Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:15]([O:17][CH3:18])=[O:16])([CH3:14])[CH2:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:26][C:27]1[C:31]([N:32]=[C:33]=[O:34])=[C:30]([CH3:35])[O:29][N:28]=1>C(Cl)Cl>[CH3:26][C:27]1[C:31]([NH:32][C:33]([N:11]2[CH2:12][C:13]([C:15]([O:17][CH3:18])=[O:16])([CH3:14])[C:9]([C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=3)=[N:10]2)=[O:34])=[C:30]([CH3:35])[O:29][N:28]=1
Reactant: COC(=O)C1(C)CNN=C1c1ccc(Cl)cc1
Reactant: Cc1noc(C)c1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(C)CN(C(=O)Nc2c(C)noc2C)N=C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
3-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole hydrochloride (10 mmole), triethylamine (20 mmole), methylene chloride (30 ml and 3,5-dimethylisoxazole-4-yl isocyanate (Maybridge Chemical Co. Ltd.) (10 mmole) were reacted by stirring at room temperature for 30 minutes. The reaction mixture was then washed twice with water, dried with magnesium sulfate concentrated giving a 95% yield of N-(3,5-dimethylisoxazol-4-yl)-3-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide mp 214°-216° C. NMR data was consistent with the structure.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].[N:34]1[C:41]([F:42])=[N:40][C:38](F)=[N:37][C:35]=1[F:36].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([C:38]3[N:40]=[C:41]([F:42])[N:34]=[C:35]([F:36])[N:37]=3)[N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Reactant: Fc1nc(F)nc(F)n1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)Nc2c(C)cc3cn(-c4nc(F)nc(F)n4)nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a solution of 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropyl amide (0.300 g, 0.641 mmol) in chloroform (2.0 ml) was added cyanuryl fluoride (2,4,6-trifluoro-1,3,5-triazine) (0.220 g, 1.669 mmol) followed by triethylamine (0.090 ml, 0.046 mmol). The reaction mixture was stirred at 20° C. for three hours, then evaporated to dryness and submitted to high vacuum. The residue was taken up in a small amount of chloroform and separated from some less soluble material, then evaporated to give the compound showing the physical data described in the table under P.43.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:17])[CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[C:5]([CH2:18][CH:19]=[CH2:20])=[C:4]([OH:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:28]([O:21][C:4]1[CH:3]=[C:2]([OH:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8]([O:7][C:6]=2[C:5]=1[CH2:18][CH:19]=[CH2:20])=[C:9]([O:17][CH2:18][C:5]1[CH:6]=[CH:15][CH:2]=[CH:3][CH:4]=1)[CH:10]=[CH:11][CH:12]=3)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C=CCc1c(O)cc(O)c2c(=O)c3cccc(O)c3oc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1c(OCc2ccccc2)cc(O)c2c(=O)c3cccc(OCc4ccccc4)c3oc12
Temperature: 110 °C
Yield: 160.7 %

