Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH3:1][N:2]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1)[C:23](=[O:26])[CH:24]=[CH2:25]
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(NC)c3)c12
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC(=O)N(C)c1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-(3-(methylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (96 mg, 0.32 mmol) in THF (3.0 mL) at room temperature was added acryloyl chloride (40 μL, 0.49 mmol), and the solution was allowed to stir at room temperature for 30 minutes. Saturated aqueous sodium carbonate (5 mL) was added and the mixture was extracted with ethyl acetate (×3). The combined organic layers were washed with water (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier to give ethyl 4-(3-(N-methylacrylamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C19H19N4O3 [M+H]+: 351, found 351. 1H NMR (600 MHz, DMSO-D6) δ 13.03 (bs, 1H), 8.92 (s, 1H), 8.33 (s, 1H), 7.61 (d, J=7.63 Hz, 1H), 7.55 (t, J=8.21 Hz, 1H), 7.47 (s, 1H), 7.75 (d, J=7.63 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 6.17 (s, 1H), 5.57 (t, J=7.04 Hz, 1H), 3.94 (q, J=7.04 Hz, 2H), 3.27 (s, 3H), 0.96 (t, J=7.04 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]([OH:52])[CH3:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:54]([O:56][CH:57]([CH3:59])[CH3:58])=[O:55].C(N(CC)CC)C>ClCCl>[C:54](=[O:55])([O:52][CH:50]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:51])[O:56][CH:57]([CH3:59])[CH3:58]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)OC(=O)OC(C)C)(O3)C(OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.2 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 1m (0.4 g, 0.56 mmol, obtained from the synthetic method described in step 11 of example 1) in dichloromethane (30 mL) were added isopropyl chloroformate (1.0 mL, 8.34 mmol), triethylamine (1.55 mL, 11.1 mmol) and 4-dimethyl aminopyridine (cat. 5 mg) in turn at room temperature. The mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with 20 mL of saturated aqueous ammonium chloride, and then extracted with ethyl acetate (40 mL×2). The combined organic layers were washed with saturated brine (20 mL×2), dried over anhydrous brine and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 13a as a light yellow solid (244 mg, 54.2%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.41-7.30 (m, 10H), 7.24-7.11 (m, 5H), 7.08 (m, 2H), 6.90 (m, 2H), 6.76 (m, 2H), 5.01-4.80 (m, 3H), 4.79 (m, 3H), 4.32 (d, 1H), 4.21 (d, 1H), 4.05-3.81 (m, 5H), 3.82-3.71 (m, 2H), 3.66 (d, 1H), 1.40 (t, 3H), 1.29 (d, 3H), 1.26 (m, 6H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:30][C:31]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([C:5]3[C:6]([C:8]4[CH:13]=[CH:12][N:11]=[C:10]5[NH:14][CH:15]=[CH:16][C:9]=45)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=3)=[CH:18][CH:19]=2)=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: O=C=NC1CCCCC1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)NC3CCCCC3)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and cyclohexyl isocyanate provided the title compound. ESMS [M+H]+: 429.2
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:44]3[CH2:45][CH2:46][N:41]([C:38](=[O:40])[CH3:39])[CH2:42][CH2:43]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with 1-acetyl-piperazine (Aldrich) to give the title compound. LR-MS: 649.2 [(M+H)+]
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:13])[C@@H:4]([CH3:22])[CH2:3]1.[N+:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([O-:25])=[O:24].N1C=CC=CC=1.C(OCC)(=O)C>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C@H:2]([NH:1][C:29]3[CH:30]=[CH:31][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=3)[CH2:3][C@@H:4]2[CH3:22])=[O:13])=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N)C[C@@H]2C)cc1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](Nc3ccc([N+](=O)[O-])cc3)C[C@@H]2C)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-(4-amino-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(4-methoxy-phenyl)-methanone (1.00 equiv.) in DMF was added 4-nitrophenylboronic acid (2.00 equiv.), pyridine (2.50 equiv.) and copper(II)acetate (2.00 equiv.). The heterogeneous green mixture was stirred open to air for 1 h and then warmed to 60° C. and stirred over night (14 h). The mixture was then cooled to rt, poured into rapidly stirred ethyl acetate (150 mL); solids were removed by filtration through Celite®. The extracts were washed several times with water and then once with brine. The extracts were then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (95% methylene chloride/5% ethyl acetate) to afford (4-methoxy-phenyl)-[(2S,4R)-2-methyl-4-(4-nitro-phenylamino)-3,4-dihydro-2H-quinolin-1-yl]-methanone as a yellow solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[S:11][C:10](/[N:12]=C/N(C)C)=[N:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1>[NH4+].[OH-]>[NH2:12][C:10]1[S:11][C:7]([C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:6])=[CH:8][N:9]=1
Reactant: CN(C)/C=N/c1ncc(C(=O)NC2CC2)s1
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ncc(C(=O)NC2CC2)s1
Reaction time: 4 h

