Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[N:19]1.C(C)#N.O.C(=O)([O-])[O-].[K+].[K+]>C(C)#N.C(OCC)(=O)C>[N:18]1([CH2:17][CH2:16][CH2:15][NH:14][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH:22]=[CH:21][CH:20]=[N:19]1
Reactant: NCCCn1cccn1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCCn1cccn1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
A solution of 11.97 g (0.0519 mol) of o-nitrobenzenesulfonyl chloride in 90 ml of cyanomethane was added slowly over several minutes to a cold (7° C.) solution of 10.7 g (0.0540 mol) of N-(3-aminopropyl)-pyrazole in a 3:1 cyanomethane/water solution containing 16.6 g (0.12 mol) of potassium carbonate, under nitrogen. The resulting reaction solution was warmed to room temperature and allowed to react. When the reaction was complete, as determined by thin layer chromatography, the reaction solution was poured into approximately 450 ml of ethyl acetate. The resulting aqueous and organic layers were separated and the organic layer was washed with both an aqueous potassium carbonate solution and an aqueous sodium chloride solution and then reduced to dryness under reduced pressure to provide an oil. This oil was purified using column chromatography (8000 ml of a gradient eluent of from 0 to 5% methanol in methylene chloride). The fractions containing the desired product were combined, reduced to dryness under reduced pressure and then recrystallized from a 1:2 ethyl acetate/diethyl ether solution to provide 13.97 g of the desired subtitled intermediate (m.p. 105°109° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[Cl:13]N1C(=O)CCC1=O>>[Cl:13][C:10]1[S:9][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:12][CH:11]=1
Reactant: c1ccc(Nc2nccs2)nc1
Reactant: O=C1CCC(=O)N1Cl
Product: Clc1cnc(Nc2ccccn2)s1
Reaction time: 8 h

Procedure:
Pyridin-2-yl-thiazol-2-yl-amine (5-2) and 1.2 equivalents of N-chlorosuccinimide were combined in a flame dried flask and allowed to stir together overnight under argon in anhydrous dioxane (0.25 M). The dioxane solution was then diluted with water and the resulting product filtered off. 1H-NMR (DMSO-d6) δ 11.463 (1H, s) 8.30 (dd, 1H, J=4.9, 0.9 Hz) 7.73 (t, 1H, J=8.42 Hz) 7.38 (s, 1H) 7.03 (d, 1H, J=8.4 Hz) 6.96 (t, 1H, J=5.9 Hz). MS [M+H]+=211.9.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([N:11]([CH:13]2[CH2:15][CH2:14]2)C)[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[CH2:29](N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:26]2[CH2:27][CH2:28][N:23]([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[N:3]=[C:4]([NH:11][CH2:13][CH:15]2[CH2:14][CH2:29]2)[N:5]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CN(c1nc(Cl)c(C#N)c(Cl)n1)C1CC1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCC2CC2)nc1N1CCN(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4,6-dichloro-2-(cyclopropyl-methyl-amino)-pyrimidine-5-carbonitrile (example 63a) was treated with 1-(4-fluoro-phenyl)-piperazine in the presence of N-ethyl-diisopropylamine in dioxane at 90° C. to yield 4-chloro-2-(cyclopropylmethyl-amino)-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=387.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]1(C)[S:20]CN=[N:17]1)=[C:7]2[C:11]([OH:13])=[O:12].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[K+].[NH2:32][CH:33]1C(=O)N2[CH:34]1SCC(CSC1SC(C)=NN=1)=C2C(OC(C1C=CC=CC=1)C1C=CC=CC=1)=O>O.O1CCCC1>[CH3:34][C:33]1[N:17]=[C:16]([S:15][CH2:14][C:6]2[CH2:5][S:4][CH:3]3[N:8]([C:9](=[O:10])[CH:2]3[NH2:1])[C:7]=2[C:11]([OH:13])=[O:12])[S:20][N:32]=1
