Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:15](=[O:18])([O-])[O-].[K+].[K+].O>CS(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][C@H:8]2[CH2:7][CH2:5][NH:6][C:15]2=[O:18])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)/C(=N\O[C@H]1CCNC1=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.07 g of ethyl (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate are dissolved in 5 ml of dimethylsulfoxide, and one g of potassium carbonate and 1.53 g of (R)-3-(p-tosyloxy)-2-pyrrolidone are added thereto. The mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the aqueous mixture is extracted with chloroform. The extract is washed with water, dried and then concentrated under reduced pressure to dryness. The residue is crystallized with isopropyl ether, and the crystals are recrystallized from aqueous methanol. 0.86 g of ethyl (Z)-2-(2-aminothiazol-4-yl)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]acetate is obtained. The physico-chemical properties of this product are identical with those of the product obtained in Example 1-(2).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:16])=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1>C(O)(=O)CC>[F:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:16])=[C:11]([N+:1]([O-:4])=[O:2])[CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: Oc1ccnc2cc(F)ccc12
Reactant: O=[N+]([O-])O
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2cc(F)ccc2c1O
Temperature: 125 °C
Reaction time: 1.5 h

Procedure:
Nitric acid (20 mL of 70%) was added to a hot (125° C.) solution of 7-fluoro-4-quinolinol (35 g, 214 mmol) in propionic acid (200 mL). The reaction mixture was stirred at 125° C. for about 1.5 hours and then allowed to cool to ambient temperature. The resulting yellow precipitate was isolated by filtration, rinsed with water and then with ethanol, and then recrystallized from N,N-dimethylformamide/water to provide 18 g of 7-fluoro-3-nitro-4-quinolinol.
Reaction SMILES: C(O[C@H]1C2C(=CC(OC)=CC=2)[C@H](N)C1)C=C.FC1C=C(C[C@H](NC(=O)OCC2C=CC=CC=2)[C@H]2CO2)C=C(F)C=1.[CH2:41]([O:44][C@@H:45]1[C:53]2[C:48](=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2)[C@@H:47]([NH:56][CH2:57][C@@H:58]([OH:80])[C@@H:59]([NH:69]C(=O)OCC2C=CC=CC=2)[CH2:60][C:61]2[CH:66]=[C:65]([F:67])[CH:64]=[C:63]([F:68])[CH:62]=2)[CH2:46]1)[CH:42]=[CH2:43].C(O[C@H]1C2C(=CC(OC)=CC=2)[C@H](NC[C@@H](O)[C@@H](NC(=O)OCC2C=CC=CC=2)CC2C=C(F)C=C(F)C=2)C1)C=C>>[CH2:41]([O:44][C@H:45]1[C:53]2[C:48](=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2)[C@H:47]([NH:56][CH2:57][C@@H:58]([OH:80])[C@@H:59]([NH2:69])[CH2:60][C:61]2[CH:62]=[C:63]([F:68])[CH:64]=[C:65]([F:67])[CH:66]=2)[CH2:46]1)[CH:42]=[CH2:43]
Reactant: C=CCO[C@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OCc2ccccc2)c2cc(OC)ccc21
Agent: C=CCO[C@@H]1C[C@@H](N)c2cc(OC)ccc21
Agent: C=CCO[C@@H]1C[C@@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OCc2ccccc2)c2cc(OC)ccc21
Agent: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Product: C=CCO[C@@H]1C[C@@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(OC)ccc21
Yield: 69 %

