Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)=O.[CH3:18][C:19]1[CH:23]=[C:22]([CH2:24][C:25](Cl)=[O:26])[O:21][N:20]=1.Cl.CC1C=C(CC(O)=O)ON=1.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.C(N(CC)CC)C.CN(C)C=O>[Cl:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:1][C:25](=[O:26])[C:24]([C:22]1[O:21][N:20]=[C:19]([CH3:18])[CH:23]=1)=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccc(O)c1
Reactant: Cc1cc(CC(=O)Cl)on1
Agent: Cc1cc(CC(=O)O)on1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2c(-c3cccc(O)c3)c3cc(Cl)ccc3[nH]c2=O)on1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of 2-amino-5-chloro-3′-hydroxybenzophenone (0.1 g, 0.4 mmol), (3-methyl-isoxazol-5-yl)-acetyl chloride (1.18 mmol) [synthesized from the reaction between (3-methyl-isoxazol-5-yl)-acetic acid hydrochloride and oxalyl chloride catalyzed by N,N-dimethylformamide in DCM], triethylamine (Et3N) (0.20 mL) and DCM (10 mL) was heated to reflux overnight. The mixture was then cooled to room temperature and concentrated, and the residue was purified by flash chromatography on silica gel (5% methanol in DCM) to give 6-chloro-4-(3-hydroxyphenyl)-3-(3-methyl-isoxazol-5-yl)-1H-quinolin-2-one (99 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.68-7.60 (m, 2H), 7.43 (d, J=10.0 Hz, 1H), 7.25 (t, J=10.0 Hz, 1H), 7.01-6.97 (m, 1H), 6.88-6.80 (m, 1H), 6.68-6.59 (m, 1H), 6.47 (s, 1H), 2.15 (s, 3H). MS: 353.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17].N1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([S:34](Cl)(=[O:36])=[O:35])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>C1COCC1.C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:34]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=2)(=[O:36])=[O:35])=[C:3]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:4]=1
Reactant: COc1ccccc1Cc1cc(Cl)ccc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccccc1Cc1cc(Cl)ccc1NS(=O)(=O)c1ccc(OC)c(OC)c1
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To 0.57 g of (2-amino-5-chlorophenyl)(2-methoxyphenyl)methane dissolved in 5 ml of THF are successively added 0.2 ml of pyridine and 0.547 g of 3,4-dimethoxybenzenesulfonyl chloride, and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane, to give 0.832 g of the expected product.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1>C(O)C>[C:15]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:3]2[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=2)[CH:16]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2cccc(-c3ccccc3)c2)[nH]c1=O
Temperature: 80 °C

Procedure:
The mixture of ethyl 2-(methylthio)-6-oxo-1,6-dihyropyrimidine-5-carboxylate (319 mg, 1.491 mmol) and [1,1′-biphenyl]-3-amine (252 mg, 1.491 mmol) were dissolved in 10 mL of ethanol and heated at 80° C. overnight. After heating, the solution was run on thin layer chromatography and filtered. The precipitate was collected and stored. 1H-NMR confirmed the product (246 mg, 49.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20][CH2:21]C(O)=O)[N:11]([CH3:19])[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=[O:26].C(=O)=O.N[C@H:41]([C:48]([OH:50])=[O:49])[CH2:42][C:43]1N=[CH:46][NH:45][CH:44]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20][CH2:21][C:46]([N:45]3[CH2:44][CH2:43][CH2:42][CH:41]3[C:48]([OH:50])=[O:49])=[O:26])[N:11]([CH3:19])[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1c(SCC(=O)O)nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(SCC(=O)N2CCCC2C(=O)O)nc(-c2ccc(F)cc2)c1-c1ccncc1

