Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1[NH:8][C:9]([CH3:32])=[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].ClCOCC=C>C(O)(=O)C>[CH2:2]([O:1][CH2:5][N:8]1[C:9]([CH3:32])=[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]1[CH3:6])[CH:3]=[CH2:4]
Reactant: C1CCOC1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: C=CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C=CCOCN1C(C)=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C1C
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
In 10 ml. of tetrahydrofuran was dissolved 1.0 g. of diethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and after adding to the solution 0.2 g. of a 50% oil dispersion of sodium hydride, the mixture was stirred for 30 minutes at room temperature. After cooling the mixture to -10° C., 0.5 ml. of 3-chloromethoxy-1-propene was added thereto, the temperature was elevated to room temperature over a period of about 20 minutes, and then after 15 minutes the mixture was cooled again to -10° C. After adding to the reaction product 0.5 ml. of glacial acetic acid and 20 ml. of water, the product was extracted three times each time with 5 ml. of ether at room temperature. The extracts were combined, washed with 5 ml. of saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then ether was distilled away. The residue was subjected to a silica gel column chromatography using benzene as an eluant. The effluent was then subjected to a thin layer chromatography, and then the effluent or the main fraction was concentrated to provide a white crystalline material. By recrystallizing the crystals from benzene-hexane, 0.74 g. of diethyl 1-allyloxymethyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate melting at 111°-112° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>>[CH3:35][O:34][C:33]1[CH:32]=[CH:31][C:4]([CH2:5][CH:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=3)[CH2:9][CH2:8][N:7]2[CH2:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:3][C:2]=1[O:1][C:38](=[O:39])[N:37]([CH3:41])[CH3:36]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Reactant: CN(C)C(=O)Cl
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC(=O)N(C)C)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with N,N-dimethyl-carbamoyl chloride
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[C:10]([O:12]CC)=[O:11].C(OC(=O)C(=COCC)C#N)C.OCCNN>C(O)C>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)c1cnn(CCO)c1N
Agent: CCOC=C(C#N)C(=O)OCC
Agent: NNCCO
Solvent: CCO
Product: Nc1c(C(=O)O)cnn1CCO

Procedure:
Example 4 of U.S. Pat. No. 2,989,537 describes the preparation of 5-amino-4-ethoxycarbonyl-1-(2′-hydroxyethyl)-pyrazole by reacting ethyl(ethoxymethylene)-cyanoacetate with 2-hydroxyethylhydrazine in ethanol and distilling the product under vacuum at high temperature. The isolated solid product then is hydrolyzed by heating with 2N aqueous sodium hydroxide solution followed by acidification with 6N hydrochloric acid to give 5-amino-4-carboxy-1-(2′-hydroxyethyl)-pyrazole. This hydrolysis procedure in water leaves some undissolved material that must be removed by filtration. The carboxy intermediate is, heated at 160-170° C. to complete the decarboxylation and the 5-amino-1-(2′-hydroxyethyl)-pyrazole is purified by distillation under vacuum at high temperature.
Reaction SMILES: CN(C)C=O.[C:6]1(=[O:26])[N:10]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[Cl:20])[NH:13][N:12]=2)[C:9](=[O:21])[C:8]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:7]12.Br.Br[CH2:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34].[K]>O>[CH2:33]([N:32]([CH2:35][CH3:36])[CH2:31][CH2:30][CH2:29][N:13]1[C:14]2[C:19](=[C:18]([Cl:20])[CH:17]=[CH:16][CH:15]=2)[C:11]([N:10]2[C:9](=[O:21])[C:8]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:7]3[C:6]2=[O:26])=[N:12]1)[CH3:34]
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2cccc(Cl)c12
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCn1nc(N2C(=O)c3ccccc3C2=O)c2c(Cl)cccc21
Yield: 59 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 4.54 g of 3-phthalimido-4-chloroindazole obtained in the same method as described in Example 1, 4.83 g of 3-bromopropyldiethylamine hydrobromide and 6.3 g of anhydrous potassium for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. After the pH of the layer was adjusted to 14 with potassium carbonate, the layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chloroform was removed under reduced pressure to give 3.70 g of 1-(3-diethylaminopropyl)-3-phthalimido-4-chloroindazole having the following analytical values in a yield of 59 %.
Reaction SMILES: [CH3:1][CH:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH2:13][OH:14])[NH:3]1>ClCCl.O=[Mn]=O>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH:13]=[O:14])[N:3]=1
Reactant: CC1NC(CO)=NN1c1ccccc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1nc(C=O)nn1-c1ccccc1
Reaction time: 24 h
Yield: 34.9 %

