Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:15]3[CH2:16][CH2:17][CH2:18][CH:11]2[C:12](=[CH:20]O)[C:13](=O)[CH2:14]3)(=[O:9])=[O:8])=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>C(O)(=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:15]3[CH2:16][CH2:17][CH2:18][CH:11]2[C:12]2[CH:20]=[N:23][NH:24][C:13]=2[CH2:14]3)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)s1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(c1ccc(Cl)s1)N1C2CCCC1c1cn[nH]c1C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 9-(5-chloro-thiophene-2-sulfonyl)-2-hydroxymethylene-9-aza-bicyclo[3.3.1]nonan-3-one crude mixture in glacial acetic acid (3 mL) followed by hydrazine monohydrate (1 mL). The reaction mixture was stirred at 100° C. for 1 h after which the solution was cooled to room temperature and quenched by the addition of saturated NaHCO3 solution (until pH>7). The resulting solution was extracted with EtOAc (3×20 mL), the organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography (Elution with 50% EtOAc/hex, 80% EtOAc/hex, 100% EtOAc, and 5% MeOH/EtOAc) and preparative HPLC to give 12-(5-chloro-thiophene-2-sulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene as a white solid. Retention time (min)=1.649 min, Method 1, MS (ESI) 344.0 (M+H); 1H-NMR (300 MHz, CDCl3) δ 7.47 (s, 1H), 7.25 (s, 1H), 7.22 (d, J=4.4 Hz, 1H), 5.28 (b s, 1H), 4.56 (t, J=6.04 Hz, 1H), 3.11 (dd, J=17.58, 7.69 Hz, 1H), 2.66 (d, J=17.58 Hz, 1H), 2.09-1.92 (m, 2H), 1.74-1.57 (m, 3H), 1.44-1.29 (m, 1H); 13C-NMR (75 MHz, CDCl3) δ 143.4, 139.2, 137.7, 131.8, 127.4, 127.0, 117.0, 48.0, 47.9, 32.3, 31.7, 25.4, 15.3 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)=[O:8].N1CCCCC1.C(O)(=O)[CH2:30][C:31]([OH:33])=[O:32].C(=O)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:30][C:31]([OH:33])=[O:32])=[CH:14][CH:13]=1)=[O:8]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(C=O)cc1
Agent: O=C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(C=CC(=O)O)cc1

Procedure:
31.75 g. 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-benzaldehyde (m.p. 115°-116° C.) and 1 ml. piperidine are added to 11.5 g. malonic acid in 100 ml. anhydrous pyridine. The reaction mixture is heated on a waterbath until the evolution of carbon dioxide is finished. After cooling, the reaction mixture is poured on to ice/concentrated hydrochloric acid and the precipitate formed is filtered off with suction, whereafter it is recrystallized from ethanol. There are obained 23.4 g. (about 65% of theory) 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-cinnamic acid; m.p. 197°-198° C.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:20])[NH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])=[N:8][CH:9]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:5](=[O:20])[NH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: CCCOc1ccccc1-c1ncc([N+](=O)[O-])c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Product: CCCOc1ccccc1-c1ncc(N)c(=O)[nH]1

Procedure:
A mixture of 5-nitro-2-(2-propoxyphenyl)-pyrimidin-4(3H)-one (4.34 g) in methanol (120 ml) was treated with hydrogen at atmospheric pressure and ambient temperature in the presence of 10% palladium on carbon (170 mg) for five hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure affording a dark oily residue. This was eluted from a silica column with chloroform and the combined fractions containing product were evaporated under reduced pressure to afford the crude title compound as a dark yellow solid, 1.69 g. This was recrystallised from isopropylacetate, then dissolved in boiling 2 Normal hydrochloric acid, and the filtered, cooled solution was washed with chloroform. The acidic solution was neutralised with potassium carbonate which afforded a pale yellow solid, 600 mg, which was recrystallised from acetonitrile to afford the title compound, 250 mg, m.p. 157°-158° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH3:9])(=O)=O.[F:10][C:11]([F:24])([F:23])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])=[O:13].[OH-].[K+]>CC(C)=O>[CH2:6]([N:14]([C:12](=[O:13])[C:11]([F:24])([F:23])[F:10])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOS(C)(=O)=O
Reactant: O=C(Nc1ccc(F)cc1F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCN(C(=O)C(F)(F)F)c1ccc(F)cc1F
Yield: 53.4 %