Procedure:
2-[4-(4-Fluorophenyl)-1-methyl-5-pyridin-4-yl-1H-imidazol-2-ylsulfanyl]acetic acid (1 mmol/0.344 g) are dissolved in 100 ml of absolute THF, carbonyldiimidazole (1 mmol/0.162 g) is added and the mixture is stirred at room temperature until the evolution of carbon dioxide has ceased. Histidine (1 mmol) is then added, and the mixture is heated under reflux for 2 h. The mixture is then poured into 400 ml of 1 N Na2CO3 solution and concentrated in a rotary evaporator. The residue is extracted 3 times with in each case 150 ml of dichloromethane/ethanol 1:1, dried over sodium sulfate and concentrated in a rotary evaporator. The residue is dissolved in a little acetone and re-precipitated using diethyl ether. The precipitate formed is filtered off with suction and dried over P2O5.
Reaction SMILES: O=[N:2][NH2:3].Cl.C(N(CC)CC)C.[C:12]1([CH3:19])[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>>[CH:18]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[N:3][N:2]=1
Reactant: NN=O
Reactant: Cc1ccccc1C
Agent: Cl
Solvent: CCN(CC)CC
Product: c1ccc2cnncc2c1
Temperature: 25 °C
Yield: 52 %

Procedure:
1,1′-Carbonyldiimidazole (1.011 g, 6.23 mmol) was added to a stirred solution of the preceding acid (0.755 g, 5.94 mmol) in DMF (20 ml) at room temperature under nitrogen. The solution was stirred for 1.1 h before adding 3-chloro-6-hydrazino-4,5-diazatricyclo[6.2.2.2.7]dodeca-2(7),3,5-triene (1.335 g, 5.94 mmol). After 2.5 h, the solvent was evaporated in vacuo and the residue triturated with water. The solid was filtered off, washed with water and hexane, and dried in vacuo to give the ketohydrazine (1.645 g, 83%), MS (ES+) m/e 334 [MH]+. A solution of the ketohydrazine (1.855 g, 5.56 mmol) and triethylamine hydrochloride (0.186 g, 0.556 mmol) in xylene (28 ml) was heated at reflux for 3 h. The solution was cooled to room temperature and the solvent evaporated in vacuo. The residue was dissolved in dichloromethane, washed with water (×3), dried (MgSO4) and evaporated in vacuo, and the crude product was chromatographed on silica gel, eluting with 7% methanol/dichloromethane, to give the title-phthalazine (0.917 g, 52%), 1H NMR (250 MHz, CDCl3) δ1.42-1.56 (4H, m, 2 of CH2), 1.92-2.04 (4H, m, 2 of CH2), 2.62 (3H, s, Me), 3.58 (1H, br s, CH), 4.09 (1H, br s, CH), 8.59 (1H, s, Ar—H); MS (ES+) m/e 316 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](N2CCOCC2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH:3]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])[CH3:27].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=2)[N:5]=[C:6]([C:33]2[CH:34]=[C:29]([C:26](=[O:28])[CH3:27])[CH:30]=[CH:31][CH:32]=2)[N:7]=1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(N3CCOCC3)n2)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(-c2nc(Cl)cc(Nc3ccc(OC(F)(F)F)cc3)n2)c1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
To a mixture of compound (6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (0.5 g, 1.54 mmol) and 3-acetyl benzene boronic acid (0.125 g, 0.31 mmol) in DMF (10 mL) was added palladium tetrakis triphenyl phosphine (0.053 g, 0.046 mmol) and 2M Na2CO3 solution (1.3 g, 12.34 mmol) at temperature in the range of 20-40° C. The reaction mixture was heated for 12 hours under nitrogen atmosphere. After cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate (3×10 mL). Combined the organic layers were concentrated and the residue was purified by column chromatography using 15% ethylacetate in petroleum ether to afford the desired compound (0.125 g, 20%) as a white solid.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:30]=[CH:29][C:11]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>O1CCCC1>[ClH:28].[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:8]1[CH:30]=[CH:29][C:11]([C:12]([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:18][CH2:19]2)=[O:13])=[CH:10][CH:9]=1)[C:40](=[O:43])[CH:41]=[CH2:42])([CH3:3])[CH3:2]
Reactant: CC(C)OCCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N(CCOC(C)C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Product: Cl

