Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]([O:45][CH3:46])(=[O:44])[CH:42]=[CH2:43]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:46][O:45][C:41](=[O:44])/[CH:42]=[CH:43]/[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C(=O)O)c2ccccc12
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 4-bromo-1-naphthalenecarboxylic acid (which may be prepared by the methods described in Can. J. Chem. 1981, 59, 2629-41) (100 mg, 0.4 mmol), triethylamine (0.42 ml, 3 mmol), palladium acetate (12 mg, 0.04 mmol), triphenylphosphine (13 mg, 0.04 mmol) and methyl acrylate (1.19 ml, 0.11 mmol) in anhydrous DMF (8 ml) was heated to 100° C. for 4 h under nitrogen. The mixture was allowed to cool to room temperature, evaporated to dryness under reduced pressure and purified by aminopropyl cartridge, eluting with MeOH, followed by 4M HCl in dioxane and then 2M ammonia in MeOH. The ammonia in methanol fractions were combined to afford a residue that was partitioned between DCM and water, the DCM layers combined, dried over magnesium sulfate filtered and evaporated to afford the title compound (99 mg, 97%). LCMS RT=3.25 min, ES−ve m/z 255 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[C:5]([N:7]1[CH2:20][C:19]([CH3:22])([CH3:21])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:8]1)=[O:6].[CH:32]1N=CN(C(N2C=NC=C2)=O)C=1>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[C:5]([N:7]1[CH2:20][C:19]([CH3:22])([CH3:21])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[C:9]([C:23]([O:25][CH:26]([CH3:32])[CH3:27])=[O:24])=[CH:8]1)=[O:6]
Reactant: CCOC(=O)C1CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2c1[nH]c1ccccc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC(C)O
Product: CC(C)OC(=O)C1=CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2c1[nH]c1ccccc21

Procedure:
Ethyl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole-5-carboxylate was saponified, converted to the corresponding isopropyl ester using CDI and isopropanol, and then oxidized as described previously in Step D of Example 63 to give the title compound; 1H-NMR (DMSO-d6): δ 10.83 (1H, s), 7.76 (1H, d), 7.71 (1H, app t), 7.64 (1H, s), 7.52-7.61 (2H, m), 7.40 (1H, m), 7.08 (1H, app t), 6.98 (1H, app t), 5.05 (1H, sept), 1.52 (6H, s), 1.18 (6H, d); MS(ESI): 439 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[Cl:18])(C)(C)C.Cl>O1CCOCC1.CCOCC>[Cl:18][C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[CH2:7][C:6]([OH:19])=[O:5]
Reactant: CC(C)(C)OC(=O)Cc1ccc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(C(F)(F)F)cc1Cl
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A solution of (2-chloro-4-trifluoromethylphenyl)-acetic acid tert-butyl ester (40 g, 135.7 mmol) in dioxane (100 mL) containing conc. HCl (31.3 mL) was stirred at 50° C. for 5 h. After cooling the mixture to r.t., it was diluted with Et2O and the organic layer was washed with H2O (3×). The organic phase was dried (MgSO4) and the solvent was removed in vacuo. Recrystallization of the residue with AcOEt-hexane yielded the title compound as a solid showing: 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.55 (dd, 1H, J=1.0, 8.0 Hz), 7.47 (d, 1H, J=8.0 Hz), 3.92 (s, 2H). MS (ESI) m/z 237 (M−H)−.
Reaction SMILES: C1O[C:4]2([CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:14]([NH2:16])=[O:15])[CH:10]=3)[CH2:5]2)[O:3]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:5]1[C:6]2[C:11](=[CH:10][C:9]([C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=2)[CH2:12][CH2:13][C:4]1=[O:3]
Reactant: NC(=O)c1ccc2c(c1)CCC1(C2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: NC(=O)c1ccc2c(c1)CCC(=O)C2
Yield: 38.3 %

