Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC#N.C(=O)=O.[CH2:7]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:8]#[CH:9].C([Mg]Cl)(C)C.CON(C)[C:24](=[O:26])[CH3:25]>C1COCC1>[N:10]1([CH2:7][C:8]#[C:9][C:24](=[O:26])[CH3:25])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CON(C)C(C)=O
Reactant: C#CCN1CCOCC1
Agent: CC(C)[Mg]Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(=O)C#CCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a cooled (−40° C., CH3CN/CO2) solution of 4-(2-propyn-1-yl)morpholine (2.2 g, 17.58 mmol) in THF (5 mL) was added dropwise via. syringe under N2 a solution of 2 M isopropylmagnesium chloride in THF (10 mL, 20.00 mmol). The reaction was stirred for 1 hr then a solution of N-methoxy-N-methylacetamide (2.2 mL, 20.69 mmol) in THF (5 mL) was added in one portion. The reaction was stirred for 2 hr (allowed to slowly warm to RT), quenched with aq. NH4Cl, extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 80% EtOAc in hexanes). The pure fractions were combined and evaporated to dryness to give the product 5-(4-morpholinyl)-3-pentyn-2-one (2.09 g, 12.50 mmol, 71.1% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 3.62-3.57 (m, 4 H), 3.56 (s, 2 H), 2.49-2.43 (m, 4 H), 2.34 (s, 3 H). MS(ES)+m/e 168.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Sn].Cl>O>[C:1]1([C:7]([CH2:9][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: Cl
Agent: [Sn]
Solvent: O
Product: O=C(Cc1ccccc1)c1ccccc1

Procedure:
The benzoin (0.075 mole) was dissolved in 80 ml. of alcohol and 20 g. of tin (20 mesh) was added. The mixture was gently heated and a solution containing 28 ml. of concentrated hydrochloric acid, 0.8 g. of anhydrous cupric sulfate and 0.5 ml. of water was added. The reaction mixture was refluxed until thin layer chromatography no longer detected the presence of starting material. The granular tin was removed by filtration and the filtrate was evaporated to an oil which was diluted with water to 400 ml. and was extracted with chloroform. The organic extract was washed with 5% aqueous sodium carbonate solution (45 ml.×3), with water (45 ml.×2) and with brine; it was dried over anhydrous magnesium sulfate and evaporated to obtain desoxybenzoin.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26].OC1C=CC=CC=1C=O>>[CH2:25]([NH:27][C:28]([O:13][C:12]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][C:11]=1[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:29])[CH3:26]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CCN=C=O
Solvent: O=Cc1ccccc1O
Solvent: CCN(CC)CC
Product: CCNC(=O)Oc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (5 g, 20 mmol) in DNF (100 mL) was added triethylamine (3.5 mL, 25 mmol) and the solution was stirred for 15 min at room temperature. Ethyl isocyanate (1.95 mL, 25 mmol) was added and the reaction mixture was stirred for 2 h at room temperature until no more hydroxybenzaldehyde was detected by TLC (Rf=0.78 for product and 0.89 for starting material using 1:1 hexanes/EtOAc). The reaction solution was concentrated by azeotropic removal of DMF with water. The resulting suspension was filtered, washed with water and dried in a vacuum oven to afford 96% of the title compound as a light buff solid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[S:9][C:5]=2[CH:4]=1.CC1SC2C=C(OCC3CO3)C=CC=2N=1>>[CH3:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11][C:6]=2[N:7]=1
Reactant: COc1ccc2nc(C)sc2c1
Agent: Cc1nc2ccc(OCC3CO3)cc2s1
Product: Cc1nc2ccc(O)cc2s1

Procedure:
Compound 50 was prepared from the commercially available 6-methoxy-2-methyl-benzothiazole as described in partC-4 of Example 1. Synthesis of 2-methyl-6-(oxiran-2-ylmethoxy)benzothiazole (51):
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[S:9][C:5]=2[CH:4]=1.Br>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[CH3:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11][C:6]=2[N:7]=1
Reactant: COc1ccc2nc(C)sc2c1
Agent: Br
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: Cc1nc2ccc(O)cc2s1
Temperature: 105 °C
Yield: 81.5 %

