Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:11][C:10]2[C:5](=[C:6]([Cl:13])[CH:7]=[CH:8][C:9]=2[Cl:12])[CH2:4]1.C([N:17]1[CH2:21][CH2:20][NH:19][C:18]1=O)(=O)C>P(Cl)(Cl)(Cl)=O>[Cl:13][C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[C:10]2[C:5]=1[CH2:4][N:3]([NH:2][C:18]1[NH:19][CH2:20][CH2:21][N:17]=1)[CH2:11]2
Reactant: CC(=O)N1CCNC1=O
Reactant: NN1Cc2c(Cl)ccc(Cl)c2C1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(Cl)c2c1CN(NC1=NCCN1)C2
Yield: 50.9 %

Procedure:
5.9 g (0.025M) of 2-amino-4,7-dichloroisoindoline hydrochloride and 3,6 g (0.028M) of 1-acetylimidazolidin-2-one are heated to 100° C. over 2 hours in 50 ml of phosphorus oxychloride. The Cl3OP is evaporated off and the residue dissolved in 100 ml of ethanol and heated to the boiling point for 1 hour to eliminate the acetyl group. The solvent is drawn off in the vacuum, the residue picked up in water, alkalized with dilute sodium hydroxide solution, and extracted with chloroform. The chloroform is evaporated, and ethyl ether added, yielding 3.4 g of 4,7-Dichloro-2-(2-imidazolin-2-ylamino)-isoindoline as a base, which is converted with ethanolic hydrochloric acid into the hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]2[CH2:15][C@@H:11]([CH:12]=[CH:13]2)[C@@H:10]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[N:34]1C=CC=CC=1.O1CCOCC1.C(=O)(O)[O-].[NH4+]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[C@@H:10]([C:16](=[O:18])[NH2:34])[C@H:11]2[CH2:15][C@@H:14]1[CH:13]=[CH:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N[C@H]1[C@@H](C(=O)O)[C@@H]2C=C[C@H]1C2
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1[C@@H](C(N)=O)[C@@H]2C=C[C@H]1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
(1S,2S,3R,4R)-3-tert-Butoxycarbonylamino-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (6.66 g, 26.3 mmol;), Di-tert-Butyldicarbonate (8.6 g, 39 mmol;) and Pyridine (3.8 mL, 47 mmol) were added to 1,4-Dioxane (40 mL, 500 mmol) and the reaction stirred for 30 minutes at room temperature. Ammonium Bicarbonate (5.8 g, 74 mmol;) was added, and the reaction mixture was stirred overnight. The reaction was quenched by addition of water. Extraction (2×) with EtOAc, washing 2× with 0.1 N HCl, and once w/brine, drying (MgSO4), concentration, provided ((1R,2R,3S,4S)-3-Carbamoyl-bicyclo[2.2.1]hept-5-en-2-yl)-carbamic acid tert-butyl ester as a white solid (6.47 grams).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)N.N([O-])=[O:15].[Na+].O>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(O)cc(C(F)(F)F)c1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
3-Methoxy-5-(trifluoromethyl)aniline. (5 g) was suspended in 20% HCl (200 mL), stirred for 30 min, cooled to 0-5° C. and diazotized with NaNO2 (2.17 g) added in small portions. The mixture was stirred for 30 min at that temperature and added dropwise to boiling water (200 mL). The mixture was refluxed for 15 min, allowed to cool to room temperature and extracted with AcOEt, dried (MgSO4), filtered and evaporated. The residue was then purified by column chromatography (silica gel; eluent: hexane and AcOEt) to give 3-methoxy-5-(trifluoromethyl)phenol (3.6 g)
Reaction SMILES: [CH2:1](Cl)[O:2][CH3:3].C(N(CC)C(C)C)(C)C.[CH2:14]([O:16][C:17]([C@H:19]1[CH2:23][C@@H:22]([OH:24])[CH2:21][N:20]1[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:18])[CH3:15]>ClCCl>[CH2:14]([O:16][C:17]([C@H:19]1[CH2:23][C@@H:22]([O:24][CH2:1][O:2][CH3:3])[CH2:21][N:20]1[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)=[O:18])[CH3:15]
Reactant: COCCl
Reactant: CCOC(=O)[C@H]1C[C@@H](O)CN1CCc1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1C[C@@H](OCOC)CN1CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.6 %

