Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[C:30]([O:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[CH:29][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[NH:22][C:18]=2[CH:17]=1)=O>CO.O>[CH3:41][S:38]([C:35]1[CH:34]=[CH:33][C:32]([O:31][C:30]2[C:16]([CH:12]3[CH2:13][CH2:14][CH2:15][NH:11]3)=[CH:17][C:18]3[NH:22][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[N:20][C:19]=3[CH:29]=2)=[CH:37][CH:36]=1)(=[O:39])=[O:40]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(=O)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg of potassium carbonate was added to a solution of 375 mg of 2,2,2-trifluoro-1-(2-(6-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone in a mixture of 16 ml of methanol and 3 ml of water, and the reaction liquid was stirred overnight at room temperature. The reaction liquid was distilled under reduced pressure, diluted with aqueous saturated sodium bicarbonate added thereto, and then extracted with ethyl acetate. The organic layer was washed with saturated saline, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol/aqueous ammonia=10/1/0.1) to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][N:17]1[CH:22]=[C:21]([CH:23]=[CH2:24])[CH:20]=[CH:19][C:18]1=[O:25].[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:24][CH2:23][C:21]3[CH:20]=[CH:19][C:18](=[O:25])[N:17]([CH3:16])[CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(=O)n(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(=O)n(C)c2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 1-methyl-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].BrN1C(=O)CCC1=O.[N-:23]=[N+:24]=[N-:25].[Na+]>C(Cl)(Cl)(Cl)Cl.[Cl-].[Na+].O.N(C(C)(C)C#N)=NC(C)(C)C#N>[N:23]([CH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])=[N+:24]=[N-:25]
Reactant: COC(=O)c1cc(C)ccc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(CN=[N+]=[N-])ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A mixture of methyl 5-methyl-2-nitrobenzoate (5.5 g, 30 mmol), N-bromosuccinimide (NBS, 5.87 g, 33 mmol), and azobisisobutyronitrile (AlBN, 200 mg) in carbon tetrachloride (60 mL) was refluxed for 3 h. The insoluble material formed was removed by filtration and the filtrate was concentrated. The residue was dissolved in DMF (10 mL) and sodium azide (2.92 g, 45 mmol) was added. The mixture was stirred for 2 h at 50° C., poured into brine, and extracted with a 1:1 mixture of toluene and ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 4:1 hexane/ethyl acetate to give 3.97 g of the title compound (56%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH2:6][OH:7])[NH2:5].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl>[CH3:1][O:2][C:3](=[O:8])[CH:4]([NH:5][S:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=1)(=[O:26])=[O:25])[CH2:6][OH:7]
Reactant: COC(=O)[C@@H](N)CO
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 54 %

Procedure:
To a mixture of 5.0 g (32.14 mmol) of D, L-serine methyl ester and 15.7 mL (0.012 mol) of triethylamine in 100 mL of dichloromethane, cooled to 0° C., was added 6.64 g (32.14 mmol) of 4-methoxybenzenesulfonyl chloride. The mixture was then stirred under argon at room temperature for two days. The mixture was diluted with 100 mL of dichloromethane and then washed with 60 mL each of water, 2N citric acid and brine and than dried over Na2SO4. The solvent was removed under vacuum to give a solid which was recrystallized from ethyl acetate to give 5.0 g (54%) of the product as white crystals, m.p. 92-94° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[C:3]([C:9]([OH:11])=[O:10])=[CH:2]1>C(OC(=O)C)(=O)C>[S:1]1[CH:2]=[C:3]2[C:9]([O:11][C:6](=[O:8])[C:4]2=[CH:5]1)=[O:10]
Reactant: O=C(O)c1cscc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cscc21
Reaction time: 2.5 h
Yield: 97.8 %