Procedure:
A mixture of 60.8 g of n-butyl methanesulphonate and 22.5 g of trifluoroacetyl-2,4-difluoroaniline is dissolved in 50 ml of acetone at 40° C., and 22.4 g of KOH powder are added. The reaction mixture is kept at reflux for 30 minutes, filtered and evaporated on a rotary evaporator. The oily residue is rectified. 15 g of N-butyltrifluoroacetyl-2,4-difluoroaniline are obtained as a yellowish oil which distills at 106 - 110°/11.7 mbar.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]([O:18][CH3:19])=[CH:5][C:6]2[C:15]=1[S:14][C:13]1[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=1)[N:7]=2.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O>[Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=3)[NH:7][C:6]=2[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[OH:20]
Reactant: COc1ccc2nc3cc(OC)c(=O)c(Br)c-3sc2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)Sc1c(cc(OC)c(O)c1Br)N2
Reaction time: 15 h
Yield: 129.3 %

Procedure:
To a suspension of 4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one (100 g) in a mixture of ethyl acetate (2 l) and water (1 l) was added sodium hydrosulfite (200 g) in one batch with mechanical stirring. The orange reaction mixture was stirred for 15 hours under a nitrogen atmosphere. The resulting white reaction mixture was filtered and the precipitate washed with water under a nitrogen atmosphere to prevent air oxidation of the compound. The title compound (130 g) was obtained as a wet material and was used as such in the next step (Step 2). An analytical sample was air dried, m.p. 185° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH2:23][C:24](=[O:28])[NH:25]3)=[CH:21][CH:20]=2)=[O:18])[CH:13]=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH:34]=O>C(O)C.N1CCCCC1>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([C:19]2[CH:27]=[C:26]3[C:22]([C:23](=[CH:34][C:30]4[NH:29][CH:33]=[CH:32][CH:31]=4)[C:24](=[O:28])[NH:25]3)=[CH:21][CH:20]=2)=[O:18])[CH:13]=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1Cc2ccc(C(=O)Nc3cccc(NC(=O)c4ccccc4)c3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(C(=O)Nc3cccc(NC(=O)c4ccccc4)c3)ccc2C1=Cc1ccc[nH]1

Procedure:
To a solution of 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (0.20 g, 1.1 mmol) in DMF (1 ml) is added N-(3-amino-phenyl)-benzamide (0.26 g, 1.2 mmol), N,N-diisopropylethylamine (0.44 g, 3.4 mmol) and HATU (0.47 g, 1.24 mmol). The reaction is stirred for 20 hours and concentrated. The residue is purified by HPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (3-benzoylamino-phenyl)-amide as off-white solid. This amide (15 mg, 0.04 mmol) is then heated with 1H-pyrrole-2-carbaldehyde (6.0 mg, 0.06 mmol) in ethanol (2 ml) in the presence of 2 drops of piperidine at 80° C. for 20 hours. The mixture is concentrated and the desired compound is obtained after HPLC purification: 1H NMR (DMSO-d6) δ 6.41 (s, 1H), 6.93 (s, 1H), 7.31 (t, 1H, J=7.8 Hz), 7.44 (s, 1H), 7.48-7.51 (m, 3H), 7.54 (t, 2H, J=7.2 Hz), 7.59 (d, 1H, J=6.6 Hz), 7.70 (d, 1H, J=8.4 Hz), 7.78 (d, 1H, J=8.4 Hz), 7.92 (s, 1H), 7.98 (d, 2H, J=7.2 Hz), 8.33 (s, 1H), 10.27 (s, 1H), 10.31 (s, 1H), 11.13 (s, 1H), 13.38 (s, 1H); LC-MS: 449.1 (MH+).
Reaction SMILES: [CH2:1]([N:6]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:30])[N:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([C:31](O)=[O:32])[CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:60][O:61][C:62]1[CH:73]=[CH:72][CH:71]=[CH:70][C:63]=1[CH2:64][N:65]([CH3:69])[CH2:66][CH2:67][NH2:68]>>[Cl:29][C:25]1[CH:24]=[C:23]([N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:7](=[O:8])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:10][C@H:11]2[C:31]([NH:68][CH2:67][CH2:66][N:65]([CH3:69])[CH2:64][C:63]2[CH:70]=[CH:71][CH:72]=[CH:73][C:62]=2[O:61][CH3:60])=[O:32])=[O:30])[CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccccc1CN(C)CCN
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cccc(Cl)c2)[C@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cccc(Cl)c2)[C@H](C(=O)NCCN(C)Cc2ccccc2OC)C1
Yield: 84.5 %

