Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[Br:19]N1C(C)(C)C(=O)N(Br)C1=O.[OH-].[Na+]>ClCCl>[Br:19][C:8]1[CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Temperature: 35 °C
Yield: 89.6 %

Procedure:
To a solution of 1-nitro-3-trifluoromethyl-benzene (41.1 mL, 300 mmol, 97%, purchased from Aldrich) in dichloromethane (240 mL) is added 98% sulfuric acid (45.7 mL, 840 mmol) over 10 minutes. The vigorously stirred resulting biphasic mixture is warmed to 35° C. and 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (53.1 g in total, 180 mmol) is added in six equal portions over five hours. The mixture is stirred at 35° C. for additional 19 hours. Thereafter, more than 97% of the starting material is converted according to HPLC analysis. The reaction mixture is allowed to cool to room temperature and added over 20 minutes to a stirred 2 M aqueous NaOH solution (210 mL) of 0-5° C. while cooling with an ice-water bath. The internal temperature rises temporarily to about 35° C. The two layers are separated. The aqueous layer is extracted with hexane (3×200 mL). The combined organic layers are washed with water (200 mL), 5% aqueous sodium metabisulfite solution (2×200 mL), 8% aqueous NaHCO3 solution (200 mL) and 10% aqueous NaCl solution (200 mL) and, thereafter, the solvents are evaporated at reduced pressure and 45° C. The obtained liquid is distilled at 0.71 mbar and a bath temperature of 70-80° C. to give 1-bromo-3-nitro-5-trifluoromethyl-benzene as a pale yellow liquid. Yield: 89.6% (1H-NMR purity: about 95%). 1H-NMR (400 MHz, CDCl3): 8.11 ppm (m, 1H), 8.45 ppm (m, 1H), 8.58-8.59 ppm (m, 1H). Boiling point: approximately 68° C. at 0.71 mbar.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:4])=[O:3].CI.[C:21](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:21][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(N(C)S(C)(=O)=O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
A mixture of methyl 3-[(methylsulfonyl)amino]-5-nitrobenzoate obtained in Reference Example 88.22 g (30 mmol), methyl iodide 2.0 mL (32 mmol), potassium carbonate 10.4 g (75 mmol) and acetone (250 mL) was stirred at room temperature for 16 hours. The mixture was filtered to remove the precipitates and the solvent was evaporated. To the residue was added water (150 mL) and the mixture was extracted twice with ethyl acetate (100 mL). After drying of the mixture on magnesium sulfate, the solvent was evaporated to give 8.55 g (29.7 mmol) of the title compound (yield: 99%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][C:32]1[CH:31]=[C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:37])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:35]=[CH:34][N:33]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(-n4cccc4)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)ccn1
Yield: 62.3 %

Procedure:
Prepared from (2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-pyrrol-1-yl-phenyl)-carbamic acid tert-butyl ester (Example M99) (0.46 g, 0.90 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light orange solid (220 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4](SC2C=CC=CC=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35]([OH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(Sc3ccccc3)c2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(OCc3ccccc3)c2C#N)cc1
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
58 mg (0.15 mmol) of N-{4-[2-amino-3,5-dicyano-6-(phenylsulfanyl)-4-pyridinyl]phenyl}acetamide [prepared analogously to Kambe et al., Synthesis, 531-533 (1981)] are, together with 41 mg (0.3 mmol) of potassium carbonate, dissolved/suspended in 1.88 g (=1.8 ml, 17.4 mmol) of benzyl alcohol, and the mixture is stirred at 100° C. for 3.5 h. The benzyl alcohol is evaporated under reduced pressure and the evaporation residue is purified by preparative HPLC on reversed-phase silica gel (gradient: water/acetonitrile 90:1010:90 in 38 minutes).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:28]=[CH:27][C:12]2[NH:13][C:14](=[O:26])[O:15][C:16]([C:21]#[C:22][CH:23]3[CH2:25][CH2:24]3)([C:17]([F:20])([F:19])[F:18])[C:11]=2[CH:10]=1)C.[OH-].[Li+]>CO.O>[CH:23]1([C:22]#[C:21][C:16]2([C:17]([F:20])([F:19])[F:18])[O:15][C:14](=[O:26])[NH:13][C:12]3[CH:27]=[CH:28][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3])=[CH:10][C:11]2=3)[CH2:25][CH2:24]1
Reactant: CCOC(=O)CCCOc1ccc2c(c1)C(C#CC1CC1)(C(F)(F)F)OC(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCOc1ccc2c(c1)C(C#CC1CC1)(C(F)(F)F)OC(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a suspension of 45 mg (0.11 mmol) of 10 in 4 mL of 50% methanol in water was added 60 mg (2.5 mmol) of lithium hydroxide. The reaction mixture was allowed to stir at room temperature for 1 hour and concentrated under reduced pressure. To the residue 20 mL of water were added followed by 1 mL of 1N HCl. The reaction mixture was extracted with 4×30 mL of ethyl acetate. The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (silica gel, 2 mm thickness, E. Merck) using 5% methanol in dichloromethane to give 35 mg (0.091 mmol, 83%) of 11.
Reaction SMILES: [Na].[CH3:2][C:3]1[O:4][C:5](=O)[C:6](=[CH:8][OH:9])[N:7]=1.Cl.[CH3:12][O:13][C:14](=[NH:16])[NH2:15]>C(#N)C>[CH3:12][O:13][C:14]1[NH:16][C:8](=[O:9])[C:6]([NH:7][C:3](=[O:4])[CH3:2])=[CH:5][N:15]=1
Reactant: CC1=NC(=CO)C(=O)O1
Reactant: COC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC#N
Product: COc1ncc(NC(C)=O)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 48 h
Yield: 74.1 %

