Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[OH:18].C(OCC)C.[F:24][C:25]1[C:33]([F:34])=[C:32]([O:35][CH2:36][CH3:37])[CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:36]([O:35][C:32]1[CH:31]=[CH:30][C:26]([C:27]([O:18][C:3]2[CH:4]=[CH:5][C:6]([C@H:9]3[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH3:17])[CH2:13][CH2:14]3)=[C:7]([F:8])[C:2]=2[F:1])=[O:28])=[C:25]([F:24])[C:33]=1[F:34])[CH3:37]
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)c(F)c2F)CC1
Reactant: CCOc1ccc(C(=O)O)c(F)c1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCC[C@H]1CC[C@H](c2ccc(OC(=O)c3ccc(OCC)c(F)c3F)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 500 mL three-neck flask, 3.20 g of 2,3-difluoro-4-ethoxybenzoic acid (a) and 3.84 g of 2,3-difluoro-4-(trans-4-propylcyclohexyl)phenol (1) were dissolved in 230 mL of methylene chloride. 0.70 g of 4-dimethylaminopyridine was added thereto and stirred at room temperature for 1 hour. A solution in which 3.54 g of N,N-dicyclohexylcarbodiimide was dissolved in 90 mL of methylene chloride was added thereto and stirred overnight. Diethyl ether was added and urea precipitated was filtered off. Saturated aqueous solution of sodium chloride was added and stirred for 1 hour. After organic layer was separated, the organic layer was washed with 3N hydrochloric acid and saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 6.60 g of 2,3-difluoro-4-(trans-4-propylcyclohexyl)phenyl 4-ethoxy-2,3-difluorobenzoate (m).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[C:10]1[CH:31]=[CH:30][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:18]=2)=[O:15])=[C:12]([CH3:32])[N:11]=1>CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[C:13]2[CH:30]=[CH:31][C:10]([N:4]3[CH:5]=[N:6][C:2]([CH3:1])=[N:3]3)=[N:11][C:12]=2[CH3:32])=[CH:18][C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: Cc1nc[nH]n1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(C)n2)n1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
A mixture of 57 mg of 3-methyl-1,2,4-triazol and 16 mg of sodium hydride in 2 mL of DMF was stirred for 10 min. 80 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide was added. The reaction was heated to 140° C. for 16 h. The reaction mixture was quenched with MeOH and evaporated. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methyl-1H-1,2,4-triazol-1-yl)nicotinamide. MS (Q1) 405.3 (M)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:10])[CH2:4][CH:5]([O:8][CH3:9])[O:6][CH3:7].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][CH:13]=1>>[CH3:7][O:6][CH:5]([O:8][CH3:9])[CH2:4][C:3]1[N:10]=[C:16]([C:15]2[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=2)[O:1][N:2]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COC(CC(=N)NO)OC
Product: COC(Cc1noc(-c2ccc(F)cc2)n1)OC

Procedure:
By using N-hydroxy-3,3-dimethoxypropanimidamide obtained in Reference Example 19 (1.0 g, 6.8 mmol) and 4-fluorobenzoic acid (0.99 g, 7.1 mmol) as the raw materials, the same procedure as in Reference Example 20 was carried out to obtain the title compound (1.4 g) (colorless oil).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)O)=[C:4]([F:14])[CH:3]=1.FC(F)(F)C(O)=O.[CH3:22][S:23]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:35]=1[NH:34][CH:33]=[CH:32]2)(=[O:25])=[O:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)[C:32]2[C:31]3[C:35](=[C:27]([CH2:26][S:23]([CH3:22])(=[O:25])=[O:24])[CH:28]=[CH:29][CH:30]=3)[NH:34][CH:33]=2)=[C:4]([F:14])[CH:3]=1
Reactant: OC(c1c(F)cc(Cl)cc1F)C1CC1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cccc2c(C(c3c(F)cc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
104 mg (0.48 mmol) of the compound from Example 156A and 0.04 ml (0.57 mmol) of trifluoroacetic acid were added to 100 mg (0.48 mmol) of the compound from Example 86A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 45 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 100 mg (51% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:26])[C@H:20]([C@H:22]([CH2:24][CH3:25])[CH3:23])[NH2:21]>>[CH3:17][O:18][C:19](=[O:26])[C@H:20]([C@H:22]([CH2:24][CH3:25])[CH3:23])[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Agent: Cl
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)Cc1ccccc1)C(=O)OC