Procedure:
To a stirred suspension of (RS)-(5-methyl-1-phenyl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-methanol (2.28 g) at r.t. in dichloromethane (75 ml) was added MnO2 (8.06 g). The black suspension was heated to reflux and stirring was continued for 24 h. The solids were filtered off and washed with CH2Cl2. The filtrate was concentrated. The crude product was purified by chromatography (silica gel, cyclohexane=>cyclohexane/EtOAc 1:4) to give 5-methyl-1-phenyl-1H-[1,2,4]triazole-3-carbaldehyde (0.78 g) as light yellow solid. MS 188.3 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[O:3]1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:16].[K+].[K+]>C(#N)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1([CH3:14])[C:6](=[O:16])[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc([N+](=O)[O-])c2O1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1(C)Oc2c(cccc2[N+](=O)[O-])C1=O
Yield: 93.5 %

Procedure:
A mixture of 37.3 g (0.193 mole) of 2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran, 156.6 g (0.58 mole) of potassium persulfate, and 48.2 g (0.193 mole) of copper(II) sulfate pentahydrate in 500 mL of acetonitrile and 500 mL of water was prepared. This mixture was heated at reflux for one hour with vigorous stirring. The reaction mixture was cooled and then extracted three times with methylene chloride. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure, leaving 37.4 g of 2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran-3-one as a residue. The NMR and IR spectra of the same product from a previous run of this reaction were consistent with the proposed structure.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:4][C@@H:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C>CN(C=O)C>[C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][C:13]([CH2:12][C@@H:3]([NH:2][C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:4][C@@H:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](C)C(=O)OCC
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of (2R,4S)-ethyl 4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride salt (1 g, 2.87 mmol) in DMF (10 mL) is added TEA (0.42 mL, 3.02 mmol) followed by ethyl 2-chloro-2-oxoacetate (392 mg, 2.87 mmol). The crude is stirred at it for 1 hr. To the crude is added an additional 0.2 ml of ethyl 2-chloro-2-oxoacetate followed by triethylamine (1.26 mL, 9.06 mmol). The crude is quenched with water and diluted in EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated. The crude is purified via flash chromatography using 30% EtOAc/heptane to 50% EtOAc/heptane to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2-methylpentanoate (970 mg).
Reaction SMILES: [Cl:1][C:2](=[CH2:13])[CH2:3][CH:4]([CH:10]([CH3:12])[CH3:11])[C:5]([O:7]CC)=[O:6].C(O)C.[OH-].[Na+]>O>[Cl:1][C:2](=[CH2:13])[CH2:3][CH:4]([CH:10]([CH3:11])[CH3:12])[C:5]([OH:7])=[O:6]
Reactant: C=C(Cl)CC(C(=O)OCC)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C(Cl)CC(C(=O)O)C(C)C
Yield: 70.1 %

Procedure:
The ethyl 4-chloro-2-isopropyl-4-pentenoate (8.0 g, 0.039 mol) was refluxed for 20 hrs. in 15 ml of water and 15 ml of ethanol containing 4.8 g (0.12 mol) of sodium hydroxide. Most of the ethanol was removed on the rotary evaporator and the residue taken up in 100 ml of water. The aqueous solution was extracted with two 50 ml portions of ether, then acidified with conc. HCl. The acidified mixture was extracted twice with 100 ml of ether. The ether was washed with water, dried (MgSO4), and removed to leave 4.83 g (70% yield) of a light yellow oil.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)=O.[OH-].[Na+]>C(O)C>[N:6]1([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(-c2cc3ccccc3c(N3CCN(C=O)CC3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2cc3ccccc3c(N3CCNCC3)n2)cc1
Yield: 85.5 %

Procedure:
To the resulting 1-(4-formylpiperazin-1-yl)-3-(4-methylsulfonylphenyl)isoquinoline (0.78 g) were added ethanol (30 ml) and a 8N aqueous solution of sodium hydroxide (740 ml), followed by heating under reflux in nitrogen atmosphere for 4 hr. The solvent was evaporated, and to the resulting residue were added water and ethyl acetate, and the organic layer was separated. Then, it was washed with brine, dried over magnesium sulfate. The solvent was evaporated, to give 1-(piperazin-1-yl)-3-(4-methylsulfonylphenyl)isoquinoline (0.62 g) as a pale yellow amorphous.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[CH:11][CH:12]=2)[C:7]([C:26](=[O:28])[CH3:27])=[CH:6]1.[OH-].[Na+]>C1COCC1.O>[C:26]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:17]([CH3:18])[CH3:19])[CH:20]([CH3:21])[CH3:22])[CH:9]=2)[N:5]([CH2:4][C:3]([OH:29])=[O:2])[CH:6]=1)(=[O:28])[CH3:27]
Reactant: COC(=O)Cn1cc(C(C)=O)c2cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cn(CC(=O)O)c2ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc12
Reaction time: 16 h