Procedure:
N-cyclopropyl-2-{[(1E)-(dimethylamino)methylidene]amino}-1,3-thiazole-5-carboxamide 23-3 (1.01 g, 4.23 mmol) was heated to 75° C. in 20 mL of concentrated NH4OH in a sealed tube. After 4 hours the hydrolysis was complete and most of the liquid was evaporated off. Additional water was then added and the pH adjusted to 6. The aqueous layer was extracted with ethyl acetate (4×) and all organics were combined, dried, evaporated and flushed with toluene (2×). 1H-NMR (DMSO): 8.06 ppm (s, 1H); 7.55 ppm (s, 1H); 7.42 ppm (s, 2H); 2.68 ppm (m, 1H); 0.64 ppm (m, 2H); 0.48 ppm (m, 2H).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[NH:2][NH2:3].[CH:13]1([CH:19]=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)(=O)C>C(O)C>[CH2:6]([O:5][C:1]([NH:2][N:3]=[CH:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=CC1CCCCC1
Reactant: NNC(=O)OCc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NN=CC1CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
Benzyl carbazate (25 g, 150.44 mmoles) was dissolved in 200 mL ethanol under a nitrogen atmosphere in a round bottom flask equipped with magnetic stirring. Cyclohexanecarbaldehyde (17.7 g, 158 mmoles) and acetic acid (1 mL) were added to the solution and the mixture was stirred at room temperature for 8 h. The resultant solid precipitate was filtered, washed with hexanes, crystallized from ethyl acetate, and dried overnight on the open bench to provide 28.87 g (73.7% yield) white crystalline N′-cyclohexylmethylene-hydrazinecarboxylic acid benzyl ester. Rf=0.67 (1:3 hexanes:ethyl acetate), 1H NMR (400 MHz, CDCl3) δ 7.8 (1H, br s), 7.4 (5H, m), 7.1 (1H, br s), 5.3 (2H, s), 2.4 (1H, m), 1.7-1.9 (4H, m), 1.3 (6H, m); HRMS (ESI) m/z calcd for C15H21N2O2 [M+H]+ 261.1603. found 261.1592, calcd for C15H20NaN2O2 [M+Na]+ 283.1426. found 283.1417.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[N+:10]([O-:13])(O)=[O:11].[Br:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21]>>[Br:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=1[N+:10]([O-:13])=[O:11])[NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C(=O)Nc1cccc(Br)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CC(C)C(=O)Nc1ccc([N+](=O)[O-])c(Br)c1

Procedure:
Prepare a solution of 260 ml. of 30-33% oleum and 20 g. of 90% nitric acid. Cool the solution to 0° and add in small portion 60.5 g. of metabromo isobutyranilide. Maintain the reaction at 0°-5° C. for an additional 30 minutes with agitation. Isolate the product by the procedure described in Example 1 to obtain 3'-bromo-4'-nitro-isobutyranilide.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[OH-].[NH4+:12]>C(#N)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH2:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(Cl)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 1.3 %

Procedure:
3 g (1 mol equiv.) 5-Chloro-thiophene-2-sulfonyl chloride was dissolved in 30 mL acetonitrile and cooled to 0° C. Dropwise, 6.5 mL (3 mol equiv.) ammoniumhydroxide was added and the reaction mixture was stirred at room temperature for 10 min. Volatiles were removed under reduced pressure, and the solid residue was washed with water and dried in vacuo to afford 2.49 g (91%) 5-chloro-thiophene-2-sulfonic acid amide. 1H NMR (400 MHz, DMSO-d6) δ 7.21 (d, J=4.0 Hz, 1H), 7.43 (d, J=4.0 Hz, 1H), 7.79 (br.s., 2H).
Reaction SMILES: [C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38](O)=[O:39])=[CH:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.[O:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH:63]1[O:68][NH2:69]>CN(C=O)C>[C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([NH:69][O:68][CH:63]3[CH2:64][CH2:65][CH2:66][CH2:67][O:62]3)=[O:39])=[CH:32]2)(=[O:29])=[O:30])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Reaction time: 1.5 h

