Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1Br.[C:8](=[O:10])=[O:9].CC(C)=O.C([Li])CCC.C(=O)=O>C(OCC)C>[Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:8]([OH:10])=[O:9]
Reactant: Clc1sccc1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(O)c1ccsc1Cl
Temperature: 25 °C
Yield: 90 %

Procedure:
To a round bottomed flask were added 2-chloro-3-bromothiophene (26.2 g, 132.7 mmole) along with diethyl ether (390 mL). The reaction was cooled to -78° C. (dry ice/acetone) and 1.6M n-butyllithium (87.0 mL, 139.0 mmole) was added dropwise. The reaction was stirred for 1.5 hours after which an excess of CO2 (~25.0 g) was added all at once. The reaction was warmed to room temperature and poured onto ice/water. The mixture was extracted with 10% sodium carbonate solution and the basic aqueous layer was washed with methylene chloride. The basic solution was then acidified to a pH 3.0 and extracted with diethyl ether. The organic layer was washed with water, brine, and dried (MgSO4). Solvent removal yielded 19.32 g of an off-white solid (90%) which was used as is.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH:9]([CH3:22])[CH2:10][C:11]1[CH:21]=[CH:20][C:14]2[O:15][CH:16]([CH2:18][NH2:19])[O:17][C:13]=2[CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:23])[N:7]([CH:9]([CH3:22])[CH2:10][C:11]1[CH:21]=[CH:20][C:14]2[O:15][CH:16]([CH2:18][NH:19][C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[O:17][C:13]=2[CH:12]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(Cc1ccc2c(c1)OC(CN)O2)N(C)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cc1ccc2c(c1)OC(CNC(=O)OCc1ccccc1)O2)N(C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of 0.31 g (0.96 mmol) of 1F in 5 mL of dichloromethane was added 0.2 mL (1.14 mmol) of N,N-diisopropylethylamine and 10 mg (0.08 mmol) of 4-dimethylaminopyridine (4-DMAP) followed by 0.15 mL of benzyl chloroformate (1.04 mmol) at room temperature. The mixture was allowed to stir for 1 hours and concentrated to dryness under reduced pressure. The residue was purified by silica gel flash column chromatography using 40% ethyl acetate in hexane to give 0.41 g (0.89 mmol, 94%) of 1G as a thick colorless gum (M+Na, 479).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]2[CH2:19][C:18](=[O:20])[O:17][C:16](=[O:21])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][N:32]([C:18](=[O:20])[CH2:19][N:14]([CH2:15][C:16]([OH:17])=[O:21])[C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[CH2:31]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C1CN(c2cccc(Oc3ccccc3)c2)CC(=O)O1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)O)c2cccc(Oc3ccccc3)c2)C1
Reaction time: 72 h