Procedure:
Acetonitrile (20 ml) was added to 2-methyl-4-hydroxymethylene-5-oxazolone sodium salt (1.00 g, 6.71 mmol) and O-methylisourea hydrochloride (0.74 g, 6.71 mmol), and the mixture was stirred at 80° C. for 2 days. The mixture was concentrated, and methanol (5 ml) and water (3 ml) were added. The mixture was stirred at room temperature for 1 hour. Then, the precipitate was collected by filtration and vacuum dried to give 2-methoxy-6-oxo-5-acetylamino-1,6-dihydropyrimidine (0.91 g, 4.97 mmol).
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=O.[NH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[OH:21]>C1COCC1>[Br:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[OH:21])=[O:5]
Reactant: Nc1cc(OCc2ccccc2)ccc1O
Reactant: O=C(O)CBr
Solvent: C1CCOC1
Product: O=C(CBr)Nc1cc(OCc2ccccc2)ccc1O
Yield: 50 %

Procedure:
Bromoacetic acid (13.9 g, 0.01 mole) and dicyclohexyldicarbodiimide (DCCD, 20.6 g, 0.01 mole) were added at room temperature under stirring to the amine (b), 21.5 g, 0.01 mole) in THF (200 ml). After 1 hour the reaction mixture was filtered and the liquid evaporated to dryness under vacuum. The residue was crystallized from acetic acid (50 ml) to give the bromoamide ((c), 17 g, 50%) as white prisms. The product strusture was confirmed by NMR analysis.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[S:11])[CH:6]=[CH:7][CH:8]=1.Br.Br[CH2:16][CH2:17][NH2:18].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl>O>[F:13][C:2]([F:12])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:18]2[CH2:17][CH2:16][S:11][C:10]2=[N:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=2)=[S:11])[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Reactant: NCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(F)(F)c1cccc(N=C2SCCN2C(=S)Nc2cccc(C(F)(F)F)c2)c1

Procedure:
A mixture of 6.1 g. of m-trifluoromethylphenyl isothiocyanate, 6.8 g. of 2-bromoethylamine hydrobromide, 3.5 g. of sodium carbonate, and about 100 ml. of chloroform was stirred at ambient temperature for about 14 hours. To the reaction mixture was added about 50 ml. of water. The aqueous phase was washed with chloroform which was added to the organic phase. The organic phase then was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtering, the solvent was removed under reduced pressure. The residue was recrystallized from petroleum ether to give N-(3-trifluoromethylphenyl)-2-(3-trifluoromethylphenylimino)-3-thiazolidinecarbothioamide, m.p. 116°-7°.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[NH2:20].N1C=CC=CC=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[NH:20][C:30]([CH:27]1[CH2:29][CH2:28]1)=[O:31]
Reactant: Cc1ccc(F)cc1-c1ccc2c(Br)c(N)ncc2c1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1-c1ccc2c(Br)c(NC(=O)C3CC3)ncc2c1

