Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][C:23]1[O:24][CH:25]=[CH:26][CH:27]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: BrCc1ccco1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccco3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 9.4 g (34.4 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 40 mL of (40 mmol) of a freshly prepared 1M solution in ethyl ether of 2-bromomethyl-furan. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up, 13.2 g (100% of yield) of 4-(1-furan-2-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]([CH2:18][CH3:19])[S:16][C:15](=[O:20])[NH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][F:11].Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[O:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][CH2:22][N:14]2[N:13]=[C:12]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][F:11])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:17]([CH2:18][CH3:19])[S:16][C:15]2=[O:20])[CH2:26][CH2:27]1
Reactant: ClCCCN1CCOCC1
Reactant: CCC1SC(=O)NN=C1c1ccc(OCF)c(OC)c1
Product: CCC1SC(=O)N(CCCN2CCOCC2)N=C1c1ccc(OCF)c(OC)c1

Procedure:
In analogy to Example 1, by reacting 5-(3-methoxy-4-fluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4thiadiazin-2-one with 1-chloro-3-morpholinopropane, 3-morpholinopropyl-5-(3-methoxy-4-fluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>C(Cl)Cl>[CH2:19]([S:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)(=[O:23])=[O:22])[CH3:20]
Reactant: CCS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of 16.5 g (0.1 mol) of ethyl 4-aminobenzoate and 16 g (0.2 mol) of pyridine in 200 mL of methylene chloride cooled to 0° C. add dropwise 13 g (0.1 mol) of ethanesulfonyl chloride. After the addition is complete stir the mixture at 20° C. for 4 hr. After this time extract the mixture with three 100 mL portions of 1N sodium hydroxide. Heat the basic extracts at reflux for 2 hr, cool to 0°-10° C. and carefully add 60 mL of concentrated hydrochloric acid. Collect the resulting precipitate to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:34](Cl)(=O)[O:35]C1C=CC([N+]([O-])=O)=CC=1.[CH:47]1([CH2:50][NH2:51])[CH2:49][CH2:48]1>O1CCCC1>[CH:47]1([CH2:50][NH:51][C:34]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=4)[CH2:15][CH2:16]3)=[CH:4][CH:3]=2)=[O:35])[CH2:49][CH2:48]1
Reactant: Nc1ccc2ccn(C3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)c2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCC1CC1
Solvent: C1CCOC1
Product: O=C(NCC1CC1)Nc1ccc2ccn(C3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.1 %

Procedure:
2-(4-((4-(6-Amino-1H-indol-1-yl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.350 mmol, 0.165 g) and 4-nitrophenyl carbonochloridate (0.350 mmol, 0.071 g) were combined and stirred in tetrahydrofuran (2 mL) for 1 hour. Cyclopropylmethanamine (0.700 mmol, 0.061 mL, 0.050 g) was added and the reaction stirred at room temperature for 2 hours. The organic phase was washed with water and dried over sodium sulfate. The solvent was removed and the resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 3% methanol/dichloromethane) to afford the title compound (24 mg). MS (ESI) m/z 569.2 [M+H]+
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3](=[O:28])[NH:4][C:5]1[C:13]([CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[C:12]([O:24][CH3:25])[C:11]([CH3:26])=[C:10]2[C:6]=1[C:7](=[O:27])[O:8][CH2:9]2.CO.O.[OH-].[Li+]>O>[CH3:29][N:2]([CH3:1])[C:3](=[O:28])[NH:4][C:5]1[C:13]([CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:12]([O:24][CH3:25])[C:11]([CH3:26])=[C:10]2[C:6]=1[C:7](=[O:27])[O:8][CH2:9]2
Reactant: COC(=O)CC/C(C)=C/Cc1c(NC(=O)N(C)C)c2c(c(C)c1OC)COC2=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C)c2c(c(NC(=O)N(C)C)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Yield: 94.6 %

