Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]([NH:15][C:16]1[C:17](=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[C:18]([OH:20])=[O:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(=O)C>[C:8]([NH:15][C:16]1[C:17](=[CH:21][C:22]([O:25][CH2:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:16]=2)=[CH:23][CH:24]=1)[C:18]([O:20][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Reaction time: 6 h
Yield: 56.3 %

Procedure:
Sodium hydride (95%, 36.2 g, 1.51 mol) was placed into a dry 5 liter 3-necked round bottom flask under an atmosphere of argon. Anhydrous dimethylformamide (DMF) (2.0 liters) was added via canula followed by the careful addition of N-Boc-5-hydroxyanthranilic acid (150 g, 0.59 mol). The reaction mixture was cooled with an ice/water bath and benzyl bromide (148 mL, 1.24 mol) was added via syringe keeping the reaction temperature below 50° C. After addition was complete, the reaction mixture was stirred at 45° C.-50° C. for 6 hours. At this time additional benzyl bromide (35 mL, 0.29 mol) was added and the reaction continued at 45° C.-50° C. for an additional 2 hours. Acetic acid (20 mL) was carefully added and the reaction mixture was transferred to a round bottom flask and concentrated to a volume of approximately 400 mL. Ethyl acetate (1.0 liters) was added and the resulting solution was decanted from any solids present. The flask was rinsed with additional ethyl acetate (2×500 mL), decanting after each rinse. The combined organics were washed with water (1.0 liter) and saturated NaCl (500 mL). The organics were filtered and concentrated in vacuo to yield crude N-Boc-5-benzyloxyanthranilic acid, benzyl ester as a reddish brown syrup. The crude product was transferred to boiling hexanes (3 liters) and refluxed an additional 10 minutes. The solution was filtered while still hot and allowed to cool for 48 hours to yield 72 g of product (28% yield).
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.FC1C(F)=C(F)C(F)=C([O:22][C:23]([CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]2[C@@H:37]3[C@@H:32]([NH:33][C:34]([NH:36]3)=[O:35])[CH2:31][S:30]2)=O)C=1>CN(C=O)C>[C:23]([NH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])(=[O:22])[CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]1[C@@H:37]2[C@@H:32]([NH:33][C:34]([NH:36]2)=[O:35])[CH2:31][S:30]1
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)Oc2cc(F)c(F)c(F)c2F)N1
Reactant: CC(N)CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CC(=O)O)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
Preparation was accomplished as described by Wilbur [Bioconj. Chem 1997, 8, 572]. To a 0.13 g (1.3 mmol) quantity of 3-aminobutyric acid dissolved in 20 mL of DMF under argon atmosphere was added 0.4 mL (2.5 mmol) of triethylamine followed by 0.5 g (1.3 mmol) of biotin tetrafluorophenyl ester. The reaction was stirred at 25° C. for 24 h and the solvent was removed under vacuum. The residue was triturated with acetonitrile and filtered. The isolated solid was dried under vacuum to yield 0.5 g (98%) of product as a colorless solid, mp 161-163° C. 1H NMR (DMSO-d6): O 7.6 (m, 1H), 6.2 (d, J=11.2 Hz, 2H), 3.9-4.2 (m, 3H), 2.6 (m, 2H), 2.35 (d, J=12.6 Hz, 1H), 1.7-2.1 (m, 4H), 0.7-1.5 (m, 10H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([O:12][CH2:13][CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[C:5](=[O:27])[N:4]2[C@H:28]([C:32]([O:34]C(C)(C)C)=[O:33])[CH2:29][CH2:30][CH2:31][N:3]12.C(N[C@@H]1C(=O)N2[C@H](C(O)=O)CCCN2C(=O)CC1)(=O)C1C=CC=CC=1.[K+].[Br-]>C(Cl)Cl>[O:1]=[C:2]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([O:12][CH2:13][CH:14]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:21]3[C:26]2=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:11])[C:5](=[O:27])[N:4]2[C@H:28]([C:32]([OH:34])=[O:33])[CH2:29][CH2:30][CH2:31][N:3]12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(=O)N12
Agent: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O)OCC1c2ccccc2-c2ccccc21
Yield: 96 %