Procedure:
A mixture of 6-methoxy-2-methyl-benzothiazole (19.71 g, 0.11 mol), tetrabutylphosphonium bromide (3.73 g, 0.01 mol), and 48% HBr (120 mL) was stirred at 105° C. for twenty-eight hours before it was cooled to room temperature, neutralized with 10N NaOH (90 mL) and 1N NaOH (45 mL) to pH=4. The resulting precipitate was filtered, washed with water (3×100 mL), dried in vacuo to give the title compound as a pale brown solid (14.81 g): 1H NMR (CDCl3, 200 MHz): δ=7.77 (m, 1H), 7.24 (m, 1H), 6.94 (m, 1H), 5.28 (s, 1H), 2.79 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[O:12][CH3:13])=[O:3].[C:14]([O:19][CH2:20]C)(=[O:18])[C:15]([O-])=[O:16].C[O-].[Na+:24].[Na]>CO.CCOCC>[Na+:24].[CH3:13][O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:4]=1[C:2]([O-:3])=[CH:1][C:15](=[O:16])[C:14]([O:19][CH3:20])=[O:18]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: COc1cccc(OC)c1C(C)=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(=O)C=C([O-])c1c(OC)cccc1OC
Reaction time: 8 h

Procedure:
A solution of 100 g of 2,6-dimethoxyacetophenone and 7.5 ml of ethyl oxalate in 520 ml of anhydrous MeOH is added slowly to a solution of sodium methylate prepared from 12.7 g of sodium and 285 ml of anhydrous MeOH. The reaction mixture is heated to reflux for 7 hours and left overnight at RT. It is poured into 2 litres of iso ether and left stirring for 15 minutes. The expected product is obtained by filtration, washing with iso ether and drying under vacuum, m=120 g, m.p.=178° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:11][C@H:10]1[C:3]2[C:2]([N:22]3[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]3)=[N:7][CH:6]=[N:5][C:4]=2[CH2:8][CH2:9]1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 110 °C
Reaction time: 8 h
Yield: 116.6 %

