Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C(C)CC[S:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:7])=[O:6].C[O-:16].[Na+:17]>C1COCC1.CO>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][S:5]([O-:16])(=[O:7])=[O:6].[Na+:17]
Reactant: C[O-]
Reactant: COC(=O)CCS(=O)(=O)CCC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a suspension of 12 (141 g, 636 mmol) in THF (1.2 L) and MeOH (700 ml) in an ice bath was added slowly sodium methoxide (144 ml of a 25% solution in MeOH, 1.05 equiv). At the end of the addition, the bath was removed and the mixture stirred at r.t. for 1 h. The solvents were than evaporated and the remaining solid was triturated in ether containing a small amount of EtOAc. The slightly hygroscopic white solid was filtered and dried under high vacuum o.n. to yield 108.7 g (98%) of 13.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=1)=[O:5])#[N:2].[H-].[Na+].[C:19](N1C=CN=C1)(=[O:21])[CH3:20].Cl>O1CCCC1.C(O)(=O)C>[CH3:16][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])/[C:3](/[C:1]#[N:2])=[C:19](\[OH:21])/[CH3:20])[CH:12]=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1cc(NC(=O)CC#N)ccc1[N+](=O)[O-]
Reactant: CC(=O)n1ccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C/C(O)=C(\C#N)C(=O)Nc1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Cyano-N-(3-methyl-4-nitrophenyl)acetamide (0.61 g; 2.8 mmol) is dissolved in tetrahydrofuran (30 ml) and sodium hydride (80% strength dispersion in oil; 0.21 g; 7 mmol) is added. The mixture is stirred at 25° C. for 15 minutes and 1-acetylimidazole (0.46 g; 4.2 mmol) is added dropwise over the course of 5 minutes and the mixture is stirred for a further 15 minutes. 2 ml of glacial acetic acid are added and the mixture is stirred at 25° C. for 1 hour and then poured into ice-cold water (100 ml). The pH of the solution is then adjusted to 1 using concentrated hydrochloric acid, and the precipitate is filtered, washed with water and brought to dryness under reduced pressure. N-(3-Methyl-4-nitrophenyl)-2-cyano-3-hydroxycrotonamide is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[C:18]([CH3:29])[CH:17]=3)[CH2:10][CH2:11][S:12][CH3:13])=[N:8][C:4]=2[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:38].ClCCl.C(O)C.ClCl>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)=[O:23])=[C:18]([CH3:29])[CH:17]=3)[CH2:10][CH2:11][S:12]([CH3:13])=[O:38])=[N:8][C:4]=2[CH:3]=1
Reactant: CSCC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: ClCl
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C(=O)N[C@@H](CCS(C)=O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 57 %

Procedure:
Prepared analogously to Example 85 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfanylpropyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide and 3-chloroperoxybenzoic acid in dichloromethane/glacial acetic acid. Yield: 57%; Rf value: 0.15 (silica gel; dichloromethane/ethanol=9:1); C24H27ClN4O3S (487.02); mass spectrum: (M+H)+=487/489 (chlorine isotope).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][CH:3]=1.[C-:10]#[N:11].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:10]#[N:11])[CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: BrCc1cccc(Br)n1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.8 %