Procedure:
Thiophene-3,4-dicarboxylic acid (12 g, 0.07 mol) is dissolved in acetic anhydride (60 ml) and boiled for 2.5 hours. The mixture is then concentrated to dryness. There is obtained 10.55 g (98%) of thiophene-3,4-dicarboxylic anhydride (m.p. 147°-149° C.).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:3]1=[O:15].[I-:16].[Na+]>CC(C)=O>[I:16][CH:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:3]1=[O:15]
Reactant: [I-]
Reactant: O=C1CC(Br)C(=O)N1c1ccc(F)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CC(I)C(=O)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27.2 g. (0.1 mole) of the 3-bromo-1-(4-fluorophenyl)-2,5-pyrrolidinedione prepared according to Example 1 were dissolved in 140 ml. acetone and a solution of 15.75 g. (0.105 mole) sodium iodide in acetone added thereto. The mixture was stirred for 2 hours at room temperature and then heated to reflux for 1 hour. Subsequently, it was cooled, filtered off from resultant sodium bromide and the filtrate evaporated. The residue was recrystallised from methanol/water (3:1) and gave the desired product with 70.5% of theory. The melting point of the derivative lay at 118° C.
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]#[CH:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:33]#[C:32][CH2:31][NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc(Nc2ccc(I)cc2)nc1Nc1ccccc1
Reactant: C#CCNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1

Procedure:
Using an analogous procedure to that described in Example 37, starting from 4-anilino-5-bromo-2-(4-iodoanilino)pyrimidine (Method 12) and 3-(t-butoxycarbonylamino) propyne, the product was obtained. NMR: 1.4 (s, 9H), 3.9 (d, 2H), 7.1–7.3 (m, 4H), 7.4 (m, 2H), 7.6 (m, 4H), 8.2 (s, 1H), 8.6 (s, 1H), 9.5 (s, 1H); MS (MH+): 494.3, 496.3.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH2:13][CH2:14][CH2:15][C:16]#[N:17])=[CH:10][CH:11]=2)[N:6]([CH3:18])[C:5]1=[O:19]>[Ni].C(O)C>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:9]1[N:8]=[C:7]2[N:6]([CH3:18])[C:5](=[O:19])[N:4]([CH2:3][C:2]([CH3:1])([CH3:20])[CH3:21])[C:12]2=[CH:11][CH:10]=1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(CCCC#N)nc21
Agent: [Ni]
Solvent: CCO
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(CCCCN)nc21
Reaction time: 8 h

Procedure:
To a mixture of Raney nickel (1 mL) in ethanol 2M NH3 solution (5 mL) under nitrogen was added 38-1 (0.40 g, 1.40 mmol) dissolved in ethanol (1 mL). The mixture was flushed with hydrogen and stirred overnight under a hydrogen filled balloon. The solution was filtered through a syringe and the filtrate was concentrated to give 38-2. (0.41 g, 100%). LRMS (ES) (M+H)+: observed=291.2, calculated=291.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]#[N:24])=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22](=[CH:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:23]#[N:24])=[CH:14]1
Reactant: COc1ccc(C=O)cc1OC
Reactant: N#CCc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C=C(C#N)c2c[nH]c3ccccc23)cc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 2.0 g (12.0 mmole) 3,4-dimethoxybenzaldehyde in 75 ml absolute ethanol are added 2.07 g (13.3 mmole) 3-indolylacetonitrile and 1.83 g (13.3 mmole) anhydrous potassium carbonate. The reaction flask is equipped with a condenser and a drying tube (using anhydrous CaSO4), and the reaction was stirred and heated. After refluxing for 24 hours, the reaction is allowed to cool to room temperature. The reaction mixture is filtered to remove the salts, and the solvent is removed by rotary evaporation. The residue is purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate, 3:1. The yellow solid is recrystallized from acetone-hexane to give 2-(3-indolyl)-3-(3,4-dimethoxy-phenyl)-2-propenenitrile, m.p. 139°-141° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([CH:18]([OH:22])[CH:19]([OH:21])[CH3:20])[CH2:16][NH:15][C:14]2[NH:13][C:12]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])=[N:11][C:10](=[O:28])[C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([NH:36][C@H:37]([C:42](O)=[O:43])[C@H:38]([CH2:40][CH3:41])[CH3:39])([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[C:1]([O:5][C:6]([N:8]1[CH:17]([CH:18]([OH:22])[CH:19]([O:21][C:42](=[O:43])[CH:37]([NH:36][C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH:38]([CH3:39])[CH2:40][CH3:41])[CH3:20])[CH2:16][NH:15][C:14]2[NH:13][C:12]([N:23]=[CH:24][N:25]([CH3:26])[CH3:27])=[N:11][C:10](=[O:28])[C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)C(O)C1CNc2[nH]c(N=CN(C)C)nc(=O)c2N1C(=O)OC(C)(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)OC(C)C(O)C1CNc2[nH]c(N=CN(C)C)nc(=O)c2N1C(=O)OC(C)(C)C
Yield: 40 %

