Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4](=O)[C:5]1C=C[CH:8]=[CH:7][CH:6]=1)([O-])=O.C1(O)C=CC=CC=1.[C:19]([OH:22])(=O)[CH3:20]>>[N:1]1[O:22][CH:19]=[C:20]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2
Reactant: O=C(c1ccccc1)[N+](=O)[O-]
Reactant: CC(=O)O
Solvent: Oc1ccccc1
Product: c1ccc2nocc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
α-Nitrobenzaldehyde (15.1 g, 0.100 mol) and phenol 9.46 (0.100 mol) were dissolved in 120 mL of glacial acetic acid in a three-necked round bottom flask. The flask was flushed with N2 (g), and the solution was cooled to 0° C. HCl (g) was bubbled through the solution and then through a sodium hydroxide solution to neutralize the acid. The reaction flask was fitted with a rubber stopper and the solution was allowed to warm to ambient temperature and then stirred for 2 h. HCl (g) was removed by bubbling N2 (g) through the solution. The resulting precipitate was filtered and washed with 15 mL of glacial acetic acid to afford 16.2 g (66%) of anthranil. The anthranil was directly reduced to 2-Amino-5-chloro-4'-hydroxybenzophenone (below) without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:15](I)=[CH:14]1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([CH:40]=1)[C:34](N(OC)C)=[O:35]>C1COCC1>[Br:28][C:29]1[CH:40]=[C:33]([C:34]([C:15]2[C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[N:13]([C:10]([CH3:12])([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:14]=2)=[O:35])[CH:32]=[N:31][CH:30]=1
Reactant: CON(C)C(=O)c1cncc(Br)c1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(Br)c2)c2cnccc21
Temperature: -5 °C
Reaction time: 0.75 h
Yield: 51.2 %

Procedure:
1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine (Preparation 65, 1.81 g, 4.20 mmol) was dissolved in THF (25 mL) and the solution was degassed and cooled to −5° C. 2M iPrMgCl in THF (2.52 mL, 5.05 mmol) was added dropwise and the reaction stirred at this temperature for 45 minutes. A solution of 5-bromo-N-methoxy-N-methylnicotinamide (1.24 g, 5.05 mmol) in THF (3 mL) was added dropwise and the reaction warmed to room temperature for 4.5 hours. The reaction was partitioned between saturated aqueous ammonium chloride solution (20 mL) and EtOAc (30 mL). The organic layer was collected, dried and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 100% DCM to 50:50 DCM:EtOAc to afford the title compound as a colourless oil (1.05 g, 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[NH:17][C:16]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15]2.N1C=CC=CC=1.Cl>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:16]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15]2
Reactant: COC(=O)Cc1cc2cc(Br)ccc2c(=O)[nH]1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1cc2cc(Br)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
Copper (II) acetate (67.5 mg, 0.371 mmol, 1.10 equiv.) and 4-fluorophenylboronic acid (95 mg, 0.675 mmol, 2.00 equiv.) were added to a stirred mixture of methyl 2-(6-bromo-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (100 mg, 0.338 mmol) and pyridine (54.6 μl, 0.675 mmol, 2.00 equiv.) in CH2Cl2 (3 mL) and the mixture was stirred in air at room temperature overnight in the presence of 4 Å molecular sieves. 1 N HCl (3 mL) was added to the reaction mixture and extracted with DCM (2×5 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0-15-20% EtOAc/hexanes to give 34 mg of methyl 2-(6-bromo-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([OH:15])=O)[CH2:9][CH2:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([Cl:18])=[O:15])[CH2:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(c1)CCC(C(=O)O)=C2
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCC(C(=O)Cl)=C2

