Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[F-].[K+]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[N+]([O-])([O-])=O.[Ag+].CS(C)=O>[Br:1][C:2]1[S:3][C:4]([C:4]2[S:3][C:2]([Br:1])=[C:6]([CH2:7][CH:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:5]=2)=[CH:5][C:6]=1[CH2:7][CH:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCC(CCCCCCCC)Cc1ccsc1Br
Agent: Cl[Pd]Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: N#Cc1ccccc1
Solvent: CS(C)=O
Product: CCCCCCCCCCC(CCCCCCCC)Cc1cc(-c2cc(CC(CCCCCCCC)CCCCCCCCCC)c(Br)s2)sc1Br
Temperature: 120 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
2-bromo-3-(2-octyldodecyl)thiophene (5.32 g, 12 mmol), PdCl2(PhCN)2 (46.5 mg, 0.12 mmol), potassium fluoride (1.39 mg, 24 mmol), and dimethyl sulfoxide (DMSO) (60 mL). AgNO3 (4.06 g, 24 mmol) was added to a 100 mL of Schlenk tube, in one portion. The resulting mixture was stirred at 120° C. for 3 h. Additional potassium fluoride (1.39 mg, 24 mmol) and AgNO3 (4.06 g, 24 mmol) were then added to the mixture and the mixture was stirred for 8 h at 120° C. The reaction mixture was then cooled and passed through a Celite pad to remove black solids. The resulting cake was washed repeatedly with ethyl acetate. The filtrate was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, resulting in a crude product. The crude product was purified by silica gel chromatography to produce 2.54 g of the final product, a light yellow oil (48%). 1H NMR (CDCl3, 400 MHz, ppm) δ 6.73 (s, 2H), 2.46-2.44 (d, 4H, J=7.2 Hz), 1.64 (m, 2H), 1.25 (br, 64H), 0.89-0.86 (t, 12H). 13C NMR (CDCl3, 100 MHz, ppm) δ 142.20, 136.03, 124.94, 108.50, 38.51, 34.27, 33.39, 31.93, 31.91, 29.97, 29.67, 29.64, 29.63, 29.59, 29.34, 29.32, 26.53, 22.68, 22.67, 14.08.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:27][C:28]1[N:29]=[C:30]([CH:33]=[CH:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([F:46])([F:45])([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[O:31][CH:32]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:23])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1)[CH2:27][C:28]1[N:29]=[C:30]([CH:33]=[CH:34][C:35]2[CH:36]=[CH:37][C:38]([S:41]([F:46])([F:42])([F:43])([F:44])[F:45])=[CH:39][CH:40]=2)[O:31][CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=CCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1coc(C=Cc2ccc(S(F)(F)(F)(F)F)cc2)n1)c1ccc(C=CCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
A solution of [4-(4-[1,2,3]triazol-1-yl-but-1-enyl)-phenyl]-carbamic acid tert-butyl ester (0.135 g, 0.43 mmol) in N,N-dimethyl formamide (3 ml) was treated with sodium hydride (0.012 g, 0.47 mmol) and stirred for 30 min at room temperature. After addition of 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole (0.149 g, 0.43 mmol) and stirring for 12 h the reaction was quenched by the addition of a sat. NH4Cl solution (8 ml). Extraction with ethyl acetate (3×10 ml), washing with water, drying over sodium sulfate and concentration in vacuo yielded crude [4-(4-[1,2,3]triazol-1-yl-but-1-enyl)-phenyl]-{2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazol-4-ylmethyl}-carbamic acid tert-butyl ester (0.27 g) which was used in the next step without any further purification.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([O:10][C:11](Cl)=[O:12])[CH:2]=1.[CH3:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:26][N:25]=2)=[CH:20][CH:19]=1)(=[O:17])=[O:16].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[CH:26][C:27]([O:30][CH2:31][CH:32]3[CH2:37][CH2:36][N:35]([C:11]([O:10][C:3]4[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=4)=[O:12])[CH2:34][CH2:33]3)=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)(=[O:16])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cn2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)Oc4ccc([N+](=O)[O-])cc4)CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
4-Nitrophenyl chloridocarbonate (268 mg, 1.33 mmol) was added to a mixture of 2-[4-(methylsulfonyl)phenyl]-5-[(4-piperidinylmethyl)oxy]pyridine (460 mg, 1.33 mmol), diisopropylethylamine (0.695 mL, 4 mmol) in CH2Cl2 (20 mL) at ambient temperature. The mixture was stirred at ambient temperature for 30 min, then concentrated, and the crude product was purified by chromatography on a silica gel column using 0 to 5% MeOH/CH2Cl2 give 456 mg (67%) of 4-nitrophenyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.43 (d, 1H, J=2.7 Hz), 8.25 (d, 2H, J=9.2 Hz), 8.14 (d, 2H, J=8.5 Hz), 8.02 (d, 2H, J=8.5 Hz), 7.76 (d, 1H, J=8.7 Hz), 7.37-7.27 (m, 3H), 4.45-4.30 (m, 2H), 3.98 (d, 2H, J=5.1 Hz), 3.16-3.03 (m, 4H), 3.00-2.88 (m, 1H), 2.21-2.06 (m, 1H), 2.04-1.92 (m, 2H), 1.55-1.35 (m, 2H); LRMS (ESI), m/z 512 (M+H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([OH:31])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([O:31][C:37]3[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)[CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc4c(c3)CCC4)CC2)c1
