Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7](F)=[C:6]([F:9])[C:5]([F:10])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[C:15]([O:17][CH3:18])=[O:16].CS(C)=O.[C:23]([NH2:28])([CH2:26][CH3:27])([CH3:25])[CH3:24]>O>[CH3:24][C:23]([NH:28][C:7]1[C:2]([F:1])=[C:3]([C:15]([O:17][CH3:18])=[O:16])[C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([F:10])[C:6]=1[F:9])([CH3:25])[CH2:26][CH3:27]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)OC
Reactant: CCC(C)(C)N
Solvent: CS(C)=O
Solvent: O
Product: CCC(C)(C)Nc1c(F)c(F)c(C(=O)OC)c(C(=O)OC)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,4,5,6-Tetrafluoro-1,2-benzenedicarboxylic acid, dimethyl ester (Example 1), 2.66 g, is treated with 8 g of dimethylsulfoxide and the mixture is warmed to dissolve the solid. The solution is cooled in an ice bath and 2.65 g of tertiary-pentylamine is added. The resulting solution is then stirred at room temperature for three hours, 50 ml of water added, and the solution extracted with heptanes (2×30 ml). The combined heptane extract is extracted with a 5% aqueous solution of hydrochloric acid (2×4 ml) and concentrated to give 4-[(1,1-dimethylpropyl)amino]-3,5,6-trifluoro-1,2-benzenedicarboxylic acid, dimethyl ester as an oil. Hydrochloric acid (36% aqueous solution), 20 ml, is added to this oil and the resulting mixture is heated at reflux for 20 hours. The solution is concentrated to 4-5 ml and then diluted with water (20 ml). Cooling gave crystals which are collected and vacuum dried to give 1.2 g of 3-amino-2,4,5-trifluorobenzoic acid (63%); mp 133° -136° C.; GC (97.9%); HPLC (94%).
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:25][CH:26]([CH2:40][CH3:41])[C@@H:27]([C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][N:30]=1)[OH:28]>>[N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([NH:25][C@H:26]([C:27]([C:29]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][N:30]=2)=[O:28])[CH2:40][CH3:41])=[O:12])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCC(N)[C@H](O)c1noc(-c2ccccc2)n1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Product: CC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1)C(=O)c1noc(-c2ccccc2)n1

Procedure:
Similarly prepared according to the procedure for Example 43 but using 4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid and (S)-2-amino-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)-butan-1-ol; MS: 569 (MH+), LCMS retention time 4.1 min; 1H NMR (CDCl3) 8.18 (d, J=7.9 Hz, 2H), 7.74–7.31 (m, 9H), 5.27 (m, 1H), 4.25 (m, 2H), 3.71–3.41 (m, 8H), 2.95 (m, 1H), 2.78–2.70 (m, 2H), 2.10 (m, 1H), 1.85 (m, 1H), 1.0 (m, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][C:25]3[N:30]=[CH:31][CH:32]=[CH:33][C:24]4=3)=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37](I)[CH:36]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[I:34][C:35]1[CH:36]=[C:37]([N:26]2[C:27]3[C:23](=[CH:22][C:21]([C:14]4[C:13]5[C:8]([C:7]([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)=[C:20]6[C:15]=4[CH:16]=[CH:17][CH:18]=[CH:19]6)=[CH:9][CH:10]=[CH:11][CH:12]=5)=[CH:29][CH:28]=3)[C:24]3[CH:33]=[CH:32][CH:31]=[N:30][C:25]2=3)[CH:38]=[CH:39][CH:40]=1
Reactant: Ic1cccc(I)c1
Reactant: c1ccc(-c2c3ccccc3c(-c3ccc4[nH]c5ncccc5c4c3)c3ccccc23)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Ic1cccc(-n2c3ccc(-c4c5ccccc5c(-c5ccccc5)c5ccccc45)cc3c3cccnc32)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 63 %