Procedure:
To a solution of 4-(3-phenoxyphenyl)morpholine-2,6-dione 26 (4.7 g, 0.0166 mol) in THF (50 mL) was added (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (4.11 g, 0.0221 mol). The reaction mixture was stirred for 3 days after which time a precipitate had formed. This material was collected by filtration, then washed with ethyl acetate to give the first crop of the title compound. A further crop was obtained by evaporating the filtrate in vacuo. The resultant residue was dissolved in ethyl acetate, washed with 10% hydrochloric acid and brine, dried (Na2SO4) and concentrated in vacuo. The second crop of title compound which precipitated was collected by filtration to give a total yield of 4.36 g (50%), as a cream solid. 1HNMR (300 MHz) (d6-DMSO, 100° C.)) δ 1.43 (9H, s), 1.75-2-20 (2H, 2×m), 2.75-3.1 (1H, br), 3.20-3.75 (4H, m), 4.09 (2H, s), 4.21 (2H, s), 6.22 (1H, br s), 6.37 2H, br t), 6.70 (1H, br), 6.99 (2H, d), 7.14 (2H, m) and 7.37 (2H, br t).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH2:12])=O.[NH4+:13].[OH-].O>>[NH2:12][C@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:5]1[C:3]([NH2:13])=[O:2]
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1N
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: NC(=O)[C@@H]1CCCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
cis-2-Aminocycloheptanecarboxylic acid methyl ester (1.65 g, 9.64 mmol) was treated with 20 mL of NH4OH/H2O and stirred at room temperature for 24 h. The solution was concentrated in vacuo and azeotroped once with toluene. The reaction afforded 2.20 g of cis-2-aminocycloheptanecarboxylic acid amide as a white solid: 1H NMR (DMSO-d6) δ 7.81 (m, 3 H), 7.20 (s, 1 H), 2.76 (m, 1 H), 1.68–1.40 (m, 11 H); MS m/e 157.28 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.C(O)(=O)/C=C\C(O)=O.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH2:34][CH2:35][NH2:36])=[CH:29][CH:28]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:36][CH2:35][CH2:34][NH:33][C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNc1ccc(Cl)cc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(NCCNc2ccc(Cl)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, N-(p-chlorophenyl)ethylenediamine maleate and DBU in DME. ES-MS m/e (%): 357 (M{37Cl}+H+, 40), 355 (M{35Cl}+H+, 100).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].CO.[C:24](OCC)(=[O:26])C>CO.CCCCCC>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:26][CH3:24])[CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(Br)cc2CN1Cc1ccccc1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: COc1ccc2c(c1)CN(Cc1ccccc1)C2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 2-benzyl-5-bromo-2,3-dihydro-isoindol-1-one (0.065 g, 0.22 mmol), 30% sodium methoxide-methanol (0.06 mL, 0.33 mmol), and CuBr (0:004 g, 0.03 mmol) in methanol (4 mL) was stirred at 100° C. for 1 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-5-methoxy-2,3-dihydro-isoindol-1-one (0.03 g, 54%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.86 (s, 3H), 4.22 (s, 2H), 4.78 (s, 2H), 6.82-7.29 (m, 7H), 7.79 (d, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.[ClH:27]>CO.C(OCC)(=O)C>[ClH:27].[ClH:27].[CH:21]1([NH:20][C:17]2[CH:18]=[CH:19][C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:15][CH:16]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(NC3CCCCC3)cc2)C1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: c1cc(C2CCCNC2)ccc1NC1CCCCC1
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 3-(4-cyclohexylaminophenyl)-piperidine-1-carboxylic acid tert-butyl ester (6.74 g, 18.8 mmol) in methanol (50 mL) was added 4N hydrochloric acid in ethyl acetate (40 mL) at room temperature. After stirring for 1 h, the resulting suspension was concentrated in vacuo. The residue was washed with ethyl acetate to furnish 3-(4-cyclohexylaminophenyl)-piperidine dihydrochloride (5.84 g, 17.6 mmol, 94%) as white crystals.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.[CH2:24](I)[C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH3:24][C:25]([CH3:28])([CH3:27])[CH2:26][N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20]
Reactant: CC(C)(C)CI
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Product: CC(C)(C)CN1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a off-white semi-solid in analogy to example 1 step E) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione and neopentyl iodide. MS (ESI): 399.1 (MH+).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Cl:24]>>[Cl:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: CCc1ccc(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: Cc1noc(N)c1Cl
Product: CCc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Cl)s2)s1
Yield: 71.1 %

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-5-(5-ethyl- 2-thienyl)thiophene-2-sulfonamide was prepared in the same manner as in Example 2. Reaction of 2-chlorosulfonyl-5-(5-ethyl-2-thienyl)thiophene (Example 141C, 200 mg, 0.68 mmol) with 5-amino-4-chloro-3-methylisoxazole (91 mg, 0.68 mmol) yielded 188 mg of the final product (71% yield). A small portion of the product was further purified by preparative HPLC to give the pure sulfonamide as a tan colored solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.O>CN(C=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[C:6]([O:8][CH3:9])=[O:7])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: COC(=O)c1ccc[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 664.9 %