Procedure:
2-Tetralone-6-carboxamide ethylene ketal (250 mg, 1.07 mmol) and catalytic p-toluenesulfonic acid were stirred in acetone (50 mL) at ambient temperature for 48 hours. The volatiles were removed in vacuo and the residue triturated in ethyl acetate. The solids were filtered, washed and dried to yield 77.5 mg (38%) of 2-tetralone-6-carboxamide as a white powder, pure by NMR, TLC. MS.
Reaction SMILES: C([O:5][C:6]1[CH2:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][N:7]=1)CCC.O>C(O)C>[C:13]1([C:10]2[CH:9]=[CH:8][NH:7][C:6](=[O:5])[CH2:12][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCOC1=NC=CC(c2ccccc2)=CC1
Solvent: CCO
Solvent: O
Product: O=C1CC=C(c2ccccc2)C=CN1
Temperature: 150 °C
Yield: 88.2 %

Procedure:
The 2-butoxy-5-phenyl-3H-azepine (908 g, 3.42 moles) is dissolved in 2B-3 ethanol (8172 mL) and de-ionized water (2724 mL). The solution is charged to an autoclave and heated to 150° C. for 20 hours. The solution is cooled to room temperature and concentrated under reduced pressure. Residual water is removed by azeotropic distillation from toluene (2×2 L). The residual solids are dissolved in toluene (1.7 L) and heated between 95 to 100° C. The solution is cooled to <90° C. and heptane (about 4.8 mL/g) is added. The solution is allowed to cool to room temperature, and then cooled to 0 to 5° C. using an ice bath. The solids are filtered, washed with heptane, and dried to give the title compound (559 g, 88%) as a light brown solid.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.[Cl-].[Na+]>[CH2:22]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:21]=[CH2:20]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: C=CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCCCCCCCCCCCCCCCC
Temperature: 50 °C
Yield: 49.6 %

Procedure:
n-Hexadecanol (24.2 g, 0.1 mol) was added to a suspension of sodium hydride (9.6 g of a 50% dispersion in mineral oil, 0.2 mol) in dimethylformamide (200 ml) and heated to 50° C. for 30 minutes. Allyl bromide (24.2 g, 0.2 mol) was then added and the mixture heated to 90° C. for 5 hours. The reaction was cooled, diluted with a solution of saturated sodium chloride (300 ml), and extracted with ether (2×300 ml). The combined ether extracts were washed with a saturated solution of sodium chloride (200 ml), filtered, dried over magnesium sulfate, treated with activated charcoal, filtered, and evaporated under reduced pressure to an oil. The resulting oil was purified by absorbing it on silica gel, placing the silica gel in a sintered glass filter, and eluting the product off with hexane (7×200 ml) followed by toluene (4×200 ml). Concentration yielded the pure ether (14 g, 50% yield): NMR (CDCl3) 3.40 (t, 2, --CH2 --O--CH2CH=CH2), 3.92 (d, 2, --O--CH2CH=CH2), 4.95-5.38 (m, 2, =CH2) and 5.58-6.20 (m, 1, --CH=CH2).
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=[O:7])=[O:4].CCN(C(C)C)C(C)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22]([O:1][NH:2][C:3]([CH:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=[O:7])=[O:4])=[O:27]
Reactant: CC(C)CC(C(=O)O)C(=O)NO
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(C(=O)O)C(=O)NOC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 55.3 %

Procedure:
Intermediate (3d) (12.7 g, 73.2 mmol, 1.0 eq) was dissolved into 180 mL DCM and cooled to 0° C. DIPEA (13.4 mL, 76.9 mmol, 1.05 eq) was added, followed by pivaloyl chloride (9.5 mL, 76.9 mmol, 1.05 eq). The mixture was warmed to room temperature and stirred for 12 hours. The mixture was concentrated under reduced pressure, dissolved into 300 mL EtOAc, washed 2×200 mL 1M H3PO4, 100 mL saturated aqueous NaCl, dried over MgSO4, and evaporated. The material was triturated with hexanes, filtered and dried the to yield the title compound (10.5 g, 55%). 1H NMR (DMSO) δ (ppm): 0.7 (m, 6H), 1.2-1.4 (m, 1H), 1.4-1.6 (m, 2H), 2.9 (t, 1H), 3.3 (quart, 1H), 8.9 (br s, 1H), 10.5 (br s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[CH:12](O)([CH3:14])[CH3:13]>>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH:12]([CH3:14])[CH3:13])=[O:7]
Reactant: CC(C)O
Reactant: O=C(O)c1cccc(CCl)c1
Product: CC(C)OC(=O)c1cccc(CCl)c1

