Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[NH:4][CH2:5][CH2:6][CH:7]=1.[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1>C1C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:4]2[CH2:5][CH2:6][CH2:7][C:3]2=[O:2])=[O:15])=[CH:12][CH:11]=1
Reactant: COC1=CCCN1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccccc1
Product: COc1ccc(C(=O)N2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.2 g. of 2-methoxypyrroline are dissolved in 25 ml. of benzene and treated at room temperature with 6.6 g. of p-methoxybenzoyl chloride dissolved in 30 ml. of benzene. The mixture is stirred at room temperature for 60 minutes and at reflux for 4 hours. 30 ml. of benzene are then added and the mixture is boiled at reflux for a further 24 hours. The volatile constituents are distilled off, the residue is taken up in ethanol, the mixture is concentrated, the residue is triturated with diethyl ether, filtered and the filter cake is taken up in ethyl acetate. The ethyl acetate solution is washed with sodium bicarbonate solution and water, dried over sodium sulfate and concentrated. The residue is sublimed in vacuo and there is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 119°-120° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:13]([O-])=O.[Na+].O.O.[Sn](Cl)[Cl:20]>Cl.O>[ClH:20].[Br:11][C:9]1[C:8]([CH3:12])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][NH2:13])[CH:10]=1
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Reactant: Cc1cc(C(=O)O)c(N)cc1Br
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(=O)O)c(NN)cc1Br
Reaction time: 0.75 h
Yield: 60.7 %

Procedure:
A suspension of 2-amino-4-bromo-5-methylbenzoic acid (2.92 g, 12.7 mmol) in a mixture of 37% aqueous HCl (12.7 mL) and water (4.3 mL), cooled in a NaCl-ice bath, was treated slowly dropwise with a solution of sodium nitrite (0.963 g, 14.0 mmol) in water (4.5 mL). The resulting mixture was stirred for 45 min, then was treated slowly dropwise with a solution of tin(II) chloride dihydrate (8.59 g, 38.1 mmol) in 37% aqueous HCl (8.2 mL). The cooling bath was removed, and the mixture was stirred at room temperature for 60 min. The mixture was filtered, and the collected precipitate was washed with water and dried. The solid was triturated and sonicated in MeOH, and the mixture was concentrated. The residue was triturated and sonicated with DCM, and the precipitate was collected by filtration and washed with DCM to give 4-bromo-2-hydrazinyl-5-methylbenzoic acid hydrochloride as a white solid (2.17 g, 61% yield). Mass spectrum m/z 245, 247 (M+H)+.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13]CC)(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:16](#[N:18])[CH3:17].O>C1(C)C=CC=CC=1>[C:5]([CH2:17][C:16]#[N:18])(=[O:13])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1ccccc1
Reactant: CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 29 h

Procedure:
To a suspension of sodium ethoxide (34.0 g. 0.500 mole) in dry toluene (200 mL were added ethyl benzoate (71.4 mL, 0.500 mole) and dry acetonitrile (32 mL, 0.60 mole). The mixture was mechanically stirred under nitrogen at 105°-110° C. for 29 hours, during which time it became quite viscous. After cooling to room temperature, water (300 mL) was added and the mixture was washed with ethyl ether (2×100 mL). The aqueous layer was then acidified to pH 5-6 with con. aq. HCl (required 30-35 mL) and the resulting crystalline precipitate was collected by suction filtration, washed twice with water, and air-dried. This subtitled material (49.23 g, 68%, m.p. 72°-73°) was sufficiently pure to be used in further transformations (lit., m.p. 80°-81°, Long, R. S., J. Am. Chem. Soc., (1947), 69, p. 990. 1NMR (CDCl3, δ) 7.95 (dd, 2H, J=7, 2 Hz, o-aryl), 7.6 (m, 3H, aryl), 4.1 (s, 2H, CH2). This benzoyl acetonitrile intermediate is also now commercially available but we prepared ours as above.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH:7]=[O:8].[C:9]1([Li])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8]
Reactant: [Li]c1ccccc1
Reactant: Cc1ncoc1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncoc1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Methyl-5-oxazolecarbaldehyde (600 mg) in dry tetrahydrofuran (10 ml) was added dropwise to a stirred solution of phenyllithium (2.0M solution in cyclohexane and diethyl ether, 2.8 ml) in tetrahydrofuran (20 ml) at -70° C. under an atmosphere of dry nitrogen. After 1 hour the mixture was allowed to warm to room temperature. After a further 1 hour saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The product was purified by flash chromatography to yield the title compound. M.p. 79°-81° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](O)[CH3:15].S(=O)(=O)(O)O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCO
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1