Procedure:
3 g of 1-{4-[N-(2-isopropyloxyethyl)amino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine are dissolved in 40 ml of absolute tetrahydrofuran and cooled to 3° with stirring. There are added thereto 1.08 g of Hunig base and then, dropwise, within a period of 5 minutes, a solution of 0.65 g of acrylic acid chloride in 5 ml of absolute tetrahydrofuran. The mixture is stirred for 30 minutes at RT and concentrated by evaporation. The residue is taken up in water and ethyl acetate and the organic phase is washed until neutral with sodium hydrogen carbonate solution and water and concentrated by evaporation. The brown oil is chromatographed over silica gel. The mixture is treated with ethereal hydrochloric acid. Recrystallisation from acetone and ether yields 1-{4-[N-(2-isopropyloxyethyl)-N-acryloylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine hydrochloride having a melting point of 132°-134°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[C:15](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[CH3:15][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(F)cc1C(F)(F)F
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A suspension of 4-fluoro-2-trifluoromethylbenzoic acid (25.6 g, 123.0 mmol) in dichloromethane (250 mL) containing a few drops of dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (11.3 mL, 129.5 mmol). After the gas evolution subsided, the reaction mixture was refluxed for an additional 15 minutes. The mixture was cooled and methanol (50 mL) was added. After stirring for 2 hrs, the reaction was concentrated, and the residue was partitioned between dichloromethane and water. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, and evaporated to dryness to give 18.0 g of the title compound as a golden oil.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[Br:6][C:7]1[CH:12]=[N:11][CH:10]([Cl:13])[N:9](Cl)[CH:8]=1.[H-].[Na+].[Cl-].[Na+].O.O>CN(C)C=O>[Br:6][C:7]1[C:8]([O:5][CH2:4][CH:2]2[CH2:1][O:3]2)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1
Reactant: ClC1N=CC(Br)=CN1Cl
Reactant: OCC1CO1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncc(Br)c(OCC2CO2)n1
Yield: 96.2 %

Procedure:
A solution of glycidol (13.0 g, 0.175 mole) and 5-bromo-2,3-dichloropyrimidine (40.0 g, 0.175 mole) in dimethylformamide (350 mL) was added dropwise to a stirring nitrogen-flushed, chilled suspension of sodium hydride (from 10.1 g, 0.21 mole, of NaH washed free of mineral oil) in dimethylformamide (350 mL). Following the addition, the reaction mixture was poured into 1:1 brine-water (4.5 l) and extracted with ethyl acetate (5×750 mL). Combined extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo to give 44.7 g of an oil which solidified. Trituration of the crude product in isopropyl alcohol-isopropyl ether gave 21.9 g (47%) of product, m.p. 63°-73°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=O)=[CH:4][CH:3]=1.C1(O[C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)C=CC=CC=1.C1(O)C=CC=CC=1.Cl.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:19]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: O=C(Oc1ccccc1)c1ccc(O)cc1
Agent: Cl
Solvent: Oc1ccccc1
Product: Oc1ccc(-c2nnc(-c3ccc(O)cc3)n2-c2ccccc2)cc1
Temperature: 220 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
Into a 500 ml three neck round bottom flask equipped with a magnetic stirbar, nitrogen inlet, glass stopper, and distillation head was placed 4-hydroxybenzoic hydrazide (60.9 g, 0.4 mol) and phenyl-4-hydroxybenzoate (85.7 g, 0.4 mol). The mixture was heated to approximately 220° C. by use of a Wood's metal bath. The solids melt and phenol began to evolve and was removed via the distillation head. After two hours, aniline hydrochloride (103.6 g, 0.8 mol) was added and the temperature was increased to 250° C. and held for two hours. The mixture was cooled and washed repeatedly in methanol to give a white solid (65.8 g, 50% yield). The solid was recrystallized from N,N-dimethylacetamide (approximately 225 ml) to give, after drying at 200° C. under vacuum, white needles (49.7 g, 37% yield) with a melting point of approximately 420° C. by differential thermal analysis (DTA). Elemental analysis for C20H15N3O2 : Calculated: C, 72.93%; H, 4.59%; N, 12.76%; O, 9.72%. Found: C, 72.97%; H, 4.63%; N, 12.84%. This monomer has the following structure: ##STR8##
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:22][O:23][CH2:24]Cl.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:22][O:23][CH3:24])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: Oc1ccc(F)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(F)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.91 g of 4-fluoro-1-hydroxynaphthalene in 40 ml of dry dichloromethane in an ice/salt bath was added by syringe 2.64 ml of diisopropylethylamine followed by 1.11 ml of methoxymethylchloride. The mixture was stirred at 0° C. for 0.5 h, allowed to warm to ambient temperature and stirred for 14 h. The reaction mixture was poured into saturated sodium bicarbonate, extracted with dichloromethane, dried (sodium sulphate), filtered and concentrated to a yellow oil. The material was purified by flash chromatography on silica gel eluting with toluene/heptanes to provide 1.98 g of 4-fluoro-1-methoxymethoxynaphthalene.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[OH-].[Na+].[CH2:12](I)[CH3:13]>CO.O>[CH2:12]([O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9])[CH3:13]
Reactant: CCI
Reactant: Cc1occc(=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1c(C)occc1=O
Yield: 71.1 %

