Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[CH2:24][C@H:23]([OH:25])[CH2:22]2)=[CH:17][CH:16]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([C@H:21]2[CH2:24][C@H:23]([OH:25])[CH2:22]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc([C@H]4C[C@H](O)C4)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc([C@H]4C[C@H](O)C4)cc3)cc12
Temperature: 90 °C
Reaction time: 5 h
Yield: 53.5 %

Procedure:
To a solution of methyl 6-chloro-5-[4-(trans-3-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylate (290 mg, 0.82 mmol) in methanol/water (20 mL, v/v=1/1) was added sodium hydroxide (326 mg, 8.17 mmol). The mixture was stirred at 90° C. for 5 hours. The mixture was then acidified with 1 M HCl to pH˜5. The resulting suspension was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to give the title compound (150 mg, 54%) as a white solid. MS (AP+) 342.0 (M+H)+: 1H NMR (500 MHz, CD3OD) δ 8.03 (s, 1 H), 8.02 (s, 1 H), 7.59 (s, 1 H), 7.41 (d, 2 H), 7.34 (d, 2 H), 4.53-4.50 (m, 1 H), 3.67-3.65 (m, 1 H), 2.55-2.43 (m, 4 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22](S(C)=O)=[N:23][CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:24]=[N:23][C:22]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[N:21][CH:20]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn3c(-c4cnc(S(C)=O)nc4)cnc3s2)cc1OC
Reactant: CN(C)CCN
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3c(-c4cnc(NCCN(C)C)nc4)cnc3s2)cc1OC
Temperature: 85 °C
Yield: 65.9 %

Procedure:
2-(3,4-Dimethoxy-phenyl)-5-(2-methanesulfinyl-pyrimidin-5-yl) -imidazo[2,1-b][1,3,4]thiadiazole (66 mg, 0.164 mmol, 1 eq) was dissolved in 1,4-dioxane (min. volume) at 75° C. N,N-dimethylethylenediamine (0.053 ml, 0.493 mmol, 3 eq) was added, and the solution was heated at 85° C. for 4 h. The solvent was removed, and the residue was triturated in Et2O, filtered and washed with more solvent to give the desired product as a pale yellow solid (46 mg, 66%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=2.87 min, [M+H]+ m/z 426.3; 1H NMR (300 MHz, CDCl3) δ 8.84 (s, 2H), 7.43-7.38 (m, 3H), 6.93 (d, J=9.0 Hz, 1H), 5.86 (s, 1H), 3.95 (d, J=9.0 Hz, 7H), 3.52 (dd, J=11.4, 5.7 Hz, 2H), 2.56 (t, J=6.0 Hz, 2H), 2.28 (s, 7H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C@@H:7]3[C:12]4[C:17]([CH2:18][C@@H:6]3[C:5]=2[CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4.I[CH3:20].[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:20])[C@@H:7]3[C:12]4[C:17]([CH2:18][C@@H:6]3[C:5]=2[CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: CI
Reactant: COc1ccc2c(c1)[C@H]1Cc3ccccc3[C@H]1N2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[C@H]1Cc3ccccc3[C@H]1N2C

Procedure:
Using the same procedure as described in Example 2 for cis-4b,5,9b,10-tetrahydro-8-methoxyindeno[1,2-b]indole (239 mg, 1.0 mmol) was methylated with iodomethane, using sodium hydride (25 mg, 1.1 mmol) as the base, in THF (2 cm3). Extraction work-up (into diethylether), and purification by "suction" flash chromatography, yielded a clear gum. Yield: 158 mg, (63%) which solidified after bulb to bulb distillation (180° C. at 0.2 mm Hg), giving the title compound M.p. 72° C. 1H NMR (CDCl3) δ: 2.87 (3H, s,), 3.03 (1H, dd,), 3.36 (1H, dd,), 3.70 (3H, s,), 4.08 (1H, ddd,), 4.80 (1H, d,), 6.28 (1H, d,), 6.61 (1H, dd,), 6.77 (1H, dd,), 7.1-7.5 (4H, m,).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:31]2[CH2:30][CH2:29][N:28]([CH:27]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:33][CH2:32]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Fc1ccc(C(OCCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c2ccc(F)cc2)cc1

Procedure:
A mixture containing 12.7 g of 2-[bis(4-fluorophenyl)methoxy]ethyl chloride, 8.6 g of 1-[bis(4-fluorophenyl)methyl]piperazine, 6.2 g of powdered anhydrous potassium carbonate and 0.5 g of potassium iodide in 90ml of methyl isobutyl ketone is refluxed for 20 hours while stirring. Aftercooling down, the mixture is evaporated under reduced pressure and water and ethyl ether are added to the residue. The ethereal phase is washed with water, dried over anhydrous magnesium sulfate and evaporated. The crude product is purified on a Kieselgel column by using a 2:1 mixture of benzene and chloroform as eluant. The appropriate fractions are combined, evaporated and the residue is recrystallized from ethanol to give the aimed compound, m.p.: 87°-88° C.
