Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[N:3]=1.F[P-](F)(F)(F)(F)F.N1([O+]=C(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[C:41]([O:45][C:46](=[O:55])[C@H:47]([NH2:54])[CH2:48][O:49][C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:44])([CH3:43])[CH3:42].C(N(C(C)C)C(C)C)C>ClCCl>[C:41]([O:45][C:46](=[O:55])[C@H:47]([NH:54][C:13]([C:4]1[N:3]=[C:2]([Cl:1])[C:11]2[C:6]([C:5]=1[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:15])[CH2:48][O:49][C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC[C@@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1nc(Cl)c2ccccc2c1O
Agent: CN(C)C(=[O+]n1nnc2ccccc21)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC[C@@H](NC(=O)c1nc(Cl)c2ccccc2c1O)C(=O)OC(C)(C)C
Reaction time: 40 h
Yield: 31.9 %

Procedure:
To a mixture of 45 mg (0.2 mmol) of 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 76 mg (0.2 mmol) of benzotriazol-1-yl-(bis-dimethylamino-methylene)-oxonium hexafluoro phosphate (HBTU), 50.8 mg (R)-2-amino-3-tert-butoxy-propionic acid tert-butyl ester hydrochloride (0.2 mmol), and 1 ml of dichloromethane was added 122.5 μl (0.7 mmol) of ethyl-diisopropyl-amine with stirring. Stirring was continued at ambient temperature for 40 h. The product was isolated from the reaction mixture by flash column chromatography on silica gel using hexanes:ethyl acetate (9:1) as the eluent to give a colorless oil. 27 mg of the title compound was obtained; MS-(+)-ion: M+1=422.8 amu.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1.[OH:14][CH:15]([CH3:19])[C:16](=[O:18])[CH3:17].N1C=CC=CC=1.CCN=C=NCCCN(C)C.Cl.Cl>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:19][CH:15]([O:14][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:12][CH:11]=1)[C:16](=[O:18])[CH3:17]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(=O)C(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)OC(C)C(C)=O)cc1

Procedure:
A mixture of terphthalic acid monomethyl ester (1.0 g, 5 mmol), 3-hydroxy-butane-2-one (0.531 g, 6.8 mmol), 4-dimethylamino pyridine (1.27 g, 10 mmol), pyridine (0.79 g, 10 mmol) and EDCl.HCl (1.6 g, 8 mmol) was stirred in dry DMF (10 mL) over night under nitrogen atmosphere. The reaction mixture was poured into ice cold water and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water (50 mL×2) and with brine, then dried over anhydrous sodium sulphate and concentrated. the obtained residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:23])([CH3:24])[C:17]=3[CH:25]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2ccc(OCCSc3ccc(Cl)c(Cl)c3)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[2-(3,4-dichlorophenylmercapto)-ethoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][S:27][CH:26]1[CH:30](C(OC(C)(C)C)=O)[NH2:31])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].FC(F)(F)C(O)=O.ClCCl.CO.N.BrCl>>[NH2:31][CH2:30][CH:26]1[N:25]([C:23]([C:22]2[CH:21]=[CH:20][C:4]([C:5]([NH:7][C@H:8]([C:10]3[NH:14][C:13]4[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=4[N:11]=3)[CH3:9])=[O:6])=[CH:3][C:2]=2[Br:1])=[O:24])[CH2:29][CH2:28][S:27]1
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCSC2C(N)C(=O)OC(C)(C)C)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClBr
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCSC2CN)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 58 %

