Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1.[O:18]([C:20]#[N:21])[Na]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:20]([NH2:21])=[O:18])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Reactant: N#CO[Na]
Solvent: CC(=O)O
Product: COC1=Cc2ccccc2N(C(N)=O)c2ccccc21
Reaction time: 7 h

Procedure:
Acetic acid (150 mL) is added dropwise to a stirred mixture of 10-methoxy-5H-dibenzo[b,f]azepine (25.0 g, 112 mmol) and NaOCN (9.25 g, 142 mmol) under a nitrogen atmosphere at room temperature. After stirring for 7 hours the resulting yellow suspension of the title compound (>95% area of the compound by HPLC) is used for synthesis of 10-oxo-10,11-dihydro-dibenzo[b,f]azepine-S-carboxylic acid amide. The title compound can be isolated by adding 1N NaOH to a pH of ≧8 followed by extraction with toluene. Drying of the combined organic layers and concentration in vacuo yields the title compound as a light yellow solid (yield≧75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH:7]2SC>[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: CSC1C(=O)Nc2c(Cl)ccc(-c3ccccc3)c21
Agent: [Ni]
Product: O=C1Cc2c(-c3ccccc3)ccc(Cl)c2N1
Yield: 94.2 %

Procedure:
A solution of 48.0 g (0.166 mole) of 7-chloro-3-methylthio-4-phenylindolin-2-one was treated with 380 g of a washed commercial preparation of Raney-nickel under vigorous agitation for 5 min. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a pale yellow powder as residue. The residue was triturated with hot absolute ethanol to give 38.1 g (94%) of the title compound as white powder, m.p. 234°-236° C.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])=[CH:11][N:12]=1.[Li+].[OH-].Cl>O1CCOCC1.O>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([OH:20])=[C:13]([C:10]2[O:9][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])=[N:12][CH:11]=2)[CH:18]=1
Reactant: COC(=O)CCCCc1ncc(-c2cc(Cl)ccc2O)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCCc1ncc(-c2cc(Cl)ccc2O)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.6 %

Procedure:
Dissolve 5-[5-(5-chloro-2-hydroxy-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (3.26 g, 10.52 mmol) in 50 mL of dioxane and add a solution of LiOH (1.2671 g, 50.91 mmol) in 25 mL of water to it. Allow the reaction to stir at ambient temperature for 18 hours. Acidify the reaction with 5N HCl and concentrate the reaction mixture in vacuo to remove the dioxane. Extract the aqueous residue with EtOAc (3×). Dry the combined organic layers with MgSO4. Filter off the drying agent and concentrate in vacuo to afford a crude residue. Triturate the residue in cold EtOAc. Collect the product via filtration to afford 1.8837 g of the titled product (60%): mass spectrum: m/z=296.1 (M+H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[CH:11]([NH:13][NH2:14])=[O:12].[C:15]([C:17]1[CH:18]=[CH:19][C:20]([O:26][C:27]([CH3:45])([C:29]2[N:33]([CH3:34])[C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:44])([F:43])[F:42])=[N:31][N:30]=2)[CH3:28])=[C:21]([CH:25]=1)[C:22](O)=O)#[N:16].O>CN(C=O)C>[CH3:45][C:27]([C:29]1[N:33]([CH3:34])[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([F:43])([F:44])[F:42])=[N:31][N:30]=1)([O:26][C:20]1[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:25][C:21]=1[C:22]1[O:12][CH:11]=[N:13][N:14]=1)[CH3:28]
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(C#N)cc1C(=O)O
Reactant: NNC=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(C#N)cc1-c1nnco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
WSC•monohydrochloride (81 mg), HOBt (57 mg) and formic hydrazide (30 mg) were sequentially added to a solution of 5-cyano-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoic acid (140 mg) in DMF (2 ml), followed by stirring at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting solid (130 mg) was dissolved in dichloromethane (2 ml) and pyridine (0.090 ml) was added thereto, followed by cooling to −78° C. Trifluoromethanesulfonic acid (0.090 ml) was added to the reaction solution and was elevated to room temperature, followed by stirring for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1). The resulting solid was washed with diisopropylether to obtain, as a white solid, 4-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)-3-(1,3,4-oxadiazol-2-yl)benzonitrile (65 mg).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:15][C:16]#[N:17])=[CH:9][NH:10]2)([O-:5])=[O:4].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CN(C=O)C>[C:16]([CH2:15][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[N+:3]([O-:5])=[O:4])[N:10]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:9]=1)#[N:17]
Reactant: N#CCc1c[nH]c2cccc([N+](=O)[O-])c12
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1cc(CC#N)c2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (198 mg of a 60% dispersion in mineral oil, 5.0 mmol) was added to a solution of (4-nitro-1H-indol-3-yl)acetonitrile from Step B (910 mg, 4.52 mmol) in DMF (15 mL). After 10 min, tert-butyl bromoacetate (0.801 mL, 5.4 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 1.5 h. The mixture was partitioned between H2O (50 mL) and EtOAc (100 mL) and the organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=316 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.CC1CCCN(C)C1(C)C.[Li].[O:18]1[C:22]2([CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:25]2([OH:28])[CH2:26][CH2:27][C:22]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:23][CH2:24]2)[N:2]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1ccnnc1
Agent: CC1CCCN(C)C1(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: OC1(c2cccnn2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 44 %