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and L-isoleucine methyl ester hydrochloride (Sigma), the title compound was prepared. The reaction was monitored by tlc (Rf=0.24 in 50% EtOAc/hexanes).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([C:34]([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:34]([C:36]2[CH:37]=[CH:38][C:39]([NH:40]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:41][CH:42]=2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: Nc1ccc(C(=O)N2CCCCC2)cc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(C(=O)N3CCCCC3)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-(piperidin-1-yl-carbonyl)-aniline
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[N+:21]([O-])([OH:23])=[O:22]>>[Cl:1][C:2]1[CH:3]([CH2:12][C:13]2[CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])[NH:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9]
Reactant: O=[N+]([O-])O
Reactant: Cn1nc(Cc2cccc(Cl)c2Cl)c(Cl)c1OC(F)F
Product: CN1NC(Cc2cc([N+](=O)[O-])cc(Cl)c2Cl)C(Cl)=C1OC(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At −10° C., 6.6 g (19 mmol) of 4-chloro-3-(2,3-dichlorobenzyl)-5-difluoromethoxy-methyl-1H-pyrazole were dissolved in 100 ml of nitric acid. After 30 minutes, the mixture was warmed to 0—5° C. and 200 g of ice were added. The product of value was then extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and finally concentrated. The product of value was purified by MPLC over silica gel (eluent: cyclohexane/ethyl acetate=4:1).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=2)[C:15]([N+:27]([O-:29])=[O:28])=[CH:14][CH:13]=1>C1COCC1>[CH2:1]([O:8][C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=2)[C:15]([N+:27]([O-:29])=[O:28])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CCc1ccc(Nc2nc(Cl)ccc2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ccc(Nc2nc(OCc3ccccc3)ccc2[N+](=O)[O-])cc1
Temperature: 65 °C
Yield: 70.1 %

Procedure:
To a solution of benzyl alcohol (1.32 g, 12.2 mmol) in THF (15 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil, 488 mg, 12.2 mmol). The mixture was stirred at room temperature for 0.5 h at which time 6-chloro-N-(4-ethylphenyl)-3-nitropyridin-2-amine (1.21 g, 4.03 mmol) was added. The mixture was heated in a sealed tube overnight at 65° C. The reaction vessel was cooled to room temperature and the mixture was quenched with saturated NaHCO3. The mixture was extracted with EtOAc and the organics were dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (2% EtOAc in hexanes gradient to 15% EtOAc in hexanes) gave the title compound (987 mg) as a yellow solid. NMR (400 MHz, CDCl3) δ ppm 1.26 (t, J=7.6 Hz, 3H), 2.66 (q, J=7.6 Hz, 2H), 5.34 (s, 2H), 6.25 (d, J=9.1 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.41-7.28 (m, 5H), 7.45 (d, J=8.4 Hz, 2H), 8.40 (d, J=9.1 Hz, 1H), 10.51 (broad s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[CH:8]([CH3:11])[C:9]#[N:10].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>O>[F:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]([CH3:11])[C:9]#[N:10])[CH:6]=1
Reactant: CC(Cl)C#N
Reactant: Fc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC(C#N)n1cc(F)cn1
Temperature: 100 °C
Yield: 82 %

Procedure:
4-Fluoro-1H-pyrazole (300 mg, 3.49 mmol), 2-chloropropanenitrile (374 mg, 4.18 mmol), cesium carbonate (1.84 g, 5.23 mmol) and anhydrous acetonitrile (5.0 mL) were added into a round bottom flask. The reaction mixture was heated to 100° C. for 2 h. Water was added and the mixture was extracted with ether (100 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (0-50% ethyl acetate in heptanes) to afford 2-(4-Fluoro-1H-pyrazol-1-yl)propanenitrile (398 mg, 82%). MS (EI+) (M+) 139, GCMS retention time: 0.78 min (Method O).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.Cl[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C(CCl)c1ccccc1
Reactant: Oc1ccc2c(c1)CCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(COc1ccc2c(c1)CCC2)c1ccccc1