Procedure:
Prepared analogously to Example 17 from 3-bromo-4-[(2R/S)-2-(tert-butoxycarbonyl-aminomethyl)thiazolidin-3-ylcarbonyl]-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]benzamide and trifluoroacetic acid. Yield: 58%; Rf value: 0.30 (silica gel: dichloromethane/methanol/ammonia=9:1:0.1); C21H21BrClN5O2S (522.853); mass spectrum: (M+H)+=522/524/526 (bromo-chlorine. isotope).
Reaction SMILES: ClC[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH3:13].[C-:14]#N.[Na+].[CH3:17][N:18](C)C=O>O>[CH3:14][C:4]1([CH2:13][C:17]#[N:18])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][CH2:3]1
Reactant: CN(C)C=O
Reactant: Cc1c(CCl)ccc2ccccc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Product: CC1(CC#N)CC=Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6.0 g of 2-chloromethyl-1-methylnaphthalene, 3.0 g of sodium cyanide and 75 ml of dimethylformamide was stirred for two hours at room temperature. Water (150 ml) was then added and stirring continued for one hour longer. The solid which had separated was collected by filtration and dried to give 5.0 g of 1-methylnaphthaleneacetonitrile as a pale tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:20][CH3:21])=[C:11]([CH:13]3[C:17](=[O:18])[CH2:16][CH2:15][C:14]3=[O:19])[N:12]=2)=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]3[C:17](=[O:18])[CH2:16][CH2:15][C:14]=3[O:19][CH3:22])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)CCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC)CCC1=O
Temperature: 40 °C
Yield: 58.3 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-ethyl-thiazol-4-yl]-cyclopentane-1,3-dione (650 mg, 2.03 mmol) in acetone (10 ml) was added potassium carbonate (553 mg, 4 mmol), followed by iodomethane (248 μl, 4 mmol), and the reaction heated to 40° C. for 6 hours. The solvent was then removed from the crude reaction mixture under reduced pressure and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, dry loaded onto silica and purified by flash chromatography to give 2-[2-(4-Chloro-phenyl)-5-ethyl-thiazol-4-yl]-3-methoxy-cyclopent-2-enone (395 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)C.[NH2:15][NH2:16].C(Cl)(Cl)=[O:18]>>[O:18]=[C:1]1[NH:16][N:15]=[C:4]([C:6]2[CH2:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:3]1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)C1=Cc2ccccc2C1
Reactant: NN
Product: O=c1[nH]nc(C2=Cc3ccccc3C2)o1

Procedure:
In the same way as above, ethyl-indene-2-carboxylate was reacted with hydrazine and phosgene to give 2-(2-oxo-3H-1,3,4-oxadiazole-5-yl)indene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]=1[NH2:12])[CH3:2].[C:14](Cl)(=O)[CH3:15].CCN(CC)CC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[O:11][C:14]([CH3:15])=[N:12][C:6]=12)=[O:13])[CH3:2]
Reactant: CCOC(=O)c1cccc(O)c1N
Reactant: CC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc2oc(C)nc12
Temperature: 25 °C

Procedure:
A mixture of 2-amino-3-hydroxy-benzoic acid ethyl ester (5.52 mmol; J. Reisch, G. M. K. B. Gunaherath Monatshefte für Chemie, 1988, 119, 1169-1178), acetyl chloride (6.07 mmol), NEt3 (6.07 mmo) and pyridinium p-toluenesulfonate (1.47 mmol) in xylene (60 mL) is heated at reflux for 16 h, cooled to rt, diluted with EtOAc and washed with water. The organic layer is dried over MgSO4 and concentrated in vacuo to give a crude product which is purified by flash chromatography (gradient: heptane to heptane/EtOAc 6/4). LC-MS: tR=0.81 min; [M+H]+=206.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][Li].Cl>O1CCCC1>[CH3:9][C:8]([CH3:11])([OH:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: CC(=O)c1ccccc1O
Reactant: [Li]C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccccc1O
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A solution of 10.0 ml (11.31 g, 83.1 mmol) of 2′-hydroxyacetophenone and 50 ml of tetrahydrofuran was placed in an ice bath and treated with 120.0 ml (168.0 mmol) of 1.4M methyllithium in tetrahydrofuran, which was added dropwise over 30 minutes. The reaction mixture first became cloudy and then cleared up. After stirring for 18 hours, the solution was acidified with 4% aqueous hydrochloric acid. The layers were separated. The organic phase was washed with 30 ml of brine, dried over sodium sulfate, and concentrated. A total of 12.05 g of 2-(dimethylhydroxymethyl)phenol was isolated.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]#N)=[CH:6][CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:12].[OH2:16]>>[Cl:1][C:2]1[C:7]([CH2:8][C:9]([OH:12])=[O:16])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: N#CCc1cccnc1Cl
Reactant: O=S(=O)(O)O
Reactant: O
Product: O=C(O)Cc1cccnc1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of the compound (11.7 g) obtained in step 3 in water (66 mL) was added concentrated sulfuric acid (55.6 mL) at 0° C., and the mixture was stirred at 90° C. for 4 hr. The reaction mixture was poured into ice-cold water, and the precipitate was filtered off. The filtrate was extracted three times with ethyl acetate. The organic layer was washed with brine, and concentrated to give (2-chloropyridin-3-yl)acetic acid (10.5 g, 80%) as a white powder.
Reaction SMILES: Cl[C:2]([CH:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4]#[N:5].[OH-].[NH4+:12]>C(O)C>[NH2:12][C:2]([CH:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4]#[N:5]
Reactant: [NH4+]
Reactant: CC(C)C(Cl)=C(C#N)C#N
Agent: [OH-]
Solvent: CCO
Product: CC(C)C(N)=C(C#N)C#N
Temperature: 0 °C
Reaction time: 1.3 h

