Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43]>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[CH2:39][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:19]1=[O:18])[CH3:2]
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: CCc1ccccc1N
Agent: NCC1CCCCC1
Product: CCc1ccccc1NC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-ethylaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[4(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-ethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (95%) as a colorless solid: mp 184-186° C.; 1H NMR (300 MHz, DMSO-d6) δ10.06 (s, 1H), 7.69-7.61 (m, 1H), 7.50-7.34 (m, 3H), 7.31-7.13 (m, 6H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.40 (s, 1H), 5.20-5.01 (m, 2H), 4.86 (d, J=8.9 Hz, 1H), 4.72 (d, J=8.9 Hz, 1H), 4.47 (t, J=8.7 Hz, 2H), 2.93 (t, J=8.7 Hz, 2H), 2.68 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.9, 168.1, 161.6, 161.2, 142.8, 139.8, 136.4, 135.8, 134.5, 132.7, 130.8, 129.1, 129.0, 128.3, 127.9, 127.8, 127.0, 126.9, 126.5, 124.2, 123.6, 120.9, 120.4, 119.6, 109.7, 92.9, 80.4, 72.6, 57.5, 41.4, 28.8, 24.5, 14.8; MS (ES+) m/z 517.2 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C@@H:10]2[CH2:20][OH:21])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C@@H:10]2[CH2:20][OH:21])=[CH:7][CH:8]=1)=[O:30]
Reactant: CSc1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CO)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CO)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of sulfide 18 (5 g, 16.7 mmol) in dichloromethane (200 mL) at −78° C. was added m-chloroperbenzoic acid (3.6 g, 16.7 mmol) in dichloromethane (150 mL) over a span of 10 minutes. The resulting mixture was stirred at −78° C. for 30 minutes. The reaction was quenched with aqueous NaHCO3 at −78° C. Extraction with dichloromethane (3×200 mL) afforded 5.22 g of the desired sulfoxide as a white solid, upon concentration. 1H NMR (200 MHz, CDCl3) 2.72 (s, 3H), 3.80-3.90 (m, 1H), 4.05-4.15 (m, 1H), 4.20-4.30 (m, 1H), 5.61 (d, J=8 Hz, 1H), 7.35-7.55 (m, 5H), 7.68 (t, J=9 Hz, 2H), 8.0 (d, J=9 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12]C[CH:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.C1(C(=NC2C=CC([C@@H]3CCC(=CC(OCC)=O)C3)=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C:10](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1CCCC(c2ccc(N)cc2)C1
Agent: CCOC(=O)C=C1CC[C@@H](c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)C1
Product: CCOC(=O)C=C1CC[C@@H](c2ccc(N)cc2)C1

Procedure:
Following the procedure described for ethyl [3-(4-aminophenyl)cyclohexyl]acetate (Intermediate 891v), replacing ethyl (3-{4[(diphenylmethylene)amino]phenyl}cyclohexyl)acetate with ethyl ((3R)-3-{4-[(diphenylmethylene)amino]phenyl}cyclopentylidene)acetate the title compound was obtained; 1H NMR δ 1.17-1.22 (3H, m), 1.57-1.68 (1H, m), 2.27-2.48 (2H, m), 2.53 (OH, s), 2.56-2.68 (1H, m), 2.74-2.76 (1H, m), 2.93-3.00 (1H, m), 3.15-3.24 (0.5H, m), 3.69-3.71 (0.5H, m), 4.01-4.12 (2H, m), 4.79-4.83 (2H, m), 5.49-5.53 (1H, m), 5.78-5.82 (1H, m), 6.47-6.52 (2H, m), 6.80-6.93 (2H, m); MS m/e M+MeCN 287.07
Reaction SMILES: [N+]([O-])(O)=O.[C:5]([NH:8][C:9]1[C:10]([Cl:17])=[N:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=1)(=[O:7])[CH3:6].[O-:18][Mn](=O)(=O)=O.[K+]>O.CC(C)=O>[C:15]([C:12]1[N:11]=[C:10]([Cl:17])[C:9]([NH:8][C:5](=[O:7])[CH3:6])=[CH:14][CH:13]=1)(=[O:18])[CH3:16]
Reactant: CCc1ccc(NC(C)=O)c(Cl)n1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: O=[N+]([O-])O
Product: CC(=O)Nc1ccc(C(C)=O)nc1Cl
Temperature: 20 °C