Procedure:
9.32 ml (123 mmol) of MOMCl was added to a solution of 25 ml (144 mmol) of N,N-diisopropylethylamine and 6.00 g (20.5 mmol) of (2R, 4R)-(+)-2-(ethoxycarbonyl)-4-hydroxy-1-(4-methoxyphenethyl) pyrrolidine in dichloromethane (100 ml) and the mixture was stirred for 14 hours at room temperature. The mixture was washed with saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate : n-hexane=1:1 ) to give 6.20 g of (2R, 4R)-(+)-2-(ethoxycarbonyl)-4-(methoxymethoxy)-1-(4-methoxyphenethyl) pyrrolidine in 89.8% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][CH2:12][OH:13])=[C:4]([CH2:8][CH2:9][OH:10])[S:5][C:6]=1[Cl:7].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:11][CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])=[C:4]([CH2:8][CH2:9][O:10][S:22]([CH3:21])(=[O:24])=[O:23])[S:5][C:6]=1[Cl:7]
Reactant: OCCc1sc(Cl)c(Cl)c1CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1sc(Cl)c(Cl)c1CCOS(C)(=O)=O
Reaction time: 0.75 h

Procedure:
A solution of the product from step (e) (1.99 g, 8.25 mmol) in CH2Cl2 (41 ml) was cooled to 0° C. and treated with triethylamine (3.4 ml, 24.7 mmol) followed by dropwise addition of methanesulfonyl chloride (1.4 ml, 18.1 mmol) over 10 min. After 45 minutes, the crude reaction was diluted with CH2Cl2 (100 ml) and washed with ice water (25 ml), 10% citric acid (2×25 ml), sat. NaHCO3 (2×25 ml) and brine (1×25 ml). The organic layer was dried (MgSO4), concentrated to 20 ml and diluted with anhydrous dioxane (76 ml). This mixture was concentrated to remove remaining CH2Cl2 and the resulting dioxane solution was carried forward to the next reaction.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:10]([NH2:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C@H:10]([NH:20][CH3:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 77.1 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylamine (1.86 g, 6.51 mmol) in THF (20 ml) was added a solution of K2CO3 (1.80 g, 13.02 mmol) in H2O (15 ml). After 10 minutes, ethyl chloroformate (0.68 ml, 7.16 mmol) was added and stirring was continued at RT for an additional 4 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (20 ml) and a solution of borane in THF (1M) was added (26 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (100 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 1.51 g (77%) of rac-[(3S,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-amine as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH2:22]O)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH2:22][N:28]2[C:27](=[O:29])[C:26]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]3[C:24]2=[O:34])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1-n1ccnc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1F)c1cc(Cl)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 17, 5-chloro-2'-fluoro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 5-chloro-2'-fluoro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1.[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>C1COCC1.O>[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: COc1cccc(CBr)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H](Cc1cccc(OC)n1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.8 %

Procedure:
To a 100-mL round-bottomed flask was added 2-(bromomethyl)-6-methoxypyridine (1.33 g, 6.58 mmol), 2-(bromomethyl)-6-methoxypyridine (1.33 g, 6.58 mmol), ethyl N-(diphenylmethylene)glycinate (1.76 g, 6.58 mmol, Acros, N.J.) and 5N sodium hydroxide (6.58 mL, 32.9 mmol) in THF (30 mL). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated NaCl (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 10% EtOAc/hexanes to give ethyl N-(diphenylmethylidene)-3-(6-methoxy-2-pyridinyl)alaninate (1.86 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1)[C:5]([OH:15])([C:10]#[C:11][CH:12]1[CH2:14][CH2:13]1)[C:6]([F:9])([F:8])[F:7].C(N(C(C)C)CC)(C)C.Br[CH:39]([CH2:43][CH2:44][Br:45])[C:40](Cl)=[O:41]>C(Cl)Cl>[Br:45][CH2:44][CH2:43][CH:39]1[O:15][C:5]([C:10]#[C:11][CH:12]2[CH2:13][CH2:14]2)([C:6]([F:7])([F:8])[F:9])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:18]=[CH:17][C:16]=2[N:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:40]1=[O:41]
Reactant: COc1ccc(CNc2ccc(Cl)cc2C(O)(C#CC2CC2)C(F)(F)F)cc1
Reactant: O=C(Cl)C(Br)CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)C(CCBr)OC(C#CC3CC3)(C(F)(F)F)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a solution of 1.64 g of 3-chloro-6-(4-methoxyphenyl)methylamino-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol and 2.0 mL of diisopropylethylamine in 30 mL of dry methylene chloride was added 1.6 g of 2,4-dibromobutyryl chloride. After stirring at room temperature overnight, the mixture was poured onto water and extracted with ether. The ether layer was washed with aqueous sodium bicarbonate, dried, and evaporated to an oil. This material was subjected to column chromatography over silica gel (elution with 5-10% ethyl acetate in hexanes) affording 1.13 g of the title compound as a mixture of diastereomers.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:3]=1[CH2:4][S:5][CH:6]1[CH2:11][CH2:10][CH2:9][C:8](=[N:12]O)[CH2:7]1.C1(C)C(S(Cl)(=O)=[O:27])=CC=CC=1.S(=O)(=O)(O)O.C(Cl)Cl>N1C=CC=CC=1>[CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:3]=1[CH2:4][S:5][CH:6]1[CH2:11][CH2:10][CH2:9][NH:12][C:8](=[O:27])[CH2:7]1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Cc1cc(C)c(CSC2CCCC(=NO)C2)c(C)c1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)c(CSC2CCCNC(=O)C2)c(C)c1