Reactant: CC1(SCC2=C(C(=O)O)N3C(=O)C(N)C3SC2)N=NCS1
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Agent: O=C([O-])O
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nsc(SCC2=C(C(=O)O)N3C(=O)C(N)C3SC2)n1
Reaction time: 0.5 h

Procedure:
18 g. of 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are suspended in 350 ml. of tetrahydrofuran. 4.1 ml. of 70% perchloric acid are added dropwise. After 30 minutes, a slightly turbid solution forms. This solution is filtered and to the filtrate is added dropwise with stirring 12 g. of diphenyldiazomethane and 20 ml. of tetrahydrofuran. After three hours, the reaction mixture is poured into 2 liters of absolute ether. The solid, light brown precipitate, which is the perchloric acid salt of the desired product, is dried over Kieselgel in a desiccator. To obtain the base, the perchloric acid salt is dissolved in water and treated with the calculated equivalent of potassium bicarbonate. The aqueous solution obtained is extracted with chloroform. The chloroform phase is treated with activated carbon and sodium sulfate to obtain the 10 g. of the product, 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2 -ene-2-carboxylic acid, diphenylmethyl ester, as a light brown powder, m.p. 157°-159°. The product is recrystallized from tetrahydrofuran/petroleum ether. The isomeric thiadiazolyl derivative is similarly obtained from the product of Example 20.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]2=[CH:12][S:13][C:14]([NH2:15])=[C:10]2[C:9](=O)[N:8]([C:17]2[CH:22]=[CH:21][C:20](OC)=[CH:19][CH:18]=2)[N:7]=1)=[O:5])C.[OH-:25].[Na+].[CH2:27]([OH:29])C>O>[NH2:15][C:14]1[S:13][CH:12]=[C:11]2[C:10]=1[C:9](=[O:25])[N:8]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([O:29][CH3:27])[CH:22]=1)[N:7]=[C:6]2[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c(=O)c2c(N)scc12
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: COc1cccc(-n2nc(C(=O)O)c3csc(N)c3c2=O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83 %

Procedure:
To a solution of 5-amino-3-(4-methoxy-phenyl)-4-oxo-3,4-dihydro-thieno[3,4-d]pyridazine-1-carboxylic acid ethyl ester (3 g, 8.69 mmol, prepared in example 23) in a mixture of ethanol (50 ml) and water (25 ml) was added sodium hydroxide (0.38 g, 9.55 mmol). The resulting reaction mixture was stirred for 2.5 h at room temperature. Water (150 ml) was added, undissolved matter was filtered off. The aqueous phase was washed with diethyl ether (2×100 ml), pH was adjusted to pH=4 by addition of concentrated hydrochloric acid. The precipitate was filtered off and washed with water (2×50 ml), heptane (2×50 ml) and dried in vacuo at 50° C. for 18 h affording 2.3 g (83%) of the title compound as a solid.