Procedure:
4-fluoro-3-nitrobenzoic acid (1 equivalent) was dissolved in ethanol (5.3 equivalents), and concentrated sulfuric acid (0.25 equivalent) was added thereto, and the resulting mixture was heated under reflux for 5 hours. After cooling the reaction mixture, the reaction mixture was concentrated under reduced pressure until the volume was reduced to about half the initial value. The resulting mixture was then neutralized by adding sodium carbonate and was subjected to extraction with ether three times. The obtained extracted liquid was washed with saturated brine and then with water, and the ether layer was dried over anhydrous sodium sulfate. The resulting layer was then evaporated to dryness under reduced pressure, whereby ethyl 4-fluoro-3-nitrobenzoate was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].O1CCCC1.C(N(CC)C(C)C)(C)C.[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32]Cl>ClCCl>[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCCOCOc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96.7 %

Procedure:
A suspension of 5 g (30 mmol) of 5-hydroxy-2-nitrobenzaldehyde (1) in 100 mL of dichloromethane and 10 mL of freshly distilled tetrahydrofuran was cooled to 0° C. To this suspension 6.25 mL (57 mmol) of N,N-diisopropylethylamine was added, and the resulting reaction mixture was stirred for 5 minutes. To this reaction mixture 3.76 mL (33 mmol) of 2-methoxyethoxymethyl chloride was added, stirred for 10 minutes at 0° C., warmed up to room temperature, and allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and 150 mL of ethyl acetate were added. The resulting off-white precipitate was filtered off, and the filtrate was transferred into a separatory funnel. The organic layer was washed with 75 mL of 1N sodium hydroxide solution, 100 mL water, and 75 mL brine. The organic layer was dried over anhydrous potassium carbonate, filtered, and concentrated to give 7.4 g (29 mmol, 97%) of 2 [LC-MS; M+Na 278].
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:23])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:22][C:17]1[CH:16]=[C:15]([NH:14][C:13]([CH:10]2[CH2:11][CH2:12][N:8]([CH2:7][C:6]([OH:24])=[O:5])[CH2:9]2)=[O:23])[CH:20]=[CH:19][C:18]=1[OH:21]
Reactant: CC(C)(C)OC(=O)CN1CCC(C(=O)Nc2ccc(O)c(Cl)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1CCC(C(=O)Nc2ccc(O)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[3-(3-Chloro-4-hydroxy-phenylcarbamoyl)-pyrrolidin-1-yl]-acetic acid tert-butyl ester was dissolved in TFA/DCM (90:10) solution. After stirring at RT for 30 min, the reaction mixture was concentrated and acetonitrile/water (10 ml, 3:1) was added. After removal of solvent, the residue was purified using Prep-HPLC to give 450 mg of product.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].[CH:9]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([NH:14][C:4](=[O:5])[C:3]([CH3:8])([CH3:7])[CH2:2][OH:1])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(CO)C(=O)O
Reactant: NC1CCCC1
Product: CC(C)(CO)C(=O)NC1CCCC1

Procedure:
Prepared as in Example 24a from hydroxypivalic acid and cyclopentyl amine as an orange oil (32%). 1H NMR (400 MHz, DMSO-d6) δ 1.00 (s, 6H), 1.32-1.40 (m, 2H), 1.43-1.49 (m, 2H), 1.57-1.65 (m, 2H), 1.73-1.81 (m, 2H), 3.34 (d, J=4.0 Hz, 2H), 3.98 (m, 1H), 4.87 (t, J=4.0 Hz, 1H), 7.22 (d, J=4.0 Hz, 1H). MS 186 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH2:3][C:4]([OH:6])=[O:5].[CH2:14](O)[CH3:15].S(Cl)([Cl:19])=O>CC1CCCO1>[NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH2:3][C:4]([O:6][CH2:14][CH3:15])=[O:5].[ClH:19].[NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH2:3][C:4]([O:6][CH2:14][CH3:15])=[O:5].[CH3:12][CH:7]1[CH2:2][CH2:3][CH2:4][O:5]1
Reactant: CCO
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1[C@@H](N)CC(=O)O
Solvent: CC1CCCO1
Product: CCOC(=O)C[C@H](N)c1ccccc1C
Product: Cl
Temperature: 80 °C
Reaction time: 16 h