Procedure:
(E)-3-{1-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylic acid (compound C15) (1.15 g, 1.16 mmol), HOBtH2O (171 mg, 1.16 mmol) and triethylamine (2 ml) is dissolved in DMF (100 ml) at room temperature. After addition of EDC HCl (786 mg, 3.48 mmol) the mixture is stirred for 1.5 hours. Then it is added O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (136 mg, 1.16 mmol) and stirred for 17 hours. After evaporation and addition of 200 ml water the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate. Then it is filtrated and evaporated. The crude product is purified by a silica gel flash chromatography using dichloromethane-methanol eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([CH3:14])[C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.C(OCC)(=O)C.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:9]1[C:8]([CH3:14])=[N:7][C:6]2[C:11]([N:10]=1)=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2
Reactant: COc1ccc2nc(C)c(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc2nc(C)c(Cl)nc2c1
Temperature: 25 °C
Yield: 34 %

Procedure:
A solution of 7-methoxy-3-methyl-1H-quinoxalin-2-one (125 g, 631 mmol, 1.0 eq) in phosphorus oxychloride (800 mL) is heated under reflux for 1 hour. Then the reaction mixture is cooled down to room temperature and the solvent is evaporated. The residue is poured into ice water and the resulting mixture is neutralized with 20% sodium hydroxide aqueous solution. The resulting precipitate is collected by filtration, washed with water to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 100:1, v/v) to afford 3-chloro-6-methoxy-2-methyl-quinoxaline as a white solid (44.4 g, 34% yield).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]([NH:17][C:18]2([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:19]2=[O:32])=[O:16])[CH:10]=[CH:11][CH:12]=1>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]([NH:17][C:18]2([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:19]2=[O:32])=[O:16])[CH:10]=[CH:11][CH:12]=1
Reactant: CCCCCN1C(=O)C(CCC(=O)OCC)(NC(=O)/C=C/c2cccc(OC)c2)c2ccccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCN1C(=O)C(CCC(=O)OCC)(NC(=O)/C=C/c2cccc(O)c2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Under ice cooling, 2 ml of boron tribromide was added dropwise to a stirred solution of 1.64 g of ethyl 3-[2,3-dihydro-3-[(E)-3-(3-methoxyphenyl)-2-propenoylamino]-2-oxo-1-pentyl-1H-indol-3-yl]propionate in methylene chloride (30 ml). After stirring under ice cooling for 1 hour, the mixture was poured into ice water and extracted with chloroform. After the extract was dried, the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography [hexane-ethyl acetate (1:1)] to afford 1.53 g of ethyl 3-[2,3-dihydro-3-[(E)-3-(3-hydroxyphenyl)-2-propenoylamino]-2-oxo-1-pentyl-1H-indol-3-yl]propionate as a colorless amorphous solid. IR (Nujol) (cm-1) : 3280, 1705, 1660, 1610, FAB-MS (m/z): 465 (MH+), 302, 256, 228, 147 (base).
Reaction SMILES: C(OC(=O)C)(=O)C.C([O-])(=O)C.[NH4+:12].[C:13]1([CH2:23][C:24]([OH:26])=O)([CH2:19][C:20](O)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.N>C(O)(CC)C.O>[CH2:16]1[CH2:17][CH2:18][C:13]2([CH2:23][C:24](=[O:26])[NH:12][C:20](=[O:21])[CH2:19]2)[CH2:14][CH2:15]1
Reactant: O=C(O)CC1(CC(=O)O)CCCCC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: N
Solvent: O
Solvent: CCC(C)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CC2(CCCCC2)CC(=O)N1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
A flask is charged with 66.5 g of acetic anhydride, 66.5 g of ammonium acetate, and 100 g of 1,1-cyclohexane diacetic acid. The reaction mass is heated to 160° C.-170° C. for eight hours, eliminating by distillation the acetic acid that has formed. It is cooled to 90° C.-110° C., and 200 g of water and 100 g of secondary butyl alcohol are added. It then undergoes further cooling to room temperature, and the pH is brought to approximately 9 using 30% of aqueous ammonia. This is followed by filtration, washing the solid with water. 87.7 g of dry 3,3-pentamethylene glutarimide are obtained (yield 97%).
Reaction SMILES: [CH3:1][N:2]([S:26]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)(=[O:28])=[O:27])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][CH2:18][S:19][CH2:20][C:21]([O:23]CC)=[O:22])[CH2:15][N:16]=1)=[CH:8]2.[OH-].[K+].Cl>O1CCCC1.CO.O>[CH3:1][N:2]([S:26]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)(=[O:28])=[O:27])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][CH2:18][S:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CSCCC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(C3=NCC(CCSCC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution of ethyl {[2-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)ethyl]thio}acetate (60 mg) in tetrahydrofuran (2 mL) and methanol (2 mL) was added, under ice-cooling, a solution prepared by dissolving potassium hydroxide (purity 85%, 20 mg) in water (0.5 mL). The reaction mixture was allowed to warm to room temperature, and stirred for 1 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to give the title compound (35 mg, yield 61%) as white crystals. MS: 496 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH3:34])=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[C:25]([F:33])[CH:24]=3)=[CH:21][CH:22]=2)=[CH:11][C:10]=1[CH3:35])([CH3:7])[CH3:6])C.[OH-].[Na+]>C1COCC1.CCO>[F:33][C:25]1[CH:24]=[C:23]([C:20]2[N:19]=[C:18]([CH3:34])[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:36])=[O:3])=[C:10]([CH3:35])[CH:11]=3)=[CH:22][CH:21]=2)[CH:28]=[CH:27][C:26]=1[C:29]([F:31])([F:32])[F:30]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)c(F)c3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)c(F)c3)nc2C)ccc1OC(C)(C)C(=O)O
Reaction time: 2 h

