Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CO>[C:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCCCCO
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)NCCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-amino-1-hexanol (0.650 g, 6.31 mmol) in methanol (15 mL) is cooled to 0° C. and treated with triethylamine (1.62 mL, 11.6 mmol) followed by acetic anhydride (0.891 mL, 9.45 mmol). The reaction mixture is stirred at room temperature overnight. Additional triethylamine (1.6 mL, 11.6 mmol) and acetic anhydride (0.9 mL, 9.5 mmol) is added at room temperature and the solution is stirred 16 h further. Concentration in vacuo and flash chromatography affords 6-acetamido-1-hexanol. To a solution of 6-acetamido-1-hexanol (22.2 mmol) in dry dichloromethane (50 mL) is added 2,6-di-tert-butyl-4-methylpyridine (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 6-acetamido-1-hexyl triflate (25) which is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23](B(O)O)=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:7]3[C:6](=[CH:11][C:10]([C:23]4[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][C:24]=4[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:9][CH:8]=3)[C:5]([CH3:16])([CH3:17])[C:4]=2[CH:3]=1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: COc1ccc(B(O)O)c(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc3c(c2)C(C)(C)c2cc(Br)ccc2-3)c(-c2ccccc2)c1
Temperature: 110 °C
Yield: 75 %

Procedure:
A mixture of 3.52 g (10 mmol) of 2,7-dibromo-9,9-dimethyl-9H-fluorene, 2.75 g (12 mmol) of 5-methoxybiphenyl-2-ylboronic acid, 0.12 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium, 15 ml of 2M Na2CO3, 20 ml of EtOH and 60 ml toluene was degassed and placed under nitrogen, and then heated at 110° C. for 8 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica(hexane-dichloromethane) afforded a white solid (3.4 g, 7.5 mmol, 75%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:21])[CH:14]([F:20])[N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[CH:9][CH:8]=1>CO.O>[Cl:3][C:4]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:21])[CH:14]([F:20])[N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[CH:9][CH:8]=1
Reactant: O=C(c1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(F)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(c1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(F)n1cncn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
With stirring, 0.6 g of sodium borohydride is added at 5°-10° C. to a suspension of 12.1 g of 1-[4-(2,4-dichlorophenoxy)phenyl]-2-fluoro-2-(1H-1,2,4-triazol-1-yl)ethanone in 100 ml of methanol and 2 ml of water and the resultant mixture is stirred further first for 1 hour at 5°-10° C. and then for 2 hours at room temperature, whereupon a clear solution gradually forms. This solution is then poured into ice-water and extracted twice with dichloromethane. The organic phase is separated, washed twice with water, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography through a column of silica gel eluted with diethyl ether, affording the following three fractions: The first fraction is concentrated by evaporation and the residue is recrystallised from petroleum ether, affording beige crystals with a melting point of 138°-139° C. Analytic and spectroscopic data show the presence of the pure diastereoisomer A. The second fraction is also concentrated by evaporation and the residue is recrystallised from diethyl ether, affording beige crystals with a melting point of 115°-116° C. Spectroscopic data shows that a mixture of both diastereoisomers A and B (approx. 1:1) is obtained. Similar working up of the third fraction affords the third pure diastereoisomer B with a melting point of 107°-108° C.
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:15]2[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2.C(N(CC)CC)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>O1CCCC1>[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:1][N:2]=[C:3]2[C:4]3[CH:5]=[CH:6][C:7]([O:18][CH3:19])=[CH:8][C:9]=3[C:10]3[C:15]2=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: COc1ccc2c(c1)-c1cc(OC)ccc1C2=NO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)-c1cc(OC)ccc1C2=NOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
3.8 g (0.015 mol) of 9-hydroxyimino-3,6-dimethoxyfluorene and 2.3 g (0.0225 mol) of triethylamine are suspended in 80 ml of tetrahydrofuran (THF) and, at 0° C., a solution of 3.1 g (0.0165 mol) of para-toluenesulfonic acid chloride in 20 ml of THF is added dropwise. After 4 hours, the ice-bath is removed and the reaction mixture is stirred overnight at room temperature. Then 40 ml of CH2Cl2 are added and the resulting ammonium salts are filtered off. The filtrate is washed with water and saturated NaCl, dried over magnesium sulfate and concentrated in a rotary evaporator. The resulting crude product is purified by flash chromatography on silica gel (eluant: petroleum ether/ethyl acetate 2:1). The fraction containing the main product is taken up in 100 ml of hot ethanol and the solution is filtered while hot. On cooling, the product precipitates and is filtered off and dried in vacua. 3.2 g (52%) of 9-(4-methylphenylsulfonyl-oxyimino)-3,6-dimethoxyfluorene are obtained in the form of yellow crystals having a melting point of 143-148° C. The UV spectrum (acetonitrile) of the substance shows absorption bands with a maximum at 314 nm (ε=21100) that extend to 450 nm. Elemental analysis: C22H19NO5S (409.6)
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[C:12]([S-])=[S:13])C.[K+].O.Cl>N1C=CC=CC=1>[O:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[C:12]1[SH:13]
Reactant: CCOC(=S)[S-]
Reactant: Nc1ncccc1O
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: Sc1nc2ncccc2o1
Yield: 67.4 %

