Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([S:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[Cl:14].C([O-])(=[O:17])C.[K+].CS(C)=O>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:14][C:4]1[CH:5]=[CH:6][C:7]([S:9][C:10]([F:13])([F:12])[F:11])=[CH:8][C:3]=1[CH2:2][OH:17]
Reactant: CC(=O)[O-]
Reactant: FC(F)(F)Sc1ccc(Cl)c(CCl)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: OCc1cc(SC(F)(F)F)ccc1Cl
Temperature: 60 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
A mixture of 55.7 g of crude 2-chloromethyl-4-(trifluoromethylthio)chlorobenzene, 23 g of potassium acetate, 150 ml of dimethyl sulfoxide and 10 g of triethylbenzylammonium chloride is stirred for 5 hours at 60° C. It is decomposed by pouring into water, extracted with benzene and the benzene evaporated. The oily residue is dissolved in 200 ml of ethanol, 100 ml of water and 20 ml of hydrochloric acid are added and the mixture is stirred and refluxed for 7 hours. Ethanol is distilled off, the residue mixed with water and extracted with benzene. The oil obtained by evaporation of the dried extract, is distilled in vacuo. There are obtained 40.2 g crude 2-chloro-5-(trifluoromethylthio)benzyl alcohol boiling at 140°-150° C./2 kPa. According to the 1H-NMR spectrum the product contains approximately 80% of the named compound and the remainder is the position isomer. In this state the substance is suitable for further processing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.[CH2:22](Br)[CH2:23][CH2:24]C>>[CH2:20]([O:19][C:18]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:21])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCBr
Reactant: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1
Product: CCCCOc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 3-N-(4-chlorophenyl)-4-methoxyisophthalamide and butyl bromide by the same procedure as in the manufacturing method described in Example 1-1-2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:22])[CH:16]=[C:17]([NH2:21])[O:18][CH2:19][CH3:20])[CH3:13]>C(O)(C)C>[CH2:12]([O:14][C:15]([C:16]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:16]([C:15]([O:14][CH2:12][CH3:13])=[O:22])[C:17]([O:18][CH2:19][CH3:20])=[N:21][C:17]=1[NH2:21])=[O:22])[CH3:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C=C(N)OCC
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 68 %

Procedure:
Upon heating a solution of 7.6 g of 3-nitrobenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of isopropanol for 6 hours, 2-amino-4-(3-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 129° (isopropanol) is obtained. Yield: 68% of theory.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH:11]([CH2:12][O:13][CH3:14])[CH2:10][CH2:9][CH:8]1[CH2:15][O:16][Si](C(C)(C)C)(C)C)=[O:6])[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH:11]([CH2:12][O:13][CH3:14])[CH2:10][CH2:9][CH:8]1[CH2:15][OH:16])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C(COC)CCC1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C(CO)CCC1COC
Temperature: 25 °C
Yield: 86.8 %

Procedure:
To a solution of 1-allyloxycarbonyl-2-t-butyl-dimethylsilyloxymethyl-5-methoxymethylpyrrolidine (9.67 g) in tetrahydrofuran (97 ml) was added dropwise a solution of tetrabutylammonium fluoride in tetrahydrofuran (31 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for an hour. The mixture was poured into water and ethyl acetate, and the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layer was washed twice with 1N hydrochloric acid, and with saturated aqueous sodium bicarbonate, water and brine successively, dried over magnesium sulfate and evaporated under reduced pressure to give 1-allyloxycarbonyl-2-hydroxymethyl-5-methoxymethylpyrrolidine (5.60 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C.C1C=CC=CC=1.O.CN(C)C=O>[CH2:21]([O:20][C:18]([CH2:17][N:2]([CH3:1])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)=[O:19])[CH3:22]