Procedure:
The product of Example 5, step b) was treated by the same method as that described in Example 5, step c) except N-Boc-L-Isoleucine (3.70 g, 16 mmol) was used to give the sub-title compound as a light yellow solid (0.29 g, 40%). The product obtained after chromatography still contained impurities and was used for the next step without further purification. MS: ESI (positive): 610 (M+H).
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2C=CC=C[C:5]=2[N:6]=1.[C:11]([CH2:15][CH2:16][C:17](Cl)=[O:18])([O:13]C)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:11]([CH2:15][CH2:16][C:17]([C:5]1[NH:6][C:2]([OH:1])=[N:3][CH:4]=1)=[O:18])([OH:13])=[O:12]
Reactant: Oc1nc2ccccc2[nH]1
Reactant: COC(=O)CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(O)CCC(=O)c1cnc(O)[nH]1

Procedure:
Carbon disulfide (110 ml), 2-hydroxybenzimidazole (5 g) and 3-carbomethoxypropionyl chloride (5.6 g) are added to a flask containing aluminum chloride (25 g) under an atmosphere of nitrogen. The resulting suspension is refluxed for about 20 hours, quenched with ice cold hydrochloric acid (6N), stirred and filtered. The filtered solid is washed with water and dried in a vacuum oven, affording the desired compound as a solid, which is used in the next step without further purification, M.P. 295° C. (dec).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[C:21]([O:25][C:26](=[O:38])[NH:27][C:28]1([C:36]#[CH:37])[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.CC#N.CC#N.Cl[Pd]Cl.O>[C:21]([O:25][C:26](=[O:38])[NH:27][C:28]1([C:36]#[C:37][C:2]2[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:6]([C:7]#[N:8])[CH:9]=2)[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: N#Cc1cc(Br)ccc1OCCCCc1ccccc1
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C#Cc2ccc(OCCCCc3ccccc3)c(C#N)c2)COC(C)(C)OC1

Procedure:
Compound 2-1 (0.544 g), (5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester (0.459 g), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.36 g), bis(acetonitrile)palladium(II) dichloride (0.007 g) and cesium carbonate (0.538 g) were stirred in acetonitrile (8.3 ml) at 70-80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, 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 to give (5-{2-[3-cyano-4-(4-phenylbutoxy)phenyl]ethynyl}-2,2-dimethyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester as a yellow oil. This oil was dissolved in ethyl acetate (6 ml), 10% palladium carbon (containing water about 50%, 0.080 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3.5 hr. The solution was filtered, and the filtrate was concentrated to give the object product (0.519 g) as a pale-yellow powder.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH2:34]>>[CH3:31][C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH:34][CH2:22][C:21]1[CH:20]=[C:19]([C:18]2[C:17]3[C:12](=[C:13]([C:27]([F:29])([F:30])[F:28])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cc1ccccc1N
Product: Cc1ccccc1NCc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 2-methylaniline according to the procedure of Example 66. MS (ES) m/z 497.3.
Reaction SMILES: O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[N+:12]([C:15]1[CH:16]=[C:17]([C:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:27]=[O:28])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].[BH4-].[Na+].[Cl-].[NH4+]>CO.C1COCC1>[N+:12]([C:15]1[CH:16]=[C:17]([C:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH2:27][OH:28])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: O=CC1=C(c2cccc([N+](=O)[O-])c2)CCCC1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cccc(C2=C(CO)CCCC2)c1
Reaction time: 0.5 h