Procedure:
To a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.5 g, 3.0 mmol) in NMP (10 mL) was added 1-Boc-piperazine (1.2 g, 2.17 mmol). The mixture was stirred at 110° C. overnight. After cooling, the mixture was diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate to afford (R)-tert-butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.806 g, 86%). 1H NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 3.68 (m, 2H), 3.60-3.40 (m, 7H), 2.84 (m, 2H), 2.30 (m, 1H), 1.67 (m, 1H), 1.49 (m, 9H), 1.18 (d, J=6.8 Hz, 3H). MS (APCI+) [M+H] +319.
Reaction SMILES: [O-]S([O-])(=O)=O.[Ca+2].[N+:7]([O-:10])(O)=[O:8].[N+](C1C=CC=CC=1)([O-])=O.[C:20]1([CH3:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N+:7]([C:23]1[CH:24]=[CH:25][C:20]([CH3:26])=[CH:21][CH:22]=1)([O-:10])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
An 86 gram portion of soluble anhydrite regenerated from Example II by first heating in a vacuum at 100°C for 7 hours for removal of organic material and then over night at 200°C. was added to a 100 milliliter portion of toluene. This mixture was heated to 45°C. and stirred while an 18.1 gram portion of anhydrous nitric acid was added drop by drop over a 30-minute period. Agitation was continued for 1 1/2 hours, then a 26 gram portion of nitrobenzene was added to the reaction mixture and stirring was continued for an additional hour. After this one hour period, the reaction mixture was filtered and the filtrate analyzed by gas chromotography using the nitrobenzene as the internal standard. A yield of 61% mononitrotoluene was obtained based on the nitric acid charged. The mononitrotoluene had the following composition: 44.1% ortho-nitrotoluene, 2.8% meta-nitrotoluene, and 53.1% paranitrotoluene. Thus the results show a substantial increase in the proportion of para-isomer was obtained by the addition of the soluble anhydrite to the reaction medium.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:38])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:38])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (from Aldrich, 690 mg, 3.7 mmol) and N,N-dimethylformamide (290 μL, 3.7 mmol) was stirred at room temperature for 10 minutes and then a solution of 5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (869 mg, 2.49 mmol) in methylene chloride (14 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The product was purified by silica gel chromatography, eluting with 0 to 100% EtOAc in hexanes.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN(CC)CC.[Cl:14][CH2:15][C:16](Cl)=[O:17]>C1COCC1>[Cl:14][CH2:15][C:16]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:17]
Reactant: C1COCCN1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)N1CCOCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To the solution of morpholine (10 mmol, 0.872 mL) and Et3N (15 mmol, 2.09 mL) in THF (20 mL) at 0° C. was dropped in chloroacetyl chloride 1 (12 mmol, 0.956 mL). The mixture was stirred at 0° C. for 4 h and then r.t. overnight. The reaction was quenched with H2O and evaporated to dryness. Purification by column chromatography (CH2Cl2/CH3OH=50/1) gave 2-chloro-1-morpholin-4-yl-ethanone 2 (1.62 g, 100%). 2 (1.6 g, 0.98 mmol) was treated with piperazine-1-carboxylic acid t-butyl ester (10 mmol, 1.86 g) in DMF (20 mL) at 70° C. for 12 h in the presence of K2CO3 (3 mmol, 4.14 g). Solvents were evaporated and the crude product was purified by flash chromatography (CH2Cl2/CH3OH=30/1) to give 4-(2-morpholin-4-yl oxo-ethyl)-piperazine-1-carboxylic acid t-butyl ester 4, which was treated with TFA (5 mL) in CH2Cl2 (5 mL) at r.t. for 2 h. Evaporation of all solvents furnished the TFA salt of 1-morpholin-4-yl-2-piperazin-1-yl-ethanone 4 (4.1 g, 93%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN(CC)CC.[Cl:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)Cl>[Cl:14][CH2:15][C:16]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:17]
Reactant: C1COCCN1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
A solution of morpholine (0.50 g, 5.7 mmol) in CH2Cl2 (10 mL) was treated with Et3N and cooled to 0° C. The mixture was treated with chloroacetyl chloride (0.50 mL, 6.3 mmol) as a solution in CH2Cl2 (2 mL). The reaction was stirred at 0° C. for 15 min and then at room temperature for 30 min. The reaction was diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.72 g, 76%) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 4.06 (s, 2H), 3.73-7.67 (m, 4H), 3.62 (app t, 2H, J=4.0 Hz), 3.52 (app t, 2H, J=4.0 Hz).
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+]#N)=[CH:10][CH:9]=1.[CH2:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:10][CH:9]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2ccccc2)cc1
Reaction time: 22 h
Yield: 22.8 %

Procedure:
[BMIM][BF4] as Solvent: Palladium(II) acetate (0.5 mg, 0.002 mmol) was added to a solution of 1 (10.5 mg, 0.0330 mmol) and styrene (29.0 mg, 0.278 mmol) in 96.6 mg of [BMIM][BF4]. The mixture was stirred at room temp. for 22 h and was extracted with diethyl ether (0.5 mL×3). The solvent of the combined organic layer was evaporated to give a brown oil, which was purified by SiO2 column chromatography (9:1 hexane/CH2Cl2) to give 2a (2.3 mg, 23% yield) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:7]([O:8][CH3:9])[C:4]=1[O:5][CH3:6].[Cl:13][S:14](O)(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[CH3:9][O:8][C:7]1[C:4]([O:5][CH3:6])=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=1[S:14]([Cl:13])(=[O:16])=[O:15]
Reactant: COc1cccc(OC)c1OC
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)c(OC)c1OC

Procedure:
2,3,4-Trimethoxybenzenesulfonyl chloride is synthesized by reaction of pyrogallol trimethyl ether with chlorosulfonic acid in chloroform at 0° C. according to the procedure described in G. Pifferi and R. Monguzzi, Journal of Pharmaceutical Sciences, 1973, 62, 1393.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:34]=[N:35]2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([C:2]3[N:3]=[C:4]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:13][CH2:14][CH:15]([N:18]([CH3:19])[CH3:20])[CH2:16][CH2:17]5)=[CH:8][C:6]=4[N:7]=3)=[CH:33][CH:34]=[N:35]2)=[CH:30][CH:29]=1
Reactant: CC1(C)OB(c2ccnc3cc(Cl)ccc23)OC1(C)C
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)C1CCN(Cc2cc3nc(-c4ccnc5cc(Cl)ccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 130 °C
Yield: 42.8 %