Procedure:
Methyl 1H-pyrrole-2-carboxylate (1 g, 8.0 mmol) was dissolved in DMF (14 mL). The mixture was cooled down at 0° C. and sodium hydride (350 mg, 8.8 mmol) was added. After 5 min 1-fluoro-4-nitro-benzene (1.13 mmol, 7.99 mmol) was added and the mixture stirred at 80° C. for 3 hours. Water was added, the solid collected by filtration and washed with water to give (i) (1.85 g). 1H NMR (400 MHz, DMSO) δ 8.30 (d, J=9.0 Hz, 2H), 7.87-7.49 (m, 2H), 7.38 (dd, J=2.7, 1.8 Hz, 1H), 7.13 (dd, J=3.9, 1.7 Hz, 1H), 6.41 (dd, J=3.8, 2.8 Hz, 1H), 3.66 (s, 3H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][CH:14]([CH3:20])[CH2:15][CH2:16][C:17]([OH:19])=O.[NH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>ClCCl>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:17](=[O:19])[CH2:16][CH2:15][CH:14]([CH3:13])[CH3:20]
Reactant: Cc1ccccc1N
Reactant: CC(C)CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)CCC(C)C

Procedure:
Carbonyldiimidazole (65 g) was mixed with 500 ml of dry dichloromethane in a 2-L round bottom flask and stirred magnetically. A solution of 4-methylvaleric acid in 200 ml of dichloromethane was added dropwise over 45 minutes and the mixture was stirred for another 1.25 hours. o-Toluidine (45 g) in 100 ml of dichloromethane was then added over about 20 minutes. After stirring for 2 hours the mixture was washed with water and then the solvent was stripped on a rotary evaporator. The residue was mixed with 150 ml of methanol and 75 ml of water and put in the freezer. Filtration of the precipitate, dilution of the filtrate with water and refiltration of the precipitate gave 75 g (94%) of vacuum dried N-(2-methylphenyl)-4-methylvaleramide which was used without further treatment in the next step.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]=[C:5]([C:21](OCC)([O:24]CC)[CH2:22][Cl:23])[C:6]([NH:8][CH:9]1[C:19](=[O:20])[N:11]2[C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH2:14][S:15][C@H:10]12)=[O:7]>C(Cl)Cl>[CH3:2][O:3][N:4]=[C:5]([C:21](=[O:24])[CH2:22][Cl:23])[C:6]([NH:8][CH:9]1[C:19](=[O:20])[N:11]2[C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH2:14][S:15][C@H:10]12)=[O:7]
Reactant: CCOC(CCl)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: Cl
Solvent: ClCCl
Product: CON=C(C(=O)CCl)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Yield: 44.1 %

Procedure:
6 N Hydrochloric acid (2.4 ml), 7-(2-methoxyimino-3,3-diethoxy-4-chlorobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 301.5 mg) and methlene chloride (3 ml) were treated in a similar manner to that of Example 48 to give 7-(2-methoxyimino-3-oxo-4-chlorobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 110.4 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[OH-].[K+]>C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: Clc1ccccn1
Reactant: CC(O)c1ccc(Br)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(Oc1ccccn1)c1ccc(Br)cc1
Yield: 93.5 %

Procedure:
A solution of 1-(4-bromophenyl)ethanol (2.0 g, 10.0 mmol), 2-chloropyridine (1237 mg, 11.0 mmol), potassium hydroxide (1839 mg, 32.8 mmol) and 18-crown-6 (132 mg, 0.5 mmol) in toluene (40 mL) was stirred at reflux for 3 hrs. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=20:1) to give 2-(1-(4-bromophenyl)ethoxy)pyridine as a white solid (2.6 g, 94%). LRMS (M+H+) m/z: calcd 277.01. found 277.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH:9]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:22])([CH3:21])[CH2:10]2)[CH:3]=1.[CH3:23][O-:24].[Na+].[Na]>CO>[C:19]([C:16]1[CH:17]=[CH:18][C:13]2[O:12][C:11]([CH3:22])([CH3:21])[CH2:10][CH:9]([C:4]3[CH:3]=[C:2]([O:24][CH3:23])[CH:7]=[CH:6][N+:5]=3[O-:8])[C:14]=2[CH:15]=1)#[N:20]
Reactant: C[O-]
Reactant: CC1(C)CC(c2cc(Cl)cc[n+]2[O-])c2cc(C#N)ccc2O1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc[n+]([O-])c(C2CC(C)(C)Oc3ccc(C#N)cc32)c1
Temperature: 25 °C