Procedure:
To 4-bromo-7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (46 mg, 140 μmol) and pyridine (110 μl, 1.4 mmol) in dichloromethane (3.0 mL) at ambient temperature was added dropwise cyclopropanecarbonyl chloride (60 μl, 0.66 mmol). After 1 h the mixture was poured into saturated aqueous sodium bicarbonate, extracted twice into dichloromethane and the combined organic phases dried over sodium sulfate, filtered and concentrated in vacuo to afford a residue that was purified by reverse phase HPLC (gradient of acetonitrile in water with 0.1% formic acid) to yield the title compound as a white amorphous solid (57 mg, quant.). 1H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 9.26 (s, 1H), 8.27-8.14 (m, 2H), 7.97 (d, J=8.6 Hz, 1H), 7.49-7.33 (m, 1H), 7.21 (t, J=9.2 Hz, 2H), 2.25 (s, 3H), 1.98-1.84 (m, 1H), 0.90-0.78 (m, 4H). LCMS (Method E): RT 5.299 min, M+H+=399.0 & 401.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18](=[O:25])[NH:17]1>>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([O:25][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=3)[O:11][C:2]([CH3:1])([CH3:15])[CH:3]2[OH:14])=[N:17]1
Reactant: O=c1[nH]sc2ccccc12
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)Oc2ccc(C#N)cc2C(Oc2nsc3ccccc23)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and benzo[d]isothiazol-3-one as starting material, the title compound was prepared as a white solid.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1)([CH3:5])([CH3:4])[CH3:3].[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O>[F:31][C:19]([F:18])([F:30])[C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:16][C@@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:7]([O:6][C:2]([CH3:3])([CH3:5])[CH3:4])=[O:17])=[CH:13][CH:12]=2)[CH3:15])(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: C[C@@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](NS(=O)(=O)c1ccc(C(F)(F)F)cc1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a vial containing tert-butyl-4-[(1R)-1-aminoethyl]benzoate hydrochloride from Step 1 was added N,N-dimethylaminopyridine (3.91 mg, 0.032 mmol), 4-(trifluoromethyl)benzenesulfonyl chloride (0.059 g, 0.24 mmol), N,N-dimethylformamide (2 mL), and triethylamine (0.18 mL, 1.28 mmol). The mixture was stirred at rt for 16 h, after which the solvent was fully evaporated. To the residue was added 1,2-dichloroethane (3 mL), sat. NaHCO3 solution (0.5 mL), and water (0.5 mL). After separation, the aqueous layer was extracted with 1,2-dichloroethane (2×3 mL). The combined organic phases were evaporated to dryness to give (R)-tert-butyl 4-(1-(4-(trifluoromethyl)phenylsulfonamido)ethyl)benzoate as a brown solid. LC-MS: (FA) ES+ 430.
Reaction SMILES: [OH-].[Na+].[C:3](#[N:6])[CH:4]=[CH2:5].[CH2:7]([OH:10])[CH2:8][OH:9]>>[CH2:8]([CH2:7][O:10][CH2:5][CH2:4][C:3]#[N:6])[O:9][CH2:5][CH2:4][C:3]#[N:6]
Reactant: C=CC#N
Reactant: OCCO
Agent: [Na+]
Agent: [OH-]
Product: N#CCCOCCOCCC#N

Procedure:
To a 2000 ml. flask fitted with a stirrer, reflux condensor and an additional funnel and immersed in an ice water bath was added 248 g. of ethylene glycol and 20 g. of 40% aqueous NaOH. The stirrer was started and the 424 g. of acrylonitrile was added from the funnel over a period of about 15 minutes. The temperature remained in the range of 25°-35° C. during the addition of the acrylonitrile. The stirring was continued for one additional hour after which 170 g. of the reaction mixture was withdrawn from the flask and neutralized by contacting with 70 g. of a sulfonic acid resin. The withdrawn mixture contained more than 95 wt. % of 3,3'-ethylenedioxy-bis(propionitrile), and essentially no acrylonitrile. This run was performed with gradual addition of acrylonitrile to produce the 3,3'-ethylenedioxy-bis(propionitrile) for use in the subsequent run with rapid addition of acrylonitrile.
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5]([C:7]1[N:16]=[C:15]2[N:9]([CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([Cl:21])[N:18]=[CH:17][C:14]=32)[CH:8]=1)=O.Cl.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH:32]N>C(O)(=O)C>[Cl:21][C:19]1[N:18]=[CH:17][C:14]2[C:15]3[N:9]([CH2:10][CH2:11][O:12][C:13]=2[CH:20]=1)[CH:8]=[C:7]([C:5]1[N:32]([C:26]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=2[F:24])[N:2]=[CH:3][N:4]=1)[N:16]=3
Reactant: NNc1ccc(F)cc1F
Reactant: CN(C)C=NC(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Agent: Cl
Solvent: CC(=O)O
Product: Fc1ccc(-n2ncnc2-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)c(F)c1
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 77.8 %

Procedure:
8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylic acid 1-dimethylamino-methylideneamide (0.00907 mol) was dissolved in Acetic acid (36 mL). 2,4-Difluorophenylhydrazine hydrochloride (1.965 g, 0.01088 mol) was added and the reaction was stirred at 95° C. for 2.5 hours. The AcOH was removed in vacuo. The crude was triturated in iPrOH to afford 2.828 g (78% yield over 2 steps) of 8-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene as a light brown powder clean by 1H NMR. MS(ESI+) 401.1
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][N:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][N:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ncc(C)s2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)s1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[5,6-dihydro-5,5-dimethyl-8-(5-methylthiazol-2-yl)-2-naphthalenyl]ethynylbenzoate (Compound 15) (100 mg, 0.23 mmol) and 4 ml of EtOH at room temperature was added aqueous NaOH (1 ml, 1 M, 1 mmol). The resulting solution was warmed to 50° C. for 1 hour and concentrated in vacuo. The residue was suspended in a solution of CH2Cl2 and ether (5:1) and acidified to pH 5 with 1M aqueous HCl. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered and the solvents removed under reduced pressure to give the title compound as a white solid. 1H NMR (d6-DMSO): δ 7.96 (1H, d, J=1.7 Hz), 7.95 (2H, d, J=8.0 Hz), 7.65 (2H, d, J=8.0 Hz), 7.64 (1H, s), 7.53 (1H, dd, J=1.7, 8.0 Hz), 7.46 (1H, d, J=8.0 Hz), 6.59 (1H, t, J=4.5 Hz), 2.50 (3H, s), 2.39 (2H, d, J=4.5 Hz), 1.27 (6H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[C:15]=2[F:33])[C:11]([NH2:13])=[S:12])=[CH:5][CH:4]=1)#[N:2].F[B-](F)(F)F.[C:39](=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[CH3:39][S:12][C:11](=[NH:13])[CH:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:32])[CH3:31])[CH:24]([CH3:26])[CH3:25])[C:15]=1[F:33]
Reactant: O=C([O-])O
Reactant: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(Nc2ccc(C#N)cc2)C(N)=S)c1
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(Nc2ccc(C#N)cc2)C(=N)SC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 57.96 g of 2-(4-cyanophenylamino)-2-(2-fluoro-5-methoxy-3-triisopropylsilanyloxyphenyl)thioacetamide in 200 ml of acetonitrile there was added 18.5 g of Me3O+BF4−, and the mixture was stirred at room temperature for 3 hours. After adding 2.1 g of Me3O+BF4− to the reaction mixture, it was further stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. After washing the organic layer with saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-(4-cyanophenylamino)-2-(2-fluoro-5-methoxy-3-triisopropylsilanyloxyphenyl)thioacetimidic acid methyl ester (crude product).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]([NH:15][C:16]2([S:22][CH3:23])[CH:19]([CH3:20])[NH:18][C:17]2=[O:21])=[O:14])=[O:10])[C:5](=[O:30])[C:4]1=[O:31])[CH3:2].C(OO)(=[O:34])C>O1CCOCC1.C(O)(=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:13]([NH:15][C:16]2([S:22]([CH3:23])=[O:34])[CH:19]([CH3:20])[NH:18][C:17]2=[O:21])=[O:14])=[O:10])[C:5](=[O:30])[C:4]1=[O:31])[CH3:2]
Reactant: CC(=O)OO
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2(SC)C(=O)NC2C)c2ccccc2)C(=O)C1=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCN1CCN(C(=O)NC(C(=O)NC2(S(C)=O)C(=O)NC2C)c2ccccc2)C(=O)C1=O