Procedure:
To a solution of pyridazine (17.7 mmol, 1.28 mL) in THF (60 mL) was added 2,2,6,6, lithium tetramethylpiperidine (71 mmol, 10 g) at −78° C. The reaction was then stirred for 6 min and 1,4-dioxa-spiro[4.5]decan-8-one (71 mmol, 11 g) was added. The reaction was stirred for 5 h at −78° C. at which point the reaction was quenched using a solution of ethanol, hydrochloric acid and THF (30 mL, 1:1:1). The reaction was allowed to warm to ambient temperature and the reaction mixture was extracted using EtOAc. The organic layers were combined and dried over MgSO4. The residue was then purified using flash chromatography to afford the desired alcohol (44%, 1.84 g). MS [M+H]+ 237.1.
Reaction SMILES: C([Mg]Br)C.[CH3:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.CN(C)P(N(C)C)(N(C)C)=O.[CH2:25]=[O:26].Cl>C(OCC)C.C1(C)C=CC=CC=1>[CH3:5][S:6][C:7]1[CH:12]=[C:11]([CH:25]=[O:26])[C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: CSc1ccc(O)cc1
Reactant: C=O
Agent: CC[Mg]Br
Agent: Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CSc1ccc(O)c(C=O)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
Ethyl magnesium bromide (38 mL of a 3.0 M solution in diethyl ether, 113.8 mmole) was chilled with an ice-water bath. To the chilled solution was added a solution of 4-(methylthio)phenol (15.95 g, 113.8 mmole) in diethyl ether (30 mL) over 0.15 hour during which time gas was evolved. The reaction was held at 0° C. for 0.5 hour, at room temperature for 0.5 hour, and the addition funnel replaced with a distillation head. Toluene (250 mL) and the diethyl ether were distilled out of the reactor. The reaction was cooled, toluene (250 mL) and hexamethylphosphoramide (HMPA) (19.8 mL, 20.4 g, 113.8 mmole) were added, and the resulting mixture was stirred for 0.25 hours. The distillation head was replaced with a condenser and paraformaldehyde (8.5 g, 284.4 mmole) was added. The reaction was heated to 90° C. for 3 hours. The reaction mixture was cooled to room temperature, was acidified with 1N HCl and the layers separated. The organic phase was washed with water, and with brine, dried over MgSO4, filtered, and concentrated in vacuo to yield a solid. This solid was purified by silica chromatography (hexanes-ethyl acetate, 5:1) yielding the salicylaldehyde as a yellow crystalline solid (6.01 g) of suitable purity to be used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:12][C:10]1[CH:11]=[C:2]([NH:1][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[C:3]([O:13][CH3:14])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)cc(N)c1OC
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1OC
Yield: 73.2 %