Reactant: CNC1(c2ccccc2)CCC(=O)CC1
Reactant: CCOC(=O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(C)C1(c2ccccc2)CCC(=O)CC1
Yield: 63 %

Procedure:
A reaction mixture consisting of 8.77 gm. (0.031 mole) of 4-methylamino-4-phenylcyclohexanone, ethylene ketal hydrochloride (prepared as in Example 17, Part G, above), 5.16 gm. (3.42 ml.) ethyl bromoacetate, 4.29 gm. potassium carbonate, and 120 ml. dimethylformamide is heated in an oil bath to 100° C. and then held at that temperature with stirring for eighteen (18) hours. After removing the solvent medium by evaporation under reduced pressure, the residue obtained is dissolved in a mixture of 25 ml. water and 150 ml. benzene. The benzene layer is allowed to separate from the water and is recovered. It is washed with water and then with brine. The benzene is then removed by evaporation under reduced pressure. The residue thus obtained is dissolved in diethyl ether and to the ether solution is added 5.9 gm. p-toluenesulfonic acid dissolved in the minimum possible amount of diethyl ether. A gummy precipitate forms which is recrystallized two times from a mixture of methylene chloride and ethyl acetate. There is thus obtained 10.0 gm. (63% yield) of 4-[[(ethoxycarbonyl)methyl]methylamino]-4-phenylcyclohexanone, ethylene ketal, p-tetrenesulfonate having a melting range from 108° to 115° C. An analytical sample melts from 115° to 117° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[NH:18]1[CH2:21][CH2:20][CH2:19]1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)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].O1CCCC1>[N:18]1([C:2]2[CH:3]=[C:4]3[CH2:10][C@:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[O:8][C:5]3=[N:6][CH:7]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reactant: C1CNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: c1nc2c(cc1N1CCC1)C[C@@]1(CN3CCC1CC3)O2
Temperature: 75 °C

Procedure:
(R)-(−)-5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (295 mg, 1 mmol), azetidine (0.101 mL, 1.5 mmol), sodium tert-butoxide (135 mg, 1.4 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (62 mg, 0.1 mmol) and anhydrous tetrahydrofuran (9 mL) were combined in a heavy-walled threaded glass tube containing a magnetic stir bar, purged with argon, and sealed with a Teflon plug and FETFE O-ring. The mixture was stirred and heated at 75° C. for 4 hours, cooled to room temperature, dissolved in chloroform (20 mL), washed with brine (3×10 mL), dried (MgSO4), evaporated under reduced pressure, and purified by flash chromatography through silica gel (eluting with ammoniated chloroform/methanol 95:5) to procure the title compound (230 mg, 0.0.85 mmol, 85%) as a light tan solid: chemical ionization MS (m/z, relative intensity) 272 ([MH]+, 56).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([CH2:21][O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[C:18]([Cl:33])=[CH:17][C:3]=1[C:4](O[Si](C(C)C)(C(C)C)C(C)C)=[O:5].CSC.B.CO.O>C1COCC1>[Br:1][C:2]1[CH:20]=[C:19]([CH2:21][O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:24]([CH3:25])[CH3:26])[CH:27]([CH3:28])[CH3:29])[C:18]([Cl:33])=[CH:17][C:3]=1[CH2:4][OH:5]
Reactant: CC(C)[Si](OCc1cc(Br)c(C(=O)O[Si](C(C)C)(C(C)C)C(C)C)cc1Cl)(C(C)C)C(C)C
Agent: B
Solvent: CSC
Solvent: O
Solvent: CO
Product: CC(C)[Si](OCc1cc(Br)c(CO)cc1Cl)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
To a solution of silyl ester 29 (38.0 g, 65.8 mmol) in THF (300 mL) was added borane dimethylsulfide complex (1 M in THF, 13 mL) at 0° C. The mixture was stirred 0° C. for 15 min, at room temperature at 30 min, and at 75° C. for 15 h. The mixture was cooled to 0° C. MeOH and H2O were added to the cooled mixture to quench the reaction. After dilution with water, the mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography to provide the titled compound 30 (22.9 g, 85%).