Procedure:
To a solution of (3-acetyl-5-triisopropylsilanyloxymethyl-indol-1-yl)-acetic acid methyl ester (109 mg, 0.138 mmol) in THF (5 mL) and water (0.5 mL) was added 1N NaOH (0.69 mL, 0.69 mmol), and stirring was continued at RT for 16 h. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAC (2×), the combined organics were dried (phase separator) and concentrated in vacuo to afford the title compound as a yellow wax. MS (LC/MS): 404 [M+H]+; tR (HPLC conditions k): 4.35 min.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][NH2:11])([O-:7])=[O:6].[O:12]=[C:13]1[NH:17][CH:16]([C:18](O)=[O:19])[CH:15]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[S:14]1>>[N+:5]([O:8][CH2:9][CH2:10][NH:11][C:18]([CH:16]1[CH:15]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[S:14][C:13](=[O:12])[NH:17]1)=[O:19])([O-:7])=[O:6]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)C(c2cccnc2)S1
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2cccnc2)S1

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 300 mg of N-(2-nitrooxyethyl)amine nitrate and 330 mg of 2-oxo-5-(3-pyridyl)thiazolidine-4-carboxylic acid, to obtain 140 mg of the title compound as colorless crystals, melting at 139°-140° C. (after recrystallization from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C@H:20]2[C@H:25]([O:26]CC3C=CC=CC=3)[C@@H:24]([O:34]CC3C=CC=CC=3)[C@H:23]([O:42]CC3C=CC=CC=3)[C@@H:22]([CH2:50][O:51]CC3C=CC=CC=3)[O:21]2)=[CH:16][C:3]=1[CH2:4][C:5]1[N:6]=[N:7][C:8]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:9]=2[N:10]=1.[Si](I)(C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C@H:20]2[C@H:25]([OH:26])[C@@H:24]([OH:34])[C@H:23]([OH:42])[C@@H:22]([CH2:50][OH:51])[O:21]2)=[CH:16][C:3]=1[CH2:4][C:5]1[N:6]=[N:7][C:8]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: Cc1ccc2nc(Cc3cc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)ccc3Cl)nnc2c1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Cc1ccc2nc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)nnc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.9 %

Procedure:
3-(2-Chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)-7-methylbenzo[e][1,2,4]triazine (115 mg, 0.15 mmol) in acetonitrile (10 ml) reacted with TMSI (146 mg, 0.73 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 day. After quenching the reaction with methanol, solvent was evaporated under reduced pressure. The residue was purified with silica gel (10% MeOH in CH2Cl2) to afford title compound (33 mg, 52% yield) as a light yellow solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[O:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]1[CH2:51][CH:52]=[O:53]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:52]([OH:53])[CH2:51][CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50][O:45]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCC1CCCCO1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCCCO2)cc2cccnc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (5.0 g, 19.4 mmol) in dry tetrahydrofuran (125 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (18 mL, 29 mmol) to a 0° C. solution of diisopropylamine (4.4 mL, 31 mmol) in dry tetrahydrofuran (17 mL)] dropwise. The mixture was stirred at −78° C. for 5 min and then treated with (tetrahydro-pyran-2-yl)-acetaldehyde (4.6 g, 26 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-2-yl)-ethanol (4.5 g, 60%) as a colorless oil: LC/MS m/e calcd for C20H22N2O4S [M+H]+ 387.47, observed 387.2.
Reaction SMILES: [OH:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]2[C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][O:8][C:4]=2[C:3]=1[CH3:16].[CH2:17](O)[CH3:18]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]2[C:6]([CH2:9][C:10]([O:12][CH2:17][CH3:18])=[O:11])=[CH:7][O:8][C:4]=2[C:3]=1[CH3:16]
Reactant: Cc1cc2c(CC(=O)O)coc2c(C)c1O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1coc2c(C)c(O)c(C)cc12
Yield: 75 %