Procedure:
4.937 g (0.124 mol) of MgO are suspended in 112 ml of water and the suspension is brought to pH 6 with about 16.7 ml (0.242 mol) of 65% strength HNO3. 10 g (49.4 mmol) of 3-acetamido-2-chloro-6-ethylpyridine, dissolved in 112 ml of acetone, are then added, 19.5 g (0.124 mol of KMnO4 are introduced and the mixture is stirred at 20° C. until the reaction is complete (48 hours). The solid is then filtered off with suction and the filter cake is washed thoroughly with hot acetone. The filtrate is diluted with 500 ml of water and extracted three times with 200 ml of CHCl3 each time, and the combined extracts are washed with water, dried with Na2SO4 and evaporated. For purification, the product is recrystallized from toluene/petroleum ether.
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1.CC([O-])=O.[K+].CC(O)=O>CO.O>[C:22]([O:21][CH2:20][C@H:18]1[O:19][C@@H:7]([N:6]2[C:5]3[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=3[N:3]=[C:2]2[Br:1])[C@H:8]([OH:9])[C@@H:13]1[OH:14])(=[O:24])[CH3:23]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 52a (1.048 g, 2.0 mmol) and KOAc (0.98 g, 10.0 mmol) in MeOH/H2O (40 mL/4 mL) was stirred at room temperature for 24 hr. AcOH (0.572 mL, 10.0 mmol) was added and stirring was continued at room temperature for 15 min. The reaction mixture was evaporated and the residue was partitioned between EtOAc/H2O (75 mL/75 mL). The EtOAc layer was washed with sat. NaCl solution (75 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (1.9×24 cm, eluted with CHCl3, 2%, 3%, 4% MeOH/CHCl3). Evaporation of fractions 15-27 (15 mL per fraction) and recrystallization from MeOH gave 0.50 g (2 crops, 57%) of 52b as white crystals. MP: 85°-95° C. (melted slowly over a large range) MS: (EI) m/e 437.9398 (15%, M+ =437.9385). 1H NMR (DMSO-d6): d 8.00, 7.95 (2×s, 2, 7-H and 4-H), 5.90 (d, 1, 1'-H, J1'-2' =7.5 Hz), 5.58 (d, 1, 2'-OH, J2'-2'OH =6.5 Hz), 5.46 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.44 (dd, 1, 5'H, J5'-4' =4.5 Hz, J5'-5" =12.5 Hz), 4.43 (m, 1, 2'-H, J2'-3' =6.0 Hz), 4.24 (dd, 1, 5"-H, J5"-4' =2.0 Hz), 4.16 (m, 1, 4'-H, J3'-4' =3.0 Hz), 4.11 (m, 1, 3'-H), 2.15 (s, 3, 5'-OAc). 13C NMR (DMSO-d6): d 169.96 (COCH3), 142.57 (C3a), 132.49, 132.42 (C2 and C7a), 125.78, 125.74 (C5 and C6), 120.14 (C4), 113.28 (C7), 90.32 (C1'), 82.56 (C4'), 71.27 (C2'), 68.90 (C3'), 63.34 (C5'), 20.58 (COCH3). Anal. Calcd. for C14H13BrCl2N2O5 : C, 38.21; N, 6.37. Found: C, 38.37; H, 2.86; N, 6.27.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30](OCC)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([NH:36][CH2:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCN1CCOCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NCCCN3CCOCC3)c(O)c3ncc(Cc4ccccc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and N-(3-aminopropyl)morpholine employing methods similar to those described in Example 5 and was obtained as a white solid: 1H NMR (CDCl3) δ 13.29 (1H, br), 10.31 (1H, t, J=6 Hz), 8.62 (1H, d, J=1 Hz), 7.82 (2H, d, J=8.3 Hz), 7.30 (3H, m), 7.18 (2H, d, J=8.3 Hz), 7.07 (1H, s), 7.03 (2H, m), 5.40 (2H, br), 4.32 (2H, m), 4.06 (2H, s), 3.97 (2H, m), 3.60 (2H, m), 3.46 (2H, m), 3.08 (2H, m), 3.02 (3H, s), 2.87 (2H, m), 2.34 (2H, m); HRMS calcd for C31H34N4O6S+H+: 591.2277. Found: 591.2277.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]([S:14]Cl)=[O:13]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:12](=[O:13])[S:14][N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: O=c1oc(-c2ccc(F)cc2)ns1
Temperature: 60 °C

