Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4]([NH2:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.[N:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>ClCCl>[CH3:1][O:2][C:3](=[O:11])[CH:4]([NH:10][C:27]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:28])[CH2:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: O=C(Cl)N1CCOCC1
Reactant: COC(=O)C(N)CC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CC(C)(C)C)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Amino-4,4-dimethyl-pentanoic acid methyl ester (5.35 g, 27.4 mmol) was dissolved in 100 mL of dichloromethane. Hunig's base (7.07 g, 54.7 mmol) and 4-morpholinecarbonyl chloride (4.08 g, 27.4 mmol) were added and the reaction was stirred at ambient temperature 16 h. The reaction mixture was concentrated in vacuo and taken up in 150 mL EtOAc. A white precipitate formed and was filtered and washed with EtOAc. EtOAc solutions were combined and washed with 3×50 mL 1 N HCl (aq), 3×50 mL saturated NaHCO3 (aq), and 1×50 mL brine. The organic layer was dried over Na2SO4, decanted, and concentrated to a white solid (6.33 g). MS, m/z 273=M+1.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH:16]=1)[CH2:12][NH:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)N
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C=O)cc(O[Si](C)(C)C(C)(C)C)c1
Agent: Cl
Product: CCOC(=O)C(C)(C)NCc1cc(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c1
Yield: 88 %

Procedure:
Prepared as in Example 12-1b from 3,5-bis(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-3c) and ethyl 2-amino-2-methylpropanoate hydrochloride. Yield 88%, colorless liquid. MS 482 (MH+).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2.[NH3:14]>>[C:2]([C:3]1[NH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2)#[N:14]
Reactant: N
Reactant: ClC(Cl)(Cl)c1nc2ncccc2[nH]1
Product: N#Cc1nc2ncccc2[nH]1

Procedure:
2-Trichloromethyl-imidazo[4,5-b]pyridine (21.5 g) is added, in small portions, to 34% strength ammonia (250 ml), which is stirred vigorously and kept at about 10° C. After the addition, the reaction mixture is stirred for about one hour, the temperature being allowed to rise to the ambient temperature (20° to 25° C.). The reaction mixture is filtered over silica supercel and the filtrate is acidified to pH=6 with hydrochloric acid (200 ml) of density 1.19, the temperature being kept below 10° C. 2-Cyanoimidazo[4,5-b]pyridine (8 g in total) of melting point of about 200° C. is obtained by filtering off the precipitate, extracting the mother liquors with ethyl acetate and concentrating the extract. Purity: about 80%.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.Cl.[NH2:13][CH2:14][C:15]#[N:16].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[C:14]([CH2:15][NH:16][C:7]([C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[C:10]([OH:9])=[O:11])=[O:8])#[N:13]
Reactant: N#CCN
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(+)-trans-Cyclohexane-1,2-dicarboxylic anhydride (100 mg, 0.65 mmol) was weighed into a 10 mL round bottom flask and aminoacetonitrile hydrochloride (135 mg, 1.46 mmol) and 4-(dimethylamino)pyridine (7.5 mg, 61 μmol) added. After adding tetrahydrofuran (2.0 mL) and triethylamine (0.20 mL, 1.4 mmol), the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between 1 M aqueous hydrochloric acid (30 mL) and ethyl acetate (30 mL). The organic layer was separated, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to give (1R,2R)-2-{[(cyanomethyl)amino]carbonyl}cyclohexanecarboxylic acid (as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].I[CH3:22]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=3[N:10]([CH3:22])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: Nc1nccc(-n2c(=O)[nH]c3ccc(Br)cc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(-c2ccnc(N)n2)c2cc(Br)ccc21
Reaction time: 0.5 h
Yield: 115 %