Procedure:
To a solution of 0.3 g (0.74 mmol) of methyl (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate in 7.4 ml 4:1 methanol:water was added 0.13 g (2.96 mmol) of lithium hydroxide monohydrate. The solution was heated at 50°-60° C. for 4 hours. Upon cooling, the reaction was partitioned between aqueous sodium hydrogen sulfate and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoic acid. Recrystallization from hexane-ethyl acetate gave 0.27 g (0.7 mmol) of (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoic acid, mp 170°-190° C.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[O:9]=[C:10]1C2(CCNCC2)C(=O)CC1.C([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])C>C(O)C.O>[N:6]1[CH:7]=[CH:8][C:3]([N:23]2[CH2:24][CH2:25][C:10](=[O:9])[CH2:27][CH2:26]2)=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)C12CCNCC2
Reactant: Clc1ccncc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1CCN(c2ccncc2)CC1
Temperature: 150 °C
Reaction time: 22 h

Procedure:
A solution of 4-chloropyridine hydrochloride (10 g), 1,4-dioxo-8-azaspiro[4,5]decane (10 g) and triethylamine (29 ml) in a mixture of ethanol (10 ml) and water (30 ml) was stirred at 150° C. for 22 hours in a sealed tube. After completion of the reaction, the solvent was evaporated and 5N aqueous sodium hydroxide solution (25 ml) was added. The mixture was extracted with a mixed solvent of chloroform-methanol (10:1). The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. To the obtained residue was dropwise added conc. hydrochloric acid (30 ml) with ice-cooling, and the mixture was stirred at the same temperature for 10 min. After completion of the reaction, sodium hydroxide (15 g) was added. The mixture was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=9:1, 1% aqueous ammonia) and dried under reduced pressure to give the title compound (6.1 g).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])(C(C)(C)C)(C)C.Br[CH2:40][CH2:41][F:42].[H-].[Na+].[Br-].FC(F)(F)C(O)=O>CN(C=O)C>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:13]1[CH2:12][N:11]([C:23]([N:25]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:40][CH2:41][F:42])[CH2:30][CH2:31]2)[CH3:32])=[O:24])[C@:10]([CH2:9][OH:8])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=1
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO[Si](C)(C)C(C)(C)C)c1ccccc1)C1CCNCC1
Reactant: FCCBr
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=C[C@@]1(CO)c1ccccc1)C1CCN(CCF)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 60 mg (0.11 mmol) of amine 7-2 in DMF at 0° C. was added 13 μL (0.17 mmol) of 1-bromo-2-fluoroethane and 8 mg (0.17 mmol) of NaH (60% dispersion in oil). After warming to room temperature, another portion of NaH and the bromide were added, and the reaction was allowed to stir overnight. LC-MS indicated still 25% unreacted 7-2, so the mixture was heated to 60° C. for several hours. After cooling to room temperature, ˜500 μL of trifluoroacetic acid was added and the mixture was stirred for 1 h. The reaction was partitioned between EtOAc and 15% aqueous Na2CO3, the layers were separated, the organic phase was washed with saturated NaHCO3, water, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 12-1 as a white solid. Data for 12-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.4 (m, 1H), 4.8 (m, 1H), 4.6-4.4 (m, 4H), 4.0 (m, 1H), 3.75 (m, 1H), 3.1 (m, 2H), 2.9 (s, 3H), 2.75-2.65 (m, 2H), 2.2 (m, 2H), 1.9 (m, 3H), 1.7 (m, 1H) ppm. HRMS (ES) calc'd M+H for C26H30F3N3O2: 474.2363. Found: 474.2355. Resolution of the enantiomers was carried out chromatographically using a Chiralpak AD© 10×50 cm column with 30% isopropanol in hexanes (with 0.1% diethylamine) at 150 ml/min. Analytical HPLC analysis of the eluent on a 4×250 mm Chiralpak AD® column with 30% isopropanol in hexanes (with 0.1% diethylamine) at 1 ml/min indicated that inactive enantiomer has Rt=6.3 min and the active enantiomer has Rt=7.5 min.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:24]=[CH:23]C(C(Cl)=O)=[CH:18][CH:17]=1>>[C:6]([NH:5][NH:4][C:1](=[O:3])[C:2]1[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)NNC(=O)c1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)NNC(=O)c2ccccc2)cc1