Reaction SMILES: C(C1C=C2C(=CC=1)N=C(C(NCC1C=CC=C(NC(=O)CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=3)C=1)=O)NC2=O)#N.[CH3:53][C:54]1[C:62]2[C:61](=[O:63])[NH:60][C:59]([C:64]([NH:66][CH2:67][C:68]3[CH:73]=[CH:72][CH:71]=[C:70]([NH:74][C:75]([C:77]4[N:81]=[CH:80][N:79](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:78]=4)=[O:76])[CH:69]=3)=[O:65])=[N:58][C:57]=2[S:56][CH:55]=1>>[CH3:53][C:54]1[C:62]2[C:61](=[O:63])[NH:60][C:59]([C:64]([NH:66][CH2:67][C:68]3[CH:73]=[CH:72][CH:71]=[C:70]([NH:74][C:75]([C:77]4[N:81]=[CH:80][NH:79][N:78]=4)=[O:76])[CH:69]=3)=[O:65])=[N:58][C:57]=2[S:56][CH:55]=1
Reactant: Cc1csc2nc(C(=O)NCc3cccc(NC(=O)c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c12
Agent: N#Cc1ccc2nc(C(=O)NCc3cccc(NC(=O)CCc4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c2c1
Product: Cc1csc2nc(C(=O)NCc3cccc(NC(=O)c4nc[nH]n4)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Step 2 of Example 32 and using, instead of 6-cyano-4-oxo-N-{[3-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propanoyl}amino)phenyl]methyl}-3,4-dihydroquinazoline-2-carboxamide, 5-methyl-4-oxo-N-{[3-({[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]carbonyl}amino)phenyl]methyl}-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxamide, the title compound was obtained as a white powder (339 mg, 99%).
Reaction SMILES: [S:1]1[C:5]2[C:6](=O)[C:7]3[N:8]([CH:9]=[CH:10][CH:11]=3)[C:4]=2[CH:3]=[CH:2]1.Cl.[NH2:14][OH:15]>N1C=CC=CC=1>[OH:15][N:14]=[C:6]1[C:5]2[S:1][CH:2]=[CH:3][C:4]=2[N:8]2[CH:9]=[CH:10][CH:11]=[C:7]12
Reactant: O=C1c2sccc2-n2cccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1c2sccc2-n2cccc21
Yield: 82.8 %

Procedure:
Heat at reflux for 90 minutes a solution of 0.011 mol of 8H-thieno[2,3-d]pyrrolo[1,2-a]pyrrol-8-one (Preparation 28) and 0.0132 mol of hydroxylamine hydrochloride in 50 ml of pyridine. After cooling and after removal of the pyridine under reduced pressure, the residue is taken up in 150 ml of water and extracted with diethyl ether. The ethereal solution is dried over magnesium sulfate and then concentrated under reduced pressure to yield the title compound in the form of a mixture comprising 70% of the Z form, 30% of the E form.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[O:22]=[C:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][CH:33]=[O:34])[CH:29]=2)[NH:24]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][CH:33]=[O:34])[CH:29]=2)[NH:24][C:23]1=[O:22]
Reactant: O=CNc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ccc(NC=O)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 78.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-formamide as starting materials to give N-{3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-formamide (34 mg, 78.7%) as a red solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:27])[NH:10][C@@H:11]([CH2:21][C:22]2[N:23]=[CH:24][S:25][CH:26]=2)[C:12](=[O:20])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[O:20]=[C:12]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@@H:11]([NH:10][C:9]([C@H:8]1[O:7][C@@H:6]1[C:4]([OH:5])=[O:3])=[O:27])[CH2:21][C:22]1[N:23]=[CH:24][S:25][CH:26]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)Nc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(Nc1ccccc1)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)O