Product: COc1ccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc3c(c2)CCC3)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenol: ESMS m/e: 527.3 (M+H)+.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[O:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][O:11]2)=[CH:6][CH:5]=1.C([Li])CCC.C1(O[C:33]#[N:34])C=CC=CC=1.O>O1CCCC1.CCCCCC>[CH2:16]([C@@H:13]1[CH2:14][O:15][C@@H:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]#[C:2][C:33]#[N:34])=[CH:5][CH:6]=2)[O:11][CH2:12]1)[CH2:17][CH2:18][CH3:19]
Reactant: N#COc1ccccc1
Reactant: CCCC[C@H]1CO[C@H](c2ccc(C=C(Br)Br)cc2)OC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[C@H]1CO[C@H](c2ccc(C#CC#N)cc2)OC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 3.5 g of trans-2-[p-(2,2-dibromovinyl)phenyl]-5-butyl-1,3-dioxane in 80 ml of absolute tetrahydrofuran was placed at -78° C. in a sulphonation flask under argon gasification and treated within 5 minutes with 13.4 ml of a 1.2N solution of butyl lithium in hexane. After completion of the addition, the mixture was held at -10° C. for 1 hour, then again cooled to -78° C. and treated with 1.2 ml of phenyl cyanate within 5 minutes. The mixture was stirred at -78° C. for a further 30 minutes, then poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed with 100 ml of water and 100 ml of saturated sodium chloride solution, dried over potassium carbonate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (3.26 g) on silica gel with petroleum ether/ethyl acetate/triethylamine (97:3:0.2) gave 1.18 g (50%) of p-(trans-5-butyl-1,3-dioxan-2-yl)phenylpropiolonitrile (purity 98.7%). A recrystallization from 50 ml of hexane yielded 1.03 g of the nitrile as colourless crystals (purity 99.7%); m.p. (C-N) 54.3° C., cl.p. (N-I) 108.7° C.
Reaction SMILES: C([N:8]([C@@H](C1C=CC=CC=1)C)[C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@:10]1([CH3:26])[C:22]([O:24][CH3:25])=[O:23])C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)=O.CO.[Pd]>[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:8][C@@H:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][C@:10]2([CH3:26])[C:22]([O:24][CH3:25])=[O:23])(=[O:51])=[O:50])=[CH:45][CH:44]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)[C@@]1(C)CN(C(=O)OC(C)(C)C)CC[C@H]1N(Cc1ccccc1)[C@H](C)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=CO
Solvent: CO
Product: COC(=O)[C@@]1(C)CN(C(=O)OC(C)(C)C)CC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
(3S,4R)-1-tert-Butyl 3-methyl 4-(benzyl((R)-1-phenylethyl)amino)-3-methylpiperidine-1,3-dicarboxylate (4.777 g, 10.24 mmol) was taken up in 100 mL of 4.4% formic acid in methanol. Palladium on Carbon (10%, 1.059 g) was added and the reaction mixture was stirred under a nitrogen atmosphere for 2 h at room temperature. Filtration through celite gave a colorless solution that was concentrated to give a colorless oil. The oil was combined with 4-(benzyloxy)benzene-1-sulfonyl chloride (4.377 g, 15.48 mmol) and equivalent volumes of CH2Cl2 and saturated sodium bicarbonate, and the resultant biphasic mixture was stirred vigorously overnight. The organic layer was separated and the remaining aqueous phase was washed with CH2Cl2 (3×). the organic extracts were combined, dried over Na2SO4 and concentrated to give a beige solid that was purified by chromatography on silica gel eluting with 30% ethyl acetate/hexanes to give (3S,4R)-1-tert-butyl 3-methyl 4-(4-(benzyloxy)phenylsulfonamido)-3-methylpiperidine-1,3-dicarboxylate as a white solid (4.523 g, 8.72 mmol, 85%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.14 (s, 3 H) 1.37-1.48 (m, 11H) 1.78 (s, 1H) 2.02-2.05 (m, 3H) 2.51 (s, 1H) 3.08-3.16 (m, 1H) 3.65 (s, 3H) 4.48 (s, 1H) 5.11 (s, 2H) 5.65 (d, J=9.60 Hz, 1H) 7.01-7.06 (m, 2H) 7.31-7.43 (m, 6H) 7.78-7.82 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:12][CH2:11][CH:10]1[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7]2)=[O:5])C.[OH-].[Na+]>C(O)C>[CH2:16]([O:15][C:13]([N:8]1[CH2:9][CH:10]2[C:6]([C:4]([OH:5])=[O:3])([CH2:12][CH2:11]2)[CH2:7]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C12CCC1CN(C(=O)OCc1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CC2CCC2(C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 825 mg (2.60 mmol) of 1-ethoxycarbonyl-3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane in ethanol (10 ml) cooled in an ice bath was added 5 ml of 1N sodium hydroxide aqueous solution, followed by 2 hours of stirring at room temperature. After neutralization with 1N hydrochloric acid aqueous solution, ethanol was evaporated. The resulting residue was mixed with 1N hydrochloric acid aqueous solution and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. By evaporating the solvent, 776.6 mg (quantitative) of the title compound was obtained as a crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:23]1([N:29]=[C:30]=[S:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:30](=[S:31])[NH:29][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Reactant: S=C=Nc1ccccc1