Procedure:
2-Amino-3-hydroxypyridine (5.51 g) was dissolved in pyridine (100 mL), and potassium ethylxanthate (8.82 g) was added thereto. The mixture was refluxed for 2 hr. Iced water (400 mL) was added to the reaction mixture, and concentrated hydrochloric acid (40 mL) was added thereto. The mixture was extracted with chloroform and the extract was washed with brine and concentrated under reduced pressure to give 1,3-oxazolo[4,5-b]pyridine-2-thiol (5.13 g) as a pale-brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:14][N+:15]([O-:17])=[O:16].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]([F:12])([F:11])[F:10])=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Reactant: C[N+](=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])C=C(c1ccc(Br)cc1)C(F)(F)F

Procedure:
A stirred solution of 4′-bromo-2,2,2-trifluoroacetophenone (0.392 g, 2.00 mmol). and CH3NO2 (0.488 g, 8.0 mmol) in dry toluene (70 mL) containing N,N-diethylenediamine (30 mmol) is heated at reflux with a Dean and Stark trap until complete removal of H2O. The cooled solution is washed with 5% aqueous HCl, dried over MgSO4, filtered, evaporated in vacuo and the resulting residue when purified by chromatography gives the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH2:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.O.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl>[Na].C(O)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])[C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12
Reactant: CN(C)CCCl
Reactant: CC(=O)Cc1ccc2c(c1)Cc1cccnc1O2
Agent: [Na]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)C(CCN(C)C)c1ccc2c(c1)Cc1cccnc1O2
Yield: 56.4 %