Procedure:
To a solution of methyl 3-amino-5-chloro-2-methoxybenzoate (440 mg, 2 mmol) in 1,2-dichloroethane (8 ml) at temperature under nitrogen was added oxan-4-one (0.38 ml, 4.0 mmol) followed by acetic acid (0.7 ml, 12 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (1.3 g, 6.1 mmol) at room temperature. After stirring for 23 hours deionized water (16 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×16 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 9:1 Heptane:EtOAc to 7:3 Heptane:EtOAc) to give 439 mg (72%) of the title compound as a white solid. LC-MS 97%, m/z=300.3/302.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.06 (1H, d, J=2.52 Hz), 6.73 (1H, d, J=2.52 Hz), 4.38-4.45 (1H, m), 4.02 (2H, dt, J=11.78, 3.49 Hz), 3.91 (3H, s), 3.81 (3H, s), 3.54 (2H, td, J=11.47, 2.13 Hz), 3.40-3.50 (1H, m), 2.03 (2H, br. d, J=13.70 Hz), 1.48-1.55 (2H, m).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CCCCCC.C([Li])CCC.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]1([O:50][Si:51]([CH2:56][CH3:57])([CH2:54][CH3:55])[CH2:52][CH3:53])[C:33]2[C:28](=[CH:29][C:30](I)=[CH:31][C:32]=2[C:34]([F:37])([F:36])[F:35])[N:27]([CH2:39][C@H:40]2[CH2:43][C@H:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])[CH2:41]2)[C:26]1=[O:49].O>O1CCCC1>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]1([O:50][Si:51]([CH2:56][CH3:57])([CH2:52][CH3:53])[CH2:54][CH3:55])[C:33]2[C:28](=[CH:29][C:30]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:31][C:32]=2[C:34]([F:36])([F:35])[F:37])[N:27]([CH2:39][C@H:40]2[CH2:41][C@H:42]([N:44]([CH2:45][CH3:46])[CH2:47][CH3:48])[CH2:43]2)[C:26]1=[O:49]
Reactant: c1cocn1
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O[Si](CC)(CC)CC)(c3ccc(Cl)cc3Cl)c3c2cc(I)cc3C(F)(F)F)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O[Si](CC)(CC)CC)(c3ccc(Cl)cc3Cl)c3c2cc(-c2ncco2)cc3C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxazole (150 mg, 2.17 mmol) in tetrahydrofuran (4 mL) was added 2.67 M n-butyl lithium hexane solution (0.8 mL, 2.14 mmol) at −78° C. under nitrogen, and the mixture was stirred for 15 minutes. To the reaction solution was added 1.0M zinc chloride diethyl ether solution (2.2 mL, 2.2 mmol) at −78° C., and the mixture was stirred for 15 minutes. The reaction solution was allowed to warm to 0° C., and then thereto was added a solution of the compound of Example 14-1 (310 mg, 0.418 mmol) and tetrakistriphenylphosphine palladium (20 mg, 0.017 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 1 hour, and then the mixture was heated to stir at 60° C. for 3 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with saturated saline, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (chloroform/methanol=20/1) to give the titled compound (160 mg, 56%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]#[C:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH2:28]([NH:30][CH2:31][CH2:32][OH:33])[CH3:29]>>[CH2:28]([N:30]([CH2:22][CH2:21][CH2:20][C:19]#[C:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[CH:2])=[CH:4][CH:5]=1)[CH:10]=[CH:11]2)[CH2:31][CH2:32][OH:33])[CH3:29]
Reactant: C#Cc1ccc(-n2ccc3cc(C#CCCCOS(C)(=O)=O)ccc32)cc1
Reactant: CCNCCO
Product: C#Cc1ccc(-n2ccc3cc(C#CCCCN(CC)CCO)ccc32)cc1

Procedure:
In analogy to example 5.5, Methanesulfonic acid 5-[1-(4-ethynyl-phenyl)-1H -indol-5-yl]-pent-4-ynyl ester and 2-ethylaminoethanol were converted to yield 2-(Ethyl-{5-[1-(4-ethynyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-amino)-ethanol as light yellow viscous oil, MS: 371 (MH+).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1Cl>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:15][CH:16]=1
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2Cl)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
6.5 g of pulverised potassium hydroxide and 20 g of methyl 4-hydroxy-α-phenoxypropionate in 250 ml of dry dimethyl sulphoxide are charged at 0° C. into a three-necked flask. With stirring, and at a temperature between 0° and 5° C., 19.5 g of 3,4-dichloro-nitrobenzene are added by small amounts and stirring is continued for 12 hours at room temperature. Thereafter the reaction mixture is poured into ice-water and extracted with ethyl acetate. The extract is dried over sodium sulphate and the solvent distilled off to yield an oily product which is then subjected to high vacuum distillation. The resultant substance, viz. methyl 4-(2'-chloro-4'-nitrophenoxy)-α-phenoxypropionate (yield 27 g), boils at 194° C./0.01 Torr (compound 1).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:32])=[C:9]([C:12](=[O:31])[C:13](=[O:30])[N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:16][CH2:15]2)[C:10]=1[CH3:11])=[O:5])C.O>C(O)C>[CH3:11][C:10]1[C:9]([C:12](=[O:31])[C:13](=[O:30])[N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=3)[CH2:18][CH2:19]2)=[C:8]([CH3:32])[NH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)c1C
Solvent: CCO
Solvent: O
Product: Cc1[nH]c(C(=O)O)c(C)c1C(=O)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 85.5 %