Procedure:
(S)-3-Amino-3-(2-methyl-phenyl)propionic acid (10.0 g, 55.8 mmol) was suspended in 2-methyltetrahydrofuran (100 ml) and ethanol (25.7 g, 558 mmol) was added. The mixture was heated to 80° C. and thionyl chloride (6.64 g, 55.8 mmol) was added slowly. After 2 h at 80° C. the solvents were almost completely removed by distillation. After cooling the mixture was stirred at room temperature for 16 h. Then more solvent was removed under reduced pressure to give the title compound in the form of ethyl (S)-3-amino-3-(2-methyl-phenyl)-propionate hydrochloride together with some 2-methyltetrahydrofuran in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:23]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: Cc1cccc(C(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)c1
Yield: 77 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.9 μL (0.051 mMol) 3-methylbenzoyl chloride, 12.3 mg (77%) of the title compound were recovered as a beige solid.
Reaction SMILES: [CH3:1][Mg]I.[CH:4]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])([CH3:6])[CH3:5].S(=O)(=O)(O)O>CCOCC>[C:13]([C:7]1([CH:4]([CH3:6])[CH3:5])[CH2:11][CH2:10][CH2:9][C:8]1([CH3:1])[OH:12])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C1(C(C)C)CCCC1=O
Reactant: C[Mg]I
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCOC(=O)C1(C(C)C)CCCC1(C)O

Procedure:
Methylmagnesium iodide (0.22 mole) in ether (200 ml.) was added dropwise to a solution of 2-isopropyl-2-carbethoxycyclopentanone (40 g, 0.2 mole) in ether (150 ml.), and the mixture was heated under reflux for 17 hours. Dilute sulphuric acid was then added and the ether layer was separated and dried (MgSO4). The ether was removed to leave 2-carbethoxy-1-methyl-2-isopropylcyclopentanol. This compound was dissolved in pyridine (200 ml.) and cooled to -10° C. Thionyl chloride (25 ml.) was then added keeping the temperature at -5° C. After 2 hours at -5° C., ether (500 ml) and an excess of 2 N sulphuric acid were added and the organic layer was separated. The aqueous layer was extracted with ether and the combined extracts were dried (MgSO4). The solvent was removed and the residue was distilled to give 1-carbethoxy-1-isopropyl-2-methylcyclopent-2-ene, bp. 107°-110°/17 mm.
Reaction SMILES: [I-].[Na+].Br[CH:4](Br)[C:5]1[C:6]([CH:11](Br)Br)=[CH:7][CH:8]=[CH:9][CH:10]=1.[C:15](#[N:20])/[CH:16]=[CH:17]/[C:18]#[N:19].S([O-])(O)=O.[Na+]>CN(C)C=O>[C:18]([C:17]1[C:16]([C:15]#[N:20])=[CH:11][C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]=1)#[N:19]
Reactant: N#C/C=C/C#N
Reactant: BrC(Br)c1ccccc1C(Br)Br
Agent: O=S([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc2ccccc2cc1C#N
Temperature: 75 °C
Reaction time: 7 h
Yield: 73 %