Procedure:
was prepared from 211f in 96% yield by the same method as for 212e: mp 120-126° C.; [αD25 -72.5° (c 0.1, CH2Cl2). IR (KBr) 3406, 2950, 1725, 1670, 1526, 1449, 1421, 1272, 1248, 1223, 1175, 761, 741; 1H NMR (CDCl3) δ 7.76 (2H, m), 7.62-7.26 (4H, m), 6.07, 5.76 (2H, brs, d, d, J=2.9), 5.46, 5.36 (1H, 2m), 4.79-4.54 (2H, m), 4.77 (2H, m), 4.21 (1H, m), 3.41 (1H, m), 2.89 (1H, m), 2.69 (1H, m), 2.35 (2H, m), 1.98, 1.73 (4H, 2m). MS(ES-, m/z) 462 (M+ -1, 50%), 240 (100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:9][C:10]=1[F:11])[C:6]([OH:8])=[O:7].C(O)(=O)C.C(O[Cl:22])(C)(C)C>ClCCl.C(OCC)(=O)C>[Cl:22][C:3]1[C:2]([F:1])=[C:10]([F:11])[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH2:12]
Reactant: CC(C)(C)OCl
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1c(C(=O)O)cc(F)c(F)c1Cl
Reaction time: 2 h
Yield: 100.8 %

Procedure:
To a solution of 4,5-difluoroanthranilic acid (2.45 g, 14.2 mmol) in dichloromethane (25 mL) is added acetic acid (10 mL) and hypochlorous acid tert-butyl ester (1.75 mL, 15.6 mmol). After 2 hours, the reaction mixture is diluted with ethyl acetate and washed with water and brine. The organic layer is dried over MgSO4, filtered, and concentrated. The resulting residue is purified via flash column chromatography (5% isopropyl alcohol/1% formic acid/94% dichloromethane) to afford 3-chloro-4,5-difluoroanthranilic acid as an oil (2.97 g). MS CI: m/z 206 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.CO.Cl[CH2:17]Cl.C[Si](C=[N+]=[N-])(C)C>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:17])=[O:12])=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: Nc1ccc(CCCC(=O)O)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 4-(4-aminophenyl)butanoic acid (180 mg, 1 mmol) in a mixture of THF (4 ml), MeOH (1 ml) and dichloromethane (1 ml) in a 20-mL vial was added dropwise (trimethylsilyl)diazo-methane (1 ml, 2N in hexane) at 0° C. After the addition was complete, the resulting mixture was stirred at room temperature for 1 hr. The volatile material was removed under reduced pressure and the residue was purified by chromatography on silica gel using hexane/dichloromethane (2:1) followed by dichloromethane as eluent to give methyl 4-(4-aminophenyl)butanoate as an yellowish oil (55 mg, 28% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH:14]=[CH:13][N:12]3[CH:15]=[CH:16][CH:17]=[C:11]3[CH2:10]2)[CH2:3][CH2:2]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>N1C=CC=CC=1>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]3[CH2:15][CH2:16][CH2:17][CH:11]3[CH2:10]2)[CH2:3][CH2:2]1)=[O:24]
Reactant: C1=Cn2cccc2CN1CCC1CCNCC1
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: O=C(c1cccs1)N1CCC(CCN2CCN3CCCC3C2)CC1

Procedure:
In the manner of Example 2, 2-(4-piperidylethyl)-pyrrolo[1,2-a]pyrazine and 2-thienylcarbonyl chloride will react in pyridine solution to produce the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11]NCC)[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(O[C:24]([C:26]1C(C)=NC(NNCCCC)=[C:30]([N+]([O-])=O)[C:31]=1Cl)=O)C>>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]([CH3:15])=[N:5][C:6]=1[NH:11][CH2:24][CH2:26][CH2:31][CH3:30]
Reactant: CCNNc1nc(C)c(C(=O)OCC)c(Cl)c1[N+](=O)[O-]
Reactant: CCCCNNc1nc(C)c(C(=O)OCC)c(Cl)c1[N+](=O)[O-]
Product: CCCCNc1nc(C)c(C(=O)OCC)c(Cl)c1N
Yield: 72 %

