Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:22]N1C(=O)CCC1=O.O>C(O)(C)C>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)=[C:12]([Cl:22])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCN(c2ccc(NC(=O)OC(C)(C)C)cc2)CC1
Solvent: CC(C)O
Solvent: O
Product: CN1CCN(c2ccc(NC(=O)OC(C)(C)C)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
583 mg (2 mmol) of [4-(4-methyl-piperazin-1-yl)-phenyl]-carbamic acid tert-butyl ester (Example 65c) are dissolved in 10 ml of isopropanol and 286 mg (2.1 mmol) of N-chlorosuccinimide are added. The solution is stirred for 1 h at r.t. and 100 ml of water are added. The suspension is extracted with EtOAc and the organic phase is washed with water, dried over MgSO4 and evaporated to dryness. The residue is purified by MPLC to provide the title compound. Title compound: ES-MS: 326.3 (M+H)+; analytical HPLC: tret=4.43 minutes (Grad 2).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:4]([OH:5])[C:3]=1O.CC(C)CC(=[O:16])C>>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[CH:6]=[C:7]([CH3:9])[C:8]=1[OH:16]
Reactant: CC(=O)CC(C)C
Reactant: Cc1cc(C)c(O)c(O)c1
Product: Cc1cc(O)cc(C)c1O

Procedure:
By following in the same manner as in Example 53, except that 0.25 g. (2.5 m. moles) of 4-methyl-2-pentanone was used instead of 3.61 g. (26.1 m. moles) of it, 3.09 g. (22.4 m. moles) of 3,5-dimethylcatechol and 2.07 g. (15 m. moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 73.6 percent.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.CC(C)=O.Br[CH2:18][CH2:19][CH2:20][Cl:21].[OH-].[Na+]>O>[Cl:21][CH2:20][CH2:19][CH2:18][N:10]1[CH2:11][CH2:12][N:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: ClCCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture of 1-(2-pyrimidinyl)piperazine (2 g; 12.2 mmol), acetone (2 ml), 1-bromo-3-chloropropane (2.5 g; 15.9 mmol) and a 25% aqueous sodium hydroxide solution (1.9 ml) was stirred at room temperature for 6 hours. After completion of the reaction, the resultant mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 1-(3-chloropropyl)-4-(2-pyrimidinyl)piperazine. IR νmaxFilm (cm-1): 1595, 1550, 1500.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]3=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1.[CH:20]1[C:32]2[N:31]([C:33]3[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([N:39]4[C:51]5[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=5[C:45]5[C:40]4=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH:38]=3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]1[C:32]2[N:31]([C:33]3[CH:34]=[C:35]([C:2]4[CH:11]=[N:10][C:9]5[C:4](=[C:5]6[CH:19]=[CH:18][CH:17]=[CH:16][C:6]6=[C:7]6[CH:15]=[CH:14][CH:13]=[CH:12][C:8]6=5)[N:3]=4)[CH:36]=[C:37]([N:39]4[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=5[C:46]5[C:51]4=[CH:50][CH:49]=[CH:48][CH:47]=5)[CH:38]=3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: Clc1cnc2c3ccccc3c3ccccc3c2n1
Reactant: OB(O)c1cc(-n2c3ccccc3c3ccccc32)cc(-n2c3ccccc3c3ccccc32)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc2c(c1)c1ccccc1c1nc(-c3cc(-n4c5ccccc5c5ccccc54)cc(-n4c5ccccc5c5ccccc54)c3)cnc21
Yield: 94 %