Procedure:
Using the method of Example 1, step A, 5-hydroxyindane is reacted with α-chloroacetophenone in benzene in the presence of sodium carbonate to provide α-(5-indanoxy)acetophenone as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.CCCCCC>C1(C)C=CC=CC=1>[C:22]([C:16](=[CH:15][NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][N:3]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:23]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CCCCc1ccc(N)nc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCc1ccc(NC=C(C#N)C(=O)OCC)nc1

Procedure:
A solution of 2-amino-5-n-butylpyridine (3.72 g., 23.43 mmoles) and ethyl ethoxymethylenecyanoacetate (3.96 g., 23.43 mmoles) in toluene was heated for 10 minutes by means of an oil bath maintained at 100°. The solution was cooled and treated with Skellysolve B (200 ml.). The mixture was triturated for 18 hours at room temperature and then filtered. The collected title compound (4.3 g., 67.2%) had m.p. 69°-73°.
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.[CH:16]1([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=2)[CH2:18][CH2:17]1.[OH-].[K+]>CN1C(=O)CCC1>[CH:16]1([C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH2:26][CH:3]3[C:4]4[C:12]5[CH:11]=[C:10]([CH3:13])[CH:9]=[CH:8][C:7]=5[NH:6][C:5]=4[CH2:14][CH2:15][N:2]3[CH3:1])=[CH:23][CH:24]=2)[CH2:18][CH2:17]1
Reactant: C=Cc1ccc(C2CC2)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2[nH]c3c(c2c1)C(CCc1ccc(C2CC2)nc1)N(C)CC3

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-cyclopropyl-5-vinylpyridine 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: [NH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12](O)=O)[C:2]([CH3:4])=[O:3].[NH2:15][C:16]1[C:17](=[O:35])[N:18]([CH2:32][CH2:33][CH3:34])[C:19](=[O:31])[N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]=1[NH2:22]>>[NH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]1[NH:15][C:16]2[C:17](=[O:35])[N:18]([CH2:32][CH2:33][CH3:34])[C:19](=[O:31])[N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:21]=2[N:22]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccccc1CC(=O)O
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccccc2)c1=O
Product: CCCn1c(=O)c2[nH]c(Cc3ccccc3NC(C)=O)nc2n(CCc2ccccc2)c1=O

Procedure:
By the method of Example 2, 2-(acetamino)phenylacetic acid is reacted with 5,6-diamino-1-(2-phenylethyl)-3-propyluracil to yield 8-(2-acetaminobenzyl)-3-(2-phenylethyl)-1-propylxanthine. By methods well known in the art, 8-(2-acetaminobenzyl)-3-(2-phenylethyl)-1-propylxanthine is hydrolyzed with base to yield 8-(2-aminobenzyl)-3-(2-phenylethyl)-1-propylxanthine. In turn, 5,6-diamino-1-(2-(phenylethyl)-3-propyluracil is made by the synthetic methods of Example 1, starting with phenethylamine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][C:13]#[N:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Li][CH2:16]CCC.CI>C1COCC1>[CH3:1][C:2]1[C:3]([CH:12]([CH3:16])[C:13]#[N:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2ccccc2cc1CC#N
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2ccccc2cc1C(C)C#N
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
To a stirred solution of (3-methyl-2-naphthalenyl)acetonitrile (2.17 g, 12 mmol) in dry THF (125 mL) cooled to -78° C. was added n-BuLi (8.44 mL, 13.5 mmol; 1.6M solution in hexanes)dropwise over 10 minutes. The resulting orange solution was stirred for 20 minutes at -78° C. and MeI (1.92 g, 13.5 mmol) was added in one portion. The reaction mixture was stirred at -78° C. for 1.25 hours and quenched with saturated NH4Cl (20 mL). After warming to room temperature, the volatiles were removed in vacuo and the residue was diluted with H2O (150 mL). The aqueous phase was extracted with Et2O (2×150 mL). The combined organic layers were washed with saturated NaCl (1×150 mL) and dried (MgSO4). Removal of the solvent in vacuo afforded the product as a light yellow solid (2.34 g, 100%). This material was of sufficient purity to be used as such.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.Cl.[NH2:11]O>CO>[CH3:1][CH:2]1[CH2:7][NH:11][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1
Reactant: CC1CC(=O)CC(=O)C1
Reactant: NO
Agent: Cl
Solvent: CO
Product: CC1CNC(=O)CC(=O)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.3 %