Procedure:
By replacing 4-chloro-6-(1-ethyl)hydrazino-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester in Example 1 c with 6-(1-butyl)hydrazino- 4-chloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester, 5-amino-6-butylamino-4-chloro-2-methylpyridine-3-carboxylic acid, ethyl ester is obtained. Yield 72%, b.p. 200°-210° /0.01.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.N1C2C(=CC=CC=2)C=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 63.7 %

Procedure:
To a mixture of 306 mg (purity: 98.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 833 mg (5.53 mmol) of 2-cyclopropyl-6-methylphenol were added quinoline (2.76 g) and 327 mg (5.55 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 321 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 64%) and 3.4 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.7%) were obtained.
Reaction SMILES: COC(=O)[C@@H](NC([C@@H]1CC2C=C3C(O[C@H](C4C=CC(O)=CC=4)C(=O)N3C)=CC=2CN1[C@H](C1C=CC=CC=1)CC)=O)CC1C=CC(C2C=CC(Cl)=CC=2)=CC=1.C[O:56][C:57](=[O:117])[C@@H:58]([NH:73][C:74]([C@@H:76]1[CH2:89][C:88]2[CH:87]=[C:86]3[C:81]([O:82][C@H:83]([C:92]4[CH:97]=[CH:96][C:95]([O:98][CH2:99][C:100]5[CH:105]=[CH:104][C:103]([Cl:106])=[C:102]([Cl:107])[CH:101]=5)=[CH:94][CH:93]=4)[C:84](=[O:91])[N:85]3[CH3:90])=[CH:80][C:79]=2[CH2:78][N:77]1[C@H:108]([C:111]1[CH:116]=[CH:115][CH:114]=[CH:113][CH:112]=1)[CH2:109][CH3:110])=[O:75])[CH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=2)=[CH:62][CH:61]=1>>[Cl:72][C:69]1[CH:70]=[CH:71][C:66]([C:63]2[CH:62]=[CH:61][C:60]([CH2:59][C@H:58]([NH:73][C:74]([C@@H:76]3[CH2:89][C:88]4[CH:87]=[C:86]5[C:81]([O:82][C@H:83]([C:92]6[CH:97]=[CH:96][C:95]([O:98][CH2:99][C:100]7[CH:105]=[CH:104][C:103]([Cl:106])=[C:102]([Cl:107])[CH:101]=7)=[CH:94][CH:93]=6)[C:84](=[O:91])[N:85]5[CH3:90])=[CH:80][C:79]=4[CH2:78][N:77]3[C@H:108]([C:111]3[CH:112]=[CH:113][CH:114]=[CH:115][CH:116]=3)[CH2:109][CH3:110])=[O:75])[C:57]([OH:117])=[O:56])=[CH:65][CH:64]=2)=[CH:67][CH:68]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Yield: 88 %

Procedure:
(S)-3-(4′-chloro, -biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (74 mg) was converted to (S)-3-(4′-chloro-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (60 mg) using general procedure K. This ester upon hydrolysis furnished title compound (52 mg) using general procedures B. LC-MS (m/z): 888.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:45])[C:29]([CH3:44])([CH3:43])[NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[N:37][N:36]2[CH:42]=1)=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[ClH:41].[ClH:41].[CH2:25]([O:27][C:28](=[O:45])[C:29]([CH3:44])([CH3:43])[NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)=[N:37][N:36]2[CH:42]=1)=[O:32])[CH3:26]
Reactant: CCOC(=O)C(C)(C)NC(=O)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)NC(=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Product: Cl
Temperature: 70 °C
Reaction time: 9.5 h
Yield: 22.3 %