Procedure:
Step X (3): trans-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-amine from Step X (2) was reacted with benzyl (S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethylcarbamate according to the conditions described in Step V (1). The crude product was purified using silica gel column chromatography to provide 900 mg (69% yield) of a mixture of benzyl (2S,3R)-4-((1S,3S)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate and benzyl (2S,3R)-4-((1R,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate. LRMS (M+H)+=553.3; 1H NMR (500 MHz, CDCl3) δ ppm 1.87-2.05 (m, 1H) 2.38-2.50 (m, 1H) 2.69-2.92 (m, 3H) 2.96-3.12 (m, 1H) 3.41-3.51 (m, 1H) 3.72-3.91 (m, 4H) 4.01 (t, J=5.49 Hz, 2H) 4.37-4.47 (m, 1H) 4.80 (d, J=9.16 Hz, 1H) 4.92 (dd, J=15.26, 4.58 Hz, 1H) 4.97-5.08 (m, 2H) 5.17 (d, J=10.38 Hz, 1H) 5.23-5.33 (m, 1H) 5.84-5.99 (m, 1H) 6.60-6.68 (m, 1H) 6.74 (d, J=6.41 Hz, 2H) 6.82 (dd, J=8.24, 1.83 Hz, 1H) 6.91 (s, 1H) 7.20-7.38 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH:5]([CH3:18])[C:6](/[N:8]=[C:9]1\[N:10]([NH2:17])[C:11]([CH3:16])=[CH:12][N:13]=[C:14]\1[CH3:15])=O>C(O)(=O)C>[CH3:16][C:11]1[N:10]2[N:17]=[C:6]([CH:5]([CH3:18])[CH2:4][C:3]([O:2][CH3:1])=[O:19])[N:8]=[C:9]2[C:14]([CH3:15])=[N:13][CH:12]=1
Reactant: COC(=O)CC(C)C(=O)/N=c1/c(C)ncc(C)n1N
Solvent: CC(=O)O
Product: COC(=O)CC(C)c1nc2c(C)ncc(C)n2n1
Yield: 111.9 %

Procedure:
A solution of (Z)-methyl-4-(1-amino-3,6-dimethylpyrazin-2(1H)-ylideneamino)-3-methyl-4-oxobutanoate (1.10 g, 4.14 mmol) in acetic acid (15 mL) was stirred at 140° C. for 2 h in a microwave reactor. The solution was evaporated to give 1.15 g of the product as a brown solid. ESI MS: m/z 248 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:24])[C:15]2[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:14]=2[NH:13][C:12](=[O:23])[O:11]1>>[CH3:9][C:10]1([CH3:24])[O:11][C:12](=[O:23])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:2]3[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=3)=[CH:16][C:15]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#Cc1ccc(Br)s1
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)s3)cc21

Procedure:
5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile was prepared, according to the procedure of Example 5 using 5-bromo-2-thiophenecarbonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid, as an off-white solid: mp 264–266° C.; 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 7.97 (d, 1H, J=7.9 Hz), 7.60–7.66 (m, 3H), 6.96 (d, 1H, J=8.1 Hz), 1.65 (s, 6H); MS(APCI) m/z 285 (M+H)+, 302 (M+NH4)+. Anal. Calc. For C15H12N2O2S: C, 63.36; H, 4.25; N, 9.85. Found: C, 63.01; H, 4.36; N, 9.39.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[F:21][C:22]1([F:27])[CH2:26][CH2:25][NH:24][CH2:23]1.CC(C)([O-])C.[Na+].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]>[F:21][C:22]1([F:27])[CH2:26][CH2:25][N:24]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:23]1
Reactant: FC1(F)CCNC1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2N2CCC(F)(F)C2)C1
Yield: 29.8 %

Procedure:
A solution of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (328 mg, 1.04 mmol), 3,3-difluoropyrrolidine hydrochloride (150 mg, 1.04 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl(X-phos) m (39.8 mg, 0.0835 mmol), tris(dibenzylideneacetone)dipalladium(0) (19.0 mg, 0.0208 mmol) and sodium tert-butoxide (250 mg, 2.60 mmol) in toluene (10 ml) was stirred under an argon atmosphere at 100° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (110 mg, 29.8%) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([CH2:22][CH3:23])[C:15]3[N:16]([N:17]=[C:18]([CH:20]=O)[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:30]>CO.[Pd]>[NH2:30][CH2:20][C:18]1[N:19]=[C:15]2[N:14]([CH2:22][CH3:23])[C:13](=[O:24])[C:12]3[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:9]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[N:10][C:11]=3[N:16]2[N:17]=1
Reactant: N
Reactant: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(C=O)nc12
Agent: [Pd]
Solvent: CO
Product: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CN)nc12
Yield: 32.4 %