Procedure:
A mixture of 7-methoxy-1,2-dihydro-3-naphthoic acid [Jacques et al., Bull. Soc. Chim. Fr., 512 (1950)] (2 g), benzene (50 ml) and thionyl chloride (2 ml) is heated under reflux for one hour. After distilling off the solvent under reduced pressure, benzene (50 ml) is added and the benzene is distilled off again under reduced pressure. The 7-methoxy-1,2-dihydro-3-naphthoyl chloride thus obtained is dissolved in dioxane (10 ml). The solution is added dropwise to a mixture of 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (2.6 g), dioxane (50 ml) and triethylamine (5 ml) at room temperature with stirring. Then the mixture is stirred at room temperature for 30 minutes. Water (300 ml) is added to the mixture, which is extracted with ethyl acetate. The extract solution is washed with a dilute aqueous solution of sodium hydroxide and water, then the solvent is distilled off under reduced pressure. The resulting oily substance is purified by silica gel column chromatography (hexane:acetone=1:1). The product thus obtained is dissolved in ethanol and the solution is treated with on ethanolic hydrogen chloride (5 ml) to give 1-(7-methoxy-1,2-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (2.9 g) as colorless crystals, m.p. 210°-215° C. (decomp.).
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][C@@H:15]([C:18]([OH:20])=O)[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C[O:22][C:23](=[O:73])[C@@H:24]([NH:40][C:41]([C@@H:43]1[CH2:52][C:51]2[CH:50]=[C:49]3[O:53][CH2:54][C@H:55]([C:57]4[CH:62]=[CH:61][C:60]([O:63][CH2:64][C:65]5[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=5)=[CH:59][CH:58]=4)[O:56][C:48]3=[CH:47][C:46]=2[CH2:45][NH:44]1)=[O:42])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=2[CH3:39])=[CH:28][CH:27]=1>C(Cl)Cl>[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][C@@H:15]([C:18]([N:44]2[C@H:43]([C:41]([NH:40][C@@H:24]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=4[CH3:39])=[CH:30][CH:31]=3)[C:23]([OH:73])=[O:22])=[O:42])[CH2:52][C:51]3[CH:50]=[C:49]4[O:53][CH2:54][C@H:55]([C:57]5[CH:62]=[CH:61][C:60]([O:63][CH2:64][C:65]6[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=6)=[CH:59][CH:58]=5)[O:56][C:48]4=[CH:47][C:46]=3[CH2:45]2)=[O:20])[CH2:14]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)[C@@H]3CC[C@H](NC(=O)OC(C)(C)C)C3)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C
Reaction time: 0.67 h

Procedure:
EDC (3 eq.) and (1R,3S)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic acid (6 eq.) were dissolved in DCM and stirred for 40 minutes. To this solution was added (S)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (25 mg) and stirred for 12 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 950.
Reaction SMILES: [OH-].[Na+:2].[C:3]([NH:7][C:8]([CH3:15])([CH3:14])[CH2:9][S:10]([OH:13])(=[O:12])=[O:11])(=[O:6])[CH:4]=[CH2:5]>O>[C:3]([NH:7][C:8]([CH3:15])([CH3:14])[CH2:9][S:10]([O-:13])(=[O:11])=[O:12])(=[O:6])[CH:4]=[CH2:5].[Na+:2]
Reactant: C=CC(=O)NC(C)(C)CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC(=O)NC(C)(C)CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
174.4 parts of a 50% NaOH solution are dissolved in 373.8 parts of deionized water to make a 16% solution. The solution is cooled to room temperature. 452 parts of 2-acrylamido-2-methylpropane sulfonic acid monomer (AMPS) are added to the solution at between about 25 and about 30° C. After the AMPS has fully dissolved, the solution is cooled to 20° C. and the pH is adjusted to 9.1. The solvent is removed to yield sodium 2-acrylamido-2-methylpropane sulfonate monomer.
Reaction SMILES: CC1(C)[O:6][C@H:5]2[C@H:7]([NH:12][C:13]3[N:21]=[CH:20][N:19]=[C:18]4[C:14]=3[N:15]=[CH:16][NH:17]4)[CH2:8][C@H:9]([CH2:10][OH:11])[C@H:4]2[O:3]1.CCN(CC)CC.Cl[S:31]([NH2:34])(=[O:33])=[O:32].C(#N)C.Cl.O>C(Cl)Cl.CN(C=O)C>[S:31](=[O:33])(=[O:32])([O:11][CH2:10][C@H:9]1[CH2:8][C@@H:7]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][NH:17]3)[C@H:5]([OH:6])[C@@H:4]1[OH:3])[NH2:34]
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3ncnc4[nH]cnc34)[C@@H]2O1
Reactant: NS(=O)(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)OC[C@H]1C[C@@H](Nc2ncnc3[nH]cnc23)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 29 %