Procedure:
To a solution of xanthone 5 (48 g, 168 mmol) in dry DMF was added potassium carbonate (46 g, 336 mmol) and benzyl bromide (90 g, 526 mmol) and the mixture was heated to 110° C. for 8 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (1.4L) and the remaining potassium carbonate was destroyed with 2M Sulfuric acid. The organic layer was washed with brine (2×500 mL), dried over magnesium sulfate and concentrated in vacuo to afford the xanthone 6 as a solid (63 g, 135 mmol, 81%).
Reaction SMILES: C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.Cl[C:24]1[C:25]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:26]=2[S:27][C:28]=1[C:29]([NH2:31])=[O:30].Cl.[N:39]1([CH2:45][CH2:46][SH:47])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C=O)C.C(OCC)(=O)C>[CH3:37][O:36][C:34]1[CH:33]=[CH:32][C:26]2[S:27][C:28]([C:29]([NH2:31])=[O:30])=[C:24]([S:47][CH2:46][CH2:45][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:25]=2[CH:35]=1
Reactant: SCCN1CCOCC1
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2sc(C(N)=O)c(SCCN3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
Diazabicycloundecene (DBU) (990 μL, 6.62 mmol) is added to a suspension of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (200 mg, 0.83 mmol) and 4-morpholineethanethiol hydrochloride (608 mg, 3.31 mmol) in 4 mL of DMF. The mixture is stirred at room temperature for 3 hours then diluted with ethyl acetate and washed with water followed by aqueous citric acid. NaHCO3 is added to the acidic extracts and the precipitated solids are collected and washed with water. Recrystallization from methanol:water provides 5-methoxy-3-[[2-(4-morpholinyl)ethyl]thio]benzo[b]thiophene-2-carboxamide in 83% yield; mp=158.5°-159.5° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](N)[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3].S(=O)(=O)(O)[OH:16].N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O.C(O)C>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3]
Reactant: O=S(=O)(O)O
Reactant: CS(=O)(=O)n1ccc2ccc(N)cc21
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)n1ccc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-methansulfonyl-6-amino indole (2.10 g, 10.0 mmol), prepared as described in Forbes, et al., J. Med. Chem. (1996) 39:4968, was suspended in 40 ml of water, then cooled in an ice bath. Concentrated sulfuric acid (3 ml) was added slowly dropwise. The mixture was warmed to room temperature for 5 min then cooled back down to 0° C. A solution of NaNO2 (Mallinckrodt, 0.76 g, 11.0 mmol) in 10 ml of water was added slowly and the resultant foam was treated with 10 ml of ethanol. The mixture was added in portions to a boiling solution of CUSO4 (J. T. Baker, 16.0 g, 0.1 mol) in 75 ml of water. After 15 min, the mixture was cooled. The brown solid which had formed was broken up with a glass stirring rod. NaHCO3 was added to neutralize the reaction and the product was extracted with ethyl acetate (2×100 ml). The extracts were dried (anhydrous MgSO4) and concentrated to give 1-methansulfonyl-1H-indol-6-ol (1.62 g), a brown oil which was used with out purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([NH2:13])[CH:5]=1.CCN(CC)CC.[Cl:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([NH:13][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][Cl:22])[CH:5]=1
Reactant: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)CCCCl)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of 3-amino-5-nitro-benzoic acid methyl ester (D1) (38 g, 194 mmol, 1 equiv) in CH2Cl2 (350 ml) was added NEt3 (32 ml, 230 mmol, 1.2 equiv) followed by 4-chlorobutyryl chloride (24.7 ml, 220 mmol, 1.13 equiv) dropwise over 20 nm. The resulting mixture was allowed to warm to room temperature and stirred for 30 min. The organic phase was then washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with iso-hexane and Et2O to give 3-(4-chloro-butanoylamino)-5-nitro-benzoic acid methyl ester D2 (56 g, 96%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1.O>[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (200 mg) in tetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 50 mg), and the mixture was stirred at room temperature for 10 min. 4-(Benzyloxy)benzenesulfonyl chloride (210 mg) was added and the mixture was further stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a colorless oil (yield 360 mg, quantitative).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:10])=[O:18])=[CH:15][CH:14]=1
Reactant: Cc1ccccc1CCN
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)NCCc2ccccc2C)cc1

Procedure:
1-Amino-2-(2-methylphenyl)ethane was reacted with 4-methoxybenzoyl chloride in the same way as in step (a) of Example 1 to afford 1-(4-methoxybenzoylamino)-2-(2-methylphenyl)ethane having a melting point of 81.8° to 82.1° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>S(=O)(=O)(O)O>[C:16]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CCCCC1OC(=O)c2cc(NC(C)=O)ccc21
Reaction time: 0.25 h

Procedure:
A mixture of 0.3 g (1.55 mmol) of compound obtained in Example 4 and 3 ml of acetic anhydride and 1 drop of sulphuric acid is heated until dissolved and kept for 15 minutes. On cooling, white crystals are separated and recrystallised from ethanol to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](I)[CH3:26]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:25][CH3:26])[C:12]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)C1(NS(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(C1(C(=O)OC)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Compound 13B (800 mg, 2.76 mmol) dissolved in DMF (10 ml) was added with K2CO3 (1.1 equiv., 420 mg) and ethyl iodide (1.1 equiv., 0.3 ml) and the reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed several times with water and finally with Brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from ethyl ether and petroleum ether afforded 750 mg of 14B as a semisolid. Yield=85.5%. 1HNMR (DMSO, 200 MHz) δ 1.096 (3H, t, J=7.2 Hz), 1.17 (2H, m), 1.43 (2H, bs), 3.34 (2H, m), 3.43 (3H, s), 7.68 (2H, m), 7.79 (2H, m)
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:9]1([CH2:12]O)[CH2:11][CH2:10]1>>[C:1]([O:8][CH2:12][CH:9]1[CH2:11][CH2:10]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OCC1CC1
Reactant: CCCCCC(=O)O
Product: CCCCCC(=O)OCC1CC1

