Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:8])[C:6]=1Br.C[CH2:10][O:11]CC.C([Li])CCC.CN(C)C=O>CCCCCC>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:8])[C:6]=1[CH:10]=[O:11]
Reactant: Cc1csc(C)c1Br
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1csc(C)c1C=O
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 15 g. (79.0 mmol) of 2,4-dimethyl-3-bromothiophene in 120 ml. of dry ether was cooled to -70° C. and 36 ml. of a hexane solution of n-butyl lithium (2.4 molar, 86.4 mmol) were added dropwise. The reaction mixture was allowed to warm up to -20° C. for 10 min., cooled again to -70° C. and then quenched by adding dropwise 15 g. (0.205 mol) of dimethylformamide. The mixture was stirred at room temperature overnight, poured into ice water, stirred for 15 min. and extracted four times with ether. The ether phase was washed with saturated sodium chloride solution, dried and evaporated. The resulting oily residue was distilled to yield 2,4-dimethylthiophene-3-carboxaldehyde, b.p. 50°-55° C./0.1 mm.
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:31])[C:10]2[N:11]=[CH:12][N:13]([C:29]=2[N:30]=1)[C@@H:14]1[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:16]([OH:17])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.C(OC(=O)C)(=O)C.C([O-])([O-])=O.[K+].[K+].[CH3:49][S:50]([CH3:52])=O>>[C:1]([NH:6][C:7]1[NH:8][C:9](=[O:31])[C:10]2[N:11]=[CH:12][N:13]([C:29]=2[N:30]=1)[C@@H:14]1[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:23])[CH3:22])[C@@H:16]([O:17][CH2:49][S:50][CH3:52])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]1
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CSCO[C@H]1C[C@H](n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 69 %

Procedure:
5 g of N2-isobutyryl-5′-O-(tert-butyldimethylsilyl)-2′-deoxyguanosine (11.0 mmol) dissolved in 21 mL dry DMSO was treated with 10 mL acetic acid and 32 mL acetic anhydride, and stirred for 48 h at room temperature. The crude reaction mixture was then neutralized by adding a K2CO3 solution, and extracted with ethyl acetate (100×3 mL). The combined organic extract was then washed with saturated NaHCO3 solution, dried over Na2SO4 and concentrated under vacuum. Then reaction mixture was purified by a silica gel column chromatography resulting the product 11 as white powder (3.9 g, 69% yield; Rf=0.35, CH2Cl2:MeOH/20:1). HR-MS: Obs. m/z 512.2344 cald. for C22H38O5N5SiS 512.2363 [M+H]+. 1H-NMR (CDCl3): δH 12.0 (s, 1H), 8.95 (brs, 1H), 8.09 (s, 1H), 6.24 (t, J=6.8 Hz, 1H), 4.73 (m, 2H), 4.66 (m, 1H), 4.16 (m, 1H), 3.81 (m, 2H), 2.76 (m, 1H), 2.59 (m, 1H), 2.54 (m, 1H), 2.21 (s, 3H), 1.29 (m, 6H), 0.91 (s, 9H), and 0.10 (s, 6H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=1.CC(O)C.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[CH3:17][O:16][C:13]1[N:14]=[CH:15][C:10]([NH:9][C:2]2[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(N)cn1
Reactant: Nc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2cc(N)ncn2)cn1
Temperature: 90 °C
Reaction time: 36 h

Procedure:
A mixture of 6-chloro-pyrimidin-4-ylamine (0.65 g, 5 mmol), 5-amino-2-methoxypyridine (0.62 g, 5 mmol) and 2-propanol (5 mL) is shaken for 36 h at 90° C. After cooling to room temperature, the reaction mixture is distributed between half-saturated Na2CO3-solution and ethyl acetate. The organic layer is dried over Na2SO4 and evaporated. The solid residue is washed consecutively with CH3OH, ethyl acetate and CH2Cl2 and dried in vacuo.
Reaction SMILES: [F:1][C:2](=[CH2:13])[CH2:3][N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8].[CH2:14]([NH:21][CH2:22]C(O)=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[CH2:14]([N:21]1[CH2:22][CH2:13][C:2]2([F:1])[CH:11]1[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:3]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: C=C(F)CN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2N(Cc3ccccc3)CCC2(F)C1