Reaction SMILES: [CH:1]1([CH:4]([O:12][CH2:13][CH:14](OCC)OCC)[CH2:5]/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])[CH2:3][CH2:2]1.C(OC[C@H](OCC=[N:37][OH:38])CC=C)C1C=CC=CC=1.C(OC(OCC)CO[C@H](CC=C)COCC1C=CC=CC=1)C.C(OC[C@@H]1OCC2=NOC[C@@H]2C1)C1C=CC=CC=1>>[CH:1]1([CH:4]([O:12][CH2:13][CH:14]=[N:37][OH:38])[CH2:5]/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])[CH2:3][CH2:2]1
Reactant: C=CC[C@H](COCc1ccccc1)OCC=NO
Reactant: CCOC(COC(C/C=C/C(=O)OC)C1CC1)OCC
Agent: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Agent: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Product: COC(=O)/C=C/CC(OCC=NO)C1CC1

Procedure:
Methyl (2E)-5-cyclopropyl-5-(2,2-diethoxyethoxyl)pent-2-enoate (C34) was converted to the product using the method described for synthesis of 2-{[(2R)-1-(benzyloxy)pent-4-en-2-yl]oxy}-N-hydroxyethanimine (C3) in the section “Alternate conversion of C2 to C4.” The product was obtained as an oil: 1H NMR analysis indicated a roughly 1:1 mixture of geometric isomers around the oxime. Yield: 3.50 g, 15.4 mmol, 73%. 1H NMR (400 MHz, CDCl3) δ 7.73 and 7.47 (2 br s, total 1H), [7.49 (dd, J=5.8, 5.6 Hz) and 6.90 (dd, J=3.7, 3.6 Hz), total 1H], 6.99-7.09 (m, 1H), 5.87-5.93 (m, 1H), [4.54 (dd, half of ABX pattern, J=16.1, 3.6 Hz), 4.37 (dd, half of ABX pattern, J=16.0, 3.7 Hz), 4.28 (dd, half of ABX pattern, J=12.8, 5.5 Hz) and 4.14 (dd, half of ABX pattern, J=12.7, 5.8 Hz), total 2H], 3.74 and 3.74 (2 s, total 3H), 2.71-2.81 (m, 1H), 2.51-2.57 (m, 2H), 0.80-0.90 (m, 1H), 0.63-0.72 (m, 1H), 0.48-0.57 (m, 1H), 0.38-0.47 (m, 1H), 0.06-0.13 (m, 1H).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([I:14])=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17](OS(C3C=CC=C([N+]([O-])=O)C=3)(=O)=O)[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:35].[Li+].CN(C)C=O>O>[CH2:1]([C:8]1[C:13]([I:14])=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@@H:17]([Cl:35])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1Cl
Temperature: 75 °C
Reaction time: 9 h
Yield: 48.9 %

Procedure:
A mixture of 553 g of 2-benzyl-6-((3R,4R)-3-(3-nitrobenzenesulfonyl)oxy-4-methoxypyrrolidine-1-yl]-3-iodopyridine, 79 mg of lithium chloride and 5.0 ml of N,N-dimethylformamide was heated under stirring at 75° C. for 9 hours. After cooling as it was, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (10:1) and then with hexane/ethyl acetate (5:1), to give 391 mg of the target compound.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][O:30]COC)=[CH:24][CH:23]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CO>[O:1]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][OH:30])=[CH:26][CH:27]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: COCOCCc1ccc(Cc2ccc(OC)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2ccc(CCO)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
To a solution of 5-methoxy-2-{4-[2-(methoxymethyl-oxy)ethyl]benzyl}phenyl β-D-glucopyranoside (0.053 g) in methanol (2.3 mL) was added p-toluenesulfonic acid monohydrate (0.032 g), and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was cooled to ambient temperature, triethylamine (0.5 mL) was added to the reaction mixture, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=6/1) to give 2-[4-(2-hydroxyethyl)benzyl]-5-methoxyphenyl β-D-glucopyranoside (0.023 g).