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromo-2,3-dihydro-1H-1,3-benzodiazol-2-one (500 mg, 1.63 mmol) in DMF (10 ml) at 0° C. was added sodium hydride (60% oil suspension, 65.33 g, 1.63 mmol). The reaction mixture was allowed to warm to RT over 5 minutes before addition of iodomethane (0.1 ml, 1.63 mmol) and stirring for 30 minutes. The mixture was quenched by addition of water (5 mL), EtOAc was then added resulting in formation of a precipitate. The precipitate was collected by suction filtration. The filtrate was extracted with EtOAc (×2). The combined organic fractions were washed with water and dried (Na2SO4), filtered and concentrated in vacuo. Combining the extract residue and the precipitate gave the crude title compound (600 mg); 1H NMR (500 MHz, CDCl3) delta 3.23 (3H, s), 5.55 (2H, s), 6.72 (1H, d, J=8.3 Hz), 7.20-7.04 (1H, m), 7.42 (1H, d, J=5.7 Hz), 8.12 (1H, d, J=5.7 Hz), 8.39 (1H, d, J=1.8 Hz); LC-MS: m/z=+321.8 (M+H)+.
Reaction SMILES: CC1C=CC=C(C#CC=C2CCNCC2)N=1.[OH:17][CH:18]([CH:28]1[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1)[C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1>>[CH3:27][C:23]1[N:22]=[C:21]([C:20]#[C:19][CH:18]([CH:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]2)[OH:17])[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccc(C#CC(O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cc1cccc(C#CC=C2CCNCC2)n1
Product: Cc1cccc(C#CC(O)C2CCNCC2)n1

Procedure:
The title compound was prepared following the procedure described for the compound of Example 3, using the Compound of Example 39 instead of the Compound of Example 2. After the usual work-up procedure, the crude was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:24][NH2:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:25][CH2:24][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([Cl:15])[CH:17]=2)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: COc1ccc(CN)cc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 47.5 °C
Yield: 91.7 %

Procedure:
(1)-b) To a stirred suspension of 2-methylthio-4-chloro-5-ethoxycarbonylpyrimidine (145.0 g, 0.62 mol) and (3-chloro-4-methoxyphenyl)methylamine (129.0 g, 0.62 mol) in dimethylformamide (435 ml) is added triethylamine (131.8 g, 1.30 mol) below 20° C. The mixture is stirred at the same temperature for about an hour. After the completion of the reaction, ethyl acetate (1450 ml) and water (870 ml) are added to the reaction mixture and stirred. The organic layer is separated and washed with water (870 ml) and a solution of sodium chloride (72.5 g) in water (290 ml), and dried over anhydrous magnesium sulfate (29.0 g). After removal of the drying agent by filtration and washed with ethyl acetate (145 ml), the filtrate and washings are combined and concentrated under reduced pressure. The resultant solid is suspended in 2-propanol (145 ml) and the mixture is concentrated under reduced pressure. The resultant solid is dissolved in hot 2-propanol (1450 ml) and the solution is seeded with 2-methylthio-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine crystals at 55° C. The mixture is cooled down to 45-50° C. and continuously stirred at the same temperature for more than an hour. Then the mixture is cooled down below 10° C. and continuously stirred for more than 30 minutes. The precipated crystals are collected by filtration, washed with 2-propanol (145 ml) and dried at 50° C. for about 16 hours to produce 2-methylthio-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine (209.2 g, 91%). mp. 86-88° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[C:13]([CH:18]4[O:22][CH2:21][CH2:20][O:19]4)[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:23])=[CH:5][CH:4]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>ClCCl.O>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH2:11][CH2:10][C:9](=[O:23])[N:8]2[CH2:7][C:6]1[CH:24]=[CH:25][C:3]([CH2:2][N:27]([CH3:26])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:4][CH:5]=1
Reactant: O=C1CCc2c(C3OCCO3)cccc2N1Cc1ccc(CCl)cc1
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CN(Cc1ccc(CN2C(=O)CCc3c(C4OCCO4)cccc32)cc1)c1ccccc1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
1-(4-Chloromethylbenzyl)-5-(1,3-dioxolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (100 mg, 0.28 mmol), N-methylaniline (0.045 ml, 0.42 mmol) and potassium carbonate (57.9 mg, 0.42 mmol) were added to acetonitrile (1 ml), followed by heating under reflux for 4 hours. After cooling to room temperature, water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was washed with water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dry product was concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 80 mg (yield: 67%) of 5-(1,3-dioxolan-2-yl)-1-(4-[(N-methyl-N-phenylamino)methyl]benzyl)-3,4-dihydro-1H-quinolin-2-one as a light yellow amorphous solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][N:4]=1.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].N1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:15]1([CH2:2][C:3]2[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][N:4]=2)[CH2:16][CH2:17][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccnc(CCl)c1
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCNC1
Solvent: ClCCl
Product: COC(=O)c1ccnc(CN2CCCC2)c1
Reaction time: 0.08 h