Procedure:
20.8 g (0.11 mol) of ethyl N-(2-fluoroallyl)-N-(2-oxoethyl)-carbamate are heated under reflux with 19 g (0.115 mol) of N-benzylglycine in 300 ml of toluene until evolution of CO is complete. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[C:4]([F:16])[CH:3]=1.[CH3:17][Mg]Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:9][S:10]([C:12]([CH3:13])([CH3:15])[CH3:14])=[O:11])[CH3:17])=[C:4]([F:16])[CH:3]=1
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(Br)cc1F
Reactant: C[Mg]Cl
Solvent: ClCCl
Product: C[C@@H](NS(=O)C(C)(C)C)c1ccc(Br)cc1F

Procedure:
To a solution of N-[(1E)-(4-bromo-2-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (32.65 g, 0.1066 mol) in 550 mL CH2Cl2 at −48° C. was added methylmagnesium chloride (3.0 M solution is ether, 53.31 mL, 0.1599 mol) dropwise. The reaction was quenched with aqueous ammonium chloride and the aqueous layer was extracted with methylene chloride. The combined organics were dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was subjected to column chromatography on silica gel eluted with 10-50% ethyl acetate in hexanes to afford N-[(1R)-1-(4-bromo-2-fluorophenyl)ethyl]-2-methylpropane-2-sulfinamide as a white solid that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 324.14 for M+H+ (81Br).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([S:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]2[CH2:29][OH:30])(=[O:22])=[O:21])=[C:15]([CH3:31])[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH3:31])[C:16]([S:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]2[CH:29]=[O:30])(=[O:21])=[O:22])=[C:17]([CH3:19])[CH:18]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CO)c(C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2C=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
DMSO (12.76 mmol, 4 eq.) was dissolved in methylene chloride (10 ml), oxalyl chloride (6.38 mmol, 2 eq) was added under nitrogen at −78° C. and the mixture was then stirred at this temperature for 30 min. (1-(4-Methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methanol (3.1 mmol, 1 eq) was dissolved in methylene chloride (10 ml), the solution was added dropwise to the reaction solution at −78° C. and this was then stirred for 30 min. Triethylamine (12.76 mmol, 5 eq) was added and the reaction solution was warmed to room temperature and stirred for 1 h. Water (20 ml) was added to the reaction mixture and the mixture was extracted with methylene chloride (3×60 ml). The organic phase was dried over sodium sulfate and filtered and the filtrate was concentrated to dryness under reduced pressure. The crude product was employed in the next stage without further purification. Yield: 90%
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([N:26]([CH3:28])[CH3:27])=[N:8][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([N+:17]([O-])=O)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[NH2:17][C:10]1[C:9]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:8][C:7]([N:26]([CH3:28])[CH3:27])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c(N(C)C)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(N(C)C)nc(-c2ccccc2)c(N)c1C(=O)OCC
Reaction time: 5.5 h

Procedure:
In 2 ml of ethyl acetate Was dissolved 52 mg of 3,4-diethoxycarbonyl-2-dimethylamino-5-nitro-6-phenylpyridine, whereto 50 mg of 10% Pd-C (50% wet) was added. Catalytic reduction reaction was conducted for 5.5 hours. After the catalyst was removed, the solvent was distilled off and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane 1:2).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1>CN(C=O)C>[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1cnccc1Cl
Reactant: CSc1ccc(S)cc1
Solvent: CN(C)C=O
Product: CSc1ccc(Sc2ccncc2C=O)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 114.8 %

Procedure:
4-Chloronicotinaldehyde [prepared according to D. Albanese, M. Penso, M. Zenoni, Synthesis 1999, 1294-1296] (500 mg, 3.5 mmol), 4-methylsulfanyl-benzenethiol (606 mg, 3.88 mmol) potassium carbonate (586 mg, 4.24 mmol) and DMF (7 mL) were combined, the mixture was heated together at 50° C. for 1.5 h and then stirred at room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and 10% aqueous K2CO3 (100 mL). The organic layer was dried (MgSO4) and evaporated to give the title compound (1.05 g) as a yellow oil. The 1H NMR spectrum showed the material to be of sufficient purity (90-95%) to be used without further purification; δH (CDCl3, 400 MHz) 2.54 (3H, s), 6.69 (1H, d), 7.35 (2H, d), 7.4 (2H, d), 8.35 (1H, d), 8.87 (1H, s), 10.24 (1H, s); MS m/z (TS+) 262 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C[Si]([C:17]#[N:18])(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:18][CH2:17][C:8]1([OH:12])[C:9]2[C:4](=[CH:3][C:2]([NH2:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: Nc1ccc2c(c1)CCCC2=O
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1(O)CCCc2cc(N)ccc21

