Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([OH:22])=[O:21].C([O-])(O)=O.[Na+:27]>C(O)C.O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O-:22])=[O:21].[Na+:27]
Reactant: Cc1nc2cccc(OC3CCCCC3)c2c(N)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc2cccc(OC3CCCCC3)c2c(N)c1C(=O)[O-]
Temperature: 60 °C
Yield: 99.7 %

Procedure:
To a solution of 4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylic acid (Example 36, 1.0 g, 3.33 mmol) in ethanol (20 mL) was added a solution of NaHCO3 (294 mg, 3.50 mmol) in water (15 mL). The mixture was stirred and warmed up to 60° C. until the solution become clear then evaporated to dryness to provide sodium 4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate (1.07 g, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.25-1.45 (m, 3H), 1.50-1.70 (m, 5H), 1.53-1.72 (m, 5H), 1.98-2.00 (m, 2H), 2.64 (s, 3H), 4.59-4.63 (m, 1H), 6.87-6.89 (d, J=7.6 Hz, 1H), 7.20-7.22 (d, J=8.0 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H). MS 301 (MH+-H-Na).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])[CH:12]=[C:11]([Cl:21])[C:10]=1[F:22])(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])[CH:12]=[C:11]([Cl:21])[C:10]=1[F:22]
Reactant: COCCN(C)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COCCN(C)c1cc(Cl)c(F)c(CN)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of {3-chloro-2-fluoro-5-[(2-methoxy-ethyl)-methyl-amino]-benzyl}-carbamic acid tert-butyl ester (60 mg, 0.17 mmol) in MeOH (2 mL) was added a solution of 4N HCl in dioxane (2 mL). The reaction mixture was stirred for 1 h at ambient temperature and the solvent was removed in vacuo to give the title compound. MS (LC/MS): 247.0 [M]+. tR (HPLC conditions c): 3.15 min.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[OH-].[K+].C(=O)=O.CC(C)=O.[O:35]1[CH2:40][CH2:39]C(O)[CH2:37][CH2:36]1>CCOCC.O1CCCC1>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([O:24][CH:25]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: OC1CCOCC1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC12C(CO)C3=C(C(=O)C(C)=C(OC4CCOCC4)C3=O)N1CC1NC12
Product: NC(=O)O
Yield: 21 %

Procedure:
A solution of mitomycin A (100 mg) in 2 ml of tetrahydro-4H-pyran-4-ol was stirred at room temperature and under nitrogen for 45 minutes with 500 mg of a 1.6% solution of KOH in tetrahydro-4H-pyran-4-ol. The reaction mixture was diluted with a little ether and then decomposed with dry ice. Additional ether was added and the solid that deposited (42 mg) was filtered off and discarded. The pink filtrate was concentrated under reduced pressure and the residue was isolated twice on a silica gel plate, using 20% of tetrahydrofuran in ether as a solvent in the first isolation and 15% of acetone in ether in the second isolation. This procedure gave 25 mg (21%) of the title compound, having a melting point of 115°-120° C. (decomposition) and providing the following analysis:
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:9]=1)[C:4](O)=[O:5])#[N:2].C(Cl)(=O)C([Cl:26])=O>ClCCl.CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:7]=[C:3]([C:4]([Cl:26])=[O:5])[C:1]#[N:2])=[CH:9]1)[CH3:22]
Reactant: CCOC(=O)Cn1cc(C=C(C#N)C(=O)O)c2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(C=C(C#N)C(=O)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a stirred suspension of 2-cyano-3-(1-ethoxycarbonylmethyl-1H-indol-3-yl)-acrylic acid (3.0 g, 10 mmol) in dry dichloromethane (120 ml), in the presence of a few drops of dry DMF, was added oxalyl chloride (1.7 ml, 20 mmol). After stirring at rt overnight, the volatiles were removed under reduced pressure, the residue azeotoped twice with dry toluene and dried in vacuo, affording crude title compound (3.18 g) in quantitative yield. This material was stored under argon and was used without further purification.
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30]Br)(C)(C)C.[F:33][C:34]([F:43])([F:42])[C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOCC>[CH3:23][C:22]1[O:21][C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:19][C:18]=1[CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:5])=[O:32])=[C:10]([CH2:30][O:41][C:38]2[CH:39]=[CH:40][C:35]([C:34]([F:33])([F:42])[F:43])=[CH:36][CH:37]=2)[CH:11]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)c(COc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 107 %