Procedure:
6-(10-phenylanthracen-9-yl)-9H-pyrido[2,3-b]indole (1.76 g, 4.19 mmol), 1,3-diiodobenzene (2.76 g, 8.37 mmol), CuI (319 mg, 1.67 mmol), K3PO4 (1.78 g, 8.37 mmol), trans-1,2-dicyclohexanediamine (0.2 mL, 1.67 mmol) were put in a 250 mL two-neck flask and dissolved in 1,4-dioxane. The solution was refluxed and stirred at 120° C. for 12 hours. After completion of the reaction, the solution was extracted with methylenechloride and H2O and was distilled under reduced pressure to remove the solvent. The resultant was columned with a solution of hexane and methylenechloride (1:5). The solution was re-crystallized in a solution of methylene chloride and petroleum ether such that the white solid compound was obtained, (1.66 g, yield: 63%).
Reaction SMILES: Cl.CO[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17]CCN2CCSCC2)=[C:12]([NH2:26])[CH:11]=1)=O.[C:28]([O:31][CH2:32]C)(=[O:30])[CH3:29].C(O)C>>[CH3:32][O:31][C:28]([CH:29]1[CH2:4][CH2:6][CH2:7][N:8]1[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([NH2:26])[CH:11]=1)=[O:30]
Reactant: CCOC(C)=O
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c(N)c1
Agent: Cl
Solvent: CCO
Product: CNc1ccc(C(=O)N2CCCC2C(=O)OC)cc1N

Procedure:
The same procedure is used as in (2). Rf value: 0.41 (silica gel; ethyl acetate/ethanol=9:1)
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH2:25][CH:26]=O)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3].[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([O-:30])=[O:29].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH2:25][CH2:26][N:40]3[CH2:41][CH2:42][N:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N+:28]([O-:30])=[O:29])[CH2:38][CH2:39]3)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3ccccc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.9 %

Procedure:
To a stirred solution of 3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde (0.060 g, 0.15 mmol) and 1-(2-nitro-phenyl)-piperazine (0.032 g, 0.157 mmol) in CH2Cl2 (0.5 mL), glacial AcOH (8.5 μL, 0.15 mmol) was added and stirred for 15 min at room temperature. NaBH(OAc)3 (0.041 g, 0.19 mmol) was added and stirred under nitrogen overnight. Saturated NaHCO3 (0.5 mL) was then added and stirred for 15 min. The layers separated and the aqueous layer was extracted with CH2Cl2 (0.5 mL). MPLC purification (silica, 2-15% MeOH/CH2Cl2) afforded the desired product as a white solid (0.063 g, 71%). TLC (silica, 12% MeOH/CH2Cl2): Rf=0.67. MS (electrospray): exact mass calculated for C27H31F3N6O4S, 592.21; m/z found, 593.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.80 (dd, J=1.6, 8.2 Hz, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.52 (ddd, J=1.6, 7.3, 8.3 Hz, 1H), 7.19 (dd, J=1.2, 8.3 Hz, 1H), 7.09 (m, 1H), 4.59 (s, 2H), 4.17 (t, J=6.9 Hz, 2H), 3.71 (t, J=5.8 Hz, 2H), 3.13 (br t, J=4.8 Hz, 4H), 2.96 (t, J=5.6 Hz, 2H), 2.95 (s, 3H), 2.66 (br t, J=4.4 Hz, 4H), 2.51 (t, J=7.0 Hz, 2H), 2.17 (q, J=6.9 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH2:14].[I:16]I>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([I:16])[C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH2:14]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1N
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A mixture of 2-amino-4-trifluoromethyl-benzoic acid methyl ester (51.5 g, 235 mmol), iodine (55.1 g, 217 mmol) and silver sulfate (73.3 g, 234 mmol) in EtOH (1560 mL) was stirred for 1 h at r.t. under nitrogen. The suspension was then filtered and the filtrate diluted with EtOAc and washed once with a 10% aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (67.5 g, 196 mmol, 83%) as a brown solid, m.p. 101-103° C., ESI-MS: m/z 346 [M+H]+.
Reaction SMILES: C[NH:2][NH:3][C:4]([NH:6][C:7](=O)[CH2:8][NH:9][C:10]1[C:15]([CH2:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:18][CH3:19])=[S:5].[OH-].[K+].[CH2:23](O)C>O>[CH2:16]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:18][CH3:19])[C:10]=1[NH:9][CH2:8][C:7]1[N:6]([CH3:23])[C:4](=[S:5])[NH:3][N:2]=1)[CH3:17]
Reactant: CCc1cccc(CC)c1NCC(=O)NC(=S)NNC
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCc1cccc(CC)c1NCc1n[nH]c(=S)n1C
Yield: 97 %