Yield: 44.5 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 19a (112 mg, 0.28 mmol); LiOH (6.9 mg, 0.29 mmol); THF/MeOH/H2O (2.5 mL: 1.0 mL: 1.0 mL); yielded 32 as a white solid (45 mg, 43.3%). 1H NMR (MeOD-d4, 400 MHz): δ 8.97 (s, 1H); 7.52-7.50 (d, 2H); 7.32 (s, 1H); 7.30-7.26 (t, 3H); 4.94-4.92 (t, 1H): 3.62 (s, 1H); 3.52-3.45 (q, 2H); 3.43 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): 172.48, 169.65, 168.87, 153.83, 152.41, 138.16, 128.33, 124.04, 120.73, 115.89, 54.49, 53.60, 52.89 32.87. ESI-HRMS (m/z): [M+H+] calcd. for C16H15N3O5S: 360.0660, observed: 360.0673; HPLC method 2: Rt=16.4 min; Purity: 95.2%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C[CH2:15][N:16]=[C:17]=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CNC>C1COCC1>[CH3:15][N:16]([CH3:17])[C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)=[O:13]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cc(Br)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-bromo-1H-indole-2-carboxylic acid (2.40 g, 10.0 mmol) in THF (100 mL) were added EDCl (2.11 g, 30.0 mmol), HOBt (1.49 g, 11.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Then, a solution of N,N-dimethyl amine (2.0 M solution in THF, 15 mL, 30.0 mmol) was added. The mixture was stirred for 16 hours at room temperature. Solvent was evaporated, the residue was taken in ethyl acetate (200 mL), and water (200 mL) was added. The organic phase was separated; the aqueous phase was extracted with ethyl acetate (200 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous sodium sulfate. Solvent was evaporated and dried under vacuum to give 5-bromo-1H-indole-2-carboxylic acid dimethylamide as an off-white solid. Yield: 2.56 g (96%).
Reaction SMILES: [CH:1]1([N:4]([CH3:11])[CH2:5]/[CH:6]=[CH:7]/[C:8](O)=[O:9])[CH2:3][CH2:2]1.CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[CH:1]1([N:4]([CH3:11])[CH2:5]/[CH:6]=[CH:7]/[C:8]([Cl:20])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C/C=C/C(=O)O)C1CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C/C=C/C(=O)Cl)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (E)-4-(cyclopropyl(methyl)amino)but-2-enoic acid (2.00 g, 12.9 mmol) in DCM (60 mL) was added DMF (0.2 mL) and oxalyl chloride (4.42 mL, 51.6 mmol). The mixture was stirred at RT for 4 h and concentrated in vacuo to dryness to afford (E)-4-(cyclopropyl(methyl)amino)but-2-enoyl chloride. In a similar manner as described in Example 70, (R,E)-3-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide (85) was prepared using (E)-4-(cyclopropyl(methyl)amino)but-2-enoyl chloride. MS found for C27H35N9O4 as (M+H)+ 550.2, (M−H)− 548.3. UV: λ=248 nm.
Reaction SMILES: C(Cl)(=O)OC.C(N(CC)CC)C.[CH2:13]([C:15]1[C:20]([O:21]C(OC)=O)=[CH:19][C:18]([O:26]C(OC)=O)=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)[C:16]=1[CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])[CH3:14].[BH4-].[Na+].N>CO.O1CCCC1.O>[CH2:13]([C:15]1[C:20]([OH:21])=[CH:19][C:18]([OH:26])=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)[C:16]=1[CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])[CH3:14]
Reactant: CCc1c(OC(=O)OC)cc(OC(=O)OC)c(-c2cccc(O)c2)c1CCOCCOC
Agent: COC(=O)Cl
Agent: N
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(O)cc(O)c(-c2cccc(O)c2)c1CCOCCOC
Yield: 24 %

Procedure:
In the same manner as in Example 118, 1-{3-(3-hydroxyphenyl)-2-[2-(2-methoxyethoxy)ethyl]-4,6-bis(methoxycarbonyloxy)phenyl]ethanone was obtained from Compound 165 (320 mg, 0.92 mmol) obtained in Example 165, using methyl chlorocarbonate (0.2 mL, 2.6 mmol), triethylamine (0.4 mL, 2.9 mmol) and tetrahydrofuran (10 mL); and from the resulting compound, obtained was 4-ethyl-2-(3-hydroxyphenyl)-3-[2-(2-methoxyethoxy)ethyl]-1,5-bis(methoxycarbonyloxy)benzene, using sodium borohydride (210 mg, 5.5 mmol), water (3.0 mL) and tetrahydrofuran (5.0 mL). Then, the resulting compound was treated with methanol solution (5.0 mL) of 7 mmol/L ammonia to obtain Compound 166 (72 mg, 24%).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:8][C:9]1[CH:10]=[C:11]([CH:17]2[C:21]3[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=3[O:19][C:18]2=[O:34])[CH:12]=[C:13]([CH3:16])[C:14]=1[OH:15].CS(O)(=O)=O>C1(C)C(C)=CC=CC=1>[CH3:8][C:9]1[CH:10]=[C:11]([CH:17]2[C:21]3[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:27])([CH3:28])[CH3:29])[C:20]=3[O:19][C:18]2=[O:34])[CH:12]=[C:13]([CH3:16])[C:14]=1[O:15][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc(C)c1O