Procedure:
General procedure for parallel synthesis using the DynaVac Carousel apparatus. A 50 mL glass tube with screw cap and nitrogen inlet was charged with 3-{2-bromomethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid tert-butyl ester (0.040 g, 0.080 mmol), 4-trifluoromethylphenol (0.019 g 0.12 mmol), anhydrous DMF (0.5 mL), and then cesium carbonate (0.039 g, 0.12 mmol). The mixture was stirred at ambient temperature for 16 h. MS analysis of the reaction indicated formation of the intermediate ester product [MS (ES) m/e 582 (M+1)]. The reaction mixture was poured into ether (30 mL). The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated. The residue was diluted with CH2Cl2 (1 mL) and trifluroacetic acid (0.25 mL) was added. The mixture was stirred at ambient temperature for 1.5 h and was concentrated. The crude product mixture was purified by mass-directed reverse phase HPLC to provide the title compound (0.045 g, 64%). MS (ES) m/e 526 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9](I)=[CH:10]3)[C:6]=2[CH:16]=1.CC1(C)C(C)(C)OB([C:25]2[C:26]([C:30]([F:33])([F:32])[F:31])=[N:27][NH:28][CH:29]=2)O1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:25]4[C:26]([C:30]([F:33])([F:32])[F:31])=[N:27][NH:28][CH:29]=4)=[CH:10]3)[C:6]=2[CH:16]=1
Reactant: CC1(C)OB(c2c[nH]nc2C(F)(F)F)OC1(C)C
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1n[nH]cc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 80 °C
Yield: 2.6 %

Procedure:
A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (750 mg, 1.91 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-1H-pyrazole (550 mg, 2.10 mmol), PdCl2dppf.DCM (156 mg, 0.19 mmol) and Cs2CO3 (1.55 g, 4.77 mmol) in dioxane (12 mL) and H2O (3 mL) was purged with argon and heated at 80° C. for 18 h. Further 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-1H-pyrazole (225 mg, 1.05 mmol) and PdCl2dppf.DCM (78 mg, 0.09 mmol) were added and the mixture heated at 85° C. for a further 24 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-5% MeOH in DCM) affording 9-Bromo-2-(3-trifluoromethyl-1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a white solid (20 mg, 3%). LCMS: RT 4.42 min [M+H]+ 399.0 and 401.0. 1H NMR (CDCl3, 400 MHz): δ 13.65 (1H, s), 8.57 (1H, d, J=2.61 Hz), 8.30 (1H, s), 7.43-7.42 (2H, m), 7.00 (1H, d, J=8.71 Hz), 4.52-4.45 (4H, m)
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: Fc1ccc(CNc2nc(-c3cccnc3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:29]=[CH:28][C:13]([C:14]([NH:16][NH:17]C(OCC2C=CC=CC=2)=O)=[O:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].C>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:28][CH:29]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)NNC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)NN)cc1
Yield: 95.1 %

Procedure:
A solution of the product of step (a) (5.7 g) in methanol (120 ml) was hydrogenolysed over 10% palladium on carbon (0.5 g) until hydrogen uptake ceased (1 hour). Activated charcoal was added and the mixture was stirred, filtered through diatomaceous earth and concentrated to give 4-(t-butoxycarbonylaminomethyl)benzoylhydrazine (3.6 g) as a colourless solid; m.p. (from toluene) 114-116° C.; NMR Spectrum 1.4 (9H, s); 3.2-4.0 (2H, br s); 4.2 (2H, s); 7.3 (2H, d); 7.4 (1H, t); 7.8 (2H, d); 9.7 (1H, s).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[NH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][CH:4]=[CH2:5]
Reactant: C1CCNC1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCCN1CCCC1
Temperature: 120 °C

Procedure:
4-Bromo-but-1-ene (81 mg, 0.6 mmol) was added dropwise to a stirred suspension of pyrrolidine (50 μL, 0.6 mmol) and Cs2CO3 (196 mg, 0.6 mmol) in 1 mL DMF. The mixture was heated to 120° C. using microwave for 20 min, then filtered and used for the next step directly without purification.
Reaction SMILES: O.[NH2:2][NH2:3].CCO.Cl[C:8]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:9]=1[C:10](OC)=[O:11].Cl>O>[N+:18]([C:15]1[CH:14]=[C:9]2[C:8](=[CH:17][CH:16]=1)[NH:3][N:2]=[C:10]2[OH:11])([O-:20])=[O:19]
Reactant: NN
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]nc(O)c2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Hydrazine monohydrate (19 ml) was added to an EtOH (15 ml) solution containing methyl 2-chloro-5-nitrobenzoate (10 g), followed by stirring at 90° C. for 1 hour. The reaction solution was adjusted to room temperature. Water and concentrated hydrochloric acid (32 ml) were added dropwise to the reaction solution. A solid precipitate was collected by filtration and washed with water. A brown solid of 5-nitro-1H-indazol-3-ol (5.42 g) was thus obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>C(O)C>[CH:36]1([NH:39][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[C:22]2[CH:31]=[CH:30][C:29]3[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=3[CH:23]=2)[CH2:38][CH2:37]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCBr)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(OCCNC3CC3)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 61.2 %