Procedure:
0.214 g (0.423 mmol) of the above prepared 2-{4-[6-(3-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridin-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was dissolved in 0.85 ml of THF/EtOH=1/1, treated with 1.27 ml (3 eq.) of 1N NaOH and kept at ambient temperature for 2 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Recrystallisation from AcOEt/hexane yielded finally 0.191 g of the title compound as white crystals of mp. 175–76°C.
Reaction SMILES: [C:1]([CH2:3][S:4][C@H:5]1[CH2:9][O:8][CH2:7][C@@H:6]1[C@:10]([N:19](CC1C=CC(OC)=CC=1OC)[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[CH3:11])#[N:2].FC(F)(F)C(O)=O>>[C:1]([CH2:3][S:4][C@H:5]1[CH2:9][O:8][CH2:7][C@@H:6]1[C@:10]([NH:19][C:20](=[O:25])[C:21]([F:22])([F:24])[F:23])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[CH3:11])#[N:2]
Reactant: COc1ccc(CN(C(=O)C(F)(F)F)[C@](C)(c2ccccc2F)[C@H]2COC[C@@H]2SCC#N)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@](NC(=O)C(F)(F)F)(c1ccccc1F)[C@H]1COC[C@@H]1SCC#N

Procedure:
A solution of N-[rel-(S)-1-((3S,4R)-4-cyanomethylsulfanyl-tetrahydro-furan-3-yl)-1-(2-fluoro-phenyl)-ethyl]-N-(2,4-dimethoxy-benzyl)-2,2,2-trifluoro-acetamide (1.65 g, 3.13 mmol) in trifluoroacetic acid (14.5 ml, 188 mmol) was stirred at room temperature overnight. The reaction mixture was extracted with a mixture of a saturated solution of sodium hydrogencarbonate and ethyl acetate/tetrahydrofuran. The combined organic layers were dried over sodium sulphate and evaporated at reduced pressure. The crude N-[rel-(S)-1-((3S,4R)-4-cyanomethylsulfanyl-tetrahydro-furan-3-yl)-1-(2-fluoro-phenyl)-ethyl]-2,2,2-trifluoro-acetamide was obtained as a white solid and engaged in the following step without further purification. MS (ISP): m/z=375.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][CH:23]([CH3:27])[CH2:24][O:25][CH3:26]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:22][CH:23]([CH3:27])[CH2:24][O:25][CH3:26])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(C)N
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Solvent: C1COCCO1
Product: COCC(C)Nc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 195 °C

Procedure:
A mixture of (3-chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine (10.0 g, 0.03 mol) and 2-amino-1-methoxypropane (14.0 g, 0.16 mol) in dioxane (75 ml) is heated in an autoclave at 195° C. for 12 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic phase is separated, dried over magnesium sulfate, filtered and evaporated under reduced presssure. The residue is purified by silicagel chromatography to give the title compound, m.p. 143–144° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13](=[O:24])[CH:14]=[C:15]([CH:17](OCC)[O:18]CC)[O:16][C:11]=2[C:10]=1[CH2:27][CH2:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13](=[O:24])[CH:14]=[C:15]([CH:17]=[O:18])[O:16][C:11]=2[C:10]=1[CH2:27][CH2:28][CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1c(OCc2ccccc2)ccc2c(=O)cc(C(OCC)OCC)oc12
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCCc1c(OCc2ccccc2)ccc2c(=O)cc(C=O)oc12
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
7-Benzyloxy-2-diethoxymethyl-8-propyl-4H-1-benzopyran-4-one (5.0 g) was dissolved in glacial acetic acid (50 ml), and 10% sulphuric acid (25 ml) was added. Steam was passed through the solution for 30 minutes. On cooling the yellow crystals which formed were filtered off, washed with light petroleum (bp 40°-60°), chromatographed on silica gel with ether, and then crystallised from ether to give the aldehyde (1.67 g), mp 150°.