Procedure:
A solution of 828 mg of 3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexanone-oxime and 570 mg of toluenesulfonylchloride in 5 ml of pyridine is stirred at RT for 4 hours and additional 2 hours at 60°. The mixture obtained is distributed between diluted sulfuric acid (2 ml H2SO4 conc. in 15 ml H2O) and CH2Cl2, the organic phase obtained is dried, solvent is evaporated and the evaporation residue is subjected to chromatography. 4-(R/S)-(2,4,6-Trimethyl-benzyl-sulfanyl)-azepan-2-one is obtained. 1H-NMR(d-6-DMSO): 7.5 (m,1H,NHCO), 6.8 (s,2H,arom.H), 3.75 (s,2H,C6H5CH2S—),3.2 (m, 1H,CHN), 3.1(m,3H, CH2NH,CHS)AB-system: vA=2.72,vB=2.65(2H,CH2C═O, J=13.4 Hz, J=4.5 Hz) 2.13 2.15,2.3(9H, 3×CH3)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]1.C([O-])(=O)C.[Na+].CC(O)=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH2:20][N:27]4[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]4)[CH:22]=[CH:23][CH:24]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(C=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(Cc2cccc(-c3nnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
To a solution of 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylbenzaldehyde (D11) (44 mg) and ethyl 4-piperidinecarboxylate (89 mg) in methanol (10.00 mL) stirred at room temperature was added sodium acetate (55 mg) and AcOH (0.033 mL). The reaction mixture was stirred at room temperature for 10 min. And the solvent was removed by evaporation. The residue was dissolved in dichloromethane (DCM) (10 mL), and sodium triacetoxyborohydride (72.3 mg) was added. Stirring continued for 2 h. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated to afford ethyl 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-4-piperidinecarboxylate (D12) (60.1 mg). MS (ES): C28H34ClN3O3S requires 527. found 528.2 (M+H+).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:8]=1[CH3:28]>C1COCC1.CO>[CH2:26]([S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:29])=[O:4])=[C:8]2[CH3:28])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[CH3:27]
Reactant: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)OC)c3cccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)O)c3cccnc32)cc1

Procedure:
1M Aqueous NaOH (1 ml) is added to a stirring solution of [1-(4-ethanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (89 mg, 0.23 mmol) in 1:1 THF/MeOH (4 ml). After 1 hour the reaction is evaporated and the resulting oil is dissolved in water (8 ml) and acidified to pH 3. The resulting precipitate is collected by filtration and dried in vacuo to afford [1-(4-ethanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid (MH+ 373)
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH3:33])[C:6]([C:8]1[S:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11](=[O:30])[C:10]=2[C:9]=1[O:31][CH3:32])=[O:7].C(N(CC)CC)C.[C:41]([O:44][CH2:45][C:46](Cl)=[O:47])(=[O:43])[CH3:42]>C1COCC1.C(=O)([O-])O.[Na+]>[C:41]([O:44][CH2:45][C:46]([NH:2][CH2:3][CH2:4][N:5]([C:6]([C:8]1[S:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:11](=[O:30])[C:10]=2[C:9]=1[O:31][CH3:32])=[O:7])[CH3:33])=[O:47])(=[O:43])[CH3:42]
Reactant: COc1c(C(=O)N(C)CCN)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(C(=O)N(C)CCNC(=O)COC(C)=O)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of the compound of Example 103 (150 mg, 0.31 mmol) and triethylamine (69 mg, 0.68 mmol) in THF (10 mL) was added acetoxyacetyl chloride (46 mg, 0.34 mmol) under ice-cooling. After stirring at room temperature for 1 hr, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluate; ethyl acetate to ethyl acetate/methanol=50/1) to give a white solid. Recrystallization of the white solid from ethyl acetate-hexane gave the title compound (140 mg, 82%) as white crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](=[O:11])[CH2:8][C:7]=2[CH:12]=1.C(O)C>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](=[O:11])[CH2:8][C:7]=2[CH:12]=1
Reactant: O=C1Cc2cc(CCl)ccc2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc2c(c1)CC(=O)O2
Reaction time: 2 h