Procedure:
According to the procedure of Example 1, Step E above, 43 mg (0.079 mmole) of (S)-4-(dipentylcarbamoyl)-1-(N-(3-chlorophenyl)-N-phenylcarbamoyl)piperazine-2-carboxylic acid, 12 mg (0.087 mmole) of HOBt, 21 mg (0.111 mmole) of EDAC, and 31 mg (0.158 mmole) of N-(2-methoxybenzyl)-N-methylethylenediamine after purification by flash chromatography on 16 g of silica gel eluting with 100:4 CH2Cl2 :methanol provided 48 mg (84%) of an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:16][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[S:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(Sc2cccc(O)c2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: Cc1ccc(Sc2cccc(O)c2)c(N)c1

Procedure:
The product from Example 25a was reduced with SnCl2 following the procedure from Example 7f giving the title compound.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(Cl)Cl>[Cl:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:5](=[O:7])[CH3:6])=[CH:15][CH:14]=1
Reactant: ClCCCc1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(CCCCl)cc1
Temperature: -7 °C

Procedure:
84 mL of CH2Cl2 and 14.4 g (1.1 eq.) of aluminum trichloride (AlCl3) are placed in a reactor at 20° C. with stirring. The reaction medium is cooled to −7° C. and 8.5 g (1.1 eq.) of acetyl chloride are then added. The mixture is stirred for 30 minutes and 15 g of 1-chloro-3-phenylpropane are then added at 0° C. At the end of the reaction, the reaction mixture is poured over about 30 minutes with vigorous stirring into 75 mL of 5% hydrochloric acid solution. The mixture is stirred for 1 hour at 10° C., the phases are then separated by settling and the aqueous phase is extracted with CH2Cl2. The organic phases are combined and washed successively with 2N HCl solution, 1N sodium hydroxide solution and water.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[CH2:13][CH3:14].C[O-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]([C:4]1[O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]=1[CH2:13][CH3:14])=[O:16]
Reactant: CCC(=O)c1ccccc1OCC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1c(C(=O)OC)oc2ccccc12
Temperature: 60 °C
Yield: 38 %

Procedure:
(2-Propionyl-phenoxy)-acetic acid methyl ester (432 mg, 1.94 mmol, 1 eq.) was added to a solution of sodium methoxide (105 mg, 0.94 mmol, 1 eq.) in methanol (10 mL) and the reaction was heated at 60° C. for 4 h. The reaction was acidified using 1N HCl, diluted with water, extracted twice with ethyl acetate, and the combined organic layers were washed with saturated aqueous NaHCO3. The aqueous layers were extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo. 3-Ethyl-benzofuran-2-carboxylic acid methyl ester is obtained in 38% yield after flash column chromatography purification (1-5% ethyl acetate/hexanes). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.2 (t, J=7.6 Hz, 3 H) 3.1 (q, J=7.6 Hz, 2 H) 3.9 (s, 3 H) 7.4 (m, 1 H) 7.5 (m, 1 H) 7.7 (m, 1 H) 7.9 (dd, J=7.8, 0.8 Hz, 1 H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[NH:3]1.[OH-].[Ca+2].[OH-].[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].Cl>C1C=CC=CC=1.O1CCOCC1>[CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[Cl:14])[C:4]([CH2:8][CH2:9][CH3:10])=[N:3]1
Reactant: CCCc1cc(=O)n(C)[nH]1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: CCCc1nn(C)c(O)c1C(=O)c1ccccc1Cl
Temperature: 50 °C
Yield: 9.2 %

Procedure:
1.4 g. of 1-methyl-3-n-propyl-5-pyrazolone is dissolved in 10 ml. of dioxane with heating and then 1.5 g. of calcium hydroxide is added to the resulting solution. 1.75 g. of 2-chlorobenzoyl chloride is added dropwise with stirring at 50° C. After completion of the dropwise addition, the mixture is heated under reflux for 1 hour. After completion of the reaction, the reaction mixture is allowed to cool and 100 ml. of a 2N hydrochloric acid solution is added thereto. The mixture is extracted with 70 ml. of chloroform and an organic layer is separated. The layer is washed with water, dried over anhydrous sodium sulfate and the solvent is distilled off from the layer to give 2 g. of brown oily residue. The residue thus obtained is dissolved in a small amount of benzene and adsorbed on a silica gel column, which is then eluted with benzene: ethanol (50:1) to give 0.6 g. of crystals. The crystals are recrystallized from methanol-water (7:3) to give 0.25 g. of the desired product as colorless columns having a melting point of 125°-126° C. Yield 9.2%
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:10][C:11]1[CH:12]=[C:13]([C@H:17]2[O:19][C@@H:18]2[CH2:20][OH:21])[CH:14]=[CH:15][CH:16]=1>C(OCC)(=O)C>[N:1]1([C@@H:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=2)[C@H:18]([OH:19])[CH2:20][OH:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: OC[C@H]1O[C@@H]1c1cccc(F)c1
Reactant: c1ccc2c(c1)CCN2
Solvent: CCOC(C)=O
Product: OC[C@@H](O)[C@H](c1cccc(F)c1)N1CCc2ccccc21
Temperature: 125 °C
Yield: 74.6 %