Procedure:
A suspension of [(3aR,4R,6R,6aS)-2,2-dimethyl-6-(9H-purin-6-ylamino)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol (288 mg, 0.943 mmol) and Et3N (0.400 mL, 2.87 mmol) in DCM (5.00 mL) was cooled to 0° C. A 2.00 M solution of chlorosulfonamide in ACN (0.94 mL, 1.88 mmol, as prepared in Example 1d) was added dropwise, and DMF (1.50 mL) was added to bring the mixture into solution. The solution was allowed to warm to 23° C. and was stirred for 5 h before being concentrated in vacuo to dryness. The crude mixture was treated with a 1.00 M solution of HCl in H2O (5.00 mL, 5.00 mmol) and stirred for 10 min. The mixture was concentrated to dryness and purified via reverse phase C18 preparative HPLC eluting with a gradient of 0 to 40% of 0.1% FA/95% ACN/5% H2O in 0.1% FA/99% H2O/1% ACN over 16 min to afford the title compound (95.0 mg, 29%). 1H NMR (DMSO-d6, 400 MHz) δ: 12.9 (bs, 1H), 8.25-8.01 (m, 2H), 7.68-7.29 (m, 3H), 5.12-4.30 (m, 3H), 4.10 (dd, J=5.8, 9.6 Hz, 1H), 4.01 (dd, J=7.0, 9.6 Hz, 1H), 3.85 (dd, J=5.6, 5.6, 1H), 3.75 (dd, J=5.2, 5.2 Hz, 1H), 2.35-2.13 (m, 2H), 1.33-1.19 (m, 1H) ppm. LC/MS: Rt=1.02 min, ES+ 345 (AA standard).
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:53]([OH:56])([CH3:55])[CH3:54])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([C:53]([OH:56])([CH3:55])[CH3:54])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:51])([F:50])[F:52])=[CH:43][CH:42]=1
Reactant: CC(C)(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Product: CC(C)(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To a solution of 2-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxyl) phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]propan-2-ol 18c (156 mg, 0.20 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 15 mL) were added o-dichlorobenzene (0.11 mL, 0.99 mmol) and 10% Pd/C (21.0 mg, 0.02 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours under H2 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/1 to give the title compound 18 as pale yellow oil (62.5 mg, 62.5%, HPLC: 95.60%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 563.3 [M+CHOO]−; and 1H NMR (600 MHz, DMSO-d6) δ(ppm): 7.43 (d, 1H), 7.39 (d, 1H), 7.33 (d, 1H), 7.15 (q, 2H), 6.97 (q, 2H), 4.70 (q, 2H), 4.02 (m, 3H), 3.80 (d, 1H), 3.70 (d, 1H), 3.45 (m, 2H), 1.20 (s, 3H), 1.15 (s, 3H).
Reaction SMILES: C(C1ON=C(N)C=1)(C)C.[CH:10]1([C:15]2([CH2:20][C:21](=[N:23][OH:24])[NH2:22])OCCO2)[CH2:14][CH2:13][CH2:12][CH2:11]1.Cl>C(O)C>[CH:10]1([C:15]2[O:24][N:23]=[C:21]([NH2:22])[CH:20]=2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: NC(CC1(C2CCCC2)OCCO1)=NO
Agent: CC(C)c1cc(N)no1
Agent: Cl
Solvent: CCO
Product: Nc1cc(C2CCCC2)on1
Yield: 6.2 %

Procedure:
According to the procedure described for 5-isopropylisoxazol-3-amine in Example 133A Step 4, 2-(2-cyclopentyl-1,3-dioxolan-2-yl)-N′-hydroxyacetimidamide (1.99 g, 93 mmol) was dissolved in ethanol (2 mL) and acidified with 37% aq. hydrochloric acid to give 5-cyclopentylisoxazol-3-amine (875 mg, 62%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 5.52 (s, 1H), 3.86 (bs, 2H), 3.09-3.04 (m, 1H), 2.04 (d, 2H), 1.75-1.62 (m, 6H); LC-MS (ESI) m/z 153 (M+H)+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[N:8]=1)=O.[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32]N)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1>>[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([N:32]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(O)c2)ccc1=O
Reactant: NNc1ccc2c(c1)OCCO2
Product: O=c1ccn(-c2cccc(O)c2)nc1-c1ccnn1-c1ccc2c(c1)OCCO2