Procedure:
2 g of 6-benzyl-7-cyclopentyl-4-ethyl-2-formyl-imidazo[4.5-e]-s-triazolo[1.5-a]pyrimidin-5-one (for preparation see synthesis example II) are hydrogenated together with 1 g of ammonia in 30 ml of methanol on 0.2 g of 10% palladium on charcoal (5 bar, 20° C., 2.3 hours). For working up, the catalyst is filtered off and the solvent is distilled off in vacuo. The crude product is purified by chromatography on silica gel (dichloromethane:methanol 95:5) and yields 0.65 g of the title compound in the form of a colourless amorphous solid.
Reaction SMILES: S(Cl)(Cl)=O.C(OCCC(O)=O)C.C(OCCC(Cl)=O)C.[CH2:21]([O:23][CH2:24][CH2:25][C:26]([N:28]=[C:29]=[S:30])=[O:27])[CH3:22].[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[N:39]=[CH:38][CH:37]=[C:36]2[O:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[N:39]=[CH:38][CH:37]=[C:36]2[O:45][C:46]1[CH:47]=[CH:48][C:49]([NH:50][C:29]([NH:28][C:26](=[O:27])[CH2:25][CH2:24][O:23][CH2:21][CH3:22])=[S:30])=[CH:51][CH:52]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCOCCC(=O)N=C=S
Agent: CCOCCC(=O)Cl
Agent: CCOCCC(=O)O
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOCCC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-ethoxypropanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-ethoxypropanoyl isothiocyanate was prepared using the resultant 3-ethoxypropanoyl chloride as a starting compound according to the description of the literature. 3-Ethoxypropanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (55 mg, yield 72%).
Reaction SMILES: COC1C=CC(C[N:8]([C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:19][CH2:18][O:17][C:16]=3[CH:32]=2)(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:31][O:30][CH2:29][CH2:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:32]=[C:12]([S:9]([NH:8][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]1=2
Reactant: COCCOc1ccccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.1 %

Procedure:
To a solution of N-(4-methoxybenzyl)-4-(2-(2-methoxyethoxyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (300 mg, 0.529 mmol) in DCM (6 mL) was added TFA (3 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with DCM (2×10 mL). The organic layer was dried over sodium sulfate and concentrated reduced pressure to obtain the crude material (36% by LCMS) that was purified by prep purification to obtain 4-(2-(2-methoxyethoxyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (38 mg, 16.1%) as white solid. 1H NMR (400 MHz, DMSO) δ 12.49 (s, 1H), 7.38-7.25 (m, 2H), 7.25-7.13 (m, 2H), 7.14-6.95 (m, 3H), 6.75 (d, J=4.6 Hz, 1H), 6.22 (d, J=8.5 Hz, 1H), 4.28 (t, J=4.3 Hz, 2H), 4.07 (dd, J=5.6, 3.5 Hz, 2H), 3.62 (t, J=4.1 Hz, 2H), 3.47 (t, J=4.5 Hz, 2H), 3.10 (s, 3H); MS (ESI, positive ion) m/z: 448.09 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[CH:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]>CC(OC)(C)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C#Cc1ccc(Cl)cc1C(=O)OC
Agent: [Pd]
Solvent: COC(C)(C)C
Product: CCc1ccc(Cl)cc1C(=O)OC
Reaction time: 2.17 h
Yield: 93.7 %

Procedure:
To a solution of methyl 5-chloro-2-ethynylbenzoate (1.13 g, 5.8 mmol) in TBME (50 ml) was added Pd/C (10%) (50% water, 0.61 g, 0.29 mmol). The reaction mixture was stirred under a hydrogen atmosphere for 130 minutes. The mixture was filtered through Celite and the filter cake was washed with TBME. The filtrate was concentrated in-vacuo to give the title compound (1.08 g, 74%) as a pale brown oil. LC-MS 79%, m/z=198.9/200.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.85 (s, 1H) 7.40 (d, J=8.20 Hz, 1H) 7.22 (d, J=8.20 Hz, 1H) 3.91 (s, 3H) 2.95 (q, J=7.46 Hz, 2H) 1.22 (t, J=7.49 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[CH:12]1([CH2:15]Br)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH:12]1([CH2:15][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])[CH2:14][CH2:13]1
Reactant: BrCC1CC1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCC(F)(F)F)CC1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.7 %