Reaction SMILES: B(O)(O)O.[OH:5][N:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][C:7]1([CH3:24])[CH3:23].[C:25](#N)[CH3:26].OO>O.B(O)(O)O.C1CCCCC1>[CH:26]1([O:5][N:6]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([O:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][C:7]2([CH3:24])[CH3:23])[CH2:25][CH2:9][CH2:8][CH2:7][CH2:23]1
Reactant: CC#N
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: OB(O)O
Agent: OO
Solvent: O
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1
Temperature: 52 °C
Yield: 68 %

Procedure:
A solution of 0.100 g (0.360 mmol) of ferrous sulfate heptahydrate and 0.112 g (1.82 mmol) of boric acid in 4 ml of water is added to a mixture of 5.00 g (18.1 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 27 ml of acetonitrile, and 19 ml of cyclohexane. The mixture is heated to 52° C. A solution of 4.98 g (73 mmol) of 50% aqueous hydrogen peroxide is added dropwise over 2.75 hours to the reaction mixture while the temperature is brought to and maintained at reflux (63° C.). A solution of 0.051 g of ferrous sulfate heptahydrate and 0.042 g of boric acid in 2 ml of water is added to the reaction mixture 1.25 hours after the peroxide addition is started. After the peroxide is added, the reaction mixture is heated at reflux for 30 minutes, then allowed to cool slowly. Work-up and purification according to the procedure of Example 5 afford 4.42 g (68% yield) of the title compound, a colorless syrup, GC assay 99.3%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:23][CH2:24][CH:25]=[CH2:26].O>O1CCCC1>[CH2:10]([O:9][C:7](=[O:8])[C:6]([CH2:4][CH2:3][CH:2]=[CH2:6])([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:23][CH2:24][CH:25]=[CH2:26])[CH3:11]
Reactant: C=CCCBr
Reactant: CCOC(=O)Cc1cccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(CCC=C)(C(=O)OCC)c1cccs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-(thiophen-2-yl)acetate (2.35 g) was dissolved in tetrahydrofuran (30 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide (2.31 g) in THF (1M solution, 13.8 mL) was added and the solution was stirred for 30 minutes. 4-Bromo-but-1-ene (1.4 mL) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was re-cooled to −78° C. and lithium bis(trimethylsilyl)amide (2.31 g) in THF (1M solution, 13.8 mL) was added and the solution was stirred for 30 minutes. 4-Bromo-but-1-ene (1.4 mL) was added and the reaction mixture was allowed to warm to room temperature and stand overnight. HPLC-MS analysis indicated that the reaction was incomplete so the reaction was again cooled to −78° C. and further aliquots of lithium bis(trimethylsilyl)amide (1M solution, 10 mL) and 4-bromo-but-1-ene (1.0 mL) were added following the procedure outlined above. After stirring for a further 2 hours, water (30 mL) was added and the reaction was extracted with diethyl ether (2×60 mL). The combined organic extracts were dried (MgSO4) and evaporated. The resulting oil was purified by column chromatography on silica eluting with ethyl acetate/isohexane (1/99) afford the sub-titled compound (3.18 g).
Reaction SMILES: P[C-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C-:7]1(P)[CH:11]=[CH:10][CH:9]=[CH:8]1.[Fe+2:13].[Li]CCCC.CO>C1COCC1.CCCCCC>[CH-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[Fe+2:13]
Reactant: P[c-]1cccc1
Agent: [Fe+2]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CO
Product: c1cc[cH-]c1