Reactant: CC(C)(C)C(=O)Cl
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: Cc1cc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc(C)c1OC(=O)C(C)(C)C
Yield: 92.3 %

Procedure:
180.1 g (1.49 mol) of pivaloyl chloride are added dropwise over a period of 25 minutes to a suspension of 274.5 g (0.75 mol) of 3-(3,5-dimethyl-4-hydroxyphenyl)-5,7-di-tert-butylbenzofuran-2-one, (compound (107), Table 1, Example 2) in 600 ml of xylene and 7.5 ml (115.7 mmol) of methanesulfonic acid which is stirred at 95° C. under a nitrogen atmosphere. The clear, homogeneous reaction mixture is then refluxed for another 2.5 hours and then concentrated under a slight vacuum. 50 ml of 1-butanol and 600 ml of methanol are carefully poured into the liquid, hot residue at about 170° C. through the condenser and the mixture is cooled with ice/water. The precipitated product is filtered and washed with 350 ml of cold methanol. Drying gives 311.9 g (92%) of 3-(3,5-dimethyl-4-pivaloyloxyphenyl)-5,7-di-tert-butylbenzofuran-2-one, melting point 140°-142° C. (compound (110 ), Table 1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:18]O>>[Br:1][C:2]1[C:3]([C:10]([O:12][CH3:18])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CO
Reactant: CSc1ncc(Br)c(C(=O)O)n1
Agent: O=S(=O)(O)O
Product: COC(=O)c1nc(SC)ncc1Br
Reaction time: 24 h
Yield: 80 %

Procedure:
A solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (7.64 g, 30.7 mmol) in MeOH (60 mL) was treated with sulfuric acid (2 mL) and boiled for 24 hours. The mixture was poured onto ice water and extracted with DCM. The DCM phase was washed with saturated aqueous sodium hydrogen carbonate solution, dried and evaporated to give the title compound (6.42 g, 80%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][OH:12].[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.O>[C:20]([O:19][C:17](=[O:18])[CH2:16][O:12][CH2:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[C:7]([CH3:8])[C:2]=1[Br:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc(C)c(Br)c(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)c(Br)c(COCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of (2-bromo-5-methoxy-3-methyl-phenyl)-methanol ((Example 192: step c) 0.800 g, 3.46 mmol) in DMF (10 mL) was cooled to 0° C. and treated with NaH (0.100 g of 95% dispersion, 4.15 mmol) and allowed to warm to room temperature 30 min. The mixture was then treated with tert-butyl bromoacetate (0.614 mL, 4.15 mmol) and stirred at room temperature 1 h. The reaction was diluted with water and extracted with EtOAc (2×125 mL). The combined organic layers were washed well with water (3×300 mL), dried over MgSO4, and concentrated in vacuo to afford the product (2-bromo-5-methoxy-3-methyl-benzyloxy)-acetic acid tert-butyl ester (1.19 g, 98%) as a yellow oil. 1H NMR (CDCl3): δ 6.967 (d, 1H, J=2.8 Hz), 6.745 (d, 1H, J=3.2 Hz), 4.683 (s, 2H), 4.086 (s, 2H), 3.794 (s, 3H), 2.380 (s, 3H), 1.496 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)=[O:28])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: Nc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)Nc3cccnc3)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 3-aminopyridine (152 mg, 1.62 mmol), triethylamine (0.451 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective product as a solid material.