Procedure:
A solution of product of stage (iii) (1.6 g) in dry dichloromethane (50 ml) at -50° was treated with triethylamine (1.07 ml) and the mixture was stirred for 5 min. A pre-cooled solution of pyrrolidine (1.28 ml) in dry dichloromethane (30 ml) was added at -60° and the mixture was stirred at -60° to 0° for 1 h and at ambient temperature for 72 h. The mixture was poured into aqueous sodium carbonate (1M; 50 ml) and the product was extracted with dichloromethane (50 ml). The organic solution was dried and evaporated leaving an oily residue (1.7 g) which was purified by flash chromatography eluting with dichloromethane/methanol/ammonia 200:10:1 to give the title compound as an oil (0.3 g).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[O:22]([CH2:29][CH2:30][NH2:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[N+:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:19]=[C:20]([NH:31][CH2:30][CH2:29][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:8][CH2:9][C:10]=2[CH:15]=1)([O-:18])=[O:17]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: NCCOc1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Yield: 95.8 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (1.95 g, 6.0 mmol; HPLC: 4.446 min) and 2-phenoxyethylamine (CAS 1758-46-9) (807 mg, 6.0 mmol; HPLC: 0.381 min) according to the procedure described for Example 1. Obtained the title compound as a yellow solid (1.80 g, 96%, HPLC 1.789 min), MS (ISP) m/e=314.0 [(M+H)+].
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][C:11]([O:15][CH3:16])=[N:12]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4].[Br:18][CH2:19][CH2:20][CH:21](Br)C.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[Br:18][CH2:19][CH2:20][CH2:21][N:12]1[C:11]([O:15][CH3:16])=[N:10][C:9]2[C:13]1=[N:14][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][C:8]=2[NH2:17]
Reactant: CCCCOc1nc(N)c2[nH]c(OC)nc2n1
Reactant: CC(Br)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCBr)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of 2-butoxy-8-methoxyadenine (5 g, 14.2 mmol) in dimethylformamide (50 ml) were added 1,3-dibromobutane (7.2 ml) and potassium carbonate (9.2 g), and the mixture was stirred at room temperature for 1.5 hour. Water (200 ml) and ethyl acetate (75 ml) were added thereto, and the mixture was extracted, and further extracted with ethyl acetate (75 ml) twice. The organic layers were combined, dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. To the residue was added diethyl ether (25 ml), and the precipitated crystals were collected by filtration, washed with ether (5 ml), and dried to give the subtitle compound (3.6 g) as a white solid. Yield: 71%
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2cccc(Br)c2o1
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cccc2cc(C(=O)O)oc12
Temperature: 90 °C
Reaction time: 18 h