Procedure:
A sealable tube was charged with [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.150 g, 0.380 mmol), 7-chloroquinoline-4-boronic acid pinacol ester (0.132 g, 0.456 mmol), dichlorobis(triphenylphosphine) palladium(II) (0.013 g, 0.02 mmol), 1 N aqueous sodium carbonate solution (1 mL) and acetonitrile (3 mL). The vessel was evacuated and back-filled with argon three times then sealed and heated at 130° C. for 90 min. The reaction mixture was cooled, concentrated, redissolved in ethyl acetate and filtered through celite. The filtrates were concentrated then purified by chromatography (silica, 10 to 20% methanol in dichloromethane) to give 104 (0.085 g, 43%) as a yellow solid. MS m/e 531 [M+H]+; 1H NMR (300 MHz, METHANOL-d4) δ ppm 1.48-1.67 (m, 2 H) 1.82-1.96 (m, 2 H) 2.07-2.26 (m, 3 H) 2.30 (s, 6 H) 3.07 (d, J=11.7 Hz, 2 H) 3.82-3.91 (m, 6 H) 4.02-4.11 (m, 4 H) 7.36 (s, 1 H) 7.60 (dd, J=9.1, 2.3 Hz, 1 H) 7.95 (d, J=4.5 Hz, 1 H) 8.10 (d, J=2.3 Hz, 1 H) 8.67 (d, J=9.4 Hz, 1 H) 8.98 (d, J=4.9 Hz, 1 H)
Reaction SMILES: [CH2:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:17]N=O)(C)(C)C.ON1C(=O)C2=CC=CC=C2C1=O.[OH-].[Na+].C1(=NO)CCCCCCCCCCC1.[N+](C1CCCCCCCCCCC1)([O-])=O>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[C:1]1(=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)ON=O
Reactant: C1CCCCCCCCCCC1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=[N+]([O-])C1CCCCCCCCCCC1
Agent: ON=C1CCCCCCCCCCC1
Solvent: CC(=O)O
Product: O=C1CCCCCCCCCCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Cyclododecane (1.66 g; 9.88 mmol), t-butylnitrite (2 mmol), N-hydroxyphthalimide (0.4 mmol), and acetic acid (2 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas for 1 hour. The resulting mixture was further treated with zinc chloride (20 mg) with stirring at 80° C. for 30 minutes. The reaction mixture was neutralized with sodium hydroxide and was then analyzed to find that cyclododecanone oxime, nitrocyclododecane, and cyclododecanone were formed in yields of 35%, 7%, and 3%, respectively.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)C>[C].[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 78.8 %

Procedure:
A mixture of tert-butyl (2E)-3-[4-(benzyloxy)phenyl]acrylate (13.3 g, 42.8 mmol), 10% palladium carbon (1.3 g), ethanol (100 mL) and ethyl acetate (30 mL) was stirred under a hydrogen atmosphere at room temperature for 19 hrs. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (7.5 g, yield 79%) as colorless crystals.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[CH2:8][CH3:9].[CH3:10][O:11][C:12](=[O:24])[C:13]1[CH:22]=[C:21]([OH:23])[CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=1>CC(C)=O>[CH3:19][O:18][C:16](=[O:17])[C:15]1[CH:20]=[C:21]([O:23][CH2:8][CH3:9])[CH:22]=[C:13]([C:12]([O:11][CH3:10])=[O:24])[CH:14]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
K2CO3 (31.6 g, 223 mmol, 2.23 equiv) and iodoethane (17.8 ml, 230 mmol, 2.3 equiv) were added to a solution of 5-hydroxy-isophthalic acid dimethyl ester (D42) (21 g, 100 mmol, 1 equiv) in acetone (500 ml) at room temperature. The resulting solution was refluxed for 16 h, then cooled to room temperature and concentrated in vacuo. The residue was partitioned between H2O and AcOEt. The aqueous phase was extracted with AcOEt and the combined organic layers were washed with 2N aqueous NaOH solution and brine, dried over MgSO4 and concentrated in vacuo to give 5-ethoxy-isophthalic acid dimethyl ester (D43) (23 g, 96%) as a white solid. RT=3.13 min
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:21])[S:12][CH2:13][C:14](=O)[CH2:15][O:16]C(=O)C.Cl>C(O)C>[OH:16][CH2:15][C:14]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])[C:11](=[S:21])[S:12][CH:13]=1
Reactant: CC(=O)OCC(=O)CSC(=S)Nc1ccc(F)c(F)c1F
Agent: Cl
Solvent: CCO
Product: OCc1csc(=S)n1-c1ccc(F)c(F)c1F
Yield: 68.1 %

