Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)(=[O:10])=[O:9].[H-].[Na+].Br[CH2:31][CH:32]([CH3:34])[CH3:33]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3Cl)s2)c1
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 1, step 2, 2-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide (example 4, step 2) was reacted with sodium hydride in N,N-dimethylacetamide at 0° C. followed by reaction with 1-bromo-2-methylpropane at r.t. overnight to give 2-chloro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as an off-white solid. MS: 515.3 ([M+NH4]+)
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[C:8]=1[S:15][CH3:16].C[O:18][B:19](OC)[O:20]C>O1CCCC1>[F:14][C:9]1[C:8]([S:15][CH3:16])=[C:7]([B:19]([OH:20])[OH:18])[CH:12]=[C:11]([F:13])[CH:10]=1
Reactant: COB(OC)OC
Reactant: CSc1c(F)cc(F)cc1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CSc1c(F)cc(F)cc1B(O)O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
Charge a flask with isopropyl magnesium chloride (145 mL, 2M in THF, 290 mmol) and dilute with tetrahydrofuran (150 mL) and heat to 40° C. under nitrogen. Add 1-bromo-3,5-difluoro-2-methylsulfanyl-benzene (28 g, 117 mmol) slowly over 5 minutes. After 30 minutes, cool the reaction to 0° C. and add trimethylborate (46 mL, 410 mmol) diluted with tetrahydrofuran (100 mL) via an addition funnel over 5 minutes. Partition the resulting gelatinous mixture between methylene chloride and 1N HCl. Acidify the aqueous layer to pH˜1 (if needed) and vigorously stir the biphasic mixture until all solids are dissolved. Separate the organic layer. Dry over sodium sulfate, filter and concentrate. Triturate with hexanes and filter to yield 14.7 g (61%) of the title compound.
Reaction SMILES: [CH2:1]([C:6]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>>[CH3:5][CH2:4][CH2:3][CH2:2][CH2:1][CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH:7]1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: [H][H]
Reactant: CCCCCC1=C(CC(=O)OC)CCC1=O
Product: CCCCCC1C(=O)CCC1CC(=O)OC

Procedure:
To a reactor (a volume of 50 ml) was respectively charged 1 g (4.5 mmol) of methyl (2-pentyl-3-keto-1-cyclopentenyl-)acetate (a compound in which R1 represents an n-pentyl group and R2 represents a methyl group in the above formula (1)) and 0.2 g of each catalyst shown in Table 1. Thereto was respectively added 10 ml of a solvent shown in Table 1, and the mixture was held at a temperature shown in Table 1. Pressure reduction and hydrogen introduction were repeated while stirring the mixture, and the air in the reactor was replaced with hydrogen at ordinary pressure. The mixture was continuously stirred in this state for 4 hours. Subsequently, the catalyst was removed from the reaction mixture by filtration, and then thereto were added 30 ml of water and 30 ml of toluene followed by stirring to extract a product into the toluene phase. Toluene was distilled off from this toluene phase, yielding methyl dihydrojasmonate (a compound in which R3 represents an n-pentyl group and R4 represents a methyl group in the above formula (2)). The yield and isomer ratio (cis-isomer/trans-isomer) of the resulting methyl dihydrojasmonate were determined by gas chromatography. The results are shown in Table 1.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[Cl:15].I[CH:17]([CH3:19])[CH3:18]>CN(C=O)C>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:17]([CH3:19])[CH3:18])=[CH:10][C:9]=1[Cl:15]
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Br)c(Cl)c1
Temperature: 60 °C
Yield: 81 %