Procedure:
A solution of 191.3 g of 3-chloro-2-cyano-4-methyl- 2-pentenenitrile in 300 ml of ethanol was added slowly, maintaining the temperature below 40°, during 1.3 hours, to a mixture of 800 ml of concentrated ammonium hydroxide and 1000 ml of ethanol. The mixture was stirred for 3 hours, then poured over 2000 ml of ice. The solid was collected, washed with water and dried to obtain 122.0 g of 3-amino-2-cyano-4-methyl-2-pentenenitrile, mp 186°-188°.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8]C(C#N)=[C:4]([Cl:10])[C:3]=1[F:11].[OH-:12].[Na+].[CH2:14]([OH:16])[CH3:15].Cl>C(OCC)(=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:15]([C:14]([OH:12])=[O:16])=[C:4]([Cl:10])[C:3]=1[F:11]
Reactant: N#Cc1ccc(N)c(F)c1Cl
Reactant: CCO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)O)c(Cl)c1F
Temperature: 25 °C

Procedure:
4-Amino-2-chloro-3-fluorobenzonitrile (500 mg, 2.93 mmol) and sodium hydroxide (4M, 18 mL) were mixed with ethanol (8 mL) and heated to reflux for 18 hours. After this time the mixture was allowed to cool to room temperature and 1M hydrochloric acid was added until pH 1 was achieved. Ethyl acetate was added and the organic layer was separated and washed with water and brine. The organic phase was dried with sodium sulfate, filtered and concentrated under vacuum to give the title compound (500 mg),
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH2:12][CH2:13][C:14]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]2[C:15]=1[N:16]=[C:17]([O:29][CH3:30])[C:18]([O:27][CH3:28])=[N:19]2>COC(C)(C)C>[CH3:28][O:27][C:18]1[C:17]([O:29][CH3:30])=[N:16][C:15]2[C:20](=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:14]=2[CH2:13][NH:12][C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:11])[N:19]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN)c2nc1OC
Solvent: COC(C)(C)C
Product: COc1ccc(NC(=O)NCc2cc([N+](=O)[O-])cc3nc(OC)c(OC)nc23)cc1
Reaction time: 3 h

Procedure:
62 mg (0.416 mmol) of 4-methoxyphenyl isocyanate are added at room temperature to a suspension of 100 mg (0.379 mmol) of 5-aminomethyl-2,3-dimethoxy-7-nitro-quinoxaline in 2 ml of tert-butyl methyl ether, and the mixture is stirred for 3 hours. The suspension is then filtered off, and the filter residue is washed with tert-butyl methyl ether and dried under a high vacuum. The title compound is obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1>CN(C=O)C.O.CCOC(C)=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[N:19][CH:20]=1)([O-:26])=[O:25]
Reactant: CN(C)CCO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.2 %

Procedure:
To a solution of 2-(dimethylamino)ethanol (339 mg, 3.80 mmol) in DMF (5 mL) was added sodium bis(trimethylsilyl)amide (4.75 mL, 1M solution in THF, 4.75 mmol). The mixture was stirred at room temperature for 15 min. 2-Chloro-5-nitropyridine (500 mg, 3.16 mmol) was then added. The vial was capped and subjected to microwave irradiation (150° C. for 10 minutes). The mixture was diluted with water (250 mL) and EtOAc (250 mL). The two layers were separated, and the aqueous layer extracted two more times with EtOAc. The organic extracts were combined, washed with water and brine, dried over sodium sulfate and evaporated to give the crude material as brown oil. Purification by column chromatography on silica gel using 5% methanol/methylene chloride yielded 2-(5-nitropyridin-2-yloxy)-N,N-dimethylethanamine as a light yellow solid (295 mg, 44%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([O-:10])=[O:9].C1(C)C(S([CH2:20][N+:21]#[C-:22])(=O)=O)=CC=CC=1.[H-].[Na+].[CH2:26](OCC)[CH3:27]>CS(C)=O>[CH2:26]([O:9][C:8]([C:7]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:22][NH:21][CH:20]=1)=[O:10])[CH3:27]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: O=C([O-])C=Cc1cccs1
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c[nH]cc1-c1cccs1
Reaction time: 3 h
Yield: 42 %