Procedure:
To a stirred solution of the above crude 6-bromo-2-bromomethylpyridine (70 g, 0.28 mol) in dioxane (500 mL) and water (250 mL), was added NaCN (28 g, 0.74 mol) at 0° C. and then stirred at RT for 16 h. The reaction mixture was quenched with 3 Lit of water and extracted with ethylacetate (4×500 mL). The organic layer was washed with water (400 L), brine (250 mL), dried over Na2SO4 and concentrated to give crude product. The crude was purified by column chromatography over silica gel (pet. ether/ethylacetate, 8:2) to give 6-bromopyridine-2-yl-acetonitrile (22.5 g, 40%). [TLC: Pet. ether/ethylacetate, 7:3, Rf=0.35]
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4]P(=O)(OCC)OCC.[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH:26]=1)[CH:24]=O.CC(C)([O-])C.[K+].CCCCCC>O1CCCC1.CCOCC>[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](/[CH:24]=[CH:4]/[C:3]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:2]=2[F:1])[CH:26]=1
Reactant: CCOP(=O)(Cc1cc(F)ccc1F)OCC
Reactant: O=Cc1cncc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Fc1ccc(F)c(/C=C/c2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a stirred solution of diethyl 2,5-difluorobenzylphosphonate (63.5 g, 240 mmol) and 5-bromonicotinaldehyde (50.7 g, 264 mmol) in tetrahydrofuran (1923 ml) was added potassium tert-butoxide in tetrahydrofuran (312 ml, 312 mmol) at −10° C. After three hours, the reaction mixture was allowed to warm to ambient temperature and stirring was continued for another 16 hours at which time the reaction mixture was diluted with ether (800 mL) and washed with H2O. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to provide a yellow wax to which was added 300 mL of hexane and after sonication filtered to provide (E)-3-bromo-5-(2,5-difluorostyryl)pyridine (54 g, 173 mmol, 72.1%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.78 (d, J=1.8 Hz, 1H), 8.63 (d, J=2.1 Hz, 1H), 8.44 (t, J=2.0 Hz, 1H), 7.67 (ddd, J=9.4, 6.0, 3.2 Hz, 1H), 7.56-7.48 (m, 1H), 7.46-7.40 (m, 1H), 7.34 (td, J=9.6, 4.6 Hz, 1H), 7.24 (tt, J=8.3, 3.6 Hz, 1H). MS Anal. Calcd. for [M+H]+ C13H9BrF2N: 296.0. found 298.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](Cl)(=[O:13])=[O:12])[C:7](=[O:15])[CH2:6][CH2:5]2.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CC(C)=O>[CH2:16]([NH:23][S:11]([C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:15])=[CH:3][C:2]=1[Cl:1])(=[O:13])=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCc2cc(Cl)c(S(=O)(=O)Cl)cc21
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(Cl)c(S(=O)(=O)NCc3ccccc3)cc21

Procedure:
According to Example 2(a), 13.26 g (50 mmoles) of 5-chloro-6-chlorosulfonyl-1-indanone, 5.89 g (55 mmoles) of benzylamine and 5.05 g (50 mmoes) of triethylamine in a total of 100 ml of acetone yield 6-benzylsulfamoyl-5-chloro-1-indanone having a melting point of 203° to 205° C., from which the pure product is obtained after a recrystallization from ethanol, said product having a melting point of 228° to 231° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][S:15]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](NS(C)(=O)=O)C1
Reaction time: 2 h

Procedure:
tert-Butyl(3S)-3-aminopyrrolidine-1-carboxylate (0.09 mL, 0.5 mmol) was combined with methanesulfonyl chloride (0.050 mL, 0.64 mmol) and triethylamine (0.22 mL, 1.6 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, and concentrated. The residue was purified on silica gel (eluting with 0-10% methanol in dichloromethane) to give tert-butyl(3S)-3-[(methylsulfonyl)amino]pyrrolidine-1-carboxylate, LCMS [M+Na]+: m/z=287.1. The latter was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give the desired product, which was used directly in the next step. LCMS calculated for C5H13N2O2S (M+H)+: m/z=165.1; Found: 165.1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)([O-:24])=[O:23].C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH3:21][O:20][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][N:31]([C:28]3[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:30][CH:29]=3)[CH2:32][CH2:33]2)=[CH:19][C:10]2[C:11]3[CH2:18][CH2:17][CH2:16][C:12]=3[C:13](=[O:15])[O:14][C:9]=2[CH:8]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1)CCC3
Yield: 43 %