Procedure:
29.6 g (0.1 mol) of 1-methyl-4-[(2,6-diethylanilino)-acetyl]-thiosemicarbazide were suspended in 150 ml of ethanol and, after adding 7 g of potassium hydroxide in 20 ml of water, the mixture was heated under reflux for 1 hour. Thereafter, most of the solvent was distilled off and 250 ml of water were added to the residue. After acidifying the mixture to pH 5 with glacial acetic acid, the precipitate formed was filtered off and washed thoroughly with water. After drying, 27 g (97% of theory) of 2,6-diethyl-N-[(1-methyl-2-thiono-1,3,4-triazol-5-yl)methyl]-aniline of melting point 117° to 121° C. were obtained. ##STR88##
Reaction SMILES: FC(F)(F)S(O[C:7]1[C@@H:8]([C:31]([O:33][CH3:34])=[O:32])[N:9]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH:11]=1)(=O)=O.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>CO>[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][C:42]([C:7]2[C@@H:8]([C:31]([O:33][CH3:34])=[O:32])[N:9]([C:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][CH:11]=2)=[CH:41][CH:40]=1
Reactant: COC(=O)[C@@H]1C(OS(=O)(=O)C(F)(F)F)=CCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@@H]1C(c2ccc(C(F)(F)F)cc2)=CCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 85 °C
Yield: 62.5 %

Procedure:
To a stirred mixture of (S)-methyl 3-(trifluoromethylsulfonyloxy)-1-trityl-2,5-dihydro-1H-pyrrole-2-carboxylate ((Tetrahedron Lett. 2001, 8571) 1.71 g, 3.3 mmol), 4-(trifluoromethyl)phenylboronic acid (1.3 g, 6.6 mmol), K2CO3 (0.68 mg, 5.0 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(II) DCM adduct (0.12 g, 0.16 mmol) was added toluene (10 mL) and MeOH (1.0 mL). The mixture was stirred under nitrogen at 85° C. 15 hours. The mixture was cooled and evaporated in vacuo. The residue was dissolved in DCM, adsorbed onto silica gel and purified by flash column chromatography (eluting first with 1:5 EtOAc in hexanes and second with a gradient of hexanes to 30% DCM in hexanes) to give (S)-methyl 3-(4-(trifluoromethyl)phenyl)-1-trityl-2,5-dihydro-1H-pyrrole-2-carboxylate as a white solid (1.06 g, 62%). LCMS (M+H) 514.5 calc. for C32H27F3NO2 514.2. 1H NMR (400 MHz, CDCl3): δ ppm 6.67-8.21 (a series of m, 19H) 5.85 (s, 1H) 5.01 (d, J=4.11 Hz, 1H) 4.39 (dd, J=17.61, 2.54 Hz, 1H) 3.82 (dd, J=17.70, 2.64 Hz, 1H) 3.64 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[Br:12].C([O-])(O)=O.[Na+:17].[NH2:18][CH2:19][C:20]([OH:22])=[O:21]>CN(C=O)C.O>[Na+:17].[Br:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([NH:18][CH2:19][C:20]([O-:22])=[O:21])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Br)cc1Cl
Reactant: NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C([O-])CNc1cc(Br)c(Cl)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 65 h

Procedure:
To a stirred solution of 2,5-dichloro-4-nitrobromobenzene (1.000 g, 3.691 mmol, as prepared above) in DMF (10.0 mL) at 65° C., was added, dropwise, a solution of NaHCO3 (0.316 g, 3.76 mmol) and glycine (0.280 g, 3.73 mmol, Aldrich, used as received) in water (3.8 mL). The resulting suspension was stirred at 65° C. for 65 h. The bright orange suspension was then cooled to room temperature, filtered, washed with water (1.0 mL), and dried under vacuum to afford 0.284 g (98%, based on recovered starting material) of the pure (1H NMR) title compound as an orange powder, m.p. 264-265° C. (decomposed); 1H NMR (DMSO-d6): δ 3.451 (d, 2H, J=3.9 Hz), 7.199 (s, 1H), 8.130 (s, 1H), 8.793 (t, 1H, J=3.6 Hz). It was used as such for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[C:6]([C:9]#[N:10])[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[C:7]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([CH:5]=[CH:4][N:3]=1)[C:9]#[N:10]
Reactant: N#Cc1ccnc(Cl)c1F
Reactant: C1CCNC1
Product: N#Cc1ccnc(Cl)c1N1CCCC1
Yield: 94 %