Procedure:
To a solution of 0.100 g (0.221 mmol) 3,5-dimethyl-4-{2-oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-acetyl}-1H-pyrrole-2-carboxylic acid ethyl ester in 2 ml ethanol and 1 ml water 0.018 g (0.443 mmol) NaOH were added. The solution was stirred at 80° C. for 5 h. The solvent was evaporated and 1 N HCl was added to the residue. The precipitate was filtered off and dried to yield 80 mg (85%) of the title compound. MS 424.15 (M+H)+,
Reaction SMILES: C([NH:4][C:5]1[CH:12]=[C:11](Cl)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:6]=1[C:7]#[N:8])(=O)C.[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24].[OH-].[K+]>O>[NH2:4][C:5]1[CH:12]=[C:11]([O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: CC(=O)Nc1cc(Cl)c([N+](=O)[O-])cc1C#N
Reactant: COCCOCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCOCCOc1cc(N)c(C#N)cc1[N+](=O)[O-]

Procedure:
20 g of 2-acetylamino-4-chloro-5-nitrobenzonitrile obtained in Step (4) above was mixed with 110 ml of diethyleneglycol monomethyl ether, 11.4 g of potassium hydroxide was added thereto, and the mixture was reacted at 80° C. for 4 hours. After the completion of the reaction, the reaction mixture was cooled, then 250 ml of water was added thereto with stirring. The crystals thus-deposited were collected by filtration, washed with a mixture of water and methanol (1:1) and dried. Yield: 14.5 g (53.7%). Melting point: 106° to 108° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.Cl[C:17]1[C:26](C)=[C:25](Cl)[C:24]2[C:19](=CC=C(Cl)C=2F)[N:18]=1.C([Sn](CCCC)(CCCC)C1C=CC=CN=1)CCC>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[C:7]([Cl:14])[CH:8]=2)[N:3]=[C:2]([C:17]2[CH:26]=[CH:25][CH:24]=[CH:19][N:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)c(Cl)cc2c1Cl
Reactant: Cc1c(Cl)nc2ccc(Cl)c(F)c2c1Cl
Agent: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)c(Cl)cc2c1Cl