Procedure:
Method B (60 h at 50° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(4-nitrophenyl)piperazine; yield 43%; fusion point 226°-228° C. (decomposes; from acetone). Fumarate: method E; yield 92%; fusion point 216° C. (decomposes; from acetone).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH:28]([NH2:30])=[O:29]>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([NH:30][CH:28]=[O:29])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: NC=O
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: O=CNc1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (710 mg) described in Preparation Example 186 and formamide (89 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (213 mg) was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.CCN(C(C)C)C(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:30])=[O:29]
Reactant: COC(=O)c1cc(CCO)cc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(CCOS(C)(=O)=O)cc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a dichloromethane (0.03 M) solution of methyl 3-(2-hydroxyethyl)-1-naphthalenecarboxylate (1 eq.) from Step 2, Amine 31 and Hunig's base (1.5 eq.) was added at 0 methanesulfonyl chloride (1.3 eq.). The resulting solution was stirred at 0° C. for 30 min and then at RT for 15 min. The reaction mixture was subsequently quenched with 10% aq. HCl. The aqueous wash was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, and filtered. Concentration of the filtrate in vacuo afforded the crude title compound as a colorless oil.
Reaction SMILES: [CH2:1]([S:3][CH:4]1[N:7]([C:8](=[C:22]([S:29][C:30](=[O:32])[CH3:31])[S:23][CH2:24][CH2:25][O:26][CH2:27][CH3:28])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:33])[CH2:5]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:42])C=1>C(Cl)Cl>[CH2:1]([S:3]([CH:4]1[N:7]([C:8](=[C:22]([S:29][C:30](=[O:32])[CH3:31])[S:23][CH2:24][CH2:25][O:26][CH2:27][CH3:28])[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[O:10])[C:6](=[O:33])[CH2:5]1)=[O:42])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCCSC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1SCC
Solvent: ClCCl
Product: CCOCCSC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1S(=O)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.4 g p-nitrobenzyl 2-(4-ethylthio-2-oxo-1-azetidinyl)-3-acetylthio-3-(2-ethoxyethylthio)-acrylate in 75 ml. methylene chloride was cooled to 0° C. under a nitrogen atmosphere. A solution of 0.551 g m-chloroperbenzoic acid in 25 ml methylene chloride was added dropwise, then the reaction mixture was stirred at 0° C. for 1 hour. The methylene chloride solution was then washed with two 25 ml portions of saturated aqueous sodium bicarbonate solution and two 25 ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil. The crude title compound (1.25 g) was used without further purification. The NMR spectrum of a deuterochloroform solution showed peaks at 1.24(m, 6H); 2.27-3.74(c, 13H); 4.7-5.46 (c, 3H); 7.57(m, 2H); and 8.23(m, 2H) ppm. The infrared spectrum of a dichloromethane solution has absorption bands at 5.6 and 5.79 microns.
Reaction SMILES: C([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12](Cl)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.[CH2:17]1[C:22]2[NH:23][C:24]3[C:29]([C:21]=2[CH2:20][CH2:19][NH:18]1)=[CH:28][CH:27]=[CH:26][CH:25]=3.C(N(CC)CC)C.FC(F)(F)C(O)=O>ClCCl.ClCCl.CO>[CH3:10][CH:8]([CH3:9])[CH:7]([CH2:11][S:12]([N:18]1[CH2:19][CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]=2[CH2:17]1)(=[O:13])=[O:14])[C:6]([OH:5])=[O:16]
Reactant: CC(C)C(CS(=O)(=O)Cl)C(=O)OC(C)(C)C
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(CS(=O)(=O)N1CCc2c([nH]c3ccccc23)C1)C(=O)O
Reaction time: 2 h
Yield: 18.9 %