Procedure:
6-amino-1,2,3,4-tetrahydro-1-naphthalenone is reacted with trimethylsilylcyanide followed by lithium aluminum hydride to obtain 1-aminomethyl-1-hydroxy-6-amino-1,2,3,4-tetrahydronaphthalene. This diamine is di-acetylated with acetic anhydride, chlorinated with chlorine and acetic acid, and then heated to dehydrate the alcohol. The resulting di-chloro-di-acetamide is hydrolyzed in HCl to obtain 1-aminomethyl-6-amino-5,7-dichloro-3,4-dihydronaphthalene HCl.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.[NH2:17][CH2:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[CH:28]=[CH:29][O:30][C:23]=12)=[O:20].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([NH:17][CH2:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[CH:28]=[CH:29][O:30][C:23]=12)=[O:20])=[O:6]
Reactant: NCC(=O)Nc1ccnc2ccoc12
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(/C=C/C(F)(F)F)NCC(=O)Nc1ccnc2ccoc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (15.4 mg, 0.11 mmol) was dissolved in DCM (0.75 ml containing one drop of dimethyl formamide), oxalyl chloride was added (14 mg, 0.11 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 2-amino-N-furo[3,2-b]pyridin-7-yl-acetamide hydrochloride (25.3 mg, 0.11 mmol) and diisopropylethylamine (44 μl, 0.25 mmol) dissolved in dimethylformamide (1 ml) and the resulting mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 6.9 mg (0.022 mmol, 20%).
Reaction SMILES: [N+:1]([C:4]1[CH:39]=[CH:38][C:7]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:17][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]5[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=5)=[CH:23][CH:22]=4)=[N:19][N:20]=3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.CN(C)C=O.Cl.C(=O)([O-])[O-].[Na+].[Na+]>[Fe].O>[NH2:35][C:32]1[CH:31]=[CH:30][C:29]([CH:28]=[CH:27][C:24]2[CH:23]=[CH:22][C:21]([C:18]3[O:17][C:16]([C:13]4[CH:14]=[CH:15][C:10]([CH:9]=[CH:8][C:7]5[CH:38]=[CH:39][C:4]([NH2:1])=[CH:5][CH:6]=5)=[CH:11][CH:12]=4)=[N:20][N:19]=3)=[CH:26][CH:25]=2)=[CH:34][CH:33]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(-c3nnc(-c4ccc(C=Cc5ccc([N+](=O)[O-])cc5)cc4)o3)cc2)cc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(C=Cc2ccc(-c3nnc(-c4ccc(C=Cc5ccc(N)cc5)cc4)o3)cc2)cc1
Reaction time: 1 h
Yield: 94.3 %

Procedure:
After mixing 6.0 g of 2,5-bis[4-(p-nitrostyryl)phenyl]-1,3,4-oxadiazole, 12.0 g of iron powder and 200 g of N,N-dimethyl formamide together, by adding dilute hydrochloric acid prepared by employing 5 ml of undiluted hydrochloric acid and 17 ml of water to the resulting mixture and intensely stirring it, reaction was effected at a temperature of 90° to 100° C. for one hour. After completing the reaction, by adding a 5% aqueous solution of sodium carbonate while heating as above, the pH value of the reactant mixture was adjusted to be 8, the undissolved matter was filtered while heating, and the resulting filtrate was diluted with 70 ml of water, whereby there were separated yellow crystals. Then, said crystals were collected by filtering, washed in water and dried, whereby there were obtained 5.0 g (yield rate: 94.3%) of 2,5-bis[4-(p-aminostyryl)phenyl]-1,3,4-oxadiazole. The melting point of this crystal was 250° C. or more (decomposition point).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.[CH2:16]([S:23][C:24]1[CH:25]=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[N:29][C:28]=2Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.O>[CH2:16]([S:23][C:24]1[CH:25]=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[N:29][C:28]=2[C:4]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=1[O:2][CH3:1])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: Clc1nccc2cc(SCc3ccccc3)cnc12
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(SCc3ccccc3)cnc12
Temperature: 60 °C
Yield: 91.1 %