Procedure:
A mixture of indoline (1.42 g, 11.89 mmol) and [(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (2.0 g, 11.89 mmol) was heated at 125° C. for 5 hours in a sealed reaction vial. Upon cooling, the crude product was dissolved in ethyl acetate, absorbed on Fluorocil, and purified by Biotage chromatography (FlasH40i, silica, 0-55% EtOAc/hexane) to give 2.55 g (75%) of (2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol as a colorless oil. MS (ESI) m/z 288.1 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:5]([CH:6]=O)[C:4]=1[OH:14].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].N12CCCN=C1CCCCC2>O1CCOCC1>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([C:22]2[O:14][C:4]3[C:3]([O:2][CH3:1])=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][C:5]=3[CH:6]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COc1cc([N+](=O)[O-])cc(C=O)c1O
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc([N+](=O)[O-])cc2cc(-c3ccc([N+](=O)[O-])cc3)oc12
Temperature: 100 °C
Yield: 57.1 %

Procedure:
5.0 g (1.0 equivalent) of 3-methoxy-5-nitrosalicylaldehyde and 6.03 g (1.1 equivalents) of p-nitrobenzyl bromide were dissolved in 15 ml of 1,4-dioxane, and then 13.5 g (3.5 equivalents) of 1,8-diazabicyclo[5.4.0]undeca-7-ene was added thereto. The resulting mixture was heated at about 100° C. for three hours with stirring, and then cooled to room temperature. Thereafter, the resulting solid substance was filtered off and sufficiently washed with ethanol. Thus, 4.55 g of 2-(p-nitrophenyl)-5-nitro-7-methoxybenzo[b]furan was obtained (yield: 70%).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39]([CH3:44])([CH3:43])[CH2:38][CH:37]=[C:36]2[C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=1>>[CH3:43][C:39]1([CH3:44])[CH2:38][CH:37]=[C:36]([C:45]2[CH:46]=[CH:47][C:48]([CH3:51])=[CH:49][CH:50]=2)[C:35]2[CH:34]=[C:33](/[C:27](/[Si:28]([CH3:29])([CH3:30])[CH3:31])=[CH:26]/[C:23]3[CH:22]=[CH:21][C:20]([CH2:19][OH:18])=[CH:25][CH:24]=3)[CH:42]=[CH:41][C:40]1=2
Reactant: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)cc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)cc1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(/C(=C/c4ccc(CO)cc4)[Si](C)(C)C)cc32)cc1

Procedure:
Following General Procedure A, 4-[(trimethylsilyl)ethynyl]benzyl tert-butyldiphenylsilyl ether and 6-bromo-1,1 -dimethyl-4-p-tolyl-1,2-dihydronaphthalene (prepared as described in Klein, et al., U.S. Pat. No. 5,952,345) were coupled to give the title compound (Compound 23). PNMR (300 MHz, CDCl3): δ0.13 (s, 9 H), 1.47 (s, 6 H), 2.48 (d, J=4.4 Hz, 2 H), 2.54 (s, 3 H), 4.82 (d, J=6.1 Hz, 2 H), 6.10 (t, J=4.4 Hz, 1 H), 7.00 (d, J=2.2 Hz, 1 H), 7.18 (dd, J=2.2, 7.9 Hz, 1 H), 7.30-7.45 (m, 10 H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:4][N:3]=1.Br[CH2:14][CH2:15]Br.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:15][CH2:14]2)[O:4][N:3]=1
Reactant: CCOC(=O)Cc1cc(C)no1
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2cc(C)no2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of ethyl 2-(3-methylisoxazol-5-yl)acetate (8.22 g, 48.6 mmol) in toluene (85 mL) was sequentially added n-tetrabutylammonium bromide (1.67 g, 5.18 mmol), 1,2-dibromoethane (7.0 mL, 81 mmol), and NaOH (30 mL, 582 mmol, ˜19.4 M). The reaction mixture was vigorously stirred at room temperature. After 1 h, the reaction mixture was cooled to 0° C. and diluted with water (50 mL). The aqueous phase was extracted with MTBE (3×). The combined organic phases were washed 1 N HCl, water (2×), dried over Na2SO4, and concentrated to give the product ethyl 1-(3-methylisoxazol-5-yl)cyclopropanecarboxylate (9.49 g, 48.6 mmol, 100% yield) as a clear oil. LC/MS m/z 196 [M+H]+.
Reaction SMILES: [OH-].[K+].O.C1OCCOCCOCCOCCOCCOC1.[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl.[CH2:31]([C:33]([CH3:35])=[O:34])[CH3:32]>C1(C)C=CC=CC=1>[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][CH:31]([CH3:32])[C:33](=[O:34])[CH3:35]
Reactant: Cc1ccccc1CCl
Reactant: CCC(C)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)C(C)Cc1ccccc1C
Temperature: 85 °C
Reaction time: 11 h
Yield: 23.1 %