Procedure:
4.1 g of 5H-[1]benzopyrano[2,3-b]pyridin-7-yl-acetone is dissolved in a solution of 0.44 g of metallic sodium in 20 ml of absolute isopropyl alcohol by warming to 50°-60°C. The solution is water-cooled, 2.3 g of 2-dimethylaminoethyl chloride is added, and the mixture is stirred under reflux for 1 hour. The reaction mixture is concentrated, chloroform and water are added to the residue, and the mixture is shaken. The chloroform layer is separated and extracted with dilute hydrochloric acid, and the extract is neutralized with 10% sodium hydroxide and then extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous magnesium sulfate and concentrated to give 3 g of crude 3-(5H-[1]benzopyrano[2,3-b]-pyridin-7-yl)-5-dimethylamino-2-pentanone as a pale yellowish brown transparent oil. The product is treated with maleic acid in acetone in a conventional manner, and the crystalline precipitate is recrystallized from isopropyl alcohol to give 3-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)-5-dimethylamino-2-pentanone maleate as white needles melting at 145°-146°C.
Reaction SMILES: [F:1][C:2]([F:16])([C:12]([F:15])([F:14])[F:13])[C:3]([F:11])([F:10])[C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].[H-].[Na+].Cl[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:22][N:21]=1.O>CN(C)C=O>[Cl:26][C:25]1[C:20]([N:7]2[C:8]([CH3:9])=[C:4]([C:3]([F:11])([F:10])[C:2]([F:1])([F:16])[C:12]([F:14])([F:15])[F:13])[N:5]=[CH:6]2)=[N:21][CH:22]=[C:23]([C:27]([F:29])([F:28])[F:30])[CH:24]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cc1[nH]cnc1C(F)(F)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(F)(F)C(F)(F)C(F)(F)F)ncn1-c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
To a solution of 0.6 g (2.4 m mol) of 4-heptafluoropropyl-5-methylimidazole in 5 ml of N,N-dimethyl formamide was added slowly 100 mg (2.4 m mol) of an oily sodium hydride (60%) while cooling with ice, followed by stirring at the same temperature for 10 minutes. After the reaction was completed, to the reaction mixture was added dropwise 0.52 g (2.4 m mol) of 2,3-dichloro-5-trifluoromethylpyridine, followed by stirring at room temperature for 9 hours. After the reaction was completed, the reaction mixture was poured into water, and extracted with ethyl acetate. Further, then the residue was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained product was subjected to silica gel chromatography to give 0.4 g of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-4-heptafluoropropyl-5-methylimidazole.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][O:15][C@@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.C[O-].[Na+]>CO.ClCCl.CO>[O:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C@H:6]1[O:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OCc2ccccc2)OC[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O[C@@H]1[C@@H](OCc2ccccc2)OC[C@@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A suspension of compound 3 (20 g) in dry methanol:dichloromethane (2:1, 400 ml) containing sodium methoxide in methanol (0.46 g. Na in 100 ml of methanol) was stirred at room temperature until starting product disappeared (tlc). The solution was then made neutral with mixed-bed resin (50 ml, BioRad AG501-X8), filtered and evaporated to dryness to give 4 (10.2 g, 76%).
Reaction SMILES: CC1(C)COC([C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:40]3[CH:45]=[CH:44]C=[CH:42][CH:41]=3)([O:30][CH2:31][CH2:32][O:33]C3CCCCO3)[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][O:23]C4CCCCO4)[CH:15]=3)=[CH:9][CH:8]=2)=N1.[OH-].[Na+].CCO.[C:52]([OH:55])(=[O:54])[CH3:53]>>[OH:33][CH2:32][CH2:31][O:30][C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][OH:23])[CH:15]=1)([C:10]1[CH:9]=[CH:8][CH:7]=[CH:12][CH:11]=1)[C:40]1[CH:45]=[CH:44][C:53]([C:52]([OH:55])=[O:54])=[CH:42][CH:41]=1
Reactant: CC(=O)O
Reactant: CC1(C)COC(c2ccc(C(OCCOC3CCCCO3)(c3ccccc3)c3cccc(OCCOC4CCCCO4)c3)cc2)=N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C(OCCO)(c2ccccc2)c2cccc(OCCO)c2)cc1

Procedure:
A solution of 4 (360 mg) in 3 mL of 80% aqueous acetic acid was heated at 75° C. for 12 h. Then the solution was evaporated and the residue obtained was refluxed with 20% NaOH/EtOH (1:1, v/v, 3 mL) for 2 h. The solvent was removed and 10 mL of ice cooled water was added to the residue and the aqueous solution was acidified with 1N HCl. The precipitated yellow solid was filtered and washed several times with water and dried under high vacuum. Yield: 270 mg (100%, quantitative).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][CH:6]=1.C(Cl)(Cl)Cl.BrBr.C(=O)([O-])[O-:17].[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.[W]>[CH:1]([C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][CH:6]=1)=[O:17]
Reactant: Cc1ccc(C(=O)O)s1
Reactant: O=C([O-])[O-]
Agent: [W]
Agent: BrBr
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1ccc(C(=O)O)s1

Procedure:
2-Methyl thiophen-5-carboxylic acid was dissolved in carbon tetrachloride (150 ml.) and chloroform (10 ml.) and AZDN (0.5g.) was added. The mixture was refluxed over a 150 watt tungsten spotlight. Two molar equivalents of bromine as a 30% v/v solution in carbon tetrachloride were slowly added. A precipitate was formed but the mixture continued to take up bromine. After the addition of the two molar equivalents, solvent was boiled off until the volume was 100 ml. and the product treated with sodium carbonate solution with gentle heating for two hours to obtain 2-formyl thiophen-5-carboxylic acid in the form of a yellow solid after acidification, extraction and removal of the solvent.
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH:14]2[CH:10]([C:11]([CH3:27])([CH3:26])[N:12]([CH3:25])[CH:13]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu][C:30]#[N:31]>CN(C=O)C>[CH2:1]([N:8]1[C:9](=[O:28])[CH:10]2[C:11]([CH3:27])([CH3:26])[N:12]([CH3:25])[CH:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:30]#[N:31])=[CH:20][CH:19]=3)[CH:14]2[C:15]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1C(Cc2ccc(Br)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C2C1(C)C
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CN1C(Cc2ccc(C#N)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C2C1(C)C
Yield: 63 %