Procedure:
A sample of K2CO3 (52.8 mmol, 7.4 g) was added to the 4-bromo-3-chloro-phenol (24 mmol, 5 g) in anhydrous DMF (100 mL) followed by the addition of 2-iodopropane (100 mmol, 10 mL). This stirred and heated at 60° C. overnight. The reaction was cooled, extracted into EtOAc (150 mL), washed with H2) (2 L), dried over MgSO4, and concentrated in vacuo, yielding 1-bromo-2-chloro-4-isopropoxybenzene as a brown oil (4.85 g, 81%). 1H NMR (CDCl3, 300 MHz): 7.35 (1H, d, J 8.7 Hz), 6.89 (1H, d, J 2.9 Hz), 6.57 (1H, dd, J 8.8 and 2.9 Hz), 4.38 (1H, m), 1.22 (6H, d, J 6.2 Hz.)
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[S:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=3)[CH2:37][CH2:36]2)=[S:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3cc4ccccc4nc3C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)thiocarbamate(147 mg, 0.5 mmol) and 1-(3,5-dimethoxyphenyl)piperazine(112 mg, 0.5 mmol) were dissolved in anhydrous tetrahydrofuran and DBU(117 mg, 0.75 mmol) was added and then the mixture was stirred at room temperature for 2 hrs. The above solution was concentrated under the reduced pressure to remove tetrahydrofuran and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[C:54]1([N:60]=[C:61]=[O:62])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:61]([NH:60][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:62])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)Nc2ccccc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 99 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 99% yield. LCMS for C30H30ClN8O2 (M+H)+: m/z=569.1.
Reaction SMILES: CS([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)=O.[O-:28][CH2:29][CH3:30].[Na+].O>O1CCCC1>[CH2:29]([O:28][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)[CH3:30]
Reactant: CC[O-]
Reactant: CS(=O)c1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(methylsulfinyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (0.64 g) in tetrahydrofuran (10 mL) was added sodium ethoxide (20% ethanol solution, 1.56 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from a mixed solvent of ethyl acetate/hexane to give the title compound (0.40 g).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH2:17][CH2:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:18]1[N:22]=[CH:21][N:20]([C:23](N2C=NC=C2)=[O:24])[CH:19]=1>C(Cl)Cl>[C:1]([C:5]1[S:6][C:7]2[CH2:17][CH2:16][C:11]3[N:12]=[C:13]([NH:15][C:23]([N:20]4[CH:19]=[CH:18][N:22]=[CH:21]4)=[O:24])[S:14][C:10]=3[C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2c(s1)CCc1nc(N)sc1-2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)c1nc2c(s1)CCc1nc(NC(=O)n3ccnc3)sc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-tert-Butyl-4,5-dihydro-benzo[1,2-d;3,4-d′]bisthiazol-2-ylamine (Stage T.1, 175 mg, 0.659 mmol) was dissolved in DCM (10 mL), CDI (297 mg, 1.648 mmol) was then added, and the RM was stirred at rt for 2 h. The title compound was isolated by filtration, washed with DCM and dried under HV.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([NH:15][C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1.Br[CH2:31][CH:32]1[CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1
Reactant: BrCC1CCC1
Reactant: Cn1ccnc1-c1c2c(=O)n(C)c(=O)[nH]c2nn1Cc1c[nH]c2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccnc1-c1c2c(=O)n(C)c(=O)n(CC3CCC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-5-methyl-3-(1-methyl-1H-imidazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and (bromomethyl)cyclobutane using potassium carbonate as a base in DMF at 80° C. Mass: 478.16 (M+H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:4][CH2:3][CH2:2][Br:1]
Reactant: C1=COCCC1
Reactant: OCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: BrCCOC1CCCCO1
Reaction time: 2.5 h