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=S)Nc2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.131 g, 0.44 mmol) in dichloromethane (5 mL) was added phenyl isothiocyanate (58 μL, 0.48 mmol). The reaction mixture was shaken at room temperature for 2 hours. The solvent was then removed under reduced pressure to give 3-(4-methoxybenzyl)-N-phenyl-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carbothioamide as a solid residue (LCMS [M+H]: 430), which was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([O:33][CH3:34])[CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:32])[CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.Cl[C:38]1C=CC(OC)=C(S(Cl)(=O)=O)[CH:43]=1>>[CH2:38]([O:28][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:35][CH3:36])(=[O:10])=[O:9])=[C:15]([O:33][CH3:34])[CH:16]=2)=[O:21])=[CH:24][C:25]=1[F:32])[CH3:43]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2c(OC)cc(C(=O)Nc3ccc(C(=O)O)c(F)c3)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1F

Procedure:
4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 535.33 (M+H+.), was prepared in analogy to example 14, steps 1 to 6. Step 5 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride and yielded 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C@H:10]([CH2:11][CH2:12][OH:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[O:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20].[C@@H]1(N)CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+].N>O1CCOCC1.[Cu]I>[OH:13][CH2:12][CH2:11][C@H:10]1[C:5]2[CH:4]=[CH:3][C:2]([N:17]3[CH2:18][CH2:19][O:15][C:16]3=[O:20])=[CH:14][C:6]=2[CH2:7][CH2:8][O:9]1
Reactant: OCC[C@@H]1OCCc2cc(Br)ccc21
Reactant: O=C1NCCO1
Agent: [Cu]I
Agent: N
Agent: N[C@@H]1CCCC[C@H]1N
Solvent: C1COCCO1
Product: O=C1OCCN1c1ccc2c(c1)CCO[C@H]2CCO

Procedure:
To a stirred solution of 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (0.815 g, 3.17 mmol) in dry dioxan (5 mL) was added 1,3-oxazolidin-2-one (0.26 g, 2.95 mmol), trans-1,2-cyclohexanediamine (0.05 mL, 0.42 mmol), copper(I) iodide (0.040 g, 0.21 mmol) and potassium carbonate (1.02 g, 7.36 mmol), and the mixture heated at reflux under nitrogen overnight. 2M Ammonia was added and the mixture extracted into dichloromethane. The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=O)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[C:33]([C:34]#[N:35])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (3-amino-4′-cyano-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G40) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a light red solid (185 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:31]=[N:32][CH:33]=[N:34][CH:35]=4)[CH:25]=3)[CH2:22][C:21](=[O:37])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CNc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cncnc3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-isobutylamino-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M88) (0.28 g, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (200 mg, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[Cl-]>O>[C:2]1([NH:1][C:9](=[O:8])[CH2:10][CH2:11][CH3:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: C1CCOC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Product: CCCC(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