Procedure:
Prepared in 94% yield from 2-chloro-4-cyano-3-fluoropyridine and pyrrolidine according to the procedure described for Example 178A. MS (ESI+) m/z 207.9 (M+H)+; 1H NMR (DMSO-d6) δ 1.91-1.95 (m, 4H), 3.62-3.67 (m, 4H), 7.63 (d, J=4.7 Hz, 1H), 7.98 (d, J=4.7 HZ, 1H).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26]([OH:28])=O)=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:28])=[C:17]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[N:16]=2)=[CH:13][N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CCC(=O)O)c3n2)cn1
Reactant: C1COCCN1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CCC(=O)N4CCOCC4)c3n2)cn1

Procedure:
3-(2-(2-(Tert-butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)propanoic acid (50 mg) was reacted with morpholine via General Procedure F followed by Boc deprotection via General Procedure E to give 24.9 mg 113 as white solid following reverse phase purification. MS (Q1) 440.2 (M)+
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[C:10](I)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH2:33]([Si:35]([C:40]#[C:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH2:38][CH3:39])[CH2:36][CH3:37])[CH3:34]>CN(C=O)C>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:40]([Si:35]([CH2:38][CH3:39])([CH2:33][CH3:34])[CH2:36][CH3:37])[O:23][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(I)c(OCc2ccccc2)ccn1Cc1ccccc1
Reactant: CC[Si](C#Cc1ccccc1)(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1oc2c(c1-c1ccccc1)c(=O)ccn2Cc1ccccc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A 250-ml round bottom flask was charged with 1-benzyl-4-benzyloxy-3-iodo-2-pyridone (6.00 g, 14.40 mmol), dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (1.18 g, 1.44 mmol), DMF (60 mL), Hunig's base (3 mL, 17.30 mmol), triethylsilyl phenylacetylene (9.34 g, 43.10 mmol). The system was evacuated and purged with N2 three times, and the reaction was stirred at 110° C. for 12 hrs. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4 and the solvent was removed. The residue was purified by silica gel column chromatography, eluting with 50/50/1, EtOAc/Hexane/MeOH, to give 7-benzyl-3-phenyl-2-(triethylsily)furo[2,3-b]pyridine-4(7H)-one as a solid. MS (MH+) 416.0; Calculated 415 for C26H29NO2Si.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Cl.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClCc1ccccn1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(SCc2ccccn2)cc1
Yield: 71.4 %

Procedure:
4-nitrobenzenethiol (6.0 g) was dissolved in THF (120 ml), and to the solution was 1N sodium hydroxide (120 ml) and then, 2-(chloromethyl)pyridine hydrochloride (7.6 g), and the mixture was stirred for 15 minutes at room temperature. The solvent was removed under reduced pressure, and the obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 2-[[(4-nitrophenyl)sulfanyl]methyl]pyridine (6.8 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1.Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:16]([C:15]3[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=3)[NH:9][C:4]=2[C:3]=1[CH3:10]
Reactant: Cc1c(Br)ccc(N)c1N
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Product: Cc1c(Br)ccc2nc(-c3ccc(F)cc3)[nH]c12
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 95 %