Procedure:
150 g 5-methylcyclohexane-1,3-dione was dissolved in 1.4 L methanol and 82.5 g hydroxylamine hydrochloride was added. The mixture was stirred for 1.5 h under reflux. The solvent was removed in vacuo and the residue was dissolved in 1 L acetonitrile and was cooled to 0° C. Triethylamine was added followed by addition of a solution of 4-toluenesulfonyl chloride in 1.1 L acetonitrile. The mixture was stirred for 1 h at RT, 6.7 mL of water was added and the mixture was stirred for additional 1 h while gently warming the mixture to 55° C. The volatiles were removed in vacuo. 250 mL water was added to the residue and the pH was adjusted to 5 with 5 N aq. NaOH and the volatiles were removed in vacuo. The solids were extracted with acetone and after concentration in vacuo the residue was purified by column chromatography on silica gel with ethyl acetate to yield 82.6 g of the desired compound.
Reaction SMILES: [CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.[CH:8]([C:11]1[C:12]([O:19][CH2:20][O:21][CH3:22])=[C:13]([CH:16]=[CH:17][CH:18]=1)C=O)([CH3:10])[CH3:9]>CO.[Cl-].[NH4+]>[CH3:7][O:6][CH:1]([O:4][CH3:5])[C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([CH:8]([CH3:10])[CH3:9])[C:12]=1[O:19][CH2:20][O:21][CH3:22]
Reactant: COCOc1c(C=O)cccc1C(C)C
Reactant: COC(OC)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COCOc1c(C(C)C)cccc1C(OC)OC
Yield: 90.5 %

Procedure:
Trimethyl orthoformate (2.35 ml, 21.4 mmol) and ammonium chloride (52 mg, 0.98 mmol) were added to a solution of 3-isopropyl-2-(methoxymethoxy)benzaldehyde (4.06 g, 19.5 mmol) which was synthesized according to the method described in literature (James, R. et al., J. Med. Chem., 1980, vol. 23, pp. 1350-1357) in methanol (65 ml), and the mixture was stirred under heating with reflux for 1 hour. The solvent was removed under reduced pressure and a saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=12/0-12/1) to give 1-(dimethoxymethyl)-3-isopropyl-2-(methoxymethoxy)benzene as a colorless oil (4.49 g, yield: 91%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl[CH2:12][C:13](=O)[CH3:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:10][CH:12]=[C:13]([CH3:14])[C:8]=2[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)CCl
Reactant: CC(C)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1csc2ccc(C(C)C)cc12
Yield: 67.3 %

Procedure:
A mixture of 4-isopropyl-thiophenol (5.0 g, 32.8 mmol), chloroacetone (7.0 mL, 88 mmol) and K2CO3 (6.4 g, 46.3 mmol) in acetone (100 mL) was refluxed over night. More K2CO3 (2 g, 14.5 mmol) and chloroacetone (3.5 mL, 43 mmol) were added and the reaction mixture was heated for another 5 h. The reaction mixture was filtered and the solvent was evaporated. The crude product was mixed with polyphosphoric acid (15 g) and chlorobenzene (100 mL) and the reaction mixture was heated at reflux for 5 h. (Plé et al., (1988) J. Heterocyclic Chem. 25, 1271-1272). The reaction mixture was diluted with CH2Cl2 and washed with water. The combined organic phases were dried and the solvent was evaporated. The crude product was purified on silica using heptane as eluent, giving 4.2 g of the title compound as a colourless oil (67% over two steps). 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (d, 6 H) 2.47 (d, 3 H) 3.02-3.16 (m, 1 H) 7.08 (s, 1 H) 7.27-7.30 (m, 1 H) 7.58 (d, 1 H) 7.80 (d, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][O:15][C:19](=[O:20])[CH2:18][C:17]([CH3:16])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCCCN1Cc1ccccc1
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)OCC1CCCCN1Cc1ccccc1
Yield: 70 %