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[N:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:7]([CH3:23])=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.C1COCC1.Cl[C:41]([O:43][CH3:44])=[O:42]>N1C=CC=CC=1>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[N:4]3[N:3]=[C:2]([NH:1][C:41]([O:43][CH3:44])=[O:42])[N:34]=[C:5]3[N:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=3)[C:7]([CH3:23])=[C:8]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH:12]=1)#[N:17]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(N)nn2C1c1ccc(C#N)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(NC(=O)OC)nn2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, ethyl 2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (10 mg, 21 μmol) was dissolved in a mixture of abs. THF (3 ml) and abs. pyridine (3 ml). At 0° C., methyl chloroformate (17 mg, 180 μmol, 8.5 eq.) was added in two portions and the mixture was stirred for 12 h with warming to RT. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (10.8 mg, 96% of theory).
Reaction SMILES: [CH2:1]([O:19][C@@H:20]1[C@H:24]([OH:25])[C@@H:23]([CH2:26][OH:27])[O:22][C@H:21]1[N:28]1[C:38]2[N:37]=[C:35]([NH2:36])[NH:34][C:32](=[O:33])[C:31]=2[N:30]=[CH:29]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][CH2:16][CH2:17][CH3:18].C[Si](Cl)(C)C.[C:44](Cl)(=[O:48])[CH:45]([CH3:47])[CH3:46].[OH-].[NH4+]>N1C=CC=CC=1.O>[C:44]([NH:36][C:35]1[NH:34][C:32](=[O:33])[C:31]2[N:30]=[CH:29][N:28]([C:38]=2[N:37]=1)[C@@H:21]1[O:22][C@H:23]([CH2:26][OH:27])[C@@H:24]([OH:25])[C@H:20]1[O:19][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][CH2:16][CH2:17][CH3:18])(=[O:48])[CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)C(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
2′-O-octadecylguanosine (1.9 g) in pyridine (150 ml) was cooled in an ice bath, and treated with trimethylsilyl chloride (2 g, 5 eq) and isobutyryl chloride (2 g, 5 eq). The reaction mixture was stirred for 4 hours, during which time it was allowed to warm to room temperature. The solution was cooled, water added (10 ml) and stirred for an additional 30 minutes. Concentrated ammonium hydroxide (10 ml) was added and the solution concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with 3% MeOH/EtOAc) to yield 1.2 g of product.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](=O)[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:7]#[N:8])[CH3:2].Cl.Cl.[NH2:19][NH2:20]>C(O)C>[CH2:1]([O:3][CH2:4][C:5]1[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[C:7]([NH2:8])[NH:20][N:19]=1)[CH3:2]
Reactant: NN
Reactant: CCOCC(=O)C(C#N)c1ccc(C)cc1
Agent: Cl
Solvent: CCO
Product: CCOCc1n[nH]c(N)c1-c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
4-Ethoxy-2-(4-methylphenyl)-3-oxobutanenitrile (1.493 g) is dissolved in ethanol (50 mL). After adding hydrazine 2HCl (1.10 g), TEA (0.85 mL) and molecular sieve, the reaction mixture is heated to 80° C. After stirring for 15 hours and cooling to room temperature, the molecular sieve is removed by filtering. The reaction solvent is removed under reduced pressure. After the reaction is terminated by adding saturated aq. NaHCO3, the reaction mixture is extracted 3 times with ethyl acetate. The organic layer is washed with water and dehydrated with MgSO4. After concentration under reduced pressure, the produced solid is recrystallized to obtain the target compound (90%). 1H NMR (CDCl3, 300 MHz): δ 7.26 (m, 2H), 7.02 (m, 2H), 6.80 (br, 2H), 4.20 (s, 2H), 3.38 (m, 2H), 2.24 (s, 3H), 1.06 (t, 3H).