Procedure:
Isopropyl 3-(chloromethyl)benzoate 13b was prepared by reacting 3-(chloromethyl)benzoic acid 23 with isopropanol according to the procedure described for the compound 13a in Example 17 (scheme 7). The benzoate 13b was isolated as colorless oil in 87% yield (1.85 g). 1H NMR (400 MHz, CDCl3): δ 1.37 (6H, m); 4.62 (2H, s); 5.27 (2H, m); 7.43 (1H, m); 7.57 (1H, broad d); 7.98 (1H, broad d); 8.04 (1H, s).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[O:12][CH2:11][C:10]2=1.CCN(CC)CC>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:1](=[O:3])[CH3:2])[C:15]1[C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[O:12][CH2:11][C:10]2=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2[nH]c3c(c2c1)COc1ccccc1-3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)c1c(n2C(C)=O)-c2ccccc2OC1
Temperature: 25 °C

Procedure:
Acetyl chloride (0.064 mL, 0.896 mmoL) in CH2Cl2 (2 mL) was treated with 8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (150 mg, 0.598 mmoL) followed by Et3N (0.896 mmol., 0.125 mL) at 0° C. The reaction mixture was then slowly warmed to room temperature over 2 hours. The reaction mixture was then partitioned between CH2Cl2 and saturated NaHCO3. The aqueous phase was extracted two times with CH2Cl2. The organic layers from the two extractions were then combined, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material was then purified by column chromatography (silica gel, hexanes:EtOAc 3:1 as eluent) to yield the title compound as a pale solid.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH:22]3[C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[CH:27]=3)[N:18]=[C:17]([NH:37][C:38]3[CH:42]=[C:41]([CH3:43])[NH:40][N:39]=3)[CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:20]=[C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH:22]3[C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[CH:27]=3)[N:18]=[C:17]([NH:37][C:38]3[CH:42]=[C:41]([CH3:43])[NH:40][N:39]=3)[CH:16]=2)[CH2:13][CH2:14]1
Reactant: Cc1cc(Nc2cc(N3CCC(NC(=O)OC(C)(C)C)CC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2cc(N3CCC(N)CC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
6-(4-(N-tert-Butoxycarbonylamino)piperidin-1-yl)-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 124) (120 mg, 0.20 mmol) was stirred in DCM (10 ml) and trifluoroacetic acid (2 ml) was added and the mixture stirred at room temperature for 3 hours. The mixture was concentrated by evaporation and the residue dissolved in methanol (10 ml) and passed down a 20 g SCX-2 ion exchange column, eluting with methanol to elute impurities and then 2M methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (79 mg, 81%) as a cream powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 4-tert-butyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 9.77 (br s, 1H, NH), 8.40 (dm, 1H, J=1.8 Hz), 7.77 (dm, 1H, J=8.6 Hz), 7.71 (dd, 1H, J =8.1 Hz, J=2.2 Hz), 7.58 (dm, 2H, J=8.6 Hz), 7.50 (dd, 1H, J=9.0 Hz, J=2.4 Hz), 7.32 (d, 1H, J=2.2 Hz), 7.29 (dm, 2H, J=8.6 Hz), 7.23 (d, 1H, J=8.1 Hz), 2.63 (s, 3H), 1.20 (s, 9H). MS: m/z 443 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:14]3([CH2:20][NH2:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1.[F:24][C:25]([F:41])([F:40])[C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])[N:27]=1>>[F:40][C:25]([F:24])([F:41])[C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([NH:21][CH2:20][C:14]2([C:11]3[S:12][CH:13]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:8][CH:7]=4)[N:10]=3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:35])[N:27]=1
Reactant: NCC1(c2nc(-c3ccc(C(F)(F)F)cc3)cs2)CCOCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(c2nc(-c3ccc(C(F)(F)F)cc3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 19 %