Procedure:
In a manner similar to that of Example 1c, by reaction of 600 mg (1.15 mmol) of ethyl 4′-(2-bromoethoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 800 μl (11.5 mmol) of cyclopropylamine in 100 ml of ethanol. 360 mg of ethyl 4′-(2-cyclopropylaminoethoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (m.p.=141° C., yield=63%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: NC(=O)c1ccc(F)cc1N
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(F)ccc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 8.8 mmol) and 2-amino-4-fluorobenzamide (3.50 g, 23 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4-fluorobenzamide was isolated as a white solid (1.75 g, 43% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 6.67 (d, J=4.03 Hz, 1 H), 6.98-7.04 (m, 1 H), 7.47 (d, J=8.23 Hz, 2 H), 7.80 (d, J=4.03 Hz, 1 H), 7.89 (s, 1 H), 7.93-8.01 (m, 3 H), 8.40 (s, 1 H), 8.47 (dd, J=11.89, 2.74 Hz, 1 H), 12.95 (s, 1 H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.O.[NH2:15]N>C(O)C>[C:7]1([C:5]2[CH:4]=[CH:3][NH:2][N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)/C=C/C(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cc[nH]n2)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (2.63 g, 15 mmol) in ethanol (40 ml) was added hydrazine hydrate (1.459 ml, 30.0 mmol). The reaction was heated to 100° C. for 2 hours. Whereupon was cooled to room temperature and ethanol was removed by vacuum. The residue was partitioned between DCM and water. The organic phase was dried over MgSO4 and filtered. After evaporation the crude product was purified by triturating with a mixture of petroleumether and ethyl acetate. (Yield: 1.59 g, 73%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH2:6])[CH3:2].[C:12]([O:15][CH2:16][CH3:17])(=O)C.[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH3:12][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:7][CH2:5][C:4]([NH:6][C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:11])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:3]
Reactant: CCCCCCC
Reactant: CCOC(C)=O
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)CC
Product: CCOC(=O)[C@@H](NC(=O)CCCCCCCCCCCOC)[C@@H](C)CC

Procedure:
The title compound was prepared by the method of Example 14 using the title product of Example 44 (1.1 g, 4 mmol) instead of benzylamine. Chromatography of the crude residue on silica gel using 50--50 ethyl acetate-heptane as eluant gave the title compound (875 mg) as a white powder, m.p. 36.4-38.1° C. (DSC). The structure was supported by NMR, infrared spectroscopy, optical rotation ([α]36525 +81.9°, CHCl3), elemental analysis, and mass spectroscopy.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].[O:21]1CCOCC1>O>[NH2:3][C:4]1[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:21])=[O:1]
Reactant: C1COCCO1
Reactant: O=C1Cc2cccc(Nc3ccccc3Cl)c2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1Nc1ccccc1Cl

Procedure:
A mixture of 2-oxo-7-(2-chloroanilino)indoline (5 g.), sodium hydroxide (1.25 g.), dioxane (30 ml.) and water (60 ml.) was refluxed under heating for 53 hours with stirring. After cooling, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in water (50 ml.), washed with ethyl acetate, adjusted to pH 4 to 5 with 5% sulfuric acid and then extracted with ethyl acetate (150 ml.). The extract was evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel (60 g.) and eluted with ethyl acetate to give 2-[2-amino-3-(2-chloroanilino)phenyl]acetic acid (2.4 g.). mp 230° to 232° C.
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=3[CH:24]=2)=[CH:5][CH:4]=1.Cl[C:26]1C=CC=C(C(OO)=O)C=1.[S:36]([O-:40])([O-])(=[O:38])=S.[Na+].[Na+]>C1COCC1>[CH3:26][S:36]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=3[CH:24]=2)=[CH:7][CH:8]=1)(=[O:40])=[O:38]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(SC)cc3)ccc2OCC1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ccc2OCC1
Reaction time: 1 h

Procedure:
To a solution of ethyl 7-(4-methylthiophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (198.5 mg) in THF (20 ml) was added at 0° C. 70% 3-chloroperbenzoic acid (317 mg), and the mixture was stirred at 0° C. for 30 minutes and then at room temperature for 1 hour. To the mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes and then extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:1) to give colorless crystals of ethyl 7-(4-methylsulfonylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (221.8 mg).
Reaction SMILES: Cl[C:2]1([CH2:10][C:11]#[C:12][CH2:13][CH3:14])[C:7](=[O:8])[CH2:6][CH2:5][CH2:4]C1=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:10]([C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH:4]=1)[C:11]#[C:12][CH2:13][CH3:14]
Reactant: CCC#CCC1(Cl)C(=O)CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCC#CCC1=CCCC1=O