Procedure:
The azetidinone (60) (250 mg) in dry dioxan (10 ml) was treated with a (5.07% w/v) solution of peracetic acid in acetic acid (0.69 ml) for 1.5 hour. The solvent was then evaporated in vacuo, the complete removal of acidic residues being ensured. Silica gel chromatography of the residue gave the title compound as a pale-white solid (149 mg), νmax. (Nujol) 3300, 1760, 1710, and 1670 cm-1, δ[(CD3)2SO] 0.65, 0.93, 1.16 and 1.19 (each d, J 6.5 Hz, together 3H), 1.07 (t, J 7 Hz, 3H), 1.99, 2.14, 2.39, 2.64 and 2.68 (each s, together 3H), 3.37 (q, J 7 Hz, 2H), 3.47-3.52 (m, 2H), 3.79-3.92 (m, 2H), 3.92-4.10 (complex m, together 1H), [5.45-5.60 (complex m) and 5.86 (d, J 7 Hz), together 1H], 7.27-7.55 (m, 5H), 8.63 and 8.74 br (each s, together 1H, exch), 9.14 and 9.35 br (each s, together 1H, exch.), and 9.65-10.00 (complex m, together 1H, exch).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>N1C=CC=CC=1>[S:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)([CH3:25])(=[O:24])=[O:23]
Reactant: Nc1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Temperature: 0 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
To a stirred solution of 5-amino-3-[(7-azaindol-3-yl) methylene]-2-oxindole (2.773 g, 10 mmol) in pyridine (10 ml) was added gradually mesylchloride (1.146 g, 10 mmol) at 0°-5° C. under cooling. The reaction mixture was stirred for about 5 h at 0°-5° C. and then for 15 h at room temperature. The mixture was poured onto an ice-water mixture, the precipitate filtered off, the residue washed thoroughly with water and then chromatographed on silica gel using CHCl3 --MeOH mixtures as eluant. Thus pure title compound was obtained in about 70% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:22])[C:5]([C:8]2([F:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cl-].[Li+].[CH:25]([Mg]Cl)([CH3:27])[CH3:26].C(Br)C=C>C1COCC1.[Cu]I>[CH2:27]([C:2]1[CH:3]=[C:4]([F:22])[C:5]([C:8]2([F:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)[CH:25]=[CH2:26]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(Br)cc2F)CC1
Reactant: CC(C)[Mg]Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCc1cnc(C2(F)CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
In a dry 3-necked flask flushed with argon containing a solution of 23 (3.77 g, 10.0 mmol) in THF (50 mL) at 0° C. was added isopropyl magnesium chloride lithium chloride complex (1.3 M in THF, 10 mL, 13 mmol) over 10 min. After additional 10 min of stirring at 0° C., CuI (0.2 eq, 0.38 g) was added, the mixture was stirred for 10 minutes at 0° C. and then a solution of allyl bromide (1.73 mL, 20 mmol) in THF (4.0 mL) was added at 0° C. over 10 min. After further stirring for 1 h at 0° C., the reaction was quenched with 10% citric acid and extracted with ethyl acetate (100 mL×2). The organic layers were combined which was washed with brine, dried over Na2SO4, and concentrated. The obtained residue was chromatographed on silica gel eluted with EtOAc/hexane (0-10%) to afford 2.84 g (84%) of 24 as a colorless oil. NMR (CDCl3) δ 1.48 (9 H, s), 2.21 (4 H, m), 3.28 (2 H, m), 3.41 (2 H, d, J=6.16 Hz), 4.05 (2 H, m), 5.92 (1 H, m), 7.26 (1 H, dd, J=1.56, 12.08 Hz); LC/MS (M+1) 339.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].[CH3:29][C:30]([OH:34])([CH:32]=[CH2:33])[CH3:31]>>[OH:34][C:30]([CH3:31])([CH3:29])[CH:32]=[CH:33][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Reactant: C=CC(C)(C)O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C=CC(C)(C)O)c(Cc3ccccc3C(F)(F)F)sc21

Procedure:
Prepared using 5-bromo-3-methyl-1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione and 2-methyl-3-buten-2-ol. The crude product was purified by flash silica chromatography eluting with a gradient of 0-2% ethanol in dichloromethane to give the title compound as a cream foam (0.20 g).