Procedure:
Into a 100-mL three-neck flask were put 1.2 g (4.8 mmol) of 2-chlorodibenzo[f,h]quinoxaline, 2.1 g (4.7 mmol) of 3,5-bis(9H-carbazol-9-yl)phenylboronic acid, and the air in the flask was replaced with nitrogen. To this mixture were added 18 mL of toluene, 6.0 mL of ethanol, and 6.0 mL of an aqueous solution of potassium carbonate (2.0 mol/L). This mixture was stirred to be degassed while the pressure was reduced. To this mixture was added 0.11 g (0.096 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 80° C. for six hours under a nitrogen stream, so that a solid was precipitated. The precipitated solid was collected by suction filtration. To the obtained solid was added about 100 mL of water, washed by ultrasonic wave irradiation, and subjected to suction filtration to obtain a solid. To the obtained solid was added about 100 mL of ethanol, washed by ultrasonic wave irradiation, and subjected to suction filtration to obtain a solid. The obtained solid was dissolved in about 1.5 L of hot toluene, and this solution was suction-filtered through Celite and Florisil. A solid obtained by concentration of the filtrate was washed with toluene, so that 2.8 g of a yellow solid, which was the object of the synthesis, was obtained in a yield of 94%. The synthesis scheme of Step 3 is shown in (a-3).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.C(O)(=O)C(O)=O.[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH:60]1[CH2:64][CH2:63][NH:62][CH2:61]1>C(#N)C>[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH:60]1[CH2:64][CH2:63][N:62]([C:14]([C:10]2[CH:11]=[N:12][O:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=2)=[O:16])[CH2:61]1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: Clc1ccccc1C1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)C(=O)O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(c2ccccc2Cl)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
5-[4-(Trifluoromethyl)phenyl]isoxazole-4-carboxylic acid (30 mg, 0.12 mmol) was dissolved in acetonitrile (1.5 mL) followed by the addition of o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (52 mg, 0.16 mmol), pyridine (60 μL, 0.72 mmol) and 3-(2-chlorophenyl)pyrrolidine oxalate (38 mg, 0.14 mmol), and stirred at 60° C. for 2 h. The residue was purified on reversed phase HPLC to yield the title compound (9 mg). HRMS (ESI, pos. ion) m/z calcd for C21H16ClF3N2O2: 420.0852, found 420.0854.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:48][O:49][C:50](=[O:59])[C:51]1[CH:56]=[CH:55][C:54](O)=[C:53]([CH3:58])[CH:52]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:54]2[CH:55]=[CH:56][C:51]([C:50]([O:49][CH3:48])=[O:59])=[CH:52][C:53]=2[CH3:58])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: COC(=O)c1ccc(O)c(C)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCN2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
4-(2-Hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.2 mmol) was dissolved in THF (30 ml) and cooled down to 0° C. Polymer-supported triphenylphosphine (2.2 g, 2.2 mmol), DEAD (378 mg, 2.2 mmol) and 4-hydroxy-3-methyl-benzoic acid methyl ester from Example E29 (361 mg, 2.2 mmol) were added and the mixture was stirred for 20 h at room temperature. The resin was filtered off and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (495 mg, 60%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[N:25]1([CH:30]([C:32]2[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[CH2:40]O)=[CH:34][CH:33]=2)[CH3:31])[CH:29]=[CH:28][N:27]=[CH:26]1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:40]/[CH:39]=[CH:38]/[C:35]1[CH:34]=[CH:33][C:32]([CH:30]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH3:31])=[CH:37][CH:36]=1)=[O:9]
Reactant: CC(c1ccc(/C=C/CO)cc1)n1ccnc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(C(C)n3ccnc3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 228 mg (1 mM) of (E)-3-[4{-1-(1-imidazolyl)ethyl)phenyl]-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 519 mg (95.7%).
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[Cl:14][CH2:15][C:16](=[O:37])[C@@H:17]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:18][S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C(O)(C)C>[Cl:14][CH2:15][C@@H:16]([OH:37])[C@@H:17]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:18][S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(N[C@@H](CSc1ccccc1)C(=O)CCl)OCc1ccccc1
Agent: CC(C)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: CC(C)O
Product: O=C(N[C@@H](CSc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 79.2 %

Procedure:
To a suspension of 2.15 g aluminium isopropoxide in 35 ml of isopropanol were added 3.64 g of benzyl [3-chloro-2-oxo-(R)-1-(phenylthiomethyl)-propyl]-carbamate and the mixture was stirred at 50° C./400mbar for 4 hours. The mixture was cooled to 0° C., the pH was adjusted to 1 by adding hydrochloric acid and the isopropanol was evaporated. The residue was partitioned between water and dichloromethane and the organic layer was evaporated. The residue was chromatographed on silica to give 2.9 g (80%) of pure benzyl (1R, 2S)-[3-chloro-2-hydroxy-1-(phenylthiomethyl)-propyl]-carbamate. IR (KBr): 3360 br (NH, OH), 1690 s (C═O), 1540 s (amide II).
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27].[CH:29]([NH2:32])([CH3:31])[CH3:30]>CN(C=O)C>[OH:1][CH:2]([CH2:28][NH:32][CH:29]([CH3:31])[CH3:30])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CO1
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC(O)CNC(C)C
Temperature: 70 °C
Yield: 15.3 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy) quinazoline (100 mg, 0.27 mmol), (prepared as described for the starting material in Example 162), and isopropylamine (100 ul, 0.8 mmol) in DMF (4 ml) was heated at 70° C. for 24 hours. The solvent was removed by evaporation and the residue was purified by silica column chromatography eluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1) to give 7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4(2-methylindol-5-yloxy)quinazoline (18 mg, 16%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][C:10]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[O:20])=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][N:29](C)C=O>CN.CO>[CH3:28][NH:29][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][C:10]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[O:20])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CN1CCN(C(=O)c2cc(-c3ccccc3)n(-c3ccc(Cl)nc3)n2)CC1
Agent: CN
Solvent: CO
Product: CNc1ccc(-n2nc(C(=O)N3CCN(C)CC3)cc2-c2ccccc2)cn1
Reaction time: 72 h
Yield: 4 %