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([C:32]([F:35])([F:34])[F:33])(=[O:31])=[O:30])=[CH:25][C:24]=3[N+:36]([O-:38])=[O:37])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)(C)C.O1CCCC1>[N+:36]([C:24]1[CH:25]=[C:26]([S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:31])[CH:27]=[CH:28][C:23]=1[O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:39])=[O:3])=[CH:12][CH:11]=2)(=[O:15])=[O:14])=[CH:21][CH:20]=1)([O-:38])=[O:37]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)c2ccc(Oc3ccc(S(=O)(=O)C(F)(F)F)cc3[N+](=O)[O-])cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C(O)COc1ccc(S(=O)(=O)c2ccc(Oc3ccc(S(=O)(=O)C(F)(F)F)cc3[N+](=O)[O-])cc2)cc1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
A mixture of {4-[4-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-benzenesulfonyl]-phenoxy}-acetic acid ethyl ester [Example 17, 61 mg, 0.1 mmol] in isopropanol (3.1 mL) and tetrahydrofuran (0.6 mL) was heated to reflux to dissolve all the solids. The mixture was cooled to 35° C. followed by addition of 1M NaOH solution (0.21 mL). It was then stirred at 35° C. for 2 hours. The reaction was concentrated, acidified with 1M HCl and extracted with ethyl acetate. The organic extracts were dried and concentrated to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.2 (br s, 1H, COOH), 10.57 (s, 1H), 8.36 (d, J=2.6 Hz, 1H), 7.79 (m, 1H), 7.78 (d, J=9.0 Hz, 2H), 7.72 (d, J=8.8 Hz, 2H), 7.06 (d, J=9.0 Hz, 2H), 7.01 (d, J=9.3 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 4.77 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C@H:9]2[C@H:13]([OH:14])[CH2:12][N:11]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:10]2)=O)=[CH:4][CH:3]=1>S(Cl)(Cl)(=O)=O>[ClH:1].[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[O:14][C:13]3[CH2:12][N:11]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:10][C:9]=3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CN(C2CCCCC2)C[C@H]1O)c1ccc(Cl)cc1
Solvent: O=S(=O)(Cl)Cl
Product: Cl
Product: Clc1ccc(-c2nc3c(o2)CN(C2CCCCC2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Two grams of trans-4-chloro-N-(1-cyclohexyl-4-hydroxy-3-pyrrolidinyl)benzamide was dissolved in 50 ml of cold (0° C.) sulfonyl chloride; the solution was allowed to warm to room temperature and stirred overnight. Excess sulfonyl chloride was removed at 50° C./60 mm. Fifty milliliters of carbon tetrachloride was added to the residue and then evaporated under vacuum. When acetone was added to the residue, it crystallized to a white solid (quantitative yield). Recrystallization from absolute ethanol gave product, m.p. 303°-304° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.C([O:23][C:24]1[C:25](=[O:34])[C:26](=O)[C:27]=1[NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])CCC>O1CCCC1>[C:29]([NH:28][C:27]1[C:24](=[O:23])[C:25](=[O:34])[C:26]=1[NH:6][CH2:5][C:4]1[C:3]([Cl:2])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:11])([CH3:32])([CH3:30])[CH3:31]
Reactant: NCc1c(Cl)cccc1Cl
Reactant: CCCCOc1c(NC(C)(C)C)c(=O)c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1c(NCc2c(Cl)cccc2Cl)c(=O)c1=O
Reaction time: 16 h
Yield: 38.1 %

Procedure:
To 2,6-dichlorobenzylamine hydrochloride from Example 5, Step 2 (1.06 g, 5.0 mmol) in tetrahydrofuran (10 mL ) was added triethylamine (0.505 g, 5.0 mmol) followed by 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (1.13 g, 5.0 mmol, Example 1) and stirring was continued for approximately 16 hours. The reaction mixture was freed of solvent and the residue was triturated with water, with diethyl ether and dried. The white solid thus isolated was crystallized twice from methanol to give 0.623 g (38%) of the title compound as a white solid: mp 265°-6° C. dec (softens 263° C.); 1H NMR (DMSO-d6) δ7.55 (d, 2H), 7.49 (br m, 1H), 7.42 (m, 2H), 5.05 (d, 2H), 1.34 (s, 9H) ppm. IR (KBr): 3185, 1785, 1660 cm-1 ; MS (m/z) 326/328/330 (M+). HPLC indicates a major component (99.9%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][C:34](O)=[O:35]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[CH2:33][CH:29]5[CH2:30][CH2:31][CH2:32][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)CC1CCCO1