Procedure:
56 g of KOH, 56 ml of water, 10 g of 18-crown-6 and 5 g of KI were warmed to 75° C. with 200 ml of toluene with exclusion of air. A mixture of 100 g of 2-methylbenzyl chloride and 100 g of methyl ethyl ketone was added dropwise over 30 minutes with vigorous stirring, and the mixture was stirred at 85° C. for 11 hours. The phases were then separated, and the organic layer was washed by shaking with water and distilled through a short packed column. After removing the solvent and the preliminary fraction, 29 g of 3-(2-methylbenzyl)-butanone were obtained at 54°-55° C./0.07 mbar. 25 g of this compound was stirred with 3 g of NaBH4 in 100 ml of ethanol, initially for 2 hours at 25° C., then for a further 2 hours at the reflux temperature. After the reducing agent and solvent had been removed, the reaction product was distilled through a short Vigreux column. 15.5 g of 3-methyl-4-(2-methylphenyl)-butan-2-ol were obtained from 64°-67° C./0.07 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([CH2:16][C:17]#[CH:18])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28]>>[OH:28][NH:27][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:16][C:17]#[CH:18]
Reactant: C#CCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Product: C#CCC(Cc1cccnc1)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 25 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid (0.29 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 m, 10 mmol), 0.065 g of the product was isolated. Yield 25%; off-white solid; mp 70° C.; MS: 375.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ1.19 (brs, 1H), 2.90-3.00 (m, 2H), 3.55 (d, J=13.8 Hz, 1H), 3.67 (d, J=13.8 Hz, 1H), 3.89 (s, 3H), 7.18 (d, J=9.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H), 7.80-7.89 (m, 1H), 8.35-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.1 (brs, 1H); IR (KBr, cm−1): 3168m, 3095s, 1670m, 1593s.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])[CH3:3].[C:32](O)(=[S:34])[CH3:33]>O1CCCC1>[C:32](=[S:34])([O:1][CH:2]([C:4]1[C:9]([CH3:10])=[N:8][C:7]([O:11][CH3:12])=[C:6]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=3)[CH2:18][CH2:17]2)=[O:15])[CH:5]=1)[CH3:3])[CH3:33]
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)O)c(C)nc3OC)CC2)c1
Reactant: CC(O)=S
Solvent: C1CCOC1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)OC(C)=S)c(C)nc3OC)CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
1-{([5-(1-Hydroxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine(213 mg, 0.5 mmol) and thioacetic acid(72 μl, 1.0 mmol) were dissolved in tetrahydrofuran and was added into the above solution. The mixture solution was stirred at 0° C. for 1 hour and at room temperature for 1 hour and then was concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[C:23](OCCCC)(=[O:28])[CH2:24][C:25]([CH3:27])=O>>[OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:23](=[O:28])[CH2:24][C:25]([CH3:27])=[N:10][CH2:9][CH2:8]1
Reactant: CCCCOC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCC(O)CNCCNCCN
Product: CCCCCCCCCCCCC(O)CNCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 313.5 g (1 mole) of N-(2-hydroxy)tetradecyldiethylenetriamine and 158.1 g (1 mole) of butyl acetoacetate. At 150° to 160° C. and under a reduced pressure of 50 mmHg, 18 g of water and 74 g of butanol were distilled off to obtain 4-(2-hydroxytetradecyl)aminoethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.