Procedure:
Combine 2-bromoethanol (14.2 mL, 200 mmol) and dihydropyrane (18.25 mL, 200 mmol) in dichloromethane (20 mL). Add Pyridinium p-toluenesulfonic acid (5 g, 20 mmol). After 2.5 hours, dilute the reaction mixture with diethyl ether and extract with water, 1/1 water/brine, water, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Distill the residue to give the title compound: bp; 80-90° C. at 15-20 mm Hg.
Reaction SMILES: O=[C:2]([CH2:16][CH2:17][C:18]([O-:20])=[O:19])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:34]([O:41][C:42]([NH:44][C@H:45]1[CH2:49][O:48][NH:47][C:46]1=[O:50])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[CH2:34]([O:41][C:42]([NH:44][C@H:45]1[CH2:49][O:48][N:47]([C:2]2([C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=3)=[O:4])[CH2:16][CH2:17][C:18](=[O:19])[O:20]2)[C:46]1=[O:50])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C([O-])CCC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@H](NC(=O)OCc3ccccc3)C2=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
In 10 ml of dichloromethane was dissolved 282 mg of Compound (1), and the solution was cooled on a sodium chloride-ice bath, to which were added 140 μ1 of triethylamine and 96 μ1 of ethyl chlorocarbonate. To the mixture was added 119 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone. The mixture was stirred for one hour under ice-cooling and for one hour at room temperature. The solvent was evaporated off under reduced pressure. The residue was subjected to extraction with ethyl acetate, and the organic layer was washed with an aqueous solution of sodium hydrogen carbonate, then with a saturated saline solution, followed by drying (MgSO4). Then, the solvent was evaporated off, and the residue was subjected to a silica gel chromatography, followed by elution with 1,2-dichloroethane-ethyl acetate (9:1), then with hexane-ethyl acetate (1:1) to give 73 mg of the subject Compound (9).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>ClCCl>[C:38]([N:26]1[CH2:27][CH2:28][C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[C@H:24]([OH:29])[CH2:25]1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCNC[C@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC[C@@H](n2cnc3c(cc(Cc4ccc(Cl)nc4)c4ccccc43)c2=O)[C@H](O)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4R)-3-hydroxypiperidin-4-yl]benzo[h]quinazolin-4(3H)-one (Example 35, 0.050 g, 0.11 mmol) in 2 mL of dichloromethane at 0° C. was added triethylamine (0.023 mL, 0.16 mmol) and acetic anhydride (0.013 mL, 0.14 mmol). The reaction was stirred at 0° C. for 5 h, quenched with water, and concentrated in vacuo. The resultant residue was subjected to purification via reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 462.9 for M+H+: 1H NMR (400 MHz, CDCl3) δ 9.01-9.00 (m, 1H), 8.37 (s, 1H), 8.37 (s, 1H), 7.96 (d, J=7.1 Hz, 1H), 7.88 (s, 1H), 7.72-7.68 (m, 2H), 7.41 (d, J=8.7 Hz, 1H), 7.22-7.20 (m, 1H), 5.07-5.01 (m, 1H), 4.92-4.67 (m, 2H), 4.44 (s, 2H), 4.23-3.98 (m, 3H), 3.34-3.24 (m, 1H), 3.20-3.11 (m, 1H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][CH3:11])=[CH:5][CH:4]=1.Cl[S:13]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([CH3:11])[S:13]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)(=[O:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNCc1ccc(OC)cc1
Product: COc1ccc(CN(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-27 from 1-(4-methoxyphenyl)-N-methylmethanamine and methyl 4-(chlorosulfonyl)-benzoate (Example 5-10c). MS (M−H, 335.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.51 (s, 3H), 3.71 (s, 3H), 4.05 (s, 2H), 6.88 (d, 2H), 7.18 (d, 2H), 7.91 (d, 2H); 8.13 (d, 2H). Elemental analysis: (found): C, 57.47%, H, 4.77% and N, 4.31%; (theoretical): C, 57.30%, H, 5.11% and N, 4.18%
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].O.Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CNC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)NCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
A mixture of ethyl N-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}glycinate obtained in Example 4 (430 mg), lithium hydroxide monohydrate (420 mg), water (50 mL), and tetrahydrofuran (50 mL) was stirred at room temperature for 3 h. 6 M hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (350 mg, 89%) as a colorless solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C1(CCN2[C:34](=[O:35])[CH:33]=[CH:32][NH:31]C2=O)CCCCC=1>>[NH2:31][C:32]1[N:9]([CH2:8][CH2:7][C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[C:10](=[O:11])[N:12]([CH2:13][CH2:14][C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)[C:34](=[O:35])[CH:33]=1
Reactant: O=c1cc[nH]c(=O)n1CCC1=CCCCC1
Reactant: O=C(NCCC1=CCCCC1)NCCC1=CCCCC1
Product: Nc1cc(=O)n(CCC2=CCCCC2)c(=O)n1CCC1=CCCCC1
Yield: 85 %

Procedure:
In the manner of step (b) of Example 1, 1,3-bis[2-(1-cyclohexen-1-yl)ethyl]urea (from step (a), 55.00 g, 0.199 mol) was converted to 6-amino-1,3-bis[(2-(cyclohexen-1-yl)ethyl]uracil, isolated as a white powder (58.03 g, 85%), m.p. 172°-174° C.;
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH:9]([CH3:12])[C:10]#[CH:11])(=O)=O.[F:13][C:14]([F:24])([F:23])[CH2:15][CH2:16][S:17]([CH2:20][C:21]#[N:22])(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH3:12][CH:9]([C:10]#[CH:11])[CH2:8][CH2:7][CH2:6][CH:20]([S:17]([CH2:16][CH2:15][C:14]([F:24])([F:13])[F:23])(=[O:19])=[O:18])[C:21]#[N:22]
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Reactant: C#CC(C)CCCOS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CC(C)CCCC(C#N)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 48 h
Yield: 29 %