Procedure:
To a solution of 1-[1-(6-chloro-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazine (300 mg) obtained in Example 110 in N,N-dimethylformamide (1.5 mL), 40% methylamine-methanol solution (0.6 mL) was added. The mixture was stirred at 85>C for 3 days in a sealed tube, and then cooled in air. The reaction mixture was partitioned between 1N aqueous sodium hydroxide (30 mL) and ethyl acetate. The organic layer was sequentially washed with water, saturated aqueous sodium hydrogencarbonate, and water, and then dried over magnesium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure, and the residue was dissolved in dimethyl sulfoxide (1 mL). The solution was purified through preparative high-performance liquid chromatography (eluent: water acetonitrile), followed by recrystallization from ether-hexane, to thereby give the title compound (11.7 mg, 4%).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]2[O:31][CH:30]([CH2:32]Br)[CH2:29][C:28]=2[CH:34]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1([OH:11])[CH2:6][CH2:7][N:8]([CH2:32][CH:30]2[CH2:29][C:28]3[CH:34]=[C:24]([O:23][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:25]=[CH:26][C:27]=3[O:31]2)[CH2:9][CH2:10]1
Reactant: Cc1ccccc1CC1(O)CCNCC1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Product: Cc1ccccc1CC1(O)CCN(CC2Cc3cc(OCc4ccccc4)ccc3O2)CC1

Procedure:
The title compound MS: m/e=444.6 (M+H+) was prepared from 4-(2-methyl-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1[N+:16]([O-])=O>CO.[H][H].[Pd]>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1[NH2:16]
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OC)c(OC)c1N
Yield: 92.6 %

Procedure:
The latter nitro derivative (17.0 g) in 500 ml of methanol was reduced at room temperature and pressure with hydrogen using 4 g of 10% palladium on carbon as catalyst for 6 hr and filtered. The solvent was removed to give 14 g of 2-amino-3,4,5-trimethoxybenzoic acid methyl ester as an oil.
Reaction SMILES: [F:1][C:2]([F:17])([C:5]([F:16])([F:15])[O:6][C:7]([F:14])([F:13])[C:8]([F:12])=[C:9]([F:11])[F:10])[C:3]#[N:4].[O:18]=O>>[F:1][C:2]([F:17])([C:5]([F:15])([F:16])[O:6][C:7]([F:14])([F:13])[C:8]1([F:12])[O:18][C:9]1([F:11])[F:10])[C:3]#[N:4]
Reactant: N#CC(F)(F)C(F)(F)OC(F)(F)C(F)=C(F)F
Reactant: O=O
Product: N#CC(F)(F)C(F)(F)OC(F)(F)C1(F)OC1(F)F

Procedure:
A 100-ml stainless steel-lined tube charged with 38.5 g (0.14 mol) of perfluoro-4-oxa-6-heptenenitrile was heated at 140° while oxygen was added incrementally (over 5.5 h) until reaction was complete. Fractionation of the liquid products gave perfluoro-6,7-epoxy-4-oxaheptanenitrile, bp 65°-67°, 15.7 g (39%). IR (CCl4); 4.40 (CN), 6.47 (epoxide) and 8-9μ (CF, C-O). NMR (CCl4): -87.5 (m, 2F, OCF2), -109.2 (t, JFF 4.7 Hz, 2F, CF2CN), and -156.7 ppm (d of d of m, JFF 18.7, 16.7 Hz, 1F, CF) with AB groupings for ring CF2 at -10347 and -10389 Hz (d of t, JFF 18.7, 9.5 Hz, 1F) and -10570 and -10610 Hz (d, JFF 16.7 Hz, 1F) and for CF2 adjacent to epoxide ring at -7376, -7529, -7556, and -7707 Hz (m, 2F).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][C:6]=1[C:7]([O:9]CC(F)(F)F)=O.[NH2:27][CH:28]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1)[CH3:29]>>[F:26][C:2]([F:1])([F:25])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])=[CH:15][C:6]=1[C:7]([NH:27][CH:28]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1)[CH3:29])=[O:9]
Reactant: O=C(OCC(F)(F)F)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: CC(N)C1CCCCN1
Product: CC(NC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F)C1CCCCN1

Procedure:
Starting with 2,2,2-trifluoroethyl 2,5-bis(2,2,2-trifluoroethoxy)benzoate and 2-(1-aminoethyl)piperidine and using the procedure illustrated in Examples 21 and 22, the product 2,5-bis(2,2,2-trifluoroethoxy)-N-[1-(2-piperidyl)ethyl]-benzamide, m.p. 95°-97° C., is obtained as white needles.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=O.[NH2:14][C:15]([NH2:17])=[S:16]>CCO>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:14]=[C:15]([NH2:17])[S:16][CH:2]=1)([O-:13])=[O:12]
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(-c2ccccc2[N+](=O)[O-])cs1
Temperature: 25 °C