Procedure:
1.23 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.18 g of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl]-2,2-dimethylglycine ethyl ester were dissolved in 15 ml of N,N-dimethylformamide; 1.31 ml of N-ethyldiisopropylamine was added, followed by stirring at 70° C. for 9.5 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, concentrated under reduced pressure and dissolved in 5 ml of ethyl acetate; 0.28 ml of a 4 N hydrogen chloride solution in ethyl acetate was added, followed by concentration again. Ethyl acetate was added to the residue; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 284 mg of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[C:5](=[C:10]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[K+]>CO>[CH3:18][O:17][CH2:16][CH2:15][NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:19])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COCCNc1cccc(C(=O)OC)c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COCCNc1cccc(C(=O)O)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-(2-methoxy-ethylamino)-phthalic acid dimethyl ester (2.24 g, 8.38 mmol) in methanol (50 ml) was added 5N potassium hydroxide (10 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue dissolved in water (50 ml). The water was washed with diethyl ether (2×75 ml). The aqueous portion was cooled in an ice bath and the pH was adjusted to 2–3 by dropwise addition of concentrated hydrochloric acid. The aqueous solution was then extracted with ethyl acetate (3×75 ml). The combined ethyl acetate extracts were washed with brine (100 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the residue, which contained a mixture of diacid and monomethyl esters, was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[CH2:5][NH2:6].[I:11]Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([I:11])[C:9]=1[NH2:10])[CH2:5][NH2:6]
Reactant: ClI
Reactant: NCc1ccc(N)c(Cl)c1
Solvent: CO
Product: NCc1cc(Cl)c(N)c(I)c1
Reaction time: 1 h
Yield: 41.5 %

Procedure:
To 3-Chloro-4-aminobenzylamine (200 mg, 1.28 mmol) in methanol (5 mL) was added iodine monochloride (230 mg, 1.42 mmol). The mixture was stirred for 1 hour, then purified by HPLC to give 3-chloro-4-amino-5-iodobenzylamine (150 mg, 42%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[C:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>ClCCl.CN(C)C1C=CN=CC=1>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:27])=[CH:29][CH:30]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirring solution of methyl 2-aminobenzoate (5 g, 33.1 mmol) and pyridine (5.3 g, 66 mmol) in dichloromethane (100 mL) was added 4-dimethylaminopyridine (0.2 g, 1.6 mmol). The mixture was cooled to 0° C. and treated with 4-tert-butylbenzoyl chloride (6.5 g, 33.1 mmol). After stirring overnight, the reaction mixture was diluted with dichloromethane (100 mL) and washed twice with 1 M aqueous citric acid (100 mL). The organic layer was then washed sequentially with water (100 mL) and 5 N aqueous HCl. It was dried over MgSO4, filtered and concentrated in vacuo to give 10.68 g (quantitative) of a colorless oil.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH:7]1([NH:13][S:14](=[O:17])(=O)[OH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.P(Cl)(Cl)([Cl:20])=O>ClCCCl>[CH:7]1([NH:13][S:14]([Cl:20])(=[O:17])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=S(=O)(O)NC1CCCCC1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=S(=O)(Cl)NC1CCCCC1
Temperature: 95 °C
Yield: 95 %

Procedure:
54.2 parts of phosphorus pentachloride are added in portions to 89.6 parts of cyclohexylsulfamic acid, suspended in a mixture of 113 parts of 1,2-dichloroethane and 134 parts of phosphorus oxychloride, at 20° C, whilst stirring. The reaction mixture is then heated to 95° C in the course of 30 minutes and is stirred at from 95° to 98° C for 71/2 hours. After removing the solvent under reduced pressure distillation of the residue gives 94 parts (95% of theory) of cyclohexylsulfamic acid chloride of boiling point 103°-111° C/0.05 mm Hg (melting point 42°-44°).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: Brc1cccs1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1ccc(-c2cn(-c3cccs3)cn2)cc1
Temperature: 110 °C
Yield: 2.9 %