First, 16 g of aniline, 200 mL of tetrahydrofuran (THF), 26 g of triethylamine (Et3N) were put in a 500 mL three-neck flask, and stirred under cooling in ice. Then, a mixed solution of 18 g of btyryl chloride and 50 mL of THF was dripped to the above mixed solution through a 100 mL dropping funnel. After the dripping, the mixture was stirred for 2 hours while the temperature was increased to room temperature. After the stirring, the reaction mixture was added to 200 mL of water, and stirred at room temperature. This mixed solution was separated to an organic layer and an aqueous layer, and the aqueous layer was extracted with chloroform. The extract and the previously resulting organic layer were combined, and washed with saturated saline. After the washing, anhydrate magnesium sulfate was added to the organic layer for drying. The mixture after the drying was subjected to gravity filtration, and the filtrate was concentrated to give a solid. This solid was washed with a mixed solvent of chloroform and hexane, so that N-phenylbutyramide was prepared (a white solid, yield: 92%). The synthetic scheme of Step 1 is shown by (a-7).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[F:18].C(=O)([O-])[O-].[CH2:23](I)[CH3:24]>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:9]2[CH2:23][CH3:24])=[CH:4][C:3]=1[F:18]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2cc(Cl)c(F)cc2c1O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(Cl)c(F)cc2c1=O

Procedure:
A 59.7 g portion of the above ester was suspended in 425 ml of dimethylformamide, 76.6 g of pctassium carbonate was added and this mixture was stirred in an oil bath at 80°-90° C. An 89 ml portion of ethyl iodide was added, the mixture was stirred at 80°-90° C. for 18 hours and then evaporated. The residue was dissolved in water and then extracted with dichloromethane. The extract was washed with water, dried, filtered through hydrous magnesium silicate and evaporated in vacuo. The solid was recrystallized from ethanol, giving 38 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][NH:7][C:8]([NH:32][C:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:40])=[N:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)=[O:4].O.[OH-].[Li+].C1COCC1.CO>O>[C:3]([CH2:5][CH2:6][NH:7][C:8]([NH:32][C:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:40])=[N:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCNC(=Nc1ncnc2cc(OCCCN3CCOCC3)c(OC)cc12)Nc1c(C)cccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(N=C(NCCC(=O)O)Nc3c(C)cccc3C)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
A mixture of N-(2-methoxycarbonylethyl)-N′-(2,6-dimethylphenyl)-N″-[6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl]guanidine (0.038 g), lithium hydroxide monohydrate (0.0063 g), THF (1 ml), methanol (0.5 ml) and water (0.5 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was partitioned between water and methylene chloride. The aqueous layer was acidified by the addition of glacial acetic acid and evaporated. The resultant residue was extracted with methylene chloride. The organic extract was filtered and evaporated. There was thus obtained the title compound (0.034 g); NMR Spectrum: (CDCl3) 2.15 (m, 2H), 2.28 (s, 6H), 2.58 (s, 3H), 2.6–2.73 (m, 7H), 3.73 (t, 4H), 3.83 (s, 2H), 4.0 (s, 4H), 4.2 (t, 2H), 7.14 (s, 3H), 7.2 (s, 1H), 7.87 (s, 1H), 8.51 (s, 1H), 12.5 (s, 1H); Mass Spectrum: M+H+ 538.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([N:16]=[CH:17][C:18]([S:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]3)=[N:19]2)=[CH:14][CH:13]=1>C(#N)C>[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([N:16]=[CH:17][C:18]([S:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([NH:31][CH2:2][CH2:3][S:4][C:5]4[S:6][CH:7]=[CH:8][CH:9]=4)[CH2:29][CH2:30]3)=[N:19]2)=[CH:14][CH:13]=1
Reactant: BrCCSc1cccs1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Solvent: CC#N
Product: COc1ccc2ncc(SCCN3CCC(NCCSc4cccs4)CC3)nc2c1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
2-(2-Bromo-ethylsulfanyl)-thiophene (51 mg, 0.22 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70 mg, 0.22 mmol, 1.0 eq) in acetonitrile (5 mL). After 15 hours stirring at 90° C. the reaction mixture is concentrated to give a residue that is purified by preparative HPLC to afford {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-[2-(thiophen-2-ylsulfanyl)-ethyl]-amine as a brown waxy solid (19 mg, 20% yield).
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15](Br)=[N:14][C:13]=1[CH2:18][CH3:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)CC)C.[CH2:27]([NH2:30])[CH:28]=[CH2:29]>O1CCCC1>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:30][CH2:27][CH:28]=[CH2:29])=[N:14][C:13]=1[CH2:18][CH3:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCc1nc(Br)sc1C(=O)NC(C#N)c1cccs1
Reactant: C=CCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCNc1nc(CC)c(C(=O)NC(C#N)c2cccs2)s1
Yield: 61 %

Procedure:
1.0g of 2-bromo-4-ethyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide, 0.40ml of triethylamine and 0.66ml of allylamine were added to 10ml of tetrahydrofuran. The reaction mixture was stirred under reflux for 12 hours and then treated according to the same procedure as EXAMPLE 10 to obtain 0.57g (Yield 61%) of the title compound.