Procedure:
To a stirred suspension of 4-fluorobenzamide (70.00 g, 503.1 mmol) in toluene (900 mL) was added chlorocarbonyl sulfenyl chloride (83.0 mL, 1.00 mol). The mixture was heated overnight at 60° C. and concentrated. The resulting tan solid was triturated with methylene chloride (200 mL), collected by suction filtration and rinsed with additional methylene chloride (4×70 mL). The crude product was impregnated onto silica (100 g) and chromatographed in a large filter funnel dry loaded with silica using a hexane/ethyl acetate gradient. The product 5-(4-fluorophenyl)-1,3,4-oxathiazol-2-one was afforded as an off-white solid (55.98 g, 56%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:9]=1.CC(C)=[O:26]>>[C:8]([OH:26])(=[O:7])[CH3:17].[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([N:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[N:9]=1
Reactant: CC(C)=O
Agent: O[C@@H]1CCC[C@H]1Oc1nc(N2CCNCC2)nc2ccccc12
Product: CC(=O)O

Procedure:
4-[trans-(2-Hydroxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (cf. Example 1) (2.70 g) is dissolved in acetone (55 ml) with heating, and the solution is filtered, and to the filtrate is added acetic acid (0.52 ml), and the mixture is allowed to stand at room temperature. The precipitated crystals are separated by filtration to give 4-[trans-(2-hydroxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)quinazoline monoacetate (3.00 g) as crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4](=[O:15])[CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:23][S:24]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[C:4](=[O:15])[CH2:3]1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1=O
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 65981.7 %

Procedure:
A 100-mL round-bottom flask was charged with a solution of tert-butyl 4-hydroxy-2-oxopiperidine-1-carboxylate (1.00 g, 4.65 mmol) in dichloromethane (30 mL). Triethylamine (1.03 mL, 7.42 mmol) and 4-dimethylaminopyridine (0.057 g, 0.47 mmol) were added, and the mixture was cooled to 0° C. Methanesulfonyl chloride (0.47 mL, 6.05 mmol) was added dropwise and the resulting solution stirred for 1 h at room temperature. The reaction mixture was washed with water (2×10 mL) and 0.1 M aqueous HCl solution (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford tert-butyl 4-(methylsulfonyloxy)-2-oxopiperidine-1-carboxylate (0. 900 g, 66%) as a brown solid. MS (ESI, pos. ion) m/z 294 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[H-].[Na+].F[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1[F:40]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([N:17]([C:31]4[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=4[F:40])[CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[C:11]=3[CH:10]=[N:9]2)=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COc1ccc(Cn2ncc3c(NCCN4CCOCC4)ccnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2ncc3c(N(CCN4CCOCC4)c4ccc([N+](=O)[O-])cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
1-(4-Methoxybenzyl)-N-(2-morpholinoethyl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.025 g, 0.06804 mmol) was charged to a pressure tube in DMF (1 mL). NaH (0.004082 g, 0.1021 mmol) was added, and the reaction was allowed to stir at room temperature for 15 minutes. 1,2-difluoro-4-nitrobenzene (0.009389 ml, 0.08505 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (25 mL) and washed with water (15 mL). The organics were then dried with brine, dried over Na2SO4, filtered and concentrated. Purification via flash Si 5 g eluting with 1-5% MeOH/DCM to afford 28 mg (80%) of product as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.32 (d, 1H), 8.14 (m, 2H), 7.61 (t, 1H), 7.30 (m, 2H), 6.82 (d, 3H), 6.43 (d, 1H), 5.54 (s, 2H), 4.05 (t, 2H), 3.75 (s, 3H), 3.59 (t, 4H), 2.76 (t, 2H), 2.44 (m, 4H); 19F NMR (376 MHz, CDCl3) −113.92 (s, 1F); LRMS (apci pos): 307.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C([Sn](=O)CCCC)CCC.O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: OCc1ccccc1
Agent: CCCC[Sn](=O)CCCC
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(O)cc1
Yield: 97.3 %