Procedure:
This compound was synthesized from (4-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (9 mgs, 19% yield). 1H NMR (300 MHz, CDCl3) δ 8.44 (s, 1H), 8.24 (d, J=7.7 Hz, 1H), 8.00 (m, 2H), 7.65-7.58 (m, 4H), 7.36 (s, 1H), 4.02-3.78 (m, 4H), 3.74 (m, 2H), 2.30 (m, 2H), 2.05 (m, 2H). MS (ESI) m/z: Calculated for C26H20F6N4O3S: 582.12. found: 583.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([CH:8]=1)[NH2:7].[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1)=[O:19]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1cc(Cl)ccc1-c1nnn[nH]1
Product: O=C(Nc1cc(Cl)ccc1-c1nnn[nH]1)c1cccc(Cl)c1
Yield: 13 %

Procedure:
The title compound was prepared essentially according to the method of Example 4, but using 5-Chloro-2-(1H-tetrazol-5-yl)aniline (1.0 mmol) and 3-chlorobenzoyl chloride. After precipitation, the product was further purified by reverse phase C18 preparative HPLC (water/acetonitrile w/0.1% formic acid, 30%-100% eluant gradient) to yield the desired product (46.0 mg, 13%). 1H NMR (400 MHz, d6-DMSO): δ 13.07 (s, 1H), 8.87 (s, 1H), 8.29 (s, 1H), 8.17 (s, 1H), 7.76 (m, 2H), 7.27 (s, 1H), 6.96 (s, 2H). MS (EI) for C14H9Cl2N5O: 334.2 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:9][C:10](=[O:41])[C@H:11]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=1)[NH:12][S:13]([C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][N:22](C(=O)C(F)(F)F)[CH2:23]2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:8]>O.C(O)C>[CH2:7]([O:9][C:10](=[O:41])[C@H:11]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=1)[NH:12][S:13]([C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][CH2:23]2)=[CH:18][CH:17]=1)(=[O:14])=[O:15])[CH3:8]
Reactant: CCOC(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A solution of sodium carbonate (11.5 g, 108.5 mmol) in water (115 ml) was added to a stirred solution of N-(2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline-7-sulphonyl)-3-cyano-(S)-phenylalanine ethyl ester (Preparation 21; 11.5 g, 22.6 mmol) in ethanol (115 ml) and the resulting mixture stirred for 3 hours at room temperature. The bulk of the ethanol was then removed under reduced pressure, water added and the resulting suspension extracted with dichloromethane. The organic extract was washed with saturated brine, dried (MgSO4) and evaporated under reduced pressure, then the residue dissolved in the minimum volume of dichloromethane. Dilution of this solution with ethanol, followed by concentration and overnight standing of the mixture, provided the title compound as a white solid (6.4 g), after filtration and washing with ether. Rf 0.26 (SS 6). m/e 414 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:31])[CH2:29][OH:30])=[CH:24][C:23]=1[O:32][CH3:33].C([O-])(O)=O.[Na+].CN1CCCC1=O>O>[F:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:31])[CH2:29][OH:30])=[CH:24][C:23]=4[O:32][CH3:33])[CH2:6][CH2:5]3)=[N:8][O:9][C:10]=2[CH:15]=1
Reactant: COc1cc(C(=O)CO)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(C(=O)CO)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 3-(4piperidinyl)-6-fluoro-1,2-benzisoxazole (1.3 g, 5.8 mmol), 1-[4(3-chloropropoxy)-3-methoxyphenyl]-2-hydroxyethanone (1.5 g, 5.8 mmol), NaHCO3 (1.5 g) and 1-methyl-2-pyrrolidinone (50 ml) was stirred under N2 at 100° C. for 6 hours. The reaction was poured into H2O, and the aqueous suspension was extracted with EtOAc. The extract was washed (H2O), dried (MgSO4 and concentrated to afford the product.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:11][C:12]#[N:13])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O>C1(C)C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH:11]([C:12]#[N:13])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: N#CCC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C#N)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
A heptane washed suspension of 7.6 g (0.189 mole) of 60% NaH/mineral oil in 400 ml of anhydrous toluene was treated portion-wise with 25.0 g (0.172 mole) of benzoylacetonitrile under a nitrogen atmosphere. After stirring for 1 hour, 33.0 g (0.189 mole) of ethyl bromoacetate (97%) was added in one portion. The reaction was heated at reflux for 4 hours, then allowed to cool to room temperature and stirred for 20 hours. Water (500 ml) was added, and the toluene layer was extracted with water (500 ml). The toluene layer was dried over MgSO4, filtered, and the solvent evaporated under reduced pressure (42.9 g). The residual oil was fractionally distilled under vacuum to give 21.4 g (54%) of pure product.
Reaction SMILES: [C-]#N.[Li+].P([C:12]#[N:13])(OCC)(OCC)=O.O=[C:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:29]2[CH2:28][CH2:27][C@@:25]2([CH3:26])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:34]([O:36][CH3:37])=[O:35])=[CH:16]1>O1CCCC1>[C:12]([C:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C:17](=[CH:18][CH2:19][C@@H:20]3[C@@H:29]2[CH2:28][CH2:27][C@@:25]2([CH3:26])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:34]([O:36][CH3:37])=[O:35])[CH:16]=1)#[N:13]
Reactant: CCOP(=O)(C#N)OCC
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [C-]#N
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.0 g of lithium cyanide and 16 ml of diethyl cyanophosphate were dissolved in 200 ml of dry tetrahydrofuran, and 10 g of methyl 3-oxo-4-androstene-17β-carboxylate were added little by little at room temperature to the resulting solution. The reaction mixture was stirred at room temperature for 15 minutes, after which the tetrahydrofuran was removed by distillation under reduced pressure. The residue was dissolved in 300 ml of a 1:1 by volume mixture of ethyl acetate and benzene, and the resulting solution was washed four times with water and then once with a saturated aqueous solution of sodium chloride. It was then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was dissolved in 100 ml of dry benzene, and 2 ml of a boron trifluoride-diethyl ether complex was added to the resulting solution, which was then stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was diluted with 300 ml of diethyl ether. The diluted mixture was washed with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate, and then concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through 100 g of silica gel using a gradient elution method, with mixtures of ethyl acetate and hexane in ratios ranging from 4:96 to 12:88 by volume as the eluent, to give 9.5 g of the title compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][CH:6]=1)#[N:2].[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:21]=[C:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[S:16][C:11]([C:9]2[N:10]=[C:5]([CH2:4][CH2:3][C:1]#[N:2])[CH:6]=[CH:7][CH:8]=2)=[N:12]1
Reactant: COC(=O)c1ccccc1S
Reactant: N#CCCc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#CCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 53 %