Procedure:
3.45 g (7.82 mmol) of (3aRS,4RS,6aSR)-2-benzyl-4-(4-bromobenzyl)-5,6,6-trimethyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione and 3.52 g (39.1 mmol) of copper(I) cyanide were suspended in 150 ml of DMF under argon and heated under reflux for 56 hours. After cooling about 100 ml of DMF were removed, then 150 ml of dichloromethane and 60 ml of concentrated aqueous ammonia solution were added. The mixture was stirred vigorously for a few hours. The blue aqueous phase was separated and the organic phase was washed twice with ammonia solution and once with water. The solvent was removed and the residue was purified chromatographically (hexane/ethyl acetate 1:1+1% triethylamine). 1.91 g of (1RS,3aSR,6aRS)-4-(5-benzyl-2,3,3-trimethyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-ylmethyl)-benzonitrile were isolated as a yellowish oil. FAB-MS: 775 ([2M+H]+, 1); 663 (2); 388 ([M+H]+, 58); 271 (100); 91 (42).
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:2]=[O:3].C(N(CC)C(C)C)(C)C.[CH2:51]([N:53]1[CH2:57][CH2:56][CH:55]([OH:58])[CH2:54]1)[CH3:52]>C(Cl)Cl>[CH2:51]([N:53]1[CH2:57][CH2:56][CH:55]([O:58][C:2](=[O:3])[NH:1][C:4]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]4[C:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[O:30][CH3:31])=[CH:22][NH:21][C:18]4=[N:19][CH:20]=3)=[CH:11][C:5]=2[C:6](=[O:7])[N:8]([CH3:9])[CH3:10])[CH2:54]1)[CH3:52]
Reactant: CCN1CCC(O)C1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N=C=O)c(C(=O)N(C)C)c3)cc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCC(OC(=O)Nc2ccc(-c3cnc4[nH]cc(-c5ccccc5OC)c4c3)cc2C(=O)N(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.4 %

Procedure:
2-Isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (125 mg, 0.22 mmol), N,N-diisopropylethylamine (0.06 mL, 0.34 mmol), 1-ethyl-pyrrolidin-3-ol (253 mg, 2.2 mmol), and methylene chloride (3 mL) were combined and stirred at room temperature for 18 hours. The reaction was concentrated to dryness in vacuo. The crude material was dissolved in a solution of tetrahydrofuran (4 mL) and methanol (1 mL). To the mixture was added 0.2 mL 50% w/v aqueous potassium hydroxide and the combined mixture stirred for 30 minutes. The reaction was quenched with saturated sodium bicarbonate, and the mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate and concentrated to dryness in vacuo. The crude material was purified by preparative HPLC to give 25 mg (47 μmol, 22%) of {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-carbamic acid 1-ethyl-pyrrolidin-3-yl ester. 1H-NMR (250 MHz, CDCl3) δ 11.93 (s, 1H), 9.10 (s, 1H), 8.64 (d, J=1.9 Hz, 1H), 8.16 (d, J=2.1 Hz, 1H), 7.75-7.54 (m, 5H), 7.30 (t, J=7.1 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 5.10-5.02 (m, 1H), 3.82 (s, 3H), 2.97 (s, 3H), 2.93 (s, 3H), 2.77-2.24 (m, 7H), 1.80-1.72 (m, 1H), 1.03 (t, J=7.2 Hz, 3H); MS: m/z 528.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[C:15](Cl)(=[O:17])[CH3:16]>>[C:15]([NH:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1)(=[O:17])[CH3:16]
Reactant: Nc1ccc2sc3ccccc3c2c1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccc2sc3ccccc3c2c1