Procedure:
Synthesis and isolation were same as 1-acetyl-2-benzoylhydrazine, using 1.5 g (11.2 mmol) of benzoylhydrazide, 1.9 g (11.1 mmol) of 4-methoxybenzoylchloride and 1.1 g of TEA. Yield was 2.9 g (97%). 1H NMR (200 MHz, d6-DMSO) δ 5.13 (s, 3H), 8.36 (d, 2H), 8.86 (m, 3H), 9.23 (d, 4H) 11.72 (d, 2H); MS (EI, m/e, relative intensity %) calcd for C15H14N2O3 270, found 270 (M+, 5.1); mp 201-202° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[C:9]([CH2:12][O:13][CH3:14])=[C:10](Br)[N:6]2[N:5]=[CH:4][N:3]=1.[Li]CCCC.CN([CH:45]=[O:46])C>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[C:9]([CH2:12][O:13][CH3:14])=[C:10]([CH:45]=[O:46])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C=O
Temperature: -77 °C
Reaction time: 0.02 h

Procedure:
To a solution of THF (35 mL) was added 1-{4-[4-amino-7-bromo-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (200 mg, 0.35 mmol). The solution was cooled to −77° C., and then 2.5 M n-BuLi in hexanes (0.70 mL, 1.75 mmol) was added. The reaction was stirred for 1 min and then DMF (0.16 mL, 2.1 mmol) was added. The solution was stirred for an additional 5 min, and the ice bath was removed. The reaction was allowed to warm to rt over the following 1 h. EtOAc was added to the solution followed by water. The solution was separated and the aqueous layer was back extracted with EtOAc. The combined organic fractions were dried (MgSO4), filtered, and evaporated yielding the title compound as crude material (216 mg, 119%). MS [M+H]+=521; LCMS RT=3.49.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Br)c1
Reactant: CC(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Sc1cccc(Br)c1)C(N)=O
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 98.4 %

Procedure:
To a mixture of 5.0 g 3-bromobenzenethiol and 5.96 g potassium carbonate in 50 ml DMF were added 3.86 g 2-bromopropionamide at RT. The mixture was warmed up and stirred at 70° C. for 3.5 hrs. After cooling, 200 ml water were added and the mixture extracted 3 times with dichloromethane. Drying and evaporation of the organic phases yielded 6.5 g of the title product which was used without further purification.
Reaction SMILES: C1COCC1.[Br:6][C:7]1[CH:8]=[C:9]([Mg]Br)[CH:10]=[CH:11][CH:12]=1.[CH2:15]([N:22]1[CH2:27][CH:26]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Br:6])[CH:8]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C1=CCN(Cc2ccccc2)CC1
Reactant: Br[Mg]c1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C1CCN(Cc2ccccc2)CC1c1cccc(Br)c1
Temperature: 20 °C
Yield: 60.5 %