Procedure:
A solution of ethyl (3-(2-thienyl)prop-2-enoate (2.50 g, 13.70 mmol) and toluenesulfonylmethyl isocyanide (2.90 g, 14.90 mmol) in dimethylsulfoxide:diethyl ether (12.50 mL:20 mL) was added drop wise over a period of 15 min to a stirred solution of 60% sodium hydride in mineral oil (760 mg, 18.30 mmol) in diethyl ether (20 mL) at 10° C. Stirring was continued for 3 h at room temperature and the reaction mixture was quenched with saturated ammonium chloride solution and extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound which was purified by column chromatography over silica gel (100-200 mesh) using 18% ethyl acetate in pet ether as eluent to afford 4-thiophene-2-yl-1H-pyrrole-3-carboxylic acid ethyl ester (100 mg, 42%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)(C)N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NC(C)(C)C)cc1Br
Reaction time: 2 h
Yield: 77 %

Procedure:
3-Bromo-4-methoxyphenylsulfonyl chloride (2.80 g, 9.8 mmol) was dissolved in dichloromethane (30 mL) and the solution was treated with triethylamine (1.76 mL, 12.6 mmol), followed by the dropwise addition of t-butylamine (1.33 mL, 12.6 mmol). The mixture was allowed to stand for 2 hours and then was poured onto a mixture of 5% citric acid solution and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layers were dried and concentrated. Crystallization of the crude solid from ethyl acetate/hexane gave 3-bromo-N-tert-butyl-4-methoxybenzenesulfonamide (2.43 g, 77%).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([C@H:13]3[CH2:16][C@H:15]([CH2:17][OH:18])[CH2:14]3)[C:5]=2[N:6]=[CH:7][N:8]=1.C(=O)=O.CC(C)=O>O1CCOCC1.CC(O)C>[NH2:1][C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([C@H:13]3[CH2:16][C@H:15]([CH2:17][OH:18])[CH2:14]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: N
Reactant: OC[C@H]1C[C@H](n2cc(I)c3c(Cl)ncnc32)C1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Nc1ncnc2c1c(I)cn2[C@H]1C[C@H](CO)C1
Temperature: 90 °C

Procedure:
Gaseous ammonia (from a lecture bottle) was condensed into a suspension of trans-[3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol (172.6 mg, 0.475 mmol) in dioxane (3 mL) and iPrOH (3 mL) in a sealable glass tube, cooled by dry ice/acetone, until the volume increased by ≈2 mL, then the tube was sealed and heated to 90° C. overnight. The solvents were evaporated, water was added to the residue, and the pale yellow solid was filtered off and dried in vacuo to give the title compound as a pale yellow solid. The compound was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 2.41-2.52 (m, 2H), 2.52-2.64 (m, 3H), 3.83 (d, J=6.3 Hz, 2H), 5.30-5.40 (mc, 1H), 5.60 (brs, 2H), 7.29 (s, 1H), 8.26 (s, 1H). MS (ES+): m/z 345.1 (100) [MH+]. HPLC: tR=1.9 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1](=O)([O-])[O-:2].[Ni+2].[Ni:6](Cl)Cl.[H][H].[C]=O>>[C-:1]#[O+:2].[C-:1]#[O+:2].[C-:1]#[O+:2].[C-:1]#[O+:2].[Ni:6]
Reactant: Cl[Ni]Cl
Reactant: [H][H]
Reactant: O=C([O-])[O-]
Agent: [Ni+2]
Agent: [C]=O
Product: [C-]#[O+]
Product: [Ni]
Temperature: 40 °C

Procedure:
300.1 g of a nickel carbonate/nickel chloride mixture (10:1 w/w) was placed into an extraction reactor and treated with hydrogen (2 L/min) at 450° C. for 6 hours. Subsequently, the hydrogen was replaced with argon, the reactor cooled to 40° C. and the argon replaced with carbon monoxide at a gas temperature of 80° C., and flow rate of 4 L/min. whereby nickel carbonyl was formed, collected and subsequently decomposed to Ni and CO to provide (103 g; 70%) yield of nickel extraction yield in 6 hr.
Reaction SMILES: C1([CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])CCCCC1.C(N1[CH:41]=[CH:40]N=C1)(N1C=CN=C1)=O.Cl.[CH3:43][N:44]([CH3:46])O>C(Cl)Cl>[CH3:43][N:44]([CH3:46])[O:11][C:9](=[O:10])[C:8]([CH:41]1[CH2:40][CH2:13][CH2:12][CH2:8][CH2:7]1)([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[CH:16][CH:17]=1)[CH3:7]
Reactant: CN(C)O
Reactant: O=C(O)C(CC1CCCCC1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)OC(=O)C(C)(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 171.1 %