Procedure:
3-Hydroxy-2-methyl-4-pyrone (10 g, 79.4 mmol) was dissolved in methanol (10 mL) and sodium hydroxide (3.49 g, 87.3 mmol) in water (8 mL) was added, followed by ethyl iodide (6.97 mL, 87.3 mmol). The reaction mixture was stirred under reflux overnight. The reaction mixture was then partitioned between water (50 mL) and CH2Cl2 (100 mL). The organic phase was washed with sodium hydroxide (5%, aq.), water, dried (MgSO4) and evaporated to give the title product (8.7 g, 71%) as a solid. The crude product was used in the next step without further purification.
Reaction SMILES: C([S:5]([NH:8][C:9]1C=C[C:15]([CH:18]2CCCCC2)=[CH:14][C:10]=1[C:11](O)=O)(=[O:7])=[O:6])(C)(C)C.O.C1(C)C(S(O)(=O)=[O:32])=CC=CC=1.O.[C:37]1([CH3:43])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH:37]1([C:43]2[CH:11]=[C:10]3[C:14](=[CH:15][CH:18]=2)[S:5](=[O:7])(=[O:6])[NH:8][C:9]3=[O:32])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)S(=O)(=O)Nc1ccc(C2CCCCC2)cc1C(=O)O
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: Cc1ccccc1
Solvent: O
Product: O=C1NS(=O)(=O)c2ccc(C3CCCCC3)cc21
Temperature: 25 °C

Procedure:
The sulfonamido benzoic acid obtained from Example IV is stirred in toluene under argon atmosphere in a flask equipped with a Dean-Strark trap. Toluenesulfonic acid monohydrate (5 mol%) is added and the reaction mixture is warmed to reflux. When no further co-distillation of water is observed, the reaction mixture is cooled to room temperature and concentrated using a rotary evaporator. The resulting crude semi-solid oil is dissolved in a minimum amount of ethyl acetate at the boiling point and the resulting solution then is made cloudy by the addition of hexane. The desired cyclohexyl saccharin compound crystallizes on cooling. The dissolution and crystallization procedure may be repeated if higher purity material is desired. Spectral data for the crystallized product (IR, C=O 1720 cm-1 ; nmr delta=1-2.2 m cyclohexyl, delta=6.2 s broad N--H, delta=7-8 m aromatic) are consistent with the anticipated structure of 5-cyclohexyl saccharin.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:26][C:27]([CH3:32])=[CH:28][CH2:29][CH2:30][OH:31]>CN(C=O)C>[F:19][C:13]1[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([O:31][CH2:30][CH2:29][CH:28]=[C:27]([CH3:32])[CH3:26])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Reactant: CC(C)=CCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)=CCCOc1cncc(Nc2ccc(I)cc2F)c1C(N)=O
Temperature: 70 °C
Reaction time: 24 h