Procedure:
6-(2-Cyanoethyl)-2-pyridinecarbonitrile (0.28 g, 1.8 mmol) and methyl thiosalicylate (0.36 g, 2.1 mmol) were dissolved in toluene (2 ml), and triethylamine (0.37 ml, 2.7 mmol) was added thereto. The reaction mixture was refluxed for 6 hrs and kept at room temperature. The precipitated crystals were collected, washed with toluene and recrystallized from ethanol to give the titled compound (0.28 g, 54%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([OH:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[F:20][C:21]([F:27])([F:26])[S:22](O)(=[O:24])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13][S:22]([C:21]([F:27])([F:26])[F:20])(=[O:24])=[O:23])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(O)cc(Cl)cc1Cl
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(Cl)cc(Cl)cc1OS(=O)(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
A solution of the above ester (4.64 g, 20.99 mmol) and pyridine (1.87 mL, 23.09 mmol) in 100 mL CH2Cl2 was cooled to 0° C. Trifluoromethanesulfonic acid (4.94 mL, 29.39 mmol) was added, and the solution was stirred for 2 h. The reaction mixture was washed with aqueous sodium bicarbonate, aqueous copper sulfate and brine, dried over Na2SO4, filtered and concentrated to provide methyl 2,4-dichloro-6-{[(trifluoromethyl)sulfonyl]oxy}benzoate that gave proton NMR spectra consistent with theory.