Procedure:
Cerium chloride heptahydrate (1.22 g) was added to a mixed solution of 2-(3-nitrophenyl)cyclohex-1-enecarbaldehyde obtained in Preparation Example 4-(1) (630 mg) in methanol (60.0 mL) and THF (20.0 mL) in an ice bath. Sodium borohydride (130 mg) was added to the reaction solution at the same temperature, followed by stirring for 30 minutes. A saturated ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by NH-silica gel column chromatography to obtain the title compound (610 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13](Br)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:16])[CH:22]=3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(Br)c2ncccc2c1
Reactant: OB(O)c1cccc(Cl)c1
Product: CCCCc1cc(-c2cccc(Cl)c2)c2ncccc2c1

Procedure:
6-(n-butyl)-8-bromoquinoline and 3-chlorobenzene boronic acid can be combined to form 6-(n-butyl)-8-(3-chlorophenyl)quinoline,
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH2:19][Zn+])[CH:12]=[N:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[CH:6]=[CH:7][CH:8]=1.BrCCBr.C[Si](Cl)(C)C.BrC[C:32]1[CH:33]=[C:34](C2C=CC=C(Cl)C=2)[C:35](OC(F)F)=[N:36][CH:37]=1>C1COCC1.[Zn]>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([O:15][CH:16]([F:18])[F:17])=[N:13][CH:12]=[C:11]([CH2:19][C:35]3[CH:34]=[CH:33][CH:32]=[CH:37][N:36]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)Oc1ncc(C[Zn+])cc1-c1cccc(Cl)c1
Reactant: FC(F)Oc1ncc(CBr)cc1-c1cccc(Cl)c1
Agent: C[Si](C)(C)Cl
Agent: [Br-]
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: FC(F)Oc1ncc(Cc2ccccn2)cc1-c1cccc(Cl)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
((5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)zinc(II) bromide. To a suspension of zinc (42.77 mg, 0.65 mmol) in THF (1 mL) was added 1,2-dibromoethane (2.48 μL, 0.03 mmol). The resulting mixture was heated at 70° C. for 10 minutes before being cooled to room temperature. Once cooled, trimethylsilylchloride (2.92 μL, 0.02 mmol) was added and the solution was stirred at room temperature for an additional 30 min. To the activated zinc solution was added 5-(bromomethyl)-3-(3-chlorophenyl)-2-(difluoromethoxy)pyridine (Intermediate 12, 200 mg, 0.57 mmol) and the resulting mixture was heated at 70° C. for 8 h. The reaction mixture was cooled to room temperature and decanted from the solids to afford a −0.5 M solution of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[O:11].[CH3:12][C:13]1([CH3:26])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH3:24])([CH3:23])[CH2:15][CH:14]1[NH2:25]>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]([NH:25][CH:14]1[CH2:15][C:16]([CH3:24])([CH3:23])[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]1([CH3:26])[CH3:12])=[O:11]
Reactant: Cc1cccc(C)c1N=C=O
Reactant: CC1(C)CC(N)C(C)(C)c2ccccc21
Product: Cc1cccc(C)c1NC(=O)NC1CC(C)(C)c2ccccc2C1(C)C