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-hydroxyphenyl)-1H-pyridazin-4-one (A-17) and (2,3-dihydro-benzo[1,4]dioxin-6-yl)-hydrazine according to the method described for example 91. MS: M=389.1 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[C:9]2[C:10]([Cl:28])=[CH:11][C:12]([O:15][CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)=[C:13]([F:14])[C:8]=2[S:7][CH:6]=1.C1COCC1.[OH-].[Na+].Cl>CO>[Cl:28][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:29])=[O:2])=[CH:6][S:7][C:8]=2[C:13]([F:14])=[C:12]([O:15][CH2:16][C:17]2[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2c(F)c(OCc3ccc(C(F)(F)F)nc3C)cc(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C(F)(F)F)ccc1COc1cc(Cl)c2c(CC(=O)O)csc2c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a mixture of methyl(4-chloro-7-fluoro-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (150.2 mg), THF (dry) (1.5 mL) and MeOH (1.5 mL) was added 1N NaOH (1.01 mL). The mixture was stirred at room temperature for 2 h. The mixture was neutralized with 1N HCl. The resulting precipitate was collected by filtration to give a solid. The solid was crystallized from EtOAc-hexane to give the title compound (126.6 mg).
Reaction SMILES: [N+]([O-])([O-])=O.[Co+2:5].[N+]([O-])([O-])=O.[C:10]([OH:21])(=[O:20])[C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=[O:15])[CH:12]=1>O>[C:10]([O-:21])(=[O:20])[C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([O-:16])=[O:15])[CH:12]=1.[Co+2:5]
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: [Co+2]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: O=C([O-])c1cccc(C(=O)[O-])c1
Temperature: 75 °C
Yield: 89.7 %

Procedure:
29.1 Grams (0.1 mole) of cobalt nitrate. 6H2O in 200 ml. of water were added to 200 ml. of 1 N sodium hydroxide to precipitate cobalt (II) hydroxide. The precipitate was filtered and washed. 16.6 Grams (0.1 mole) of isophthalic acid and 300 ml. of water were added to the precipitate. The mixture was stirred and heated at 75°C. for 14 hours until all solids dissolved. The solution was evaporated to yield 20.0 grams of cobalt (II) isophthalate which analyzed: C, 39.7%; H, 3.0%; Co, 15.0%.
Reaction SMILES: C([O:4][C:5]1[CH:25]=[CH:24][C:8]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:15][CH2:16]2)=[O:10])=[CH:24][CH:25]=1
Reactant: CC(=O)Oc1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A mixture of tert-butyl 4-(4-acetoxybenzoyl)piperazine-1-carboxylate (18.5 g, 53.1 mmol) prepared in Reference Example 195 and potassium carbonate (370 mg, 2.65 mmol) in methanol (200 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 5% hydrochloric acid and methylene chloride were added to the residue, and the mixture was vigorously stirred. The resulting precipitates were collected by filtration, and washed with water and methylene chloride, and then dried in vacuo to afford tert-butyl 4-(4-hydroxybenzoyl)piperazine-1-carboxylate (14.9 g, yield 92%) as a white powder.
Reaction SMILES: C(OC(N[C@@H](C([O:19][C@H:20]1[CH2:29][C@@H:28]([CH3:30])[CH2:27][C:26]2[N:25]=[N:24][C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)=[CH:22][C:21]1=2)=O)CC1C=CC=CC=1)=O)(C)(C)C.[OH-].[Na+]>CO>[CH3:30][C@H:28]1[CH2:27][C:26]2[N:25]=[N:24][C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)=[CH:22][C:21]=2[C@@H:20]([OH:19])[CH2:29]1
Reactant: C[C@H]1Cc2nnc(-c3cccc(C(F)(F)F)c3)cc2[C@@H](OC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1Cc2nnc(-c3cccc(C(F)(F)F)c3)cc2[C@@H](O)C1
Temperature: 10 °C
Reaction time: 4 h