Temperature: -30 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,1'-bis(phosphino)ferrocene (0.2 g, 0.8 mmol) in THF (30 mL) was added dropwise via syringe n-BuLi (1.0 mL of a 1.6M solution in hexane, 2.0 equiv. ). The orange solution was allowed to stir for 1.5 h during which it became slightly cloudy. To the resulting mixture was then added a THF solution (10 mL) of (3S, 6S)-3, 6-octanediol cyclic sulfate (0.338 g, 1.6 mmol). After stirring for 1 h, n-BuLi (1.15 mL of a 1.6M hexane solution, 2.2 equiv.) was again added dropwise via syringe. The mixture was allowed to stir for 1.5 h, after which MeOH (3 mL) was added to quench any excess n-BuLi remaining. The resulting orange mixture was concentrated to produce a gelatinous residue which was extracted with pentane (150 mL) and filtered. Concentration of the filtrate to 5 mL and cooling to -30° C. for 10 h afforded the product as an orange crystalline solid which was filtered, washed with cold MeOH and dried (0.29 g, 77%). The crude product was essentially pure and may be used without any further purification. 1H NMR (C6D6) δ0.88 (m, 6H, CH3), 0.9-1.20 (m, 4H, CH2), 1.11 (t, JHH =7.3 Hz, 6H, CH3), 1.20-1.40 (m, 4H, CH2), 1.45-1.70 (m, 4H, CH2), 1.70-1.90 (m, 4H, CH), 2.10 (m (br), 2H, CH2), 2.40 (m, 2H, CH), 3.90 (m, 1H, CpH), 4.25 (m, 2H, CpH), 4.35 (m, 1H, CpH); 31P NMR (C6D6) δ-9.4; 13C NMR (C6D6) 5 14.27 (d, JPC =16.1 Hz), 14.82 (d, JPC =7.9 Hz), 23.76, 30.07, 30.49, 34.03, 34.34 (d, JPC =4.4 Hz), 42.42 (d, JCP =9.9 Hz), 44.44 (d, JCP =11.9 Hz), 70.88 (d, JCP =6.2 Hz), 71.24, 71.96 (d, JCP =7.7 Hz), 77.33 (d, JCP =32.8 Hz); HRMS (EI, direct insert): m/z 470.1976 (M+, exact mass calcd for C26H40P2Fe: 470.1955), 359.0485 (M-C8H15) , 328.1046 (M-C8H15 P).
Reaction SMILES: BrC[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8](=[O:13])[CH:7]=[CH:6]2.Cl.Cl.[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:29](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]1([CH3:28])[CH:17]=[CH:18][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH2:29][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][C:8](=[O:13])[O:9]4)=[CH:4][CH:3]=3)[CH2:26][CH2:27]2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: O=c1ccc2cc(CBr)ccc2o1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(N2CCN(Cc3ccc4ccc(=O)oc4c3)CC2)cc1
Yield: 64 %

Procedure:
A mixture of 6-bromomethyl coumarin (0.5 g, 2.09 mmol), 4-tolylpiperazine dihydrochloride (0.51 g, 2.53 mmol) and potassium carbonate (2 g, 14.5 mmol) in acetonitrile (100 mL) was heated under reflux for 18 hours. The cooled mixture was filtered and concentrated under vacuum to provide a solid. Recrystallization from ethyl acetate provided the product as plates (0.45 g, 64% yield), mp 154-155° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24](Cl)(=[O:26])=[O:25].S(Cl)(Cl)(=O)=O.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([S:24]([C:15]3[CH:16]=[CH:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=3)(=[O:26])=[O:25])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Clc1cccnc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(c1ccc2ccccc2c1)N1CCN(c2ncccc2Cl)CC1
Yield: 17 %

Procedure:
Sulfonylation of 1-(3-chloropyridin-2-yl)piperazine (632 mg, 3.2 mmol) with naphthalene-2-sulfonyl chloride (725 mg, 3.2 mmol) was carried out according to a similar procedure described for example 2A (except that the sulfonyl chloride was added before the diisopropylethylamine) using anhydrous dichloromethane (10 mL) as solvent and diisopropylethylamine (1.4 mL, 8.0 mmol) as base. 1-(3-chloropyridin-2-yl)-4-(2-naphthylsulfonyl)piperazine was obtained in 17.0% yield (210.2 mg) as white solid.