Procedure:
A 0.5 M THF solution of (3-bromophenyl)magnesium bromide (20 mL, 10 mmol) was cooled to −15° C., and methyl 1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate (1.05 g, 4.3 mmol) in toluene (3.0 mL) was slowly added for 3 h at −15° C. The reaction mixture was warmed to 20° C. and quenched by addition of saturated NH4Cl aqueous solution followed by extraction with EtOAc. The combined organic solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 9/1) to give methyl 1-benzyl-3-(3-bromophenyl)piperidine-4-carboxylate (1.0 g, 2.6 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(=O)[C@H](C1C=CC=CC=1)O.[OH-].[Na+]>C(OC)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(N)c1ccc(Cl)c(Cl)c1
Agent: O=C(O)[C@@H](O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: C[C@@H](N)c1ccc(Cl)c(Cl)c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
A solution consisting of 41 g of (RS)-1-(3,4-dichlorophenyl)ethylamine and 78 g of methyl t-butyl ether was heated to 45° C. while stirring, and a mixture of 14.6 g of L-mandelic acid and 90 g of methyl t-butyl ether was added thereto over about 30 minutes, followed by stirring at the same temperature for 30 minutes. Then, after cooled to 20° C. over 6 hours, the precipitated crystals were filtered, washed twice with 40 g of methyl t-butyl ether and dried to obtain 32.9 g of diastereomer salt. 82 g of a 5% aqueous sodium hydroxide solution was added to the crystals, followed by extraction twice with 20 g of methyl t-butyl ether. The solvent was distilled off from the resulting organic layer to obtain 18.2 g of (R)-1-(3,4-dichlorophenyl)ethylamine. This had the optical purity of 87.4%ee.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].ClC(O[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[CH3:16])=O>>[CH3:16][C:10]1[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:9]=1[Cl:1]
Reactant: [Cl-]
Reactant: Cc1cccc(OC(=O)Cl)c1C
Agent: [Al+3]
Product: Cc1cccc(Cl)c1C
Temperature: 200 °C
Yield: 18 %

Procedure:
0.4 g of anhydrous aluminium chloride was added to 20 g of 2,3-dimethylphenyl chloroformate and the mixture was heated at 200° C. for 4.5 hours at normal pressure. The reaction mixture was then cooled and worked up as described in Example 1. 2,3-Dimethylchlorobenzene was obtained in a yield of 18%, which is considerable despite the unfavourable substitution pattern.
Reaction SMILES: [S:1]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH:12]OS([O-])=O.[K+].[OH2:18]>C1COCC1>[S:1]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])([CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:12])=[O:18]
Reactant: O
Reactant: O=C(O)CCSCCC(=O)O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)CCS(=O)(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
3,3′-thiodipropanoic acid (1 equivalent) was taken in THF and to it oxone (2 equivalents) taken in water was slowly added and stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to afford the crude product I-14 in 20-30% yield.
Reaction SMILES: C(O)C.[OH-].[Na+].[CH3:6][N:7]([CH3:33])[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][C:28]([O:30]CC)=[O:29])[N:19]=2)=[CH:14][CH:13]=1.Cl>O>[CH3:33][N:7]([CH3:6])[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][C:28]([OH:30])=[O:29])[N:19]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cn1nc(-c2ccc(OCCCN(C)C)cc2)c2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)CCCOc1ccc(-c2nn(CC(=O)O)c3ncccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 90 mg of ethanol, 40 ml of water and 2.0 g of sodium hydroxide was added 13 g of ethyl 3-[4-(3-dimethylaminopropoxy)phenyl]-1H-pyrazolo[3,4-b]pyridin-1-ylacetate. The mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was adjusted to pH 7 by dilute hydrochloric acid. The mixture was purified with ion-exchange resin (Diaion HP-20) and recrystallized from hydrous methanol to give 3-[4-(3-dimethylaminopropoxy)phenyl]-1H-pyrazolo[3,4-b]pyridin-1-ylacetic acid, m.p. 221°-223° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/[N:43]=N/C(OCC)=O)=O>C1COCC1>[NH3:43].[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][Cl:12])=[CH:6][CH:5]=1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: OCCCCCCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCCCCCl)cc1
Product: N
Temperature: 0 °C
Reaction time: 72 h
Yield: 44.4 %