Procedure:
A suspension of 4-phenyl-1H-imidazole (500 mg, 3.47 mmol), 2-bromothiophene (0.4 ml, 4.16 mmol), CuI (131.9 mg, 0.694 mmol, trans-N,N′-dimethylcyclohexanediamine (0.08 ml, 0.694 mmol), and K2CO3 (1.43 g, 10.4 mmol) in dioxane (5 ml) was heated at 110° C. in a sealed tube for 16 hours. The reaction mixture was then diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by column chromatography using 15-20% ethyl acetate/hexanes to yield the desired 4-phenyl-1-(thiophen-2-yl)-1H-imidazole (23 mg, 3%). The HPLC purity of the final product was 99.7%. LC-MS [M+H] 227 (C13H10N2S+H expected 227.06).
Reaction SMILES: [C:1]([C:10]1[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[Ca+2:24]>C(O)(C)C.O>[C:1]([C:10]1[CH:18]=[C:14]([C:15]([O-:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Ca+2:24].[C:1]([C:10]1[CH:18]=[C:14]([C:15]([O-:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCC(=O)c1ccc(O)c(C(=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
39.6 g of 5-octanoylsalicylic acid (0.15 mol) in 300 ml of isopropanol and 150 ml of water were introduced into a 500 ml round-bottomed flask. 7.5 g of calcium carbonate (0.075 mol) were then added portionwise. The mixture was left stirring at room temperature for 3 hours and was then concentrated to dryness under vacuum on a rotary evaporator.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:25][C:26]1[CH:27]=[C:28]2[O:36][CH2:35][O:34][C:29]2=[C:30]([CH:33]=1)[CH:31]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:31][C:30]1[CH:33]=[C:26]([Br:25])[CH:27]=[C:28]2[O:36][CH2:35][O:34][C:29]=12
Reactant: O=Cc1cc(Br)cc2c1OCO2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1cc(Br)cc2c1OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Carbon tetrabromide (44.3 g, 0.134 mol) was added portionwise to a solution of triphenylphosphine (70.1 g, 0.267 mol) in methylene chloride (200 ml) under ice cooling. A solution of 5-bromo-2,3-methylenedioxybenzaldehyde (27.65 g, 0.121 mol) in methylene chloride (100 ml) was then added dropwise to the mixture over 20 minutes. The reaction mixture was stirred at room temperature for 2 hours, washed with water and with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was added with ethyl acetate (200 ml), and the mixture was heated to 60° C. and then added with hexane (50 ml). The mixture was cooled to room temperature, and the deposited triphenylphosphine oxide was removed by filtration and the filtrate was concentrated. Triphenylphosphine oxide was removed again in a similar manner by using 100 ml of ethyl acetate and 100 ml of hexane, and the filtrate was concentrated. The residue was purified by silica gel chromatography (Wako Gell C-300: 200 g, eluent: hexane/ethyl acetate=1/10) to give β,β-dibromo-5-bromo-2,3-methylenedioxystyrene (42.36 g).
Reaction SMILES: [C:1](=O)([O:6][C:7]1[C:15]2[O:14][C:13]([CH3:17])([CH3:16])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)[O:2]C(Cl)C.[CH3:19][N:20](C)C1C=CC=CC=1>N1C=CC=CC=1>[CH3:19][NH:20][C:1](=[O:2])[O:6][C:7]1[C:15]2[O:14][C:13]([CH3:17])([CH3:16])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(Cl)OC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: CN(C)c1ccccc1
Solvent: c1ccncc1
Product: CNC(=O)Oc1cccc2c1OC(C)(C)C2

Procedure:
The procedure is as in (a) followed by (b), but pyridine is replaced by N,N-dimethylaniline and the intermediate carbonate is not distilled. Starting with 16.4 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranol, 16.8 g (76%) of CARBOFURAN are then obtained, M.p. 147° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:20](=[O:24])[CH:21](O)O)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH2:36])[CH3:35])=[CH:29][CH:28]=1>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:20](=[O:24])[CH:21]=[N:36][C@H:34]([CH3:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12)C(O)O
Reactant: COc1ccc(C[C@@H](C)N)cc1
Solvent: CS(C)=O
Product: COc1ccc(C[C@@H](C)N=CC(=O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
One g of 8-benzyloxy-5-(dihydroxyacetyl)carbostiril 1/3 hydrate and 520 mg of (R)-N-(2-(p-methoxyphenyl)-1-methylethyl)amine are dissolved in 10 ml of dimethylsulfoxide, and the solution is stirred at room temperature for one hour. After the reaction is completed, the mixture is treated in the same manner as described in Example 10-(1). 1.06 g of 8-benzyloxy-5-{1-oxo-2-[N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)imino]ethyl}carbostyril are obtained as pale yellow scales. Yield: 75%