Procedure:
250 mg of 4-chloro-2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide were dissolved in 6 ml of methanol and added to a solution of sodium methoxide prepared from 0.5 g of metallic sodium in 50 ml of methanol. The mixture was heated at reflux for 2 hours under a nitrogen atmosphere and then allowed to cool to room temperature. The solution was evaporated and the residue was taken up in ethyl acetate and water, the organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 20% (v/v) methanol/ethyl acetate for the elution to give a solid which was recrystallized from ethyl acetate. There were obtained 65 mg of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4 -yl)-4-methoxypyridine N-oxide of melting point 196°-198° C.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:13])(=[NH:12])[CH2:8][CH2:9][CH2:10][CH3:11].[N+:14]([C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]>C1C=CC=CC=1>[N+:14]([C:17]1[CH:18]=[C:19]([NH:23][C:24]([NH:12][C:7](=[NH:13])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:25])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: CCCCC(=N)N
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCCCC(=N)NC(=O)Nc1cccc([N+](=O)[O-])c1

Procedure:
Following a procedure similar to that described in Example 1 but using 2.3 g. sodium in 150 ml. dry acetone, 13.6 g. valeramidine hydrochloride, and 16.4 g. 3-nitrophenyl isocyanate in 300 ml. benzene, there was obtained after recrystallization from ethyl alcohol-ether 11.6 g. of the hydrochloride of 1-(3-nitrophenyl)-3-(pentanimidoyl)urea; m.p. 161°-163°C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])[C:5]=1[O:17][CH2:18][C:19]([O:21]CC)=[O:20].[OH-].[Na+]>CO>[C:19]([CH2:18][O:17][C:5]1[C:6]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:24])=[O:2])([OH:21])=[O:20]
Reactant: CCOC(=O)COc1cccc(C(=O)OC)c1OCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccc(C(=O)O)c1OCC(=O)O
Yield: 68.1 %

Procedure:
To a solution of methyl[2,3-bis(ethoxycarbonylmethoxy)]benzoate (58.0 g, 170 mmol) in methanol (100 mL) at 60 ° C. was added 3N-aqueous sodium hydroxide solution over 30 minutes, and the reaction mixture was refluxed for 2 hours. The solvent was then distilled off under reduced pressure. To that residue was added 4N-hydrochloric acid. The crystal was collected with filtration, and dried to provide 31.3 g of the title compound. Yield 68%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6](O)[N:5]2[N:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=[C:4]2[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:6]1[N:5]2[N:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=[C:4]2[N:3]=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1nc2nc(C)c(C)c(O)n2n1
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1nc2nc(C)c(C)c(Cl)n2n1
Yield: 186.3 %

Procedure:
To a suspension of the product obtained in Step 1 (50 g) in 500 ml of phosphorus oxychloride N,N-dimethylaniline (30 g) was dropwise added at room temperature, the mixture was refluxed for two hours, excess phosphorus oxychloride was removed by distillation under normal pressure, and the black oil left was dissolved in 200 ml of chloroform. This solution was slowly poured into 200 ml of ice-cooled saturated sodium bicarbonate solution, the chloroform layer was collected after thorough mixing, and the aqueous layer was again extracted with 200 ml of fresh chloroform. The combined organic layers were washed with 100 ml of saturated sodium chloride solution and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure to about 50 ml, and 100 ml of n-hexane was added to this concentrate, giving 49 g of the objective compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:12](=[O:23])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=2.[I-].C[N+]1C=CN([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])C=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:12](=[O:23])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32])[CH:15]=2
Reactant: COc1ccc(OC)c(-c2c(C)c3ccc(O)cc3oc2=O)c1
Reactant: C[n+]1ccn(C(=O)N2CCOCC2)c1
Agent: [I-]
Product: COc1ccc(OC)c(-c2c(C)c3ccc(OC(=O)N4CCOCC4)cc3oc2=O)c1
Yield: 56.4 %