Agent: Cl
Product: O=C(CC1CCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (45 mg, 64%), MS (ISP) m/z=443.5 [(M+H)+], mp 173.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) rac-(tetrahydro-furan-2-yl)-acetic acid.
Reaction SMILES: N[C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([F:14])([F:13])[F:12])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2.[OH:23][C:24]([CH3:39])([C:28]([NH:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[O:29])[C:25]([OH:27])=O.O.O[N:42]1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[OH:23][C:24]([CH3:39])([C:25]([NH2:42])=[O:27])[C:28]([N:30]([C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([F:14])([F:12])[F:13])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2)[CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[O:29]
Reactant: CC(O)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: On1nnc2ccccc21
Reactant: N[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(C(N)=O)C(=O)N(CC(F)(F)C(F)(F)F)[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A solution of 144 mg (0.47 mmol) (S)-7-amino-5-(2,2,2-trifluoro-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 125 mg (0.47 mmol) (RS)-2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in 21 ml tetrahydrofuran were reacted at room temperature with 73.6 mg (0.47 mmol) 1-hydroxy-benzotriazole hydrate, 165 μl (0.94 mmol) diisopropylethylamine and 92.1 mg (0.47 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride. Stirring was continued overnight. Removal of the solvent by distillation and chromatography on silicagel with ethylacetate/heptane (gradient 15/85 to 40/60) yielded 207 mg (79%) (R/S)-2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N-(2,2,3,3,3-pentafluoro-propyl)-malonamide as a white solid, MS (m/e): 554.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[C:15]([CH3:22])[CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH3:23])[C:9]2[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>CN(C)C=O>[ClH:1].[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:2]2[N:11]=[C:10]([N:12]3[CH2:21][CH2:20][C:19]4[C:14](=[C:15]([CH3:22])[CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH3:23])[C:9]3[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:29][CH:28]=1
Reactant: COc1cccc2c(N3CCc4cccc(C)c4C3C)nc(Cl)nc12
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4cccc(C)c4C3C)nc(Nc3ccc(F)cc3)nc12
Product: Cl
Yield: 49 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 3.3 g of the compound(9 mM) prepared in Example 14 and 15 ml of dimethylformamide, 1.9 ml of 4-fluoroaniline(20 mM) was added, 1.14 g of the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:27](O)=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([O:46][CH3:47])=[O:45])=[CH:40][CH:39]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:27]([NH:36][CH2:37][C:38]4[CH:39]=[CH:40][C:41]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:43]=4)=[O:28])=[CH:24][CH:25]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C(O)C(c1ccc(Cn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)cc1)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNC(=O)C(c2ccc(Cn3nc(-c4ccc(Cl)cc4)c4ccccc4c3=O)cc2)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mg (0.127 mmol) of (4-{[4-(4-chlorophenyl)-1-oxophthalazin-2(1H)-yl]methyl}phenyl)(cyclopentyl)acetic acid (Example 65A) were dissolved in 0.6 ml of dichloromethane, and 26 mg (0.127 mmol) of methyl 4-(aminomethyl)benzenecarboxylate hydrochloride, 19 mg (0.140 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 28 mg (0.146 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 28 mg (0.273 mmol) of triethylamine were added in succession. The reaction mixture was stirred at room temperature overnight. 1 N hydrochloric acid was then added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC. This gave 36 mg (46% of theory) of the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.CS([Cl:17])(=O)=O>C(Cl)Cl>[Cl:17][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CCl)cc1
Temperature: 25 °C

Procedure:
To a solution of 100 g (0.60175 moles) of methyl 4-hydroxymethylbenzoate in 600 mL of dry CH2Cl2. add 109 mL (79.1 g) of TEA and cool the so-formed reaction mixture to 0° C. Add, dropwise over a 2 hour period, 55.8 mL (0.722 mole, 1.2 eq) of methanesulfonyl chloride in 150 mL of dry CH2Cl2. Allow the so-formed stirred reaction mixture to warm slowly to room temperature over a 48 hr period. TLC shows no starting material remains. Add water, separate the layers and wash the organic layer successively with water, saturated NaHCO3 and brine. Dry the organic layer over Na2SO4. Remove the organic solvent under reduced pressure to produce 98.45 g of (88.6 % of theory) of the title compound as a crystalline solid. ##STR120##
Reaction SMILES: C([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N.S(=O)(=O)(O)O.C(OCC)(=O)C>COCC(O)C>[CH:11]#[C:10][C:9]1[CH:12]=[CH:13][C:6]([OH:5])=[CH:7][CH:8]=1
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: COCC(C)O
Product: C#Cc1ccc(O)cc1
Reaction time: 8 h

Procedure:
In 80 g of propylene glycol monomethyl ether was dissolved 88 g of p-t-butoxystyrene, and then, 2 g of azobisisobutyronitrile was added to the solution, after which they were subjected to polymerization for 10 hours under a nitrogen atmosphere while the reaction temperature was kept at 80° C. After the polymerization, an aqueous sulfuric acid solution was added to the reaction mixture and the resulting mixture was subjected to hydrolysis at 80° C. for 8 hours. Subsequently, ethyl acetate was added to the reaction mixture and the resulting mixture was washed with water, after which the solvent was replaced by acetone. The resulting resin solution was dropped into a large amount of water to coagulate a resin. The resin was recovered and dried in a vacuum drier kept at 50° C. overnight to obtain 48 g of a white fine powder of poly(p-hydroxystyrene).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:11](/[CH:12]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2ccc(F)cc2nc1Cl
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C/c1cc2ccc(F)cc2nc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a solution of 2-chloro-7-fluoroquinoline-3-carboxaldehyde (6.3 g, 30 mmol) in dry THF (200 mL) under nitrogen was added titanium isopropoxide (17.0 g, 60 mmol) and the reaction mixture stirred at r.t. for 10 minutes. (R)-2-Methyl-2-propanesulfin-amide (3.6 g, 30 mmol) was added to the reaction mixture which was stirred at r.t. for 72 h and partitioned between water (20 mL) and DCM (150 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the title compound (7.2 g, 76%) as a pale yellow solid. δH (CDCl3) 9.09 (1H, s), 8.83 (1H, s), 7.96 (1H, dd, J=6.0 Hz), 7.69 (1H, d, J=7.2 Hz), 7.42 (1H, t, J=8.4 Hz), 1.32 (9H, s).