Procedure:
A solution of 2-chlorosulfonylmethyl-3-methylbutyric acid tert-butyl ester (271 mg) in dichloromethane (5 ml) was added to a mixture of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (172 mg) and triethylamine (0.42 ml) in dichloromethane (10 ml) at room temperature. The mixture was stirred for 2 h before addition of trifluoroacetic acid (2.4 ml), and stirring continued for a further 2 h. The mixture was evaporated to dryness and the residue partitioned between 1M aqueous sodium hydroxide (15 ml) and diethyl ether (15 ml). The organics were extracted with 1M sodium hydroxide (15 ml). The combined aqueous portions were acidified to pH=5 with 10% citric acid and extracted with ethyl acetate (4×20 ml). The combined organics were washed with water (2×10 ml) and brine (10 ml), then dried (MgSO4), filtered and the solvent removed under reduced pressure to give, after chromatography (SiO2, 20:1 dichloromethane-methanol), the title compound (66 mg, 19%) as a white foam.
Reaction SMILES: [CH:1]([OH:3])=O.C1CO[C:6]2([CH2:11]C[CH:9]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)O1>O>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:9]2[CH2:8][CH2:7][CH2:6][CH2:11][C:1]2=[O:3])=[CH:17][CH:16]=1)[CH2:19][CH3:20]
Reactant: CCCc1ccc(C2CCC3(CC2)OCCO3)cc1
Reactant: O=CO
Solvent: O
Product: CCCc1ccc(C2CCCCC2=O)cc1

Procedure:
To 300 ml of formic acid (99%) was put 84 g of the 1,1-ethylenedioxy-4-(4-n-propylphenyl)cyclohexane mentioned above, and stirred under a reflux for 2 hours. After cooled, the reaction solution was added to 500 ml of water and extracted with 500 ml of ethyl acetate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 65.6 g of 4-n-propylphenylcyclohexanone.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>C(#N)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:4][N:3]=1
Reactant: N#Cc1nc(Br)cnc1N
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1cnc(N)c(C#N)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.0 grams (0.015 mole) of 2-amino-3-cyano-5-bromopyrazine and 2.1 grams (0.021 mole) of trimethylsilylacetylene in 50 mL of acetonitrile is stirred, and 10.6 mL of triethylamine, 0.13 gram of copper iodide, and 0.29 gram of bis(triphenylphosphine)palladium(II) chloride are added in order. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 20 hours. The reaction mixture is warmed to 70° C., where it is stirred for about 7.5 hours. After this time, the reaction mixture is concentrated under reduced pressure to a residue. The residue is dissolved in ethyl acetate, and the solution is washed with 50 mL of aqueous, dilute hydrochloric acid. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. Elution is accomplished using tetrahydrofuran/methylene chloride combinations. The product-containing fractions are combined and concentrated under reduced pressure, yielding 2-amino-3-cyano-5-(trimethylsilylethynyl)pyrazine.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:29])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH2:20].O.CO>C1(OC)C=CC=CC=1.[Pd]>[CH3:16][O:17][C:18](=[O:29])[CH:19]([NH:20][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: COc1ccccc1
Product: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 40.1 %

Procedure:
To a mixture of 2-benzoylcyclohexanone (90.9 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on carbon (20 g), then the mixture is heated to reflux for 2 h while the resulting water is removed by a Dean-Stark apparatus. The mixture is cooled to 80° C., and the Pd/C is filtered and washed with anisole (3×60 ml). The mixture is cooled to 40° C., hexane (1000 ml) is added and the mixture kept at −20° C. for 48 h. The solid is filtered and washed with hexane (5×200 ml) to yield the crude 2-((2-benzoylphenyl)-amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester. The crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2×50 ml), and dried under a vacuum to give the title compound (60.2 g, 40.1%).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[Cl:16])([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:27][C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[C:32]([F:41])[CH:31]=1)[CH3:29]>C(N(CC)CC)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:27][C@@H:28]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[C:32]([F:41])[CH:31]=2)[CH3:29])=[O:13])=[CH:7][C:6]=1[Cl:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1Cl
Reactant: C[C@@H](N)c1ccc(NS(C)(=O)=O)c(F)c1
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)COc1ccc(C(C)(C)C)c(Cl)c1)c1ccc(NS(C)(=O)=O)c(F)c1
Yield: 29.8 %