Procedure:
Using the method of Example 1, but starting with 2,6-dimethylphenyl isocyanate and 1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-2-naphthylamine, there was obtained N-(2,6-dimethylphenyl)-N'-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-2-naphthalenyl)urea, mp 216°-218° C.
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[N:7]1([CH2:12][C:13]([C:15]2([CH2:20][CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH:11]=[N:10][CH:9]=[N:8]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([OH:1])[CH:12]([N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)[C:13]([C:15]1([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:14]
Reactant: CCC1(C(=O)Cn2cncn2)CCCC1
Reactant: O=CC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(C(=O)C(C(O)C(Cl)(Cl)Cl)n2cncn2)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
9.3 g (0.064 mol) of chloral were added dropwise to 10.4 g (0.05 mol) of 1-ethylcyclopentyl (1,2,4-triazol-1-yl)methyl ketone (prepared as described in Example 1) and 13.8 g (0.1 mol) of ground potassium carbonate in 100 ml of tetrahydrofuran. The reaction mixture was stirred overnight at room temperature and was then stirred with water. The solid formed was filtered off under suction and recrystallized from ethyl acetate. 7 g (39.5% of theory) of 1,1,1-trichloro-2-hydroxy-3-(1,2,4-triazol-1-yl)-4-(1-ethylcyclopentan-1-yl)-butan-4-one of melting point 194° to 196° C. were obtained.
Reaction SMILES: CS([Cl:5])(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:18][C@H:17]([CH2:19]O)[N:16]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][C@H:14]1[CH3:28])=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[CH2:18][C@H:17]([CH2:19][Cl:5])[N:16]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][C@H:14]1[CH3:28])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
Methanesulfonyl chloride (570 μL, 7.35 mmol) was added to a solution of (2R,5R)-4-benzyl-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.9 g, 6.12 mmol) containing TEA (2.6 mL, 18.4 mmol) in DCM (30 mL) at 0° C. The solution was stirred at room temperature for 18 h. The reaction was partitioned between aqueous NH4Cl and DCM. The organic phase was collected, dried over MgSO4, filtered and concentrated in vacuo. Chromatography (30% EtOAc in petrol) gave the title compound (1.6 g) as a white solid. MS: [M+H]+=339.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH3:17])[C:10]=1[CH:18]1[C:26](=[O:27])[CH:25]2[CH:20]([CH:21]3[O:28][CH:24]2[CH2:23][CH2:22]3)[C:19]1=[O:29])[CH3:8].C(N(CC)CC)C>ClCCl>[CH2:5]([O:4][C:2](=[O:3])[O:29][C:19]1[CH:20]2[CH:25]([C:26](=[O:27])[C:18]=1[C:10]1[C:11]([CH2:16][CH3:17])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[CH2:7][CH3:8])[CH:24]1[O:28][CH:21]2[CH2:22][CH2:23]1)[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: CCc1cc(C)cc(CC)c1C1C(=O)C2C3CCC(O3)C2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(c2c(CC)cc(C)cc2CC)C(=O)C2C3CCC(O3)C12
Temperature: 25 °C

Procedure:
A solution of ethyl chloroformate (0.071 g, 0.65 mmol) in dichloromethane (0.5 ml) is added dropwise to a solution of (1RS,2SR,6RS,7SR)-4-(2,6-diethyl-4-methylphenyl)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione (0.172 g, 0.55 mmol) in dichloromethane (2 ml) at 0° C. and the reaction mixture is stirred. A solution of triethylamine (0.066 g, 0.65 mmol) in dichloromethane (1 ml) is added and the reaction mixture is stirred at room temperature for 17 hours, warming slowly to room temperature. The reaction mixture is diluted with dichloromethane (3 ml) and washed with saturated aqueous sodium bicarbonate solution. The organic phase is separated, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give carbonic acid (1RS, 2SR,6RS,7SR)-5-oxo-4-(2,6-diethyl-4-methylphenyl)-10-oxatricyclo-[5.2.1.02,6]-dec-3-en-3-yl ester ethyl ester as a colourless solid.
Reaction SMILES: [CH3:1][N:2]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([OH:14])=[CH:6][CH:5]=1)[CH3:3].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19](S(C)(=O)=O)[N:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([O:14][C:7]2[C:8]([C:10]([O:12][CH3:13])=[O:11])=[N:9][C:4]([N:2]([CH3:1])[CH3:3])=[CH:5][CH:6]=2)[N:18]=1
Reactant: COC(=O)c1nc(N(C)C)ccc1O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(N(C)C)ccc1Oc1nc(OC)cc(OC)n1

Procedure:
1.4 g (7 mmol) of methyl 6-(N,N-dimethylamino)-3-hydroxypicolinate, 1.6 g (7 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.6 g (4 mmol) of potassium carbonate were added to 100 ml of dimethylformamide (DMF), and were reacted at 90° C. for 2 hours. After the reaction, the reaction content was poured into water, and was extracted with diethyl ether, and then washed with water, dried and concentrated to obtain an oily product which was thereafter crystallized with isopropyl ether. The crystal thus obtained was recrystallized with ethyl acetate/n-hexane to obtain an aimed product.