Procedure:
To a vial charged with 2-methoxy-4-(trifluoromethyl)phenyl boronic acid (Combi-Blocks, San Diego, Calif.) (0.268 g, 1.216 mmol), 3-(benzylthio)-8-chloro-1,7-naphthyridine (0.218 g, 0.760 mmol), and potassium phosphate tribasic (0.189 ml, 2.280 mmol) was added dioxane (3.05 ml) and water (1.016 ml). The mixture was purged with argon prior to the addition of 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (0.054 g, 0.076 mmol). The vessel was sealed and heated to 60° C. overnight. After cooling to ambient temperature, the mixture was loaded directly onto a silica gel loading column and purified with a 40 g HP spherical column (silicycle) (SiliCycle, Inc. Quebec City, Canada) ramping EtOAc in heptane (0 to 35%, then isocratic at 35%) to provide 3-(benzylthio)-8-(2-methoxy-4-(trifluoromethyl)phenyl)-1,7-naphthyridine (0.295 g, 0.692 mmol, 91% yield) as an off-white foam. m/z (ESI) 427.3 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[C@@H:10]([OH:11])[CH2:9][CH2:8][NH:7]1)=[O:5].CCN(C(C)C)C(C)C.[Cl:21][C:22]1[C:29]([CH3:30])=[C:28]([N:31]=[C:32]=[O:33])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>C(Cl)Cl>[CH3:2][O:3][C:4]([C@@H:6]1[C@@H:10]([OH:11])[CH2:9][CH2:8][N:7]1[C:32]([NH:31][C:28]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:21])[C:29]=1[CH3:30])=[O:33])=[O:5]
Reactant: COC(=O)[C@H]1NCC[C@@H]1O
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
A solution of ester 1A (500 mg, 2.75 mmol) in dry CH2Cl2 (10 mL) was cooled to 0° C., treated with Hunig's base (0.53 mL, 3.04 mmol) and stirred at 0° C. for 30 min. The solution was treated with isocyanate 23E (505 mg, 2.62 mmol), and the resulting suspension was stirred at rt for 3 h. The insoluble solids were filtered off and the filtrate was partitioned between aqueous NH4Cl (6.0 mL) and CH2Cl2 (3×60 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue and insoluble solids were combined and chromatographed (silica gel; EtOAc/hexane gradient) to yield the title compound (177.2 mg, 75.3%) as a white solid, mp 189-191° C. HPLC: 1.72 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O-10% CH3CN-0.1% TFA and B=10% H2O-90% CH3CN-0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm). Chiral HPLC: retention time=22.2 min (100%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 338 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[ClH:12].Cl.[CH:14]1([N:18]2[CH2:23][CH2:22][N:21]([C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1>>[ClH:12].[CH:14]1([N:18]2[CH2:23][CH2:22][N:21]([C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:2]4[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=4)[CH2:28][CH2:27]3)=[O:25])[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: O=C(C1CCNCC1)N1CCN(C2CCC2)CC1
Agent: Cl
Product: O=C(C1CCN(c2ccc(C(F)(F)F)nc2)CC1)N1CCN(C2CCC2)CC1

Procedure:
The title compound (E97) was prepared in a similar manner to that described in Example 96, using 5-bromo-2-trifluoromethylpyridine (F. Cottet and M. Schlosser, Eur. J. Org. Chem., 2002, 327-330) and 1-cyclobutyl-4(piperidine-4-carbonyl)-piperazine (free base compound from D7). 1H NMR δ [DMSO-d6]: 1.53-1.83 (6H, m), 2.15 (2H, m), 2.39 (2H, br. m), 2.70 (1H, m), 2.84 (1H, m), 2.96 (3H, m), 3.07 (IH, m), 3.32 (2H, br. m), 3.52-3.68 (2H, m), ca 4.0 (2H, br., partially obscured by H2O signal), 4.22 (1H, br. d, J≈14 Hz), 4.46 (1H, br., J≈14 Hz), 7.44 (IH, dd, J=9, 3 Hz), 7.62 (1H, d, J=9 Hz), 8.43 (1H, d, J=3 Hz), 11.54 (1H, br.); LCMS electrospray (+ve) 411 (MH+).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[S:5](=[CH:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([O:12]CC)=[O:11])(=[O:7])=[O:6]>Cl>[NH2:3][C:2]([NH2:4])=[NH:1].[S:5](=[CH:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([OH:12])=[O:11])(=[O:7])=[O:6]
Reactant: CCOC(=O)C(C=S(=O)=O)Cc1ccccc1
Agent: Cl
Agent: N=C(N)N
Product: O=C(O)C(C=S(=O)=O)Cc1ccccc1
Yield: 22.4 %