Procedure:
To a solution of 1.0 g of 4-methyl-5-hexynyl methanesulfonate and 1.1 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 30 ml of dimethyl sulfoxide was added 0.7 g of potassium carbonate at room temperature. The reaction mixture was stirred at 60° C. for 2 days. The reaction mixture was allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.45 g of 6-methyl-2-(3,3,3-trifluoropropylsulfonyl)-7-octynenitrile (hereinafter referred to as the present compound (28)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][CH:15]=[C:16]([CH3:18])[N:17]=1.[Cl:19][S:20](O)(=[O:22])=[O:21].S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][C:15]([S:20]([Cl:19])(=[O:22])=[O:21])=[C:16]([CH3:18])[N:17]=1
Reactant: Cc1c[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Product: Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1S(=O)(=O)Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-4-methylimidazole (1.0 g, 0.0034 mol) was added portionwise to chlorosulphonic acid (3 ml) and the mixture was stirred and heated at 100° C. for 2 hours. After cooling thionyl chloride (0.2 ml) was added and the mixture was reheated to 100° C. for 2 hours. The mixture was added cautiously to ice (20 g), and extracted with ethyl acetate (2×20 ml). The combined extracts were washed with water (20 ml) dried over anhydrous sodium sulphate and evaporated to dryness. Recystallisation from a mixture of ethyl acetate and petroleum spirit (bp 60°-80° C.)(1:3) gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylimidazole-5-sulphonyl chloride (0.21 g), m.p. 227°-230° C. as an off-white solid.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]=[C:5]([C:22](OCC)([O:25]CC)[CH2:23][Br:24])[C:6]([NH:8][CH:9]1[C:20](=[O:21])[N:11]2[CH:12]([C:17]([OH:19])=[O:18])[CH:13]([OH:16])[CH2:14][S:15][C@H:10]12)=[O:7]>C(Cl)Cl>[CH3:2][O:3][N:4]=[C:5]([C:22](=[O:25])[CH2:23][Br:24])[C:6]([NH:8][CH:9]1[C:20](=[O:21])[N:11]2[CH:12]([C:17]([OH:19])=[O:18])[CH:13]([OH:16])[CH2:14][S:15][C@H:10]12)=[O:7]
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: Cl
Solvent: ClCCl
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 121.5 %

Procedure:
6N Hydrochloric acid (2 ml) was added to a solution of 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 500 mg) in methylene chloride (5 ml) under ice-cooling and stirred at room temperature for 70 minutes. The precipitates were collected by filtration, washed with a saturated aqueous solution of sodium chloride (5 ml) and methylene chloride (1 ml) successively, and dried over phosphorus pentachloride to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 517 mg), purity: 57.8%.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.ClCCl.CO.N>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:15](=[O:17])/[CH:14]=[CH:13]/[C:10]3[CH:9]=[CH:8][C:7]([CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:12][CH:11]=3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: O=C(O)/C=C/c1ccc(CN2CCCC2)cc1
Reactant: COc1ccc(-c2ccc(N)cc2)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2ccc(NC(=O)/C=C/c3ccc(CN4CCCC4)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 3.1.e. from (E)-3-(4-pyrrolidin-1-ylmethylphenyl)acrylic acid and 4′-methoxybiphenyl-4-ylamine. Yield: 74 mg (15.4% of theory); melting point: 199° C.-200° C.; C27H28N2O2 (M=412.53); calc.: molecular ion peak (M+H)+: 413; found: molecular ion peak (M+H)+: 413; Rf value: 0.77 (silica gel, dichloromethane/methanol/ammonia (80:20:1)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB(/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)O1>O1CCOCC1.O>[CH3:9][O:8][C:5]1[C:4]([O:10][CH3:11])=[CH:3][C:2](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][N:6]=1
Reactant: CC1(C)OB(/C=C/c2ccccc2)OC1(C)C
Reactant: COc1cc(Br)cnc1OC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(/C=C/c2ccccc2)cnc1OC
Temperature: 100 °C
Yield: 21 %

Procedure:
A mixture of 5-bromo-2,3-dimethoxypyridine (0.50 g, 2.29 mmol), tripotassium phosphate (1.95 g, 9.17 mmol), tetrakistriphenylphosphine (0.27 g, 0.23 mmol) and (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (0.53 g, 2.29 mmol) was diluted with dioxane (6 ml) and water (1 ml) and heated in a microwave for 1 hour at 100° C. The reaction mixture was partitioned between ethyl acetate and water and the organics were dried (MgSO4), filtered and concentrated in vacuo to give yellow oil. The oil was purified by column chromatography (SiO2; 0-10% ethyl acetate in petrol) gave 2,3-dimethoxy-5-[(E)-2-phenylethenyl]pyridine as a colourless oil (116 mg, 21%).