Procedure:
A solution of the product of Step 1, above (55) (10.89 mmol), in ethanol/ethyl acetate (23 ml/5 ml) was added to 10 ml ethanol over 10% palladium catalyst on carbon (100 mg). The mixture was hydrogenated on a Parr shaker at 45 psi for 2 hours. The reaction mixture was filtered through celite and the organics were concentrated to dryness to obtain the title compound (56).
Reaction SMILES: [OH:1][CH:2]([CH2:17][OH:18])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[K+].[C:21]([O:38]C)(=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[OH:1][CH:2]([CH2:17][OH:18])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:21](=[O:38])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCNCC(O)CO
Reactant: CCCCCCCCCCCCCCCC(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCC)CC(O)CO

Procedure:
N-(2,3-dihydroxypropyl)-N-dodecylamine (0.50 g, 0.0019 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum. Methyl palmitate (0.57 g, 0.0021 mole) was heated and added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off-white solid was obtained (crude yield=0.92 g) The waxy solid was recrystalized from hot hexane (yield=0.6 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:12][S:13](O)(=[O:15])=[O:14].C(Cl)(=O)C(Cl)=O.CN(C=O)C>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:8][CH:7]=1
Reactant: ClCCCOc1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 52.75 g (0.265 mol) of (3-chloro-propoxy)-benzene in 100 ml of CH2Cl2, a solution of 19.4 ml (0.292 mol) of chlorosulfonic acid in 100 ml of CH2Cl2 is added dropwise at 0-5° C. under N2 atmosphere. The mixture is allowed to warm to ambient temperature and stirred for 2 hours. To the mixture, 29.6 ml (0.345 mol) of oxalyl chloride and 4 ml (0.052 mol) of DMF are added dropwise at r.t. and the mixture is stirred for 18 h at r.t. The reaction mixture is poured into ice-water, extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated under reduced pressure to give 58.5 g of 4-(3-chloropropoxy)benzenesulfonyl chloride; NMR (CDCl3): 2.26-2.36 (m, 2H), 3.76 (t, 2H, J=6.04 Hz), 4.24 (t, 2H, J=6.04 Hz), 7.06 (d, 2H, J=9.08 Hz), 7.98 (d, 2H, J=9.08 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([OH:12])=O)[CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1>>[NH:15]1[C:14]([NH:13][C:10]([C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][N:7]=2)=[O:12])=[N:18][N:17]=[N:16]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccn1
Reactant: Nc1nnn[nH]1
Product: O=C(Nc1nnn[nH]1)c1cc([N+](=O)[O-])ccn1
Yield: 56.6 %

Procedure:
0.48 g of 4-nitro-2-pyridinecarboxylic acid, 0.48 g of N,N'-carbonyldiimidazole and 0.27 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from ethanol, whereby 0.38 g of N-(5-tetrazolyl)-4-nitro-2-pyridinecarboxamide is obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Mn]([O-])(=O)(=O)=[O:34].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:18][CH:19]=2)[C:7]([C:11]([OH:34])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1

Procedure:
6.9 g (15 mmol) of the compound from Example I are oxidised with tetrabutylammonium permanganate analogously to Example XCV. The product is recrystallised from ethyl acetate/petroleum ether (1:1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>O1CCCC1.C(O)(=O)C.[Pd]>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)(=[O:21])=[O:20])=[CH:17][CH:18]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: O=C(O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)c1cc(CCc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O

Procedure:
A solution of 2-hydroxy-5-[2-[4-[(2-pyridinylamino)sulfonyl]phenyl]ethenyl]benzoic acid (3 g, 7.5 mmol) in tetrahydrofuran (100 ml) and acetic acid (100 ml) was hydrogenated over palladium on charcoal (10%, 0.3g) and hydrogen at atmospheric pressure and room temperature for 27 h. The catalyst was filtered off and the solvent was evaporated. The residue was dissolved in a solution of sodium hydroxide (0.3 g) in acetone (30 ml) and water (30 ml). The solution was acidified with hydrochloric acid at ca 50° C. After cooling, the product crystallized yielding 1.6g (52%).