Procedure:
5.0 g (20.7 mmol) of 7-bromo-1-benzofuran-2-carboxylic acid (Example 29A) and 3.78 g (24.9 mmol) of 2-methoxyphenylboronic acid are introduced into 50 ml of DMF. Addition of 31.1 ml of 2 M sodium carbonate solution and 1.2 g (1.04 mmol) of Pd(PPh3)4 is followed by heating to 90° C. After 18 h, the solvent is distilled out. The residue is partitioned between 1N hydrochloric acid and ethyl acetate and extracted three times with 200 ml of ethyl acetate each time. The organic phase is dried over sodium sulphate and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, mobile phase: dichloromethane/methanol/acetic acid 100:10:1). Concentration and drying under high vacuum result in 2.97 g (53.2% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[S:9][C:10]2[CH2:11][N:12](C(=O)C(F)(F)F)[CH2:13][CH2:14][C:15]=2[N:16]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[S:9][C:10]2[CH2:11][NH:12][CH2:13][CH2:14][C:15]=2[N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc2c(s1)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of [5-(2,2,2-trifluoro-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl]-carbamic acid tert-butyl ester (3.50 g, 9.86 mmol) in MeOH (75 mL) is added a solution of potassium carbonate (13.8 g; 98.6 mmol) in water (125 mL) and the reaction stirred at about 25° C. for 24 hours. The suspension is concentrated and the residue suspended in EtOAc (300 mL). This is washed with sat. NH4Cl (300 mL) then brine (100 mL). Solid product forms in the EtOAc layer. This is filtered off as crop 1. The aqueous layer is extracted with more EtOAc (3×300 mL) and the combined extracts washed with brine and dried (Na2SO4). Concentrate to a white solid and combine with the above precipitate. Triturate this in EtOAc (50 mL) and filter to give the title compound (N).
Reaction SMILES: [O:1]([NH2:3])[CH3:2].S([O-])([O-])(=O)=O.[CH3:9][NH:10][C:11](=[O:30])[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH3:29])=O.Cl>C1(C)C=CC=CC=1.CO>[CH3:9][NH:10][C:11](=[O:30])/[C:12](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH3:29])=[N:3]/[O:1][CH3:2]
Reactant: CON
Reactant: CNC(=O)C(=O)c1ccccc1COc1cc(C)ccc1C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 80 °C
Yield: 95.5 %

Procedure:
Methyl alcohol (10 ml) and a 50% aqueous solution (1.15 g, 6 mmol) of methoxylamine.1/2 sulfate were added to N-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-oxo-acetamide (1.49 g, 5 mmol). The mixture was refluxed for 6 hours. After completion of the reaction, methyl alcohol was evaporated under reduced pressure. Toluene (10 ml) and conc. hydrochloric acid (1.04 g, 10 mmol) were added to the resulting residue (E/Z=47/53). The mixture was heated at 80° C. for 2 hours. After cooling, toluene (100 ml) was added to the reaction mixture. The mixture was washed with water (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-N-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (1.56 g, Yield: 95.5%, E/Z=95/5).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[NH2:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[S:29])[NH2:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Product: NC(=S)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 37.8 %