Procedure:
4-(2-Nitro-phenyl)-thiazol-2-ylamine was prepared as follows: 2-Bromo-2′-nitroacetophenone (1.75 g, 7.2 mmol) was mixed with 50 mL of absolute EtOH along with thiourea (1.09 g, 14.4 mmol) and stirred under reflux for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was basified with 20 mL of 1 N aqueous NaOH and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated to afford essentially quantitative yield of 4-(2-nitro-phenyl)-thiazol-2-ylamine.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:17])=[O:27])=[CH:21][CH:20]=1
Reactant: Nn1nc(-c2cccs2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2cccs2)c2ccccc2c1=O

Procedure:
The product of Example 10B and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 10C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (s, 1H), 8.40 (ddd, J=7.7, 1.6, 0.8 Hz, 1H), 8.17 (ddd, J=8.1, 1.3, 0.6 Hz, 1H), 8.04 (ddd, J=8.0, 7.2, 1.6 Hz, 1H), 7.98 (ddd, J=7.8, 7.2, 1.3 Hz, 1H), 7.81 (dd, J=5.1, 1.1 Hz, 1H), 7.65 (dd, J=3.6, 1.1 Hz, 1H), 7.35-7.47 (m, 4H), 7.28 (dd, J=5.1, 3.6 Hz, 1H), 3.72 (s, 2H); MS (APCI) M/Z 396 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[S:9]1(=[O:33])=[O:32].Cl>ClCCl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[S:9]1(=[O:32])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2c3ccccc3N(c3ccccc3Cl)S2(=O)=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S1(=O)N(CCN2CCNCC2)c2ccccc2N1c1ccccc1Cl
Yield: 79.2 %

Procedure:
In an analogous manner as general procedure II, step 2, a solution of tert-butyl 4-{2-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperazine-1-carboxylate (0.22 g, 0.45 mmol) in dichloromethane (10 mL) was treated with hydrogen chloride (3.0 mL of a 4 M solution in dioxane), resulting in a white precipitate that was evaporated and dried under vacuum to provided 1-(2-chlorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.14 g, 81%) as a white solid:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[CH:8]=[CH:7][C:6]=2[CH:12]=1.[OH-:13].[Na+]>[Cl-].[NH4+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[CH2:8][CH:7]([OH:13])[C:6]=2[CH:12]=1
Reactant: [OH-]
Reactant: O=S1(=O)C=Cc2cc(Br)ccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: O=S1(=O)CC(O)c2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
5-Bromo-1-benzothiophene 1,1-dioxide (100 mg, 0.41 mmol) was suspended in 1N aqueous sodium hydroxide (2.0 mL), heated to 100° C. in a microwave, and allowed to stir for 15 minutes. The mixture was then allowed to cool to ambient temperature before the mixture was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was used without further purification. LRMS (ESI) calc'd for C8H7BrO3S [M+Na]+: 285. Found: 285.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH2:11][O:10][C:9]2=[O:20])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:28][CH3:29]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:28][CH3:29])[CH:14]=3)[CH2:11][O:10][C:9]2=[O:20])=[CH:6][CH:7]=1
Reactant: O=C1OC[C@H](c2cccc(O)c2)N1c1ccc(Cl)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc([C@H]2COC(=O)N2c2ccc(Cl)cc2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To (S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)oxazolidin-2-one (0.07 mmol), K2CO3 (0.37 mmol) in DMF (0.5 mL) is added iodoethane (0.14 mmol) and the reaction stirred at 60° C. overnight, then cooled to room temperature, filtered through a Whatman 0.42 μM filter and purified by preparative HPLC (C-18, 10-90% ACN/water (0.05% TFA)). HPLC-MS calculated for C17H16ClNO3 (M+H+): 318.1, found 318.0.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][C:9]1[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:3]([O:5]CC)=[O:4].Cl>CCOCC>[CH3:1][CH:2]([CH2:8][C:9]1[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)Cc1cccn1-c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CC(Cc1cccn1-c1ccccc1)C(=O)O
Temperature: 92.5 °C

Procedure:
A mixture of ethyl 2-methyl-3-[1-phenylpyrrol-2-yl]propanoate (0.164 mol, 42.1 g) and Claisen's reagent (78 ml) were heated at 90-95° C. for 1 h. After cooling to room temperature, the solution was diluted with 75 g of crushed ice and acidified to pH 1-2 with 6 N HCl. The brown oily precipitate was dissolved in ether, washed with brine solution, dried over MgSO4, and evaporated to an orange oil (21.65 g). The title compound was analysed by 1H-NMR spectroscopy.