Procedure:
Prepared from hexanoic acid and cyclopropanemethanol according to the ester preparation method A described above.
Reaction SMILES: O1C=CC2C=C(C3CO3)C=CC1=2.N1C=CC=C(CO)C=1.[S:21]1[CH:25]=[CH:24][C:23]2[CH:26]=[C:27]([CH:30]3[CH2:32][O:31]3)[CH:28]=[CH:29][C:22]1=2.[CH:33]([N:35]1[CH2:40][CH2:39][N:38]([CH:41]=[O:42])[CH2:37][CH:36]1[CH2:43][OH:44])=[O:34]>>[S:21]1[CH:25]=[CH:24][C:23]2[CH:26]=[C:27]([CH:30]([OH:31])[CH2:32][O:44][CH2:43][CH:36]3[CH2:37][N:38]([CH:41]=[O:42])[CH2:39][CH2:40][N:35]3[CH:33]=[O:34])[CH:28]=[CH:29][C:22]1=2
Reactant: c1cc2cc(C3CO3)ccc2s1
Reactant: O=CN1CCN(C=O)C(CO)C1
Agent: OCc1cccnc1
Agent: c1cc2cc(C3CO3)ccc2o1
Product: O=CN1CCN(C=O)C(COCC(O)c2ccc3sccc3c2)C1

Procedure:
The same procedure as in Production Example 43 was repeated, except that the 2-(benzo[b]furan-5-yl)oxirane and the 3-pyridinemethanol were replaced by 2-(benzo[b]thiophen-5yl)oxirane and 1,4-diformyl-2-piperazinemethanol, respecitvely, to obtain oily 1-(benzo[b]thiophen-5-yl)-2-[(1,4-diformylpiperazin-2-yl)methoxy]ethanol (compound No. 354).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])=[CH2:2].[F:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[N:23]=[C:22]([NH:24][CH2:25][CH2:26][CH3:27])[C:21](I)=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:6][C:5]1[CH:4]=[C:3]([CH:9]=[CH:8][CH:7]=1)/[CH:1]=[CH:2]/[C:21]1[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[N:23][C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=2)=[N:19][CH:20]=1
Reactant: C=Cc1cccc(N)c1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1/C=C/c1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-vinylaniline (19 μL), N2-(3-fluorophenyl)-5-iodo-N4-propylpyrimidine-2,4-diamine (F2, 51 mg) and palladium(II) acetate (3 mg) in acetonitrile (1.5 mL), triethylamine (68 μL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour, and then stirred at 80° C. for 14 hours. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 50% hexane in ethyl acetate) to obtain (E)-5-(3-aminostyryl)-N2-(3-fluorophenyl)-N4-propylpyrimidine-2,4-diamine (F11, 14 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:20]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:19][CH:18]=[CH:17][C:6]=1[CH2:7][CH:8]([C:14]([O-:16])=[O:15])[C:9]([O:11]CC)=[O:10]>O.CO>[CH3:3][O:4][C:5]1[C:20]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:19][CH:18]=[CH:17][C:6]=1[CH2:7][CH:8]([C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C(Cc1cccc(C(=O)c2ccc(Cl)cc2)c1OC)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(CC(C(=O)O)C(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
A solution of 86.4 g of sodium hydroxide in 180 ml of water was added with stirring to a suspension of 226.6 g of ethyl 2-methoxy-3-(p-chlorobenzoyl)-benzyl-malonate in 2.8 liters of methanol and the mixture was refluxed for 3 hours and then was cooled to room temperature. The mixture was filtered and the precipitate recovered was washed with methanol, then with ether and dried. The residue was dissolved in 800 ml of water and the solution was washed with ether and acidified to a pH of 1 by addition of 0.5N hydrochloric acid. The acid precipitate formed was extracted with ether and the combined organic phases were washed with water, dried over magnesium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The residue was crystallized from benzene to obtain 96.2 g of 2-methoxy-3-(p-chlorobenzoyl)-benzyl-malonic acid in the form of colorless crystals which melted at 142° C after crystallization from benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][C:15](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:39][S:40]([NH:43][C:44]1[CH:45]=[CH:46][C:47]2[O:52][CH2:51][CH:50]([CH2:53][NH2:54])[O:49][C:48]=2[CH:55]=1)(=[O:42])=[O:41]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][NH:54][CH2:53][CH:50]1[CH2:51][O:52][C:47]2[CH:46]=[CH:45][C:44]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[CH:55][C:48]=2[O:49]1
Reactant: COc1ccc2[nH]cc(CCCC(=O)O)c2c1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OC(CN)CO2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2[nH]cc(CCCCNCC3COc4ccc(NS(C)(=O)=O)cc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
5-Methoxyindole-3-butyric acid (0.75 g, 3.2 mmole), 1-hydroxybenzotriazole hydrate (0.52 g, 3.8 mmole) and 1,3-diisopropylcarbodiimide (1.2 ml, 7.6 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methylsulfonylamino-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (0.9 g, 3.2 mmole) in 50 ml of DMF and the mixture was further stirred for 48 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using first ethyl acetate and then 2.5% methanol in ethyl acetate as eluants. Fractions were concentrated and washed with a minimum amount of THF to remove a byproduct and to give 1.2 g (79%) of the desired product, (7-methylsulfonyl amino-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(5-methoxy-1H-indol-3-yl)-butanamide, as a oily white solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([NH:20][NH2:21])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17]>C(O)C.O>[CH:1](=[N:21][NH:20][C:14]1[CH:13]=[CH:12][C:11]([Cl:10])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccc(Cl)cc1C(=O)O
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(Cl)ccc1NN=Cc1ccccc1
Reaction time: 1 h