Reaction SMILES: [CH3:1][Li].C[CH2:4][O:5][CH2:6][CH3:7].[Br:8][C:9]1[CH:10]=C(C=O)[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][CH:14]=1.IC>C1COCC1>[CH3:4][O:5][CH:6]([C:7]1[CH:10]=[C:9]([Br:8])[CH:14]=[CH:13][C:12]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH3:1]
Reactant: Cc1ccccc1-c1ccc(Br)cc1C=O
Reactant: CCOCC
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: CI
Product: COC(C)c1cc(Br)ccc1-c1ccccc1C
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of methyllithium in Et2O (1.6M, 6.8 mL, 10.9 mmol) was added dropwise into a solution of 4-bromo-2′-methylbiphenyl-2-carbaldehyde (2.0 g, 7.3 mmol) in anhydrous THF (30 mL) cooled at −78° C. under nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 45 minutes and an additional amount of methyllithium in Et2O (1.6M, 3.4 mL, 5.5 mmol) was added. After 10 minutes, iodomethane (4.1 ml, 65.4 mmol) was added. The cooling bath was removed and the reaction mixture was stirred at RT for 5 days. The reaction mixture was diluted with MTBE (100 mL), and then washed with water (2×50 mL) and brine (50 mL). The aqueous layers were extracted with MTBE (100 mL). The organic layers were combined, dried (MgSO4) and concentrated under vacuum. After purification by flash chromatography (silica, heptane/MTBE), the title compound was obtained as a pale yellow oil (1.90 g, 86%). HPLC (Method A) Rt 5.7 min (Purity: 91%). 1H NMR (DMSO-d6, 300 MHz) δ 7.62 (d, J=2.2 Hz, 0.4H), 7.59 (d, J=2.2 Hz, 0.6H), 7.52 (dd, J=8.1, 2.2 Hz, 1H), 7.35-7.21 (m, 3H), 7.13-7.02 (m, 2H), 4.05 (q, J=6.4 Hz, 0.4H), 3.84 (q, J=6.4 Hz, 0.6H), 3.05 (s, 1.2H), 3.03 (s, 1.8H), 2.03 (s, 1.8H), 1.98 (s, 1.2H), 1.17 (d, J=6.4 Hz, 1.8H), 1.11 (d, J=6.4 Hz, 1.2H).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCOCC1.O>[CH:1]1([CH2:6][CH2:7][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCN1CCCC1
Reactant: O=C(Cl)CCC1CCCC1
Solvent: O
Solvent: C1COCCO1
Product: O=C(CCC1CCCC1)NCCCN1CCCC1
Reaction time: 4 h

Procedure:
3-Cyclopentyl propionylchloride (5 mmol) in 10 ml of dioxane was added dropwise to a solution of 10 mmol of 1-(3-aminopropyl)pyrrolidine in water. After stirring for 4 hours the solvent was evaporated under reduced pressure and the residue purified by column chromatography on silica gel (eluent: methylene chloride/methanol/aqueous ammonia (90/10/1)). The solvent was removed under reduced pressure and the residue was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])Br)=[CH:6][CH:5]=1.[CH2:24]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[CH:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C.O.C(O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C:31]2[CH:32]=[CH:33][C:28]([CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:29][CH:30]=2)=[CH:6][CH:5]=1
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(C=C(Br)C(=O)OCc2ccccc2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)c1ccc(C=C(C(=O)OCc2ccccc2)c2ccc(CC(C)C)cc2)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
4-(2-Benzyloxycarbonyl-2-bromo-vinyl)-benzoic acid methyl ester (2.0 g, 5.33 mmol) was added to a 100 mL RB flask containing 4-isobutylphenylboronic acid (2.85 g, 15.99 mmol), sodium carbonate (2.83 g, 26.65 mmol), and dichlorobis(tri-o-tolylphosphine)palladium(II) (544 mg, 0.69 mmol). Dimethoxyethane (16 mL), ethanol (8 mL), and water (4 mL) were added, and the reaction was stirred at 120° C. for 1 hour at which point TLC analysis indicated that the reaction had gone to completion. The reaction was filtered hot through celite and concentrated to dryness. Purification by flash column chromatography was performed on an ISCO Sg-100c system, using a 40 gram pre-packed column and eluting with a linear gradient of ethyl acetate in hexanes starting at 10% EtOAc and ending at 40% EtOAc over 22 minutes. This afforded the desired product, 4-[2-Benzyloxycarbonyl-2-(4-isobutyl-phenyl)-vinyl]-benzoic acid methyl ester as a pale oil, 1.8 g, 79%. LC-MS m/z=429 [C28H28O4+H]+.