Procedure:
500 mg of 3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (0.253 mmol, 1. eq.) were dissolved in 5 ml of DMF, then 1225 mg of cesium carbonate (3.759 mmol, 3 eq.) and 125 mg of 4-methyl-3-pentene-1-ol (0.253 mmol, 1 eq.) were added. The resulting mixture was stirred at 70° C. bath temperature for 24 hours. Since the reaction was not complete, the mixture was stirred for another 2 days at 70° C. bath temperature. Since the reaction was not complete, another 125 mg of 4-methyl-3-pentene-1-ol (0.253 mmol, 1 eq.) and 408 mg of cesium carbonate (0.253 mmol, 1 eq.) were added, and the mixture was stirred for another 2 days at 70° C. bath temperature. The resulting mixture was partitioned between aq. NH4Cl solution (50 ml) and dichloromethane (50 ml). The phases were separated and the aqueouse layer was reextracted twice with dichloromethane (50 ml each). The combined organic layers were washed with brine (50 ml), dried over a silicone filter and concentrated in vacuo. The residue was suspended in ethyl acetate and stirred for 1 h, after which the precipitate was filtered off and dried in vacuo to yield 252 mg (0.52 mmol, 42%) of the analytically pure target compound.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[CH:4]([C:6]1([OH:12])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:5].[CH2:15](Br)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[OH:12][C:6]1([CH:4]([CH3:5])[C:3]([N:2]([CH3:1])[CH3:14])=[O:13])[CH2:7][CH2:8][N:9]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:11]1
Reactant: BrCCc1ccccc1
Reactant: CC(C(=O)N(C)C)C1(O)CCNCC1
Solvent: CCO
Product: CC(C(=O)N(C)C)C1(O)CCN(CCc2ccccc2)CC1

Procedure:
2-(4-hydroxy-4-piperidyl)propionic acid N,N-dimethylamide and phenethyl bromide are reacted in a manner analogous to that described in Example 3. The resulting crude title compound is dissolved in ethanol, the calculated amount of fumaric acid is added and subsequently ether is added until the solution becomes turbid. The resulting hydrogen fumarate form of the title compound has a M.P. of 188°-189° after recrystallization from ethanol/ether.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].[H][H].Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>CN(C=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:16][CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 63.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 2 g) was added to a stirred solution of 4-nitrophenol (7 g) in DMF (100 ml) cooled in an ice-water bath. The mixture was stirred until evolution of hydrogen had ceased and N-(2-bromoethyl)phthalimide (12.6 g) was then added. The mixture was stirred and heated at reflux for 10 hours. The cooled mixture was then added to ice-water (500 ml). The precipitated solid was collected by filtration, washed with water and recrystallised from 95% ethanol to give N-(2-(4-nitrophenoxy)ethyl)phthalimide (9.9 g), as crystalline solid, m.p. 151°-153° C.; NMR 4.15(t, 2H), 4.35(t, 2H), 6.95(m, 2H), 7.74(m, 2H), 7.88(m, 2H), 8.18(m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([CH3:14])([CH3:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[CH3:21]I.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[C:9]([CH3:13])([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[C:6]=2[N:20]=1
Reactant: CC1(C)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21

Procedure:
Reaction of 2-chloro-9-cyclopentyl-7,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one with MeI and NaH in DMF gave 2-chloro-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:14])C>>[OH:14][CH2:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c2c(cc[n+]1[O-])OCO2
Product: OCc1nccc2c1OCO2
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-3,4-methylenedioxypyridine-N-oxide (120 mg, 0.78 mmol) was dissolved in acetic anhydride (10 ml) and the solution was heated at 110° C. for 15 min, whereupon the mixture was concentrated under reduced pressure. The residue was dissolved in methanol (20 ml) and sodium hydroxide (3 drops, 6M) was added. After 30 min at ambient temperature the mixture was neutralised with acetic acid (pH 6) and concentrated under reduced pressure. The residue was chromatographed on silica (hexane/ethyl acetate, 1:1). Yield: 90 mg (75%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])C(O)=C([CH:9]=1)C=O.Br[CH:15]([C:21]([O:23][CH2:24][CH3:25])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:24]2[O:23][CH:21]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:25]=2[CH:9]=1
Reactant: O=Cc1cc(Br)cc([N+](=O)[O-])c1O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1coc2c([N+](=O)[O-])cc(Br)cc12

Procedure:
A mixture of 5-bromo-2-hydroxy-3-nitrobenzaldehyde (8.9 g, 36.2 mmol), diethyl bromomalonate (6.3 mL, 37.3 mmol) and potassium carbonate (4.6 g) in butanone (50 mL) was heated a reflux for 4 h. The mixture was cooled, filtered and evaporated to give the crude product which was recrystallized from ethanol. Yield: 6.6 g (58%) of a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (t, J=7.0 Hz, 3H) 4.35 (q, J=7.1 Hz, 2H) 7.83 (s, 1H) 8.39 (d, J=2.0 Hz, 1H) 8.43 (d, J=2.0 Hz, 1H).