Procedure:
A solution of 4-bromo-3-methylbenzene-1,2-diamine (prepared according to the procedure of PCT Pat. Appl. WO 2008/021851, 400 mg, 1.989 mmol) in DCM (10 mL) was treated with TEA (0.693 mL, 4.97 mmol), then was treated dropwise with 4-fluorobenzoyl chloride (0.282 mL, 2.387 mmol). The mixture was stirred at rt for 70 min, then was concentrated. The residue was suspended in ethanol (25 mL), treated with concentrated hydrochloric acid (3 mL, 36.5 mmol) and heated at 90-95° C. After 42.5 h, the mixture was cooled to rt and the ethanol was removed under vacuum. The residual paste was suspended in water and the pH was adjusted to ca. 8 with NaHCO3 (aq). The precipitate was collected by filtration, washed with water and dried under vacuum to provide 6-bromo-2-(4-fluorophenyl)-7-methyl-1H-benzo[d]imidazole as a pale pink solid (636 mg, 95%). 1H NMR (400 MHz, DMSO-d6) δ 8.24 (2H, dd, J=8.9, 5.4 Hz), 7.33-7.45 (4H, m), 2.57 (3H, s). Mass spectrum m/z 305, 307 (M+H)+.
Reaction SMILES: [C:1](=[C:4](Cl)[F:5])([F:3])[F:2].[Li]C(CC)C.[Si:12](OCC)([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>CCOCC>[C:1](=[C:4]([Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[F:5])([F:3])[F:2]
Reactant: FC(F)=C(F)Cl
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)C(F)=C(F)F
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
200 ml of freshly distilled dry Et2O is added to a 500 ml vessel (under an argon atmosphere). The vessel is cooled down to −80° C. and 15 g (0.129 mol) of CF2═CFCl gas is bubbled to Et2O. 100 ml (0.13 mol) of sec-BuLi is added dropwise during three hours. The temperature of the solution is kept below −60° C. all the time. The solution is stirred for 15 minutes and 29 ml (27.08 g, 0.130 mol) of Si(OEt)4 is added in small portions. The solution is stirred for over night allowing it to warm up to room temperature. Formed red solution is filtered and evaporated to dryness to result crude trifluorovinyltriethoxysilane, CF2═CFSi(OEt)3.
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:14][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)=[CH:7][CH:6]=1>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:10]1[CH:9]=[C:8]([C@H:11]2[CH2:12][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14]2)[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: COc1ccc([C@H]2C[C@H](C(=O)OC)C2)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1ccc([C@H]2C[C@H](C(=O)OC)C2)cc1I
Reaction time: 4 h

Procedure:
Silver sulfate (0.671 g, 2.15 mmol) and iodine (0.11 mL, 2.15 mmol) were added successively to a solution of methyl trans-3-(4-methoxyphenyl)cyclobutanecarboxylate (0.474 g, 2.15 mmol) in MeOH (10.8 mL) at 25° C. and the reaction was stirred vigorously for 4 h. After this time the reaction mixture was filtered through a plug of Celite®. The filtrate was diluted with EtOAc (50 mL), washed with water (2×10 mL), aq. Na2SO3 (2×10 mL), and brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/imin, 100% hexanes for 144 mL, gradient to 20% EtOAc in hexanes over 2394 mL) to afford methyl trans-3-(3-iodo-4-methoxyphenyl)cyclobutanecarboxylate, as a colorless oil. Rf=0.54 (20% EtOAc/hexanes). LCMS calc.=347.01. found=347.02 (M+H)+. 1H NMR (500 MHz, CHCl3): δ 7.58 (d, J=2.2 Hz, 1H); 7.08 (dd, J=8.4, 2.2 Hz, 1H); 6.69 (d, J=8.4 Hz, 1H); 3.76 (s, 3H); 3.67 (s, 3H); 3.65-3.54 (m, 1H); 3.07-3.00 (m, 1H); 2.61-2.55 (m, 2H); 2.32-2.25 (m, 2H).
Reaction SMILES: [CH:1](=[C:8]1[C:12]2[O:13][C:14]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH:1](=[C:8]1[C:12]2[O:13][C:14]3[CH:21]=[C:20]([O:22][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2c(oc3cc(O)ccc13)C(=Cc1ccccc1)CC2
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c2c(oc3cc(OCCN4CCOCC4)ccc13)C(=Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
3-Benzylidene-6-hydroxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one (1.2 g) was reacted with 4-(2-chloro-ethyl)-morpholine (1.15 g) in dimethylformamide (50 ml), in the presence of anhydrous K2CO3 (1.7 g), under stirring for 4 hours at room temperature and then for 1 hour at 70° C. The reaction mixture was diluted with ice water containing NaH2PO4 and the precipitated product was filtered and washed with water. Crystallization from CH2Cl2 /isopropyl alcohol gave 0.9 g of 3-benzylidene-6-(2-morpholino-ethoxy)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one, m.p. 167°-169° C.