Procedure:
One hundred grams (0.67 mole) of sodium iodide was added to a well-stirred solution of 42.2 g (0.1 mole) of α,α,α',α'-tetrabromo-o-xylene and 13.5 g (0.173 mole) of fumaronitrile in 400 ml of anhydrous N,N-dimethylformamide, and the resulting mixture was stirred at 75° C. for about 7 hours in an atmosphere of nitrogen. After the reaction, the mixture was poured into about 2 kg of ice, and thereto was slowly added sodium hydrogen sulfite until the red-brown colored aqueous solution turned to light yellow. After adding a slightly excessive quantity of sodium hydrogen sulfite, the resulting mixture was stirred for a while and then allowed to stand overnight at room temperature. The deposited light yellow-colored solid product was collected by filtration with suction, thoroughly washed with water, and allowed to dry. The light yellow-colored solid product thus obtained was recrystallized from ethanol/chloroform mixture to obtain 13 g (73%) of 2,3-dicyanonaphthalene as a colorless crystalline material.
Reaction SMILES: CO/[CH:3]=[CH:4]/[C:5]([O:7][Si](C)(C)C)=[CH2:6].[C:12](#[N:15])[CH:13]=[CH2:14].Cl.C1COCC1>C1C=CC=CC=1>[O:6]=[C:5]1[CH2:7][CH2:14][C:13]([C:12]#[N:15])=[CH:3][CH2:4]1
Reactant: C=CC#N
Reactant: C=C(/C=C/OC)O[Si](C)(C)C
Agent: Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: N#CC1=CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a sealed tube, {[(3E)-4-methoxybuta-1,3-dien-2-yl]oxy}(trimethyl)silane (5.65 mL, 29.0 mmol) and acrylonitrile (1.91 mL, 29.0 mmol) were combined in benzene (9.67 mL), heated to reflux, and allowed to stir for 16 hours. The reaction mixture was then cooled to ambient temperature and the volatiles were removed in vacuo (23° C. water bath). The residue was stirred into a mixture of 1N aqueous HCl (29.0 mL, 29.0 mmol) and THF (9.7 mL). After being stirred at ambient temperature for 3 hours, the reaction mixture was extracted with diethyl ether. The organic layer was washed with de-ionized water (2×), brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo (23° C. water bath). The residue was purified by MPLC on silica gel (using a gradient elution of 0-50% hexanes/acetone). Desired fractions were identified, combined and concentrated in vacuo (23° C. water bath) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@:9]([OH:29])([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=3[N:16]=2)[C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[N:30]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH3:34])=[C:31]=[O:32].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@:9]2([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][C:17]=4[N:16]=3)[O:29][C:31](=[O:32])[N:30]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH3:34])[C:10]2=[O:12])=[CH:6][CH:7]=1
Reactant: CCCCC[C@@H](C)N=C=O
Reactant: CCOC(=O)[C@@](O)(Cc1ccc(F)cc1)c1nc2cc(NS(C)(=O)=O)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCC[C@@H](C)N1C(=O)O[C@](Cc2ccc(F)cc2)(c2nc3cc(NS(C)(=O)=O)ccc3[nH]2)C1=O
Temperature: 70 °C