Procedure:
3.1 g (14 mmol) of 2-(6-hydroxy-5,7-dimethyl-1-benzofuran-3-yl) acetic acid are heated at reflux overnight in 1.72 ml of conc. sulfuric acid in 861 ml of ethanol. The mixture is concentrated down to 50 ml and then diluted with water and ethyl acetate; the phases are separated and the aqueous phase is extracted with ethyl acetate. The combined phases are washed with a saturated solution of NaCl, dried over sodium sulfate and concentrated. Chromatographic purification (dichloromethane) yields 2.6 g (75%) of ethyl 2-(6-hydroxy-5,7-dimethyl-1-benzofuran-3-yl)acetate.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=1.O1CCCC1.C1(C)C=CC=CC=1.S(Cl)([Cl:37])=O>[Cl-].[Na+].O>[Cl:37][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}-methanol (300 g), tetrahydrofuran (750 ml) and toluene (750 ml) were charged and the mixture was cooled to 5° C. Thionyl chloride (88 ml) was added dropwise at not higher than 15° C. over 10 min and the mixture was reacted at 10-15° C. for 1 hr. 10% Brine (900 ml) was added dropwise at the same temperature over about 10 min, and the mixture was stood for 30 min, partitioned and activated carbon (15 g) was added to the organic layer. The mixture was stirred for about 1 hr, and the activated carbon was filtered off and the mixture was washed with toluene (300 ml). The organic layer was concentrated to about 805 g and then heated to about 60° C. to dissolve crystals, followed by standing for cooling. The mixture was cooled to about 25° C. over 30 min and n-hexane (1800 ml) was added dropwise over about 30 min. The mixture was cooled to around 5° C. and aged for 1 hr. The crystals were collected by filtration and washed with cold toluene-n-hexane (1:3) (600 ml). The crystals were dried under reduced pressure at 40° C. to give pale-yellow 4-{[4-(chloromethyl)phenoxy]methyl}-5-methyl-2-phenyl-1,3-oxazole (280.0 g) in a yield of 87.9%.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([NH2:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([NH:25][C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(CBr)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
3.22 ml of bromoacetyl bromide were added dropwise under an inert gas atmosphere at 0° C. to 19.23 g of tritylamine in 50 ml of chloroform and then the mixture was stirred for one hour while allowing the temperature to rise to ambient temperature. After filtration of the precipitate, the organic phase was washed with 1N sodium hydroxide, dried, evaporated under reduced pressure until a residue was obtained which was purified by crystallization from ether to obtain 8.5 g of the expected amide.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.N#N.[BrH:28]>>[BrH:28].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(P(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Agent: Br
Agent: N#N
Product: Oc1ccc(P(c2ccc(O)cc2)c2ccc(O)cc2)cc1
Yield: 98 %

Procedure:
To 30 ml 48% HBr in a 50 ml round-bottom flask was added 1 gram (0.0033 mole) of tri(p-methoxyphenyl)phosphine. The homogeneous solution was heated to reflux (124° C.) under a stream of N2 (to remove CH3Br) and within 40 minutes a white precipitate formed. After 2 hours reflux, the mixture was filtered, washed with water, and vacuum dried to give 1.11 g (98%) tri(p-hydroxyphenyl)phosphine hydrobromide.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:9]2[CH:14]=[C:13]([CH2:15][CH3:16])[S:12][C:10]=2[N:11]=1)=[O:5])C.[OH-].[Na+]>CO>[C:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][N:17]([C:8]2[C:9]3[CH:14]=[C:13]([CH2:15][CH3:16])[S:12][C:10]=3[N:11]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH2:22][CH2:21]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)c2cc(CC)sc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(C(=O)O)nc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
4-(4-tert-Butoxycarbonyl-piperazin-1-yl)-6-ethyl-thieno[2,3-d]pyrimidine-2-carboxylic acid ethyl ester (118.9 mg) was dissolved in methanol (0.42 mL) and NaOH (2 M in water, 0.42 mL) was added. The reaction was stirred at room temperature for 3 hours after which, it was neutralized with DOWEX acid ion exchange resin. The mixture was filtered and the filtrate was concentrated to dryness giving the desired product. Yield=100%, ES-MS: (M+H)+ 393.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>ClC(Cl)C.CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]2[S:10][CH2:11][C:12](=[O:14])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(SCC(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)C(=O)CS2
Temperature: 50 °C
Yield: 78 %

Procedure:
(4-Acetyl-phenylsulfanyl)-acetic acid (1.0 g, 4.8 mmol) is suspended in dichloroethane, under nitrogen at ambient temperature. To this is added thionyl chloride (0.694 ml, 9.6 mmol) followed immediately by 1 drop of DMF. After maintaining the reaction mixture at 50° C. for 30 min., the mixture became homogenous. After cooling to ambient temperature, nitrogen was bubbled into the mixture to remove any trace gasses (10 min.), then aluminum trichloride (1.9 g, 14.4 mmol) was added in 4 portions which caused the reaction temperature to raise to 40° C. After the reaction had cooled to ambient temperature (2 hr), the reaction mixture was poured into 200 mL of and ice/water mixture and extracted with dichloromethane (3×100 ml). The combined organic layers were washed with saturated bicarbonate solution, and brine, then dried over MgSO4, filtered and concentrated in vacuo to yield 5-acetyl-benzo[b]thiophen-3-one as a red brown solid (720 mg, 79%). This material was used without further purification. 1H NMR (250 MHz, CDCl3): δ 8.23 (d, 1H, J=2.1), 8.15 (dd, 1H, J=7.5,J=2.1), 7.48 (d, 1H, J=7.5), 3.83 (s, 2H), 2.56 (s, 3H). MS [EI+] 193 (M+H)+, [EI−] 191 (M−H)−.