Procedure:
Then, 10.0 g of the 1-benzyl-2-piperidine methanol and 4.30 g of diketene were reacted similarly as in Reference Example 1, and the reaction product was purified by silica gel column chromatography (eluent:chloroform:methanol=9:1 v/v), to obtain 9.86 g of acetoacetic acid-N-benzyl-2-piperidinylmethyl ester (yield: 69.9%). This was used in the reaction of Example 5 without distillation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][O:12][C:13](=[O:27])[CH:14](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:11][O:12][C:13](=[O:27])[CH:14]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:9][CH3:10])[CH:4]=1)[CH3:15]
Reactant: COC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccc(Br)c(OC)c1
Temperature: 65 °C
Reaction time: 96 h

Procedure:
4-Bromo-3-methoxyphenol (209 mg, 1 mmol, 1 eq.) was dissolved in MeCN (4 mL). (±)-2-(Toluene-4-sulfonyloxy)-propionic acid methyl ester (258 mg, 1 mmol, 1 eq.) and K2CO3 (276 mg, 2 mmol, 2 eq.) were added and the mixture was stirred at 65° C. for 6 hours and further at r.t. for 4 days. The mixture was partitioned between water and Et2O. The layers were separated and the aq. phase was extracted with Et2O (2×). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flashmaster (column: 25 g, flow: 30 mL/min, 30 fractions of 30 mL, Heptane 100% to Heptane+20% AcOEt) to the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:10](OCC)=O)=[C:5]([CH3:9])[C:6]=1[CH2:7][CH3:8].C=O>>[CH2:7]([C:6]1[C:5]([CH3:9])=[C:4]([CH3:10])[NH:3][C:2]=1[CH3:1])[CH3:8]
Reactant: CCOC(=O)c1[nH]c(C)c(CC)c1C
Agent: C=O
Product: CCc1c(C)[nH]c(C)c1C

Procedure:
2,4-Dimethyl-3-ethyl-5-carbethoxy-pyrrole was reductively alkylated with paraformaldehyde to yield 3-ethyl-2,4,5-trimethyl-pyrrole. ##STR85##
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[S:7][C:8]([C:11]2[CH2:18][O:17][CH:16]3[N:13]([C:14](=[O:39])[CH:15]3[NH:19][C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:40]([O:42][CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])=[CH:9][N:10]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:5][C:6]1[S:7][C:8]([C:11]2[CH2:18][O:17][CH:16]3[N:13]([C:14](=[O:39])[CH:15]3[NH:19][C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:12]=2[C:40]([O:42][CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:41])=[CH:9][N:10]=1)(=[O:3])[CH3:2]
Reactant: Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)C3OC2)s1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)C3OC2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
A solution of acetyl chloride (0.11g) in dry tetrahydrofuran (2 cc) is added, in 3 minutes, to a solution, cooled to 0° C., of 3-(2-amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-tritylamino-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (0.80 g) in dry tetrahydrofuran (10 cc), and a solution of triethylamine (0.18 cc) in dry tetrahydrofuran (2 cc) is then added. The mixture is stirred for 30 minutes at 0° C. and is then filtered over a diatomaceous earth powder. The filtrate is diluted with ethyl acetate (50 cc) and washed with distilled water (50 cc), a half-saturated sodium bicarbonate solution (50 cc) and a saturated sodium chloride solution (50 cc). The organic phase is dried over anhydrous sodium sulphate; it is filtered, the insoluble matter is washed with ethyl acetate (10 cc) and the organic solution is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue (0.89 g) is chromatographed on a column (height: 24 cm; diameter: 2.2 cm) of silica (0.04-0.06 mm), elution being carried out with a 40:60 (by volume) mixture of cyclohexane and ethyl acetate under 0.4 kPa, and 60 cc fractions being collected. Fractions 5 to 11 are combined and the solvent is evaporated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 3-(2-Acetylamino-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-tritylamino-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (0.55 g) is obtained in the form of a pale chestnut-coloured froth.