Procedure:
The stille coupled products were prepared according to Procedure E using a mixture of 2,4,6-trichloro-7-fluoro-3-methylquinoline and 2,4,6-trichloro-5-fluoro-3-methylquinoline (0.50 g, 1.90 mmol), 2-(tributylstannyl)pyridine (0.77 mL, 2.08 mmol), palladium tetrakistriphenylphosphine (0.22 g, 0.19 mmol) in toluene (1.90 mL) to give 4,6-dichloro-7-fluoro-3-methyl-2-(pyridin-2-yl)-quinoline as a white solid. Further elution gave 4,6-dichloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=307.0 (M+1). Further elution gave 4-chloro-7-fluoro-3-methyl-2,6-di(pyridin-2-yl)-quinoline.
Reaction SMILES: [CH2:1]([S:8][C@H:9]1[NH:12][C:11](=[O:13])[C@@H:10]1[Br:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:31])[CH2:29]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[K+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:31])[CH2:29][N:12]2[C@H:9]([S:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([Br:14])[C:11]2=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CBr)NCCCCCCc1ccccc1
Reactant: O=C1N[C@H](SCc2ccccc2)[C@H]1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CN1C(=O)[C@H](Br)[C@H]1SCc1ccccc1)NCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
A solution of (3S, 4R)-4-benzylthio-3-bromoazetidin-2-one (0.7 g, 2.6 mmol) in dry THF (25 ml) was treated with N-(6-phenylhexyl)bromoacetamide (0.8 g, 2.6 mmol), powdered potassium hydroxide (0.2 g 3 mmol) and tetrabutylammonium hydroxide (0.1 g, 0.3 mmol). The mixture was stirred at room temperature for 4 h and partitioned between ether and brine. The organic layer was separated, dried (MgSO4) and evaporated. The residue was purified by flash chromatography using 3:1 ether:pentane as the eluting solvent. Evaporation of the appropriate fractions gave the title compound as an oil (0.63 g, 53%). 1H NMR δ (CDCl3) 1.21-1.66 (8H, m, (CH2)4), 2.59 (2H, t, J=7.4 Hz, CH2), 3.48,3.82 (each 1H, d, J=16 Hz, NCH2), 3.21 (2H, h, J=6.00 Hz, CH2), 3.37 (1H, dd, J=5.15 Hz, H3b), 3.83 (2H, s, SCH2), 4.59 (1H, d, J=1.6 Hz, H4), 4.89 (1H, d, J=1.6 Hz, H3), 6.04 (1H, bt, NH), 7.14-7.36 (10H, m, Ph--H).
Reaction SMILES: NC1SC2C=CC=CC=2C=1C(OCC)=O.ClC1C(Cl)=C(Cl)C=CC=1[N+]([O-])=O.[Cl:28][C:29]1[C:49]([Cl:50])=[CH:48][CH:47]=[C:46]([N+:51]([O-])=O)[C:30]=1[NH:31][C:32]1[S:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[C:33]=1[C:41]([O:43][CH2:44][CH3:45])=[O:42].Cl.O.O.[Sn](Cl)Cl>C(O)C.CS(C)=O>[NH2:51][C:46]1[C:30]([NH:31][C:32]2[S:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[C:33]=2[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:29]([Cl:28])[C:49]([Cl:50])=[CH:48][CH:47]=1
Reactant: CCOC(=O)c1c(Nc2c([N+](=O)[O-])ccc(Cl)c2Cl)sc2ccccc12
Agent: CCOC(=O)c1c(N)sc2ccccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CS(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(Nc2c(N)ccc(Cl)c2Cl)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate (6.6 g), 2,3,4-trichloronitrobenzene (7.0 g) and dimethyl sulfoxide (70 ml), crude crystals (12 g) of ethyl 2-(2,3-dichloro-6-nitroanilino)benzo[b]thiophene-3-carboxylate were obtained. Without purification, in the same manner as in Starting Material Synthesis Example 21 and using ethanol (40 ml), 18% hydrochloric acid (60 ml) and tin(II) chloride-dihydrate (24.6 g), ethyl 2-(6-amino-2,3-dichloroanilino)benzo[b]thiophene-3-carboxylate (4.2 g) was obtained.
Reaction SMILES: C(O[C:5]1[C:10](C)=[CH:9][C:8]([O:12]C(=O)C)=[CH:7][N:6]=1)(=O)C.[ClH:16].C[C:18](CC)=[O:19]>>[ClH:16].[OH:12][C:8]1[CH:9]=[CH:10][C:5]([CH2:18][OH:19])=[N:6][CH:7]=1
Reactant: CCC(C)=O
Reactant: CC(=O)Oc1cnc(OC(C)=O)c(C)c1
Agent: Cl
Product: OCc1ccc(O)cn1

Procedure:
220.0 g of the above ester is added to 2,200 ml of 6N-hydrochloric acid and the resulting solution is refluxed for 18 hours. Then, the solution is evaporated to leave an oily viscous residue. This residue is digested with ethyl methyl ketone to yield 5-hydroxy-2-pyridinemethanol hydrochloride melting at 122°-123°. (The corresponding free base is prepared by adding a saturated solution of potassium carbonate to the hydrochloride, extracting the resulting suspension with chloroform, drying the chloroform extract over sodium sulfate, filtering and evaporating the filtrate to yield the free base.)
Reaction SMILES: N([O-])=[O:2].[Na+].[N+:5]([C:8]1[CH:19]=[CH:18][C:11]([CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])N)=[CH:10][CH:9]=1)([O-:7])=[O:6].Cl.OS(O)(=O)=O>O>[OH:2][CH:13]([CH2:12][C:11]1[CH:18]=[CH:19][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=1)[C:15]([OH:17])=[O:16]
Reactant: O=N[O-]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of sodium nitrite (4.6 g) in water (18 ml) was added dropwise at 0° C. over 20 minutes to a stirred mixture of p-nitrophenylalanine (6.3 g, Fluka) c.HCl (3.1 ml), 5% aqu. H2SO4 (80 ml) and water (10 ml). When addition was complete, the mixture was stirred at 0° C. for 1 hour, then allowed to warm to room temperature over 2 hours. The mixture was extracted with ethyl acetate (×4) and the extracts dried over MgSO4 and evaporated in vacuo to give the desired product as a white solid (3.1 g).