Procedure:
(4-tert-Butyl-3-chlorophenoxy)acetic acid (121 mg, 0.50 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (86 mg, 0.53 mmol), triethylamine (0.5 ml) and N{4-[(1R)-1-aminoethyl]-2-fluorophenyl}methanesulfonamide hydrochloride (134 mg, 0.50 mmol, WO 2005003084A1) were mixed in the same procedure described in Example 2(b) to give 68 mg (30% yield) of the title compound as a white solid.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[SH:10].Cl[C:12]1[S:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>C(O)C.O>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[S:10][C:12]1[S:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]
Reactant: Sc1cccc(Cl)c1Cl
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2cccc(Cl)c2Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
Sodium metal (0.126 g, 5.5 mmol) was dissolved in absolute ethanol (10 mL) and to the resulting solution was added 2,3-dichlorobenzenethiol (0.895 g, 5 mmol). Ethyl 5-chloro-4-nitrothiophene-2-carboxylate (1.18 g, 5 mmol) was added and the reaction mixture was stirred for 1 hour at ambient temperature and was allowed to stand overnight. After this time, the mixture was diluted with water (30 mL) and the resulting precipitate was collected by filtration and dried in vacuo at 40° C. for 1 hour. Initial analysis showed some minor impurities so the crude material was stirred in absolute ethanol (10 mL) for 30 min, collected by filtration and dried in vacuo at 40° C. for 1 hour to afford the title product as a white solid (0.67 g, 35% yield). 1H NMR (CDCl3) δ: 8.18 (1H, s), 7.71 (2H, m), 7.31 (1H, m), 4.31 (2H, q, J=7.11 Hz), 1.33 (3H, t, J=7.11 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][C:17](OB(O)O)=[CH:16][CH:15]=1)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>COCCOC>[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=2)[CH:7]=[O:8])=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCOc1ccc(OB(O)O)cc1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2ccc(F)c(C=O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
Under an argon atmosphere, tetrakistriphenylphosphine palladium (69 mg) was added to 5 ml of 1,2-dimethoxyethane. A mixture resulting from dissolving 5-bromo-2-fluorobenzaldehyde (406 mg) in 5 ml of 1,2-dimethoxyethane was added. A mixture resulting from dissolving 4-ethoxyphenylboric acid (398 mg) in 1.5 ml of 1,2-dimethoxyethane was added. Two milliliter of 2M sodium carbonate solution was added. Stirring was conducted for one hour and ten minutes under reflux. After cooling to room temperature, 20 ml of toluene was added and was washed with 10 ml of water twice, 10 ml of a 2N sodium hydroxide solution twice and 10 ml of water twice. After drying with anhydrous sodium sulfate, the mixture was concentrated. The concentrated matter was purified by silica gel chromatography (hexane/ethyl acetate=4/1). The resulting effective fractions were concentrated to yield 5-(4-ethoxyphenyl)-2-fluorobenzaldehyde (369 mg, Yield 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([N+:17]([O-])=O)[CH:14]=[CH:15][CH:16]=2)=[C:4]([CH:20]=[N:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:3]=1>CCO.[Pd]>[NH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=2[CH:20]=[N:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:12]=1
Reactant: CC(C)(C)OC(=O)N=Cc1cc(N)ccc1CCOc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N=Cc1cc(N)ccc1CCOc1cccc(N)c1
Reaction time: 0.42 h

Procedure:
A suspension of 3-[2-(4-amino{t-butoxycarbonylimino}methylphenyl)-ethoxy]nitrobenzene (1.47 g; 3.81 mmol; from step (iii) above) and Pd (0.236 g; 5% on charcoal) in EtOH (75 mL) was stirred under H2(g) (1 atm.) for 25 minutes. After filtration through Celite the solvent was evaporated. The residue was purified by preparative HPLC (60% CH3CN/aq:0.1M NH4OAc) to afford the sub-title compound. Yield: 1.02 g (75%).