Procedure:
0.4 g of 2-(3,3,3-trifluoropropyl)malononitrile and 0.5 g of cyclopropylmethyl bromide were dissolved in 5 ml of dimethyl sulfoxide and thereto was added 0.41 g of potassium carbonate. The mixture was stirred at room temperature for 5 hours. Then, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.34 g of 2-cyclopropylmethyl-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (18)).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Cl[CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22].O>CN(C)C=O>[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: Sc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)(CCl)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CSc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
Sodium hydride powder (0.86 g, 35.8 mmol) was added to a mixture of 4-(4-chlorophenoxy)thiophenol (3.55 g, 15 mmol) in N,N-dimethylformamide (12 mL) at 0° C. The mixture was warmed to room temperature over 5 minutes, stirred for an additional 20 minutes, and solid chloropivalic acid (1.64 g, 12.0 mmol) was added in one portion. This mixture was heated to 80° C. for 18 hours, cooled to room temperature, and water (1 mL) added. The residue was partitioned between methylene chloride (50 mL) and 2N hydrochloric acid (25 mL). The aqueous layer was separated and washed with additional methylene chloride (2×25 mL). The combined organic extracts were dried over magnesium sulfate, concentrated in vacuo. Chromatography over silica gel, and eluting with 5% methanol/methylene chloride, gave slightly impure 3-[4-(4-chlorophenoxy)phenylthio]-2,2-dimethyl propionic acid (4 g, 99%). This material was recrystallized from the minimum amount of diethyl ether/hexanes to afford analytically pure acid as a white solid (3.20 g, 80%). mp 84.4-84.9° C.; IR (KBr) 3433 (br), 1732 cm-1 ; 1HNMR (DMSO-d6) δ 1.19 (s, 6H), 3.14 (s, 2H), 6.97 (d, J=8.7 Hz, 2H), 7.01 (d, J=8.9, 2H), 7.40 (d, J=8.8 Hz, 2H), 12.36 (br s, 1H). EIMS(M+): 378. Anal. Calcd. for C17H17SO3Cl: C, 60.62; H, 5.09. Found: C, 60.31; H, 4.96.
Reaction SMILES: Br.C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14]C)[N:10]=[CH:9][NH:8][C:7]2=[O:16]>>[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[CH:9][NH:8][C:7]2=[O:16]
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Agent: Br
Product: O=c1[nH]cnc2cc(O)c(O)cc12
Temperature: 30 °C
Reaction time: 0.21 h
Yield: 98.6 %

