Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.Cl>C(Cl)Cl>[CH3:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH2:10][C:11]([N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)=[O:13])[CH3:15]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CC(=O)N1CCOCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
3-(tert-Butoxycarbonylamino)-3-methylbutanoic acid (2.7 g, 12.4 mmol), HBTU (CAN 94790-37-1, 6.1 g, 16.1 mmol) and triethylamine (CAN 121-44-8, 2.5 g, 24.8 mmol) was added to a solution of morpholine (CAN 110-91-8, 2.2 g, 24.8 mmol) in methylene chloride (50 mL). The mixture was stirred overnight at room temperature. Aqueous hydrochloride (1 N, 50 mL) was added, and the mixture extracted with methylene chloride. The organic extracts were washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (silica gel, 50 g, eluting with 30% ethyl acetate in petroleum ether) to give the product (2.1 g, 59%); MS (EI): m/e 287.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:15]Br.O>C(Cl)(Cl)Cl>[Br:15][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:6][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: COC(=O)c1ccc(C)o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(C)o1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a solution of methyl 5-methyl-2-furancarboxylate (2.33 g, 16.29 mmol) and aluminum chloride (3.3 g, 24.75 mmol) in chloroform (50 ml) at room temperature was added Br2 (1.1 ml, 21.35 mmol). The resulting solution was stirred at room temperature in a 150 mL sealed tube reactor for 2 hours. Upon completion, the solution was cooled in an ice bath, H2O added and reaction partitioned between CHCl3/H2O. The organic layer was washed with NaHCO3 and then Na2S2O3. The organic layer was dried with Na2SO4, concentrated, adsorbed onto silica and purified via column chromatography (0-20% EtOAc/Hexanes) affording the title compound (2.13 g, 9.72 mmol, 60%): LC-MS (ES) m/z=221 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[F:26][CH:27]([F:51])[O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][N:33]=[C:32]2[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.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.[Cu]I>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:32]3[C:31]4[C:35](=[CH:36][CH:37]=[C:29]([O:28][CH:27]([F:26])[F:51])[CH:30]=4)[NH:34][N:33]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2ccc(OC(F)F)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 58.3 %

Procedure:
In a 25 mL round-bottomed flask, 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (220 mg, 515 μmol) and 5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazole (268 mg, 566 μmol.10) were dissolved in DMF (1.06 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (29.7 mg, 25.7 