Procedure:
69.1 g (0.5 mole) of p-hydroxybenzoic acid, 216.2 g (2 moles) of benzyl alcohol and 1.4 g of dibutyltin oxide were fed into a four-necked glass flask, and reacted at 200° C. for 6 hours with stirring in an atmosphere of nitrogen. Water formed by the reaction and a small amount of phenol resulting from the decomposition of the p-hydroxybenzoic acid were distilled off from the reaction system. After the reaction, the excess of benzyl alcohol was evaporated under reduced pressure to give 111.0 g (yield 94.%) of crude benzyl p-hydroxybenzoate having a purity of 97.4%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][CH:16]([CH2:19][CH3:20])[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:15][CH:16]([CH2:19][CH3:20])[CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCC(C)CBr
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCC(C)COc1ccc(-c2ccc(O)cc2)cc1
Yield: 19.1 %

Procedure:
A solution of 0.20 mole(37.2 g) of 4,4'-dihydroxybiphenyl, 0.10 mole(15.1 g) of the above 2-methyl-1-bromobutane, and 0.60 mole(33.7 g) of potassium carbonate in 300 ml of ethanol was refluxed for 16 hours. After the reaction, the reaction solution was filtered and concentrated, then purified by column chromatography to obtain 4.9 g of 4'-(2-methylbutoxy)-4-hydroxybiphenyl. (yield: 58%)
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: NCCN1CCOCC1
Product: O=C(NCCN1CCOCC1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 67 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-(2-aminoethyl)morpholine (available from Aldrich Chemical Company, Inc.; 81 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(2-morpholin-4-yl-ethylcarbamoyl)-biphenyl-2-carboxylic acid (82 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (br s, 1H), 8.47 (s, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 1.8 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.94 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 2H), 3.90-4.10 (m, 2H), 3.50-3.72 (m, 4H), 3.27-3.44 (m, 4H), 3.08-3.23 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([Br:12])=[N:10][C:9]([Br:13])=[CH:8][N:7]=1)=[O:4].[I-:14].[Na+]>CC(C)=O.C(OCC)(=O)C>[Br:12][C:11]1[C:6]([NH:5][C:3](=[O:4])[CH2:2][I:14])=[N:7][CH:8]=[C:9]([Br:13])[N:10]=1
Reactant: [I-]
Reactant: O=C(CCl)Nc1ncc(Br)nc1Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(CI)Nc1ncc(Br)nc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
To a solution of 2-chloro-N-(3,5-dibromopyrazin-2-yl)acetamide (3.0 g, 9.11 mmol) in acetone (40 mL) was added sodium iodide (13.65 g, 91 mmol) dissolved in acetone (20 mL). Solution was allowed to stir at ambient temperature for 16 h. Solution was condensed under reduced pressure and diluted with ethyl acetate (500 mL) and washed consecutively with water (5×) to remove the blue color. Organics were dried over magnesium sulfate, filtered and solvent removed under reduced pressure to afford the crude product. The solid was diluted with 10% ethyl acetate in hexanes (40 mL) and sonicated while scraping the sides of the flask. The solution was then heated under a heat gun for 5 min, then cooled while sonicating at ambient temperature. The resulting solid was filtered and washed with additional hexanes and dried under vacuum to afford the title compound (3.0 g, 7.13 mmol, 78% yield). MS (ESI) m/z 420.3 [M−1]+, 422.0 [M+1]+, 424.0 [M+3]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([N:14]([CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)C(=O)CC(C)(C)C)[C:11](=[O:29])[N:10]2[CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([NH:14][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[C:11](=[O:29])[N:10]2[CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1ccc(CCN2C(=O)N(N(Cc3ccncc3)C(=O)CC(C)(C)C)CC2c2ccc(C)c(C)c2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCN2C(=O)N(NCc3ccncc3)CC2c2ccc(C)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 104.7 %