Procedure:
A solution of benzaldehyde (1.48 g) in ethanol (10 ml) was added to a stirred suspension of 5-chloro-2-hydrazinobenzoic acid hydrochloride (described in U.S. Pat. No. 4,105,766; 5.2 g) in water (100 ml). Stirring was continued for 1 hour. The mixture was then left unstirred for 16 hours and then extracted with ether. The extracts were dried (MgSO4) and evaporated to give 2-(benzylidenehydrazino)-5-chlorobenzoic acid (3.5 g) which was used without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3.[H-].[Na+].[CH3:27]I>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3
Reactant: CI
Reactant: Cc1ccc(-c2cc3c4cc(C)ccc4[nH]c3n(C)c2=O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc3c4cc(C)ccc4n(C)c3n(C)c2=O)c(C)c1
Reaction time: 0.5 h

Procedure:
400 mg of 3-(2,4-dimethylphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one (compound 101) are dissolved in 10 ml of DMF. 31 mg of 95% NaH are added and the mixture is stirred at AT for 30 minutes. 380 μl of methyl iodide are added and the mixture is stirred at AT for 18 hours. It is evaporated to dryness. The residue is taken up in CH2Cl2 and the organic phase is washed with NaCl and then water, dried and evaporated. The residue is taken up in Et2O, filtration is carried out and drying is carried out. 300 mg of the expected product are obtained, M.p.=150° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[S:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][CH:12]=1>C(Cl)(Cl)Cl>[Br:1][C:12]1[N:13]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[S:15][C:11]=1[O:10][CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cnc(-c2ccccc2)s1
Solvent: ClC(Cl)Cl
Product: COc1sc(-c2ccccc2)nc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
400 mg (2.1 mmol) of N-bromosuccinimide was added into 10 ml of anhydrous chloroform with 400 mg (2.1 mmol) of 5-methoxy-2-phenylthiazole under 0° C. condition and was stirred for 4 hours at a room temperature. After completion of reaction, the organic phase was extracted with ethyl acetate, and was dried with addition of magnesium sulfate. After removing the solvent, the product was developed with ethyl acetate:hexane=1:3 solvent on silica column to give 4-bromo-5-methoxy-2-phenylthiazole (Rf=0.50). The yield was 550 mg in weight and 97% in percentage.
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][CH2:4][CH2:5][C:6]([CH:8]=[CH2:9])=[CH2:7].[C:11]([O:17][CH:18]=[CH2:19])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>CO.O>[C:11]([O:17][CH:18]=[CH:19][CH2:7][CH:6]([CH:8]=[CH2:9])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:10])[CH3:1])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: C=COC(=O)C(C)(C)C
Reactant: C=CC(=C)CCC=C(C)C
Solvent: CO
Solvent: O
Product: C=CC(CC=COC(=O)C(C)(C)C)CCC=C(C)C
Temperature: 70 °C
Reaction time: 6 h

Procedure:
23.7 mg (0.055 mmol) of (N-2-aminomethyl-p-toluene sulfonamide) (η6-benzene) ruthenium (II) chloride obtained in the Reference Example 4 and 17.5 mg (0.068 mmol) of silver triflate were mixed in 2 ml of methanol, to which were added 2 ml (purity: 78%, 1.25 g, 9.2 mmol) of myrcene and 1.73 g (13 mmol) of vinyl pivalate. The mixture was stirred at 70° C. for 6 hours. The reaction mixture was diluted with water and the organic layer was analyzed by gas chromatography to confirm that the title compound (addition product) having a purity of 76% (regioisomer: 26%) was produced at a conversion rate of 17%.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:21])[C@H:8]([CH2:17][CH2:18][S:19][CH3:20])[NH:9]C(OC(C)(C)C)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[CH:1]1([O:6][C:7](=[O:21])[C@H:8]([CH2:17][CH2:18][S:19][CH3:20])[NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](N)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-tert-butoxycarbonyl L-methionine cyclopentyl ester (53 g.), TFA (200 ml.), triethylsilane (39 g.) and dichloromethane (2 L.) was stirred at ambient temperature for 2 hours, evaporated to dryness and then converted to the hydrochloride salt to give L-methionine cyclopentyl ester as a white crystalline solid (40.5 g.).