Procedure:
To a solution of (R)-ethyl 3-(4-fluorophenyl)-2-hydroxy-2-(5-(methylsulfonamido)-1H-benzo[d]imidazol-2-yl)propanoate (50 mg, 0.12 mmol) in THF (0.5 ml) at rt were added (R)-2-isocyanatoheptane (25 mg, 0.18 mmol) and NaOH (6 mg, 0.15 mmol). The mixture was heated at 70° C. for 25 min. The resulting mixture was filtered through a short plug of silica and concentrated. The resulting residue was purified by Combiflash (silica gel column, 5-35% ethyl acetate in hexane) to give the title product. LC/MS (m/z): 517.0 [M+1]; 1H NMR (400 MHz, CDCl3) δ 10.8-10.9 (d, 1H), 7.6 (t, 1H), 7.5 (s, 1H), 7.3 (m, 1H), 7.2 (m, 2H), 6.9 (m, 2H), 3.7-3.8 (m, 2H), 3.5 (d, 1H), 2.9 (s, 3H), 1.3 (q, 2H), 0.9-1.1 (m, 5H), 0.6-0.9 (m, 7H);
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([OH:13])(=[O:12])=O)[CH:7]=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O.[CH2:25]([NH2:27])[CH3:26]>O>[CH2:25]([NH:27][S:10]([C:6]1[CH:7]=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:13])[CH3:26]
Reactant: O=[N+]([O-])c1cncc(S(=O)(=O)O)c1
Reactant: CCN
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCNS(=O)(=O)c1cncc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 0.5g. of 5-nitro-3-pyridinesulfonic acid, 0.5g. of phosphorous pentachloride and 15 ml. of phosphorous oxychloride was heated under reflux for 6 hours. After removing the solvent by evaporation, dry chloroform was added to give a powdery crystal. After adding the crystal to 2.5 ml. of 20% ethyl amine under cooling, the mixture was stirred for 1 at room temperature. Then, the mixture was diluted with water and extracted with ethyl acetate. The extact was washed with water and dried. After removing the solvent by evaporation and purification by chromatography, 0.2g. of the desired compound was obtained. m.p. 117°-118° C. Similarly, the following compounds were synthesized.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7]Br)[CH3:2].C([O-])(=[S:12])C.[K+].[CH3:15][C:16](C)=[O:17]>>[CH2:1]([O:3][C:4](=[S:12])[CH2:5][CH2:6][CH2:7][C:16](=[O:17])[CH3:15])[CH3:2]
Reactant: CC(C)=O
Reactant: CC([O-])=S
Reactant: CCOC(=O)CCCBr
Agent: [K+]
Product: CCOC(=S)CCCC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To acetone (30 ml) were added 4-bromobutyric acid ethyl ester (1.5 ml, 10.5 mmol) and potassium thioacetate (1.8 g, 15.8 mmol), and the mixture was stirred at room temperature for 30 minutes and then filtered, and the solids were washed with acetone. The filtrate was concentrated, and then purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give 4-acetylthiobutyric acid ethyl ester (2.03 g). Then, ethyl magnesium bromide (1.04M solution in tetrahydrofuran, 31.3 ml, 32.6 mmol) in dry tetrahydrofuran (8 ml) was cooled to 0° C. under an argon atmosphere, and a solution of 886 mg of the compound obtained as above in dry tetrahydrofuran (4 ml) was added dropwise and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with an aqueous saturated ammonium chloride solution, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (221 mg, 2 steps, 29%).
Reaction SMILES: C(C([CH:10]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[CH3:26])[C:12]=2[O:11]1)N)C1C=CC=CC=1.C([N:30](C(C)C)CC)(C)C.Cl[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>>[CH2:40]([O:39][C:37](=[O:38])[NH:30][CH:10]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[CH3:26])[C:12]=2[O:11]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Cc1cc(Cl)ccc1-c1cccc2c1OC(C(N)Cc1ccccc1)C2
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)OCc1ccccc1
Product: Cc1cc(Cl)ccc1-c1cccc2c1OC(NC(=O)OCc1ccccc1)C2
Yield: 96.7 %

Procedure:
Treatment of (±)-benzyl[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.979 g, 3.15 mmol) with diisopropylethylamine (0.612 g, 4.73 mmol) and benzyl chloroformate (0.646 g, 3.79 mmol) generally according to the procedure described for Intermediate 12 provided 1.2 g (96%) of (±)-benzyl[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]carbamate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30](=[O:32])(=[O:31])[NH2:33])=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(O)c1cccc(OCc2ccc(Cl)cc2)c1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
A benzene (30 ml) solution containing 4.00 g (15.2 mmol) of 3-(4-chlorobenzyloxy)benzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.75 g (16.0 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were washed with methanol to obtain 4.70 g (yield: 74.0%) of the title compound.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[F:5][C:6]([F:16])([F:15])[C:7]1[N:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1>C(O)C>[F:16][C:6]([F:15])([F:5])[C:7]1[N:12]=[C:11]([C:13](=[NH:14])[O:1][CH2:2][CH3:3])[CH:10]=[CH:9][CH:8]=1
Reactant: N#Cc1cccc(C(F)(F)F)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=N)c1cccc(C(F)(F)F)n1
Reaction time: 2 h
Yield: 92 %

Procedure:
Sodium ethoxide (197 mg, 2.9 mmol) was added to a solution of 6-(trifluoromethyl)picolinonitrile (250 mg, 1.45 mmol) in ethanol (10 mL) at room temperature. The reaction mixture was stirred for 2 h. The solvent was removed under reduced pressure and the resulting residue was dissolved in dichloromethane, washed with water, dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (291 mg) which was used without further purification. MS (ES+) (M+H) 219.16