Procedure:
treating a solution of the resulting 2-chloro-2-(pent-2-ynyl)-cyclohexane-1,3-dione in xylene with anhydrous sodium carbonate to yield 2-(pent-2-ynyl)-cyclopent-2-enone;
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Cl[CH2:17][C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH:22]=1>CN(C)C=O.O>[O:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH:22]=[C:18]1[CH2:17][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:12])[C:3]([OH:2])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: ClCc1cc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C(=O)c1ccc(OCc2cc3ccccc3o2)cc1
Reaction time: 0.17 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.52 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.405 g), stirred for 10 minutes and treated with 2-chloromethylbenzofuran (1.4 g). The mixture was stirred at room temperature under argon for 3 hours, diluted with water, and extracted with ethyl acetate. Evaporation of the organic extracts provided crude methyl ester as a liquid. Treatment of a portion of this ester (1.02 g) with potassium hydroxide (0.18 g) in a methanol-water mixture, followed by acidification of the mixture with hydrochloric acid and filtration provided 4-[[2-benzofuranyl)methoxy]-alpha-oxobenzeneacetic acid as a white solid, mp 120° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[S:13][C:14]([CH2:32][CH3:33])=[C:15]([C:30]#[N:31])[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])=[CH:19][CH:18]=1)=[O:11])[CH3:8].[CH2:34](I)[CH2:35][CH3:36].Cl>CN(C=O)C>[CH2:7]([O:9][C:10]([C:12]1[S:13][C:14]([CH2:32][CH3:33])=[C:15]([C:30]#[N:31])[C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:34][CH2:35][CH3:36])=[CH:21][CH:22]=1)=[O:11])[CH3:8]
Reactant: CCCI
Reactant: CCOC(=O)c1sc(CC)c(C#N)c1-c1ccc(-c2ccccc2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccccc1-c1ccc(-c2c(C(=O)OCC)sc(CC)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add K2CO3 (220 mg, 1.6 mmol) to a solution of 4-cyano-5-ethyl-3-(2′-hydroxy-biphenyl-4-yl)-thiophene-2-carboxylic acid ethyl ester (200 mg, 0.53 mmol) in 2 mL of dry DMF at 0° C. and stir at this temperature for 1 hour. Treat with n-propyl iodide (0.2 mL, 2 mmol) and allow to warm to room temperature. After 3 hours pour into 25 mL cold 0.2N HCl. Extract with EtOAc (2×50 mL) and wash the combined EtOAc layers with water (2×20 mL) and brine (1×20 mL). Dry over Na2SO4, filter and evaporate to an oil. Chromatograph on silica gel (1/9-1/3 EtOAc/hexanes) to give the title compound as a tan solid, 158 mg (71%). HPLC=99%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1)=[O:3].[F:11][C:12]([F:23])([F:22])[C:13]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[NH:15][N:14]=1>>[F:23][C:12]([F:11])([F:22])[C:13]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)[N:14]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Product: CC(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 4-iodoacetophenone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 7.
Reaction SMILES: [C:1]([O:6]CC)(=O)[CH:2]([CH3:4])[OH:3].[CH2:9]([CH2:11][NH2:12])[OH:10]>C(O)C>[OH:10][CH2:9][CH2:11][NH:12][C:1](=[O:6])[CH:2]([CH3:4])[OH:3]
Reactant: NCCO
Reactant: CCOC(=O)C(C)O
Solvent: CCO
Product: CC(O)C(=O)NCCO
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 70.8 gm (0.6 mole) of ethyl lactate and 36.6 gm (0.6 mole) of ethanolamine were stirred together at 60° C. for 16 hours, and the ethanol formed was subsequently distilled off under reduced pressure. 71 gm (89% of theory) of light yellow, viscous N-(2-hydroxyethyl)-lactic acid amide of refractive index (nD20) 1.4850 were obtained.
Reaction SMILES: [CH:1]1([S:7]([CH2:10][CH2:11][CH2:12][OH:13])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][CH2:11][CH2:10][S:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:8])=[O:9])(=[O:24])=[O:23]
Reactant: O=S(=O)(CCCO)C1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCS(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-cyclohexylsulfonyl-1-propanol (37 g) and triethylamine (30 ml) in methylene chloride (400 ml) was treated dropwise at -5° C. with methanesulfonyl chloride (15 ml). After stirring for 2 h at room temperature the mixture was washed with water and dried over magnesium sulfate. Removal of solvent in vacuo gave a viscous oil (49 g) of 3-cyclohexylsulfonyl-1-propyl methanesulfonate.