Procedure:
Into a 2.0 Lt four necked round bottomed flask equipped with a mechanical stirrer, reflux condenser and thermometer socket are charged 48% (w/w) hydrobromic acid (1000 g) and 6,7-dimethoxy-4(3H)-quinazolinone (100 g). Slowly heated the reaction mass to reach 110° C. and maintained for 1 hour at the same temperature. Then raised mass temperature to reach reflux condition and refluxed for 12 hours. Monitored the completion of the reaction by TLC. Then cooled the reaction mass to 25-35° C. and filtered the mass. Transferred the wet cake into another 2.0 Lt round bottomed flask containing 1000 ml of DM water. Stirred for 10-15 minutes and adjusted the pH to 7.0-7.5, by adding aqueous ammonia solution. Filtered the resulting product and washed the cake with DM water and dried to get 85.2 g (98.62% by theory) of 6,7-dihydroxy-4(3H)-quinazolinone as off-white crystalline solid.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[NH:23][N:24]=[C:25]([CH3:26])[C:15]=3[N:14]=2)[CH:10]=[CH:11][CH:12]=1>C(Cl)Cl>[CH3:26][C:25]1[C:15]2[N:14]=[C:13]([C:9]3[CH:8]=[C:7]([OH:6])[CH:12]=[CH:11][CH:10]=3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]=2[NH:23][N:24]=1
Reactant: COc1cccc(-c2nc3c(C)n[nH]c3c3ccccc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1n[nH]c2c1nc(-c1cccc(O)c1)c1ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
380 μl of 1M boron tribromide solution in methylene chloride were added dropwise, at −78° C., to a solution of 55 mg of 5-(3-methoxyphenyl)-3-methyl-1H-pyrazolo[4,3-c]isoquinoline (3) in 3 ml of methylene chloride. The reaction solution was stirred at RT for 12 h, concentrated under reduced pressure and purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl[CH2:24][CH2:25][N:26]([CH2:34][CH2:35]Cl)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:24][CH2:25][N:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH2:35]1)=[O:22])[CH3:2]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OCC(CC)CC)cc1
Reactant: ClCCN(CCCl)Cc1ccccc1
Product: CCOC(=O)C1(S(=O)(=O)c2ccc(OCC(CC)CC)cc2)CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(2-ethyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester (6.4 g, 20 mnol) and bis-(2-chloro-ethyl)- benzyl amine (6.44 g, 24 mmol). Yield 8 g (82%); yellow oil; MS: 488 (M+H)+
Reaction SMILES: C([C@H]1CSC(=O)N1[C:14]([C@@H:16]([C@@H:29]([OH:46])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=2)=[CH:34][CH:33]=1)[CH2:17][N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]=[N:19]1)=[O:15])C1C=CC=CC=1.[OH:47]O.O.[OH-].[Li+]>O1CCCC1.O.O>[F:45][C:40]1[CH:39]=[C:38]([C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][C@@H:29]([OH:46])[C@H:16]([CH2:17][N:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[N:20]=[N:19]3)[C:14]([OH:15])=[O:47])=[CH:37][CH:36]=2)[CH:43]=[C:42]([F:44])[CH:41]=1
Reactant: O=C1SC[C@H](Cc2ccccc2)N1C(=O)[C@H](Cn1nnc2ccccc2c1=O)[C@@H](O)CCc1ccc(-c2cc(F)cc(F)c2)cc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H](Cn1nnc2ccccc2c1=O)[C@H](O)CCc1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of the compound obtained from step f above (0.2 g) in tetrahydrofuran:water (3:1, 10 mL) aqueous hydrogen peroxide solution (30%, 0.16 mL) was added at 0° C., followed by the addition of lithium hydroxide monohydrate (19.53 mg) in water (2 mL). The reaction mixture was stirred at 0° C. until the completion of the hydrolysis. The reaction mixture was concentrated and the residue was extracted with ethyl acetate. The aqueous layer was acidified with sodium hydrogen sulphate and extracted with ethyl acetate. The combined layers were washed with water and brine and dried over anhydrous sodium sulphate. The solvents were evaporated under reduced pressure, and the crude residue was purified by silica gel flash column chromatography using 10% methanol in dichloromethane as eluant to afford the title compound (0.090 g).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH:47]12[CH2:56][CH:51]3[CH2:52][CH:53]([CH2:55][CH:49]([CH2:50]3)[CH:48]1[CH2:57][OH:58])[CH2:54]2>>[CH:47]12[CH2:56][CH:51]3[CH2:52][CH:53]([CH2:55][CH:49]([CH2:50]3)[CH:48]1[CH2:57][O:58][C:19]1[C:18]([Cl:17])=[CH:32][C:22]([C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24])=[C:21]([F:33])[CH:20]=1)[CH2:54]2
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC1C2CC3CC(C2)CC1C3
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with adamantan-2-ylmethanol (J. Am. Chem. Soc. 2012, 134(2), 675), the title compound was obtained as a colorless solid (0.14 g, 27%): 1H NMR (300 MHz, CDCl3) δ 8.75-8.57 (m, 1H), 8.13-8.03 (m, 1H), 6.82-6.67 (m, 1H), 4.23-4.03 (m, 2H), 3.03 (s, 6H), 2.37-2.27 (m, 1H), 2.04-1.73 (m, 11H), 1.69-1.54 (m, 3H); MS (ES−) m/z 443.2 (M−1), 445.2 (M−1);
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[N:26]=[C:25]([S:36][CH2:37][C:38]3[N:39]=[C:40]([C:43]4[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=4)[S:41][CH:42]=3)[C:24]=2[C:50]#[N:51])=[CH:19][CH:18]=1)=[O:12])[CH3:10])=O)(C)(C)C.[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]>ClCCl>[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].[NH2:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([N:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[N:26]=[C:25]([S:36][CH2:37][C:38]3[N:39]=[C:40]([C:43]4[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=4)[S:41][CH:42]=3)[C:24]=2[C:50]#[N:51])=[CH:19][CH:18]=1)=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg (0.335 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-L-alaninate (Example 25A) were initially charged in 3.5 ml of dichloromethane. 0.258 ml (3.354 mmol) of trifluoroacetic acid was added, and the reaction solution was then stirred at RT overnight. After one day, another 0.125 ml (1.624 mmol) of trifluoroacetic acid was added to the reaction. The reaction solution was concentrated by evaporation and the residue was triturated with diethyl ether. The solid formed was filtered off. This gave 255 mg (98% of theory) of the target compound.