Procedure:
To a methanol solution (1.2 L) of (5S,7S)-5-(N-(tert-butoxycarbinyl)-D-phenylalanyl)oxy-7-methyl-3-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydrocinnoline (280 g, 0.5 mol) obtained in Example 54 was added a 1N NaOH aqueous solution (0.6 L) at room temperature, followed by reaction at 40° C. over night. The reaction liquid was cooled to 10° C., followed by adding distilled water (1.8 L), stirring under suspension for 4 hours and filtering crystal to obtain the titled compound. Thus obtained compound was the same one obtained in Example 10.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([C:17]1[S:32][C:20]2=[N:21][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][C:24]([CH3:25])=[C:19]2[C:18]=1[NH2:33])=[O:16])[CH3:13]>CC(C)=O>[CH2:12]([O:14][C:15]([C:17]1[S:32][C:20]2=[N:21][C:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:23][C:24]([CH3:25])=[C:19]2[C:18]=1[NH:33][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:11])=[O:16])[CH3:13]
Reactant: CCOC(=O)c1sc2nc(-c3ccccc3)cc(C)c2c1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)c1sc2nc(-c3ccccc3)cc(C)c2c1NC(=S)NC(=O)c1ccccc1
Yield: 92.8 %

Procedure:
5 ml (13.3 mmol) acetonic benzoyl-isothiocyanate solution (2 M) is added to 2.78 g (8.9 mmol) 3-amino-4-methyl-6-phenyl-thieno[2,3-b]pyridine-2-carboxylic acid ethyl ester in 10 ml acetone and refluxed for 2 h. The precipitate precipitated after cooling is sucked off, washed with some water and ethanol, suck dried and dried in vacuo at 50° C. 3.93 g (93%) 3-(3-benzoylthioureido)-4-methyl-6-phenyl-thieno[2,3-b]pyridine-2-carboxylic acid ethyl ester is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][Cl:21].C(OCC)(=O)C>C1COCC1>[Cl:21][CH2:20][CH2:19][CH2:18][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: ClCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C(CCCCl)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 4-chlorophenylacetic acid (1 g) in THF (30 mL) was stirred at −78° C. for 20 minutes. n-Butyl lithium (2.66 M solution in hexane, 4.41 mL) was added to the solution, and the reaction solution was stirred at −78° C. for one hour. Thereafter, the reaction solution was stirred at 0° C. for one hour, 1-bromo-3-chloropropane (0.638 mL) was added to the reaction solution, and the reaction solution was stirred at room temperature for 18 hours. Thereafter, ethyl acetate and 1 N aqueous 2hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.55 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1O)[CH:5]=[O:6].[C:11](=[O:14])([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:14][CH2:11][CH2:3][CH2:2][CH2:9][CH3:8])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(C)=O
Product: CCCCCOc1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.8 %

Procedure:
3,4-Dihydroxybenzaldehyde (5 g., 36.2 mmol, 1 equiv.) is dissolved in 80 mL of acetone. n-Pentytbromide (4.49 mL, 36.2 mmol, 1 equiv.) is added, followed by anhydrous potassium carbonate (5 g., 36.2 mmol, 1 equiv.). The mixture is stirred at room temperature for 3 days, and then poured into half-saturated ammonium chloride solution. The mixture is extracted thrice with ether, and the extracts are washed with brine, dried (MgSO4), and evaporated. Chromatography on silica gel using EtOAc/hexane affords 3-hydroxy-4-pentyloxy-benzaldehyde (0.820 g., 3.94 mmol, 11%): mp=55°-56° C.; UVmax (EtOH) 208 nm (ε=24443), 232 nm (ε=23049), 272 nm (ε=16105), 312 nm (ε=13140); 1H NMR (300 MHz, CDCl3) δ 9.80 (s, 1H, CHO), 7.42-7.24 (m, 2H, ArH), 6.94 (d, J=8 Hz, 1H, ArH), 5.82 (s, 1H, OH), 4.10 (t, J=7 Hz, 2H, OCH2R), 1.88-1.79 (m, 2H, OCH2CH2R), 1.49-1.31 (m, 4H, pentyl), 0.92 (t, J=7 Hz, 3H, RCH3); 13C NMR (75 MHz, CDCl3) δ 191.06 (C=O), 151.30, 146.16, 130.40, 124.55, 113.99, 110.84, 69.27, 28.67, 28.04, 22.39, 13.97; IR (KBr) 3400, 2950, 1680, 1600, 1580, 1280, 1250 cm-1 ; MS (DCI) m/e 209 (MH+). Anal. Calcd for C12H16O3 : C, 69.23; H, 7.69. Found: C, 69.09; H, 7.65.