Procedure:
4-Hydroxy-benzoic acid methyl ester (1.52 g, 10 mmol), 5-chloro-1-pentanol (1.22 g, 10 mmol) and triphenylphosphine (2.62 g, 10 mmol) are dissolved in dry THF (30 mL) and cooled to 0° C. Diethylazodicarboxylate (DEAD) (1.74 g, 10 mmol) is dropped into this mixture at 0° C. and stirred at room temperature for 3 days. The reaction mixture is washed with brine, dried over Na2SO4, filtered and evaporated. The crude product is purified using silica-gel column chromatography (CH2Cl2 only to CH2Cl2:2 M NH3 in MeOH=20:1) to give the desired product (1.14 g, 45%). NMR (CDCl3): δ 7.98 (d, 2H, J=8.8 Hz), 6.89 (d, 2H, J=8.8 Hz), 4.02 (t, 2H, J=6.5 Hz), 3.88 (s, 3H), 3.57 (t, 2H, J=6.7 Hz), 1.85 (m, 4H), 1.64 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Br:18]Br>C(O)(=O)C>[Br:18][C:10]1[C:11]([OH:12])=[C:2]([Cl:1])[CH:3]=[C:4]2[C:9]=1[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C1CCOc2cc(O)c(Cl)cc21
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(O)c2Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
To a stirred solution of ethyl 6-chloro-7-hydroxychroman-4-carboxylate (5.14 g, 20.0 mmol) in glacial acetic acid (50 mL) at ambient temperature was added bromine (1.2 mL, 24 mmol) in six equal portions, waiting 30-60 seconds between each addition for the bromine color to be discharged. Following completion of addition, the solution was concentrated and the residue concentrated from toluene, then partitioned between ethyl acetate (200 mL) and 5% sodium bisulfite (100 mL). The organic was layer dried over sodium sulfate, then stirred with activated charcoal (2 g) at ambient temperature for 20 minutes. The charcoal was removed by filtration through a glass microfibre filter and the filtrate was concentrated to afford ethyl 8-bromo-6-chloro-7-hydroxychroman-4-carboxylate as a light brown oil (6.05 g, 90% yield).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.O[C:10]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=1[NH2:12].N1C=CC=CC=1>C1CCCCC1.C(OCC)(=O)C>[C:2]([C:1]1[O:6][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Solvent: C1CCCCC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc2ccc(O)cc2o1

Procedure:
A mixture of 1.01 ml of pivaloyl chloride, 808 mg 2,4-dihydroxyaniline hydrochloride (formula V) and 0.4 ml of pyridine is heated at about 210° for about 18 hours. The mixture obtained is dispersed in a mixture of cyclohexane and ethyl acetate and purified by chromatography. The title compound is obtained (m.p. 204-210°).
Reaction SMILES: O=C1[CH:6]([C:7](O)([OH:12])[C:8]([F:11])([F:10])[F:9])[CH2:5][CH2:4][O:3]1.Cl.C(O)(=O)C>O>[F:9][C:8]([F:11])([F:10])[C:7](=[O:12])[CH2:6][CH2:5][CH2:4][OH:3]
Reactant: O=C1OCCC1C(O)(O)C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(CCCO)C(F)(F)F
Temperature: 125 °C
Yield: 125.1 %

Procedure:
A 500 mL three neck round bottom flask, fitted with reflux condenser, heating mantle, and magnetic stirrer was charged with 61.5 g(0.31 M) of 2,3,4,5-tetrahydro-2-oxo-3-(2,2,2-trifluoro-1,1-dihyroxyethyl)furan, 6.4 mL of concentrated HCl, 10 mL of water, and 80 mL of acetic acid. The reaction mixture was heated at 125° C. overnight. An additional 3.0 mL of concentrated HCl and 5.0 mL of water was added and the reaction mixture was heated for an additional 10 hours. The reaction was partitioned between water and ethyl ether while the water layer was neutralized with solid sodium bicarbonate (100 g). The ether solution was washed with water (2×20 mL), dried (anhydrous MgSO4), and solvent removed under reduced pressure to give 60 g(45%) of a pale yellow oil. nmr(CDCl3)α-2.14m,4H), 4.03(m,1H), 4.20(m,1H).