Procedure:
A solution of N-{4-(3,4-dimethylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-2-oxo-imidazolidin-1-yl}-3,3-dimethyl-N-pyridin-4-ylmethyl-butyramide (205 mg, 0.386 mmol) in CH2Cl2 (1.5 mL) is cooled in an ice bath and triethylsilane (0.129 mL, 0.81 mmol) is added, followed by trifluoroacetic acid (1.5 mL). The ice bath is removed and the reaction is stirred at ambient temperature for 2.5 hours. The reaction is concentrated to an oil, dissolved in ethyl acetate, and washed with 10% aqueous NaHCO3, and brine. The organic phase is dried (Na2SO4), treated with 2N HCl/ether (0.7 mL), and concentrated under reduced pressure. The solid which results is re-crystallized from dichloromethane/ether to afford 174 mg (76% yield) of the desired compound. 1H NMR (DMSO-d6) δ 8.92 (d, J=6.0 Hz, 2H), 8.21 (d, J=6.0 Hz, 2H), 7.14 (d, J=7.5 Hz, 1H), 7.00 (m, 4H), 6.82 (d, J=8.1 Hz, 2H), 4.38 (m, 3H), 3.74 (s, 3H), 3.72 (m, 1H), 3.44 (m, 1H), 3.14 (t, J=7.8 Hz, 1H), 2.68 (m, 1H), 2.52 (m, 1H), 2.24 (s, 3H), 2.20 (s, 3H). MS 431 (MH+). Anal. calcd. for C26H30N4O22HCl: C, 62.03, H, 6.41; N, 11.13. Found: C, 61.99, H, 6.41; N, 11.13.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12]C)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21]C>Br>[OH:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]3[O:21][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[C:3]=3[C:4](=[O:14])[NH:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(O)c(-c3ccccc3OC)c(=O)[nH]c2c1
Agent: Br
Product: O=c1[nH]c2cc(O)ccc2c2oc3ccccc3c12
Yield: 82.8 %

Procedure:
In 640 ml of 47% hydrobromic acid was suspended 8.0 g of 4-hydroxy-7-methoxy-3-(2-methoxyphenyl)-2quinolone, and the suspension was heated under reflux for 3-4 days. After cooling, the precipitates were collected by filtration, washed with water, and dried to obtain 5.6 g of 3-hydroxy-5H-benzofuro[3,2-c]quinolin-6-one.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([OH:13])[CH2:9][C:10]([NH2:12])=[O:11].S(O)(O)(=O)=O.CS[C:21](=[NH:23])[NH2:22].CSC(=N)N.Cl>[OH-].[Na+]>[ClH:1].[NH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([OH:13])[CH2:9][C:10]([NH2:12])=[O:11])[C:21]([NH2:23])=[NH:22]
Reactant: CSC(=N)N
Reactant: NCCCCCC(O)CC(N)=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N=C(N)NCCCCCC(O)CC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.3 %

Procedure:
To a solution of 670 mg of 8-amino-3-hydroxyoctanamide hydrochloride in 8 ml of 1N aqueous sodium hydroxide solution, was added 668 mg (2.4 mmoles) of S-methylisothiourea hemisulfate. The mixture was stirred overnight at room temperature. The reaction mixture was adjusted to pH 6 with 1N hydrochloric acid, evaporated to dryness and dissolved in 5 ml of 1M saline. The solution was passed through a column of 160 ml of Diaion® HP-20 (Mitsubishi Chemical Co.) and the column was eluted successively with 400 ml of 1M saline, 400 ml of 0.8M saline and 800 ml of 0.6M saline (15 g fraction size). Fractions No. 41 to No. 87 were combined, evaporated to dryness and extracted three times with 10 ml of methanol. The methanol layer was passed through a column of 300 ml of Sephadex® LH-20 and eluted with methanol to effect desalting (7 ml fraction size). Fractions No. 25 to 35 were combined and evaporated to dryness to obtain 687 mg (85% yield) of 8-guanidino-3-hydroxyoctanamide hydrochloride.