Procedure:
To a solution of 3-cyclohexyl-2-[4-(quinolin-2-yl-methoxy)phenyl]-propionic acid (389 mg, 1 mmol) in methylene chloride (10 mL) was added 1,1'-carbonyldiimidazole (162 mg, 1 mmol). The mixture was stirred at ambient temperature for 15 minutes and then N,N-dimethylhydroxylamine hydrochloride (147 mg, 1.5 mmol) was added. The resulting mixture was stirred at ambient temperature for an additional 20 minutes and then partitioned between ethyl acetate (50 mL) and saturated NaHCO3 (5 mL). The organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. Purification on a silica gel column eluting with 2:1 CH2Cl2 -EtOAc afforded 370 mg (86%) of the title compound. m.p. 98°-99° C. 1H NMR (DMSO-d6, 300 MHz) δ 0.9 (m, 2H), 1.1 (m, 4H), 1.63 (m, 6H), 1.8 m (m, 1H), 2.6 (s, 6H), 3.7 (t, J=7Hz, 1H), 5.35 (s, 2H), 7.04 (d, J=9Hz, 2H), 7.23 (d, J=9Hz, 2H), 7.62 (m, 1H), 7.68 (d, J =8Hz, 1H), 7.8 (m, 1H), 8.0 (t, J=8Hz, 2H), 8.42 (d, J=8Hz, 1H). IR (CDCl3): 1750,1600 cm-1. MS (DCI/NH3) m/e 433 (M+H)+. Analysis calcd for C27H32N2O3 : C, 74.97; H, 7.46; N, 6.48. Found: C, 74.81; H, 7.47; N, 6.41.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[OH:14])[CH3:2].[H][H].C([O-])=O.[NH4+]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:6]=1[OH:14])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)c1cccc(N)c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
To a solution of 2-hydroxy-3-nitrobenzoic acid ethyl ester 8.4 g (40 mmol) of step 1 in methanol 100 mL was added 5% Pd/C 0.84 g, after which the reactor was filled hydrogen gas, followed by stirring at room temperature for 5 hrs. Ammoniumformate 0.5 g was added to the reaction mixture before re-filling with hydrogen gas and re-stirring at room temperature for 24 hrs. The catalyst was removed by celite filtration, followed by vacuum concentration to afford the title compound 7.2 g (yield 99%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22](I)[CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:27][C:28]([OH:32])([C:30]#[CH:31])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C(NC(C)C)(C)C.[Cu](I)I>[NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:31]#[C:30][C:28]([OH:32])([CH3:29])[CH3:27])[CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3cccc(I)c3)n2)s1
Reactant: C#CC(C)(C)O
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cccc(Nc2nccc(-c3sc(N)nc3-c3ccccc3)n2)c1

Procedure:
A suspension of N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-iodo-phenyl)-amine (300 mg, 0.64 mmol) and 2-methyl-3-butyn-2-ol (110 mg, 1.3 mmol) in dimethylformamide (20 ml) and diisopropylamine (5 ml) are stirred in the presence of bis triphenylphosphine palladiumdichloride (20 mg), triphenylphosphine (20 mg) and copper iodide under a nitrogen atmosphere for 16 hours. After an aqueous work-up the residue is purified by chromatography (eluent: 1:2 mixture of ethyl acetate/hexane) to give the N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-[3-(3-hydroxy-3-methyl-1-butynyl)-phenyl]-amine, m.p. 262–263° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH:13]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([CH2:32][CH3:33])[CH:19]=3)[CH3:17])[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:34]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[CH3:29][C:27]([CH3:28])([CH3:30])[C:26](=[O:31])[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH:16]([CH:13]([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:34][C:9]=3[CH:10]=2)[CH2:14][CH3:15])[CH3:17])=[CH:19][C:20]=1[CH2:32][CH3:33]
Reactant: CCc1cc(C(C)C(CC)c2cc3cc(C(=O)OC)ccc3o2)ccc1OCC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(C(C)C(CC)c2cc3cc(C(=O)O)ccc3o2)ccc1OCC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
A solution of 2-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-ethyl-phenyl]-ethylpropyl}-benzofuran-5-carboxylic acid methyl ester (1.64 g, 3.53 mmol) in methanol (5.0 mL) and THF (5.0 mL) is treated with NaOH (2.0 M, 10 mL). The resulting mixture is stirred at RT for 12 h. The mixture is concentrated and neutralized with HCl (5 N) until pH˜3, and extracted with EtOAc (3×30 mL). The organic layer is dried over Na2SO4, concentrated to afford the title compound (1.57 g, 99%).