Procedure:
The title compound (120 mg, 56% yield) was prepared from 3-(2,5-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide (165 mg, 0.51 mmol).
Reaction SMILES: [CH:1](=[N:3][OH:4])[CH3:2].ClCl.[OH-].[Na+].[SH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(Cl)(Cl)Cl.C(O)C>[C:1]([S:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[N:3][OH:4])[CH3:2]
Reactant: CC=NO
Reactant: CCOC(=O)CS
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)CSC(C)=NO
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
To a solution of 30 g (0.5 m) of acetaldoxime in 100 ml of chloroform cooled at 0° was added, with stirring over a period of 30 minutes, a solution of 35 grams (0.5 mol) of chlorine in 300 ml of chloroform. The reaction mixture was stirred at 0° C. for 30 minutes at which time about one half of the chloroform was removed by evaporation, in vacuo. This residual solution was then added with stirring to a solution consisting of 20 grams (0.5 mol) of sodium hydroxide and 60 grams (0.5 mol) of ethyl mercaptoacetate in 300 ml. of ethanol at 10° C. over a period of 10 minutes. The solvent was removed in vacuo, the residue was dissolved in chloroform and the resulting solution was washed with water. After drying, the chloroform solution was evaporated to give a solid residue which was recrystallized from hexane to provide 20 g (23 percent yield) of S-(ethoxycarbonylmethylene) acetothiohydroximate, m.p. 90°-92° C., lit. 90°-91° C.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30][CH2:29]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: C1CCN(CCC2CCNCC2)CC1
Product: O=C1Nc2cccnc2N(C(=O)N2CCC(CCN3CCCCC3)CC2)c2ccccc21
Yield: 47 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[2-(1-piperidinyl)ethyl]piperidine in a yield of 47% of theory. Colourless crystals, m.p. 178°-180° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([O:21][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: ClCc1ccccn1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Agent: Cl
Product: Cc1c(C)c2c(c(C)c1OCc1ccccn1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 17 %

Procedure:
Using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 2-chloromethylpyridine hydrochloride, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][S:12][CH2:13][CH:14]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:14][CH2:13][S:12][CH2:11][CH:10]=1
Reactant: Nc1ccc(C2=CCSCC2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C2=CCSCC2)c(F)c1)OCc1ccccc1
Temperature: 25 °C

Procedure:
4-(2-Fluoro-4-aminophenyl)-3,6-dihydro-2H-thiopyran (9.8 g, 46.8 mM) was dissolved in dry dichloromethane (196 ml), pyridine (6.23 g, 79.1 mM) added, and the mixture stirred under nitrogen at −20°. A solution of benzyl chloroformate (9.54 g, 53.9 mM) dissolved in dry dichloromethane (25 ml) was added dropwise, and the mixture left to warm to ambient temperature over 18 hours. The mixture was washed with 1M hydrochloric acid (200 ml), then brine (100 ml), dried (magnesium sulfate), filtered and evaporated to a small volume. The addition of isohexane (300 ml) precipitated the desired product (15.5 g).
Reaction SMILES: C([O-])=O.[NH4+].[O:5]=[S:6]1(=[O:22])[C:11]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:10]=2[N:9]2[CH2:19][CH2:20][CH2:21][CH:8]2[NH:7]1>CO.[Pd]>[O:22]=[S:6]1(=[O:5])[C:11]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:10]=2[N:9]2[CH2:19][CH2:20][CH2:21][CH:8]2[NH:7]1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)NC1CCCN21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc2c(c1)S(=O)(=O)NC1CCCN21
Reaction time: 1.5 h

Procedure:
37 mmol of ammonium formate and 300 mg of 10% Pd/C are added to 3.71 mmol of 5,5-dioxo-7-nitro-2,3,3a,4,-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine suspended in 100 ml of methanol. After 90 minutes' stirring at reflux, the catalyst is filtered off while hot and rinsed with methanol. The filtrate is evaporated and the residue is taken up in water. The expected product is obtained by filtering off the precipitate.