Procedure:
A solution of 3.11 g (9.4 mmol) of ethyl (RS)-α-(sulphonylmethyl)hydrocinnamate guanidine salt in 400 ml of semi-concentrated hydrochloric acid is heated to reflux for 20 hours. Subsequently, the reaction solution is evaporated under reduced pressure and, for purification, the residue obtained is chromatographed on 50 g of silica gel using a 9:1 to 1:1 mixture of water and methanol as the eluent. After lyophilization from water there is obtained 0.6 g of (RS)-α-(sulphonylmethyl)hydrocinnamic acid guanidine salt as a colourless powder, MS: 243 (M-H)-.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([NH:30][C:31]4[CH:32]=[N:33][C:34]([CH3:38])=[C:35](Br)[CH:36]=4)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.O1C2C=CC(C3(C(NC4C=NC(C)=C(C5C=CC=CC=5)C=4)=O)CC3)=CC=2OC1>>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([NH:30][C:31]4[CH:32]=[N:33][C:34]([CH3:38])=[C:35]([C:9]5[CH:10]=[CH:11][C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:15])[CH3:1])=[CH:7][CH:8]=5)[CH:36]=4)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reactant: CN(C)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Product: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)N(C)C)cc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-methylpyridin-3-yl)cyclopropanecarboxamide was prepared from 4-(N,N-dimethylsulfamoyl)phenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-phenylpyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]([O:17][CH3:18])([O:15][CH3:16])OC.[CH2:19]([O:21][C:22]([CH:24]1[C:31](=[O:32])[CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:29]2[CH:25]1[CH2:26]C(=O)[CH2:28]2)=[O:23])[CH3:20].C(=O)(O)[O-].[Na+]>CO>[CH2:36]([O:35][C:33]([CH:30]1[C:31](=[O:32])[CH:24]([C:22]([O:21][CH2:19][CH3:20])=[O:23])[CH:25]2[CH:29]1[CH2:28][C:12]([O:15][CH3:16])([O:17][CH3:18])[CH2:26]2)=[O:34])[CH3:37]
Reactant: CCOC(=O)C1C(=O)C(C(=O)OCC)C2CC(=O)CC12
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1C(=O)C(C(=O)OCC)C2CC(OC)(OC)CC12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At 25° C., 330 mg of p-toluenesulfonic acid and 1.6 ml of trimethyl orthoformate are added to a solution of 9.6 g of 2,4-bisethoxycarbonylbicyclo[3.3.0]octane-3,7-dione (preparation: Reference Example 1) in 330 ml of methanol. The mixture is stirred for 3 hours at 25° C., combined with 80 ml of 5% strength sodium bicarbonate solution, extracted three times with respectively 300 ml of methylene chloride, dried over sodium sulfate, and evaporated under vacuum. The residue is purified by chromatography on silica gel. With ethyl acetate/hexane (1+1), 7 g of the title compound is obtained as a colorless oil.
Reaction SMILES: CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:53]([NH2:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.Br[C:62]1[CH:63]=[C:64]([CH2:69][CH:70]([CH:78]2[CH2:81][CH2:80][CH2:79]2)[C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH:65]=[CH:66][C:67]=1[Cl:68]>C1(C)C=CC=CC=1>[CH2:53]([NH:60][C:66]1[CH:65]=[C:64]([CH2:69][CH:70]([CH:78]2[CH2:79][CH2:80][CH2:81]2)[C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH:63]=[CH:62][C:67]=1[Cl:68])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccc(Cl)c(Br)c1)C1CCC1
Reactant: NCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(Cc1ccc(Cl)c(NCc2ccccc2)c1)C1CCC1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
Under argon, 848.6 mg (8.83 mmol) of sodium tert-butoxide, 337 mg (0.39 mmol) of tris(dibenzylidenacetone)dipalladium and 183 mg (0.29 mmol) of rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were weighed out into a dry flask, kept under high vacuum for 10 min and then vented with argon. 5 ml of abs. toluene, 0.96 ml (8.83 mmol) of benzylamine and a solution of 2.75 g (7.36 mmol) of (+/−)-tert-butyl 3-(3-bromo-4-chlorophenyl)-2-cyclobutylpropanoate in 5 ml of abs. toluene were added in succession. Three more times, the reaction mixture was evacuated and in each case vented with argon, and the mixture was then stirred at 110° C. for 3 h. After cooling, the reaction mixture was added to saturated aqueous ammonium chloride solution. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 4:1 to 2:1, then pure dichloromethane) This gave 1.95 g of the title compound (65.1% of theory).