Procedure:
Benzyl-4-carbamoylpiperidine-1-carboxylate (7.5 g, 38.6 mmol) was dissolved in THF (160 mL) and Lawesson's reagent (6.9 g, 17.1 mmol) was added. After 4 h the solvent was evaporated and the residue purified by flash-chromatography on silica gel (DCM-MeOH 95/5) affording 1.8 g (23%) of the title compound, crystallized from MeOH.
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([C:9](=[O:11])[CH3:10])[CH2:6][C:5]1=[S:12])(=[O:3])[CH3:2].C(N(CC)CC)C.S1C=CC=C1CC(O)=O>C(OCC)(=O)C>[C:1]([N:4]1[CH2:8][CH:7]([C:9](=[O:11])[CH3:10])[CH2:6][C:5]1=[S:12])(=[O:3])[CH3:2]
Reactant: CC(=O)[C@@H]1CC(=S)N(C(C)=O)C1
Agent: O=C(O)Cc1cccs1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)C1CC(=S)N(C(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
(+)-(4R)-1-Acetyl-4-acetylthio-2-pyrrolidone (3 g) and triethylamine (2.1 ml) are dissolved in ethyl acetate (30 ml), and the mixture is refluxed for three hours, and then allowed to stand at room temperature for 8 hours. To the reaction solution is added thiolacetic acid (1.2 ml), and the mixture is stirred at room temperature for 5 hours. The reaction solution is washed with water, dried, and evaporated to remove the solvent to give (±)-1-acetyl-4-acetylthio-2-pyrrolidone (2.7 g).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([O:16][C:17]2[C:22]([Cl:23])=[CH:21][C:20]([N:24]3[C:29](=[O:30])[NH:28][C:27](=[O:31])[CH:26]=[N:25]3)=[CH:19][C:18]=2[Cl:32])[CH:13]=[CH:12][C:11]=1[OH:33].C(N(CC)CC)C.[CH3:42][C@H:43]1[CH2:48][C@@H:47]([CH3:49])[CH2:46][NH:45][CH2:44]1>C(COC)OC>[Cl:32][C:18]1[CH:19]=[C:20]([N:24]2[C:29](=[O:30])[NH:28][C:27](=[O:31])[CH:26]=[N:25]2)[CH:21]=[C:22]([Cl:23])[C:17]=1[O:16][C:14]1[CH:13]=[CH:12][C:11]([OH:33])=[C:10]([C:9]([N:45]2[CH2:46][C@H:47]([CH3:49])[CH2:48][C@H:43]([CH3:42])[CH2:44]2)=[O:8])[CH:15]=1
Reactant: O=C(ON1C(=O)CCC1=O)c1cc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)ccc1O
Reactant: C[C@@H]1CNC[C@H](C)C1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: C[C@@H]1C[C@H](C)CN(C(=O)c2cc(Oc3c(Cl)cc(-n4ncc(=O)[nH]c4=O)cc3Cl)ccc2O)C1
Reaction time: 2 h

Procedure:
To solution of 5-[2,6-dichloro-4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-2-hydroxy-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester (320 mg) and triethylamine (265 μL) in dimethoxyethane (1.3 mL) was added 3,5-cis-dimethylpiperidine (189 mg). After 2 h, the reaction solution was concentrated in vacuo and flash chromatographed on silica gel (50% ethyl acetate/hexanes) to afford the title compound of this Example as a colorless solid, 130 mg. MS Calc.:505.3 Found:505.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][C:5]2=[O:13].N1C=CN=C1.[CH:19]([Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20].O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:19]([CH3:21])[CH3:20])[O:8][CH2:7][CH2:6][C:5]2=[O:13]
Reactant: Cc1cc2c(cc1O)OCCC2=O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)OCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 6-methyl-7-hydroxychroman-4-one (the compound of Preparation 32, 1.50 g, 8.42 mmol), imidazole (1.15 g, 16.9 mmol), and triisopropylsilyl chloride (2.0 mL, 9.2 mmol) in dimethylformamide (30 mL) was stirred overnight at ambient temperature. The reaction was poured into water and extracted with ether (2×). The combined organic layer was washed with 1 N lithium chloride (2×), dried over magnesium sulfate, and concentrated to afford 3.01 g (100%) of 6-methyl-7-triisopropylsilyloxychroman-4-one as a dull yellow oil which had: NMR δ 7.64 (s, 1 H), 6.30 (s, 1 H), 4.45 (t, J=6.4 Hz, 2 H), 2.70 (t, J=6.4 Hz, 2 H), 2.14 (s, 3 H), 1.40-1.25 (m, 3 H), 1.09 (d, J=7.3 Hz, 18 H). The product also had a small silyl impurity and residual dimethylformamide present but was suitable for subsequent reaction.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[CH3:12][C:4]1[CH:3]=[C:2]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CCCC2)cc1C

Procedure:
2.0 g of methyl 4-bromo-2-methylbenzoate were dissolved in 20 ml of toluene, and 1.08 ml of pyrrolidine, 4.0 g of cesium carbonate, 200 mg of tris(dibenzylideneacetone)-dipalladium (0) and 200 mg of (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were added thereto, and then the mixture was heated under reflux for 6 hours. The reaction solution was cooled, mixed with water and EtOAc, and extracted. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane-EtOAc (25:1)) to obtain 0.784 g of methyl 2-methyl-4-pyrrolidin-1-ylbenzoate.