Procedure:
The title compound was prepared following the procedure of Example 2 using 2-aminodibenzthiophene (Bull. Soc. Chim. Fr. (1996), 133(6), 597-610) and acetyl chloride. NMR: 10.13 (brs, 1H), 8.6 (d, 1H), 8.15 (m, 1H), 8.0 (m, 1H), 7.9 (d, 1H), 7.6 (dd, 1H), 7.5 (m, 2H), 2.1 (s, 3H); m/z 242.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:19])[C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1)=[O:11].I[CH3:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:19])[C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:21])[CH:17]=1)=[O:11]
Reactant: CC(C(=O)c1ccc(=O)[nH]c1)c1ccc(Cl)cc1Cl
Reactant: CI
Product: CC(C(=O)c1ccc(=O)n(C)c1)c1ccc(Cl)cc1Cl

Procedure:
In analogy to Example 195, 5-[2-(2,4-dichloro-phenyl)-propionyl]-1H-pyridin-2-one was alkylated with iodomethane to give the title compound as a colorless oil. MS (m/e)=310.1 [M+H+].
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.CC([O-])(C)C.[K+].CS(C)=O.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[C:39]3[C:34](=[CH:35][C:36](F)=[CH:37][CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:6][CH:4]4[CH2:5][NH:2][CH2:3]4)=[CH:37][CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: OC1CNC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OC4CNC4)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106 %

Procedure:
A mixture of Azetidin-3-ol hydrochloride (Oakwood) (461 mg, 4.21 mmol), KOtBu (1.02 g, 9.11 mmol), and dry DMSO (4.2 mL) was stirred at rt for 30 min until a translucent solution resulted. Then 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.46 g, 4.41 mmol), as prepared in Example 65b, was added, and the resulting opaque orange mixture (no visible precipitate) was stirred at rt for 3.5 hr. The reaction was then shaken with water (40 mL) and extracted with DCM (1×20 mL) and 9:1 DCM/MeOH (1×20 mL). The combined organic layers were washed with 0.2 M K2CO3 (3×20 mL), dried (Na2SO4), and concentrated to give 1.715 g of the title compound as an off-white solid (“106%” crude yield). LC/MS (ESI): calcd mass 384.2, found 385.3 (MH)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][C:19]#[N:20])[CH3:15]>CN(C=O)C>[C:19]([C:18]1([C:17]([O:16][CH2:14][CH3:15])=[O:21])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)#[N:20]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C#N)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (30.4 g, 0.220 mol) and 1,5-dibromopentane (13.6 mL, 0.100 mol) were sequentially added to a solution of ethylcyanoacetate (10.6 mL, 0.100 mol) in DMF (100 mL), and the reaction was stirred overnight at ambient temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic fraction was separated, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide ethyl 1-cyanocyclohexanecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([N:12]1[CH2:16][CH:15]([NH:17]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:14][O:13]1)=[O:11].C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CO>C(#N)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([N:12]1[CH2:16][CH:15]([NH2:17])[CH2:14][O:13]1)=[O:11]
Reactant: COC(=O)c1ccccc1C(=O)N1CC(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CO1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1ccccc1C(=O)N1CC(N)CO1
Reaction time: 8 h
Yield: 73.9 %

Procedure:
A solution of 2-[4-(2-Nitro-benzenesulfonylamino)-isoxazolidine-2-carbonyl]-benzoic acid methyl ester (200 mg, 0.46 mmol) and PhSH (0.035 ml, 1.1 equiv) in acetonitrile (2.3 ml) under argon at rt was treated with K2CO3 (95 mg, 1.5 equiv). The reaction mixture turned bright yellow. The reaction was left to stir overnight. As TLC indicated complete consumption of starting material, volatiles were removed in vacuo. Flash column chromatography eluting with dichloromethane:methanol (9/1) afforded 85 mg of the expected amine (0.34 mmol, 74%). LCMS (Method E) 0.55 and 1.41 min, M+H 251. 1H-NMR (CDCl3, 400 MHz): 7.95 (d, 1H), 7.63-7.52 (m, 1H), 7.51-7.36 (m, 2H), 4.17-3.92 (m, 3H), 3.87 (s, 3H), 3.80-3.55 (m, 2H), 2.04-1.75 (m, 2H).