Procedure:
3-Acetoxy-2-oxopropyl N-(2,3,4-trifluorophenyl)dithiocarbamate (1.0 g) prepared in the previous Reference Example was added to ethanol (15 ml) and thereto 10% solution of hydrogen chloride in ethanol (5 ml) was added and the mixture was refluxed for one hour and 30 minutes. After the solvent was distilled off under reduced pressure, cooled water was added to the residue and the resultant was extracted with chloroform. After the extract was washed with a NaCl solution and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane-ethyl acetate to give the title compound (0.56 g) as pale yellow crystals, m.p. 113°-116° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([O:30]CC)=[O:29])=[O:21])=[CH:14][C:13]=3[C:33]([F:36])([F:35])[F:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([OH:30])=[O:29])=[O:21])=[CH:14][C:13]=3[C:33]([F:35])([F:34])[F:36])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by hydrolysis of the compound of Example 249 under basic conditions (aq. NaOH/EtOH), resulting in a white solid, mp 90° C. (dec.). 1HNMR (DMSO-d6, 300 MHz) δ 1.15-1.50 (m, 2H), 1.50-1.70 (m, 2H), 2.16 (m, 1H), 2.56 (m, 1H), 3.15 (m, 1H), 4.30 (s, 4H), 4.32 (m, 1H), 5.20 (m, 1H), 7.02 (m, 4H), 7.30-7.52 (m, 2H), 7.84 (m, 1H), 8.15 (s, 1H). MS (APCI) m/z 494 (M+H)+. Anal. calcd. for C24H22F3NO5.0.3 H2O: C, 57.78; H, 4.57; N, 2.81. Found: C, 57.87; H, 4.5 7; N, 2.76.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]=[O:17])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a solution of 4-(2-benzyloxybenzyl)benzyl alcohol (1.0 g) in dichloromethane (50 mL) was added manganese dioxide (10 g), and the mixture was stirred at room temperature for 3 hours. After insoluble materials were removed by filtration, the solvent of the filtrate was removed under reduced pressure to give 4-(2-benzyloxybenzyl)benzaldehyde (0.97 g).
Reaction SMILES: [F-:1].[K+].[Cl-].[NH4+].CC(CC(O)CO)C.Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C1(C)C(C)=CC=CC=1>[Cl-].C[N+](C)(C)C>[F:1][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: [F-]
Agent: CC(C)CC(O)CO
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccccc1F
Temperature: 150 °C
Reaction time: 21 h

Procedure:
In a 2-liter flange flask fitted with a distillation bridge and impeller stirrer, 290.5 g (5.0 mol) of potassium fluoride, 71.1 g (0.1 mol) of trimethyl (ethoxypolyoxypropyl) ammonium chloride, 11.0 g (0.1 mol) of tetramethylammonium chloride and 17.7 g (0.035 mol) of polyethylene glycol dimethyl ether 500 were introduced at 120° C. into the melt of 630 g (4.0 mol) of 2-chloronitrobenzene. Subsequently, 100 g (0.38 mol) of xylene were added and the reaction mixture was stirred for 21 hours at a temperature of 150° C. Amount of 2-fluoronitrobenzene formed, according to GC analysis: