCNCC1
Reactant: Fc1ccccc1CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C1CCN(Cc2ccccc2F)CC1
Yield: 81.9 %

Procedure:
64.00 g (0.443 mol) of o-fluorobenzylchloride was weighed, to which 250 mL of dichloromethane was added. 62.40 g (0.406 mol) of 4-piperidone hydrochloride monohydrate was added under stirring, and then 91.00 g (0.899 mol) of triethylamine was added dropwise under cold water cooling and stirring. The reaction was stirred at room temperature for 4.5 h, and then stirred under reflux and reacted overnight. On the next day, the reaction was cooled, filtered to remove solid, washed in sequence with dichloromethane and ethyl ether, combined, washed with water and dried, and the solvent was recovered to obtain 68.95 g crude product (82.00%), which was used directly in the next reaction.
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[CH3:8][NH:9][CH2:10][N:11]=[CH:12][NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.Cl.[C:24]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([CH2:37][C:38](=[O:40])[NH2:39])=[C:32](O)[CH:31]=[CH:30]2)(=[NH:26])[NH2:25].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)(=O)C>[ClH:7].[ClH:7].[CH3:8][NH:9][CH2:10][N:11]=[CH:12][NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:20][C:32]2[CH:31]=[CH:30][C:29]3[C:34](=[CH:35][CH:36]=[C:27]([C:24](=[NH:25])[NH2:26])[CH:28]=3)[C:33]=2[CH2:37][C:38](=[O:40])[NH2:39])=[O:19])=[CH:16][CH:15]=1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: CNCN=CNc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCC(C)=O
Solvent: O
Product: CNCN=CNc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2CC(N)=O)cc1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
80 Milliliters of 20% hydrous pyridine was added to 5.76 g of 4-methylaminomethyliminomethylaminobenzoic acid.hydrochloride, 6.0 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 5.3 g of DCC and 217 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 5 days at room temperature. Then, the precipitate was collected by filtration and washed with 120 ml of warm DMF. To this collected precipitate was added 300 ml of water, followed by stirring for 24 hours at room temperature, and the precipitate was filtered. Each of the reaction filtrate, warm DMF wash liquid and aqueous filtrate obtained above was concentrated under reduced pressure. The resulting residues were combined and 70 ml of DMF was added thereto. The solution was added dropwise to 700 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To the residue were added 50 ml of methanol and 3.3 ml of concentrated hydrochloric acid, and the solution was added dropwise to a mixed liquid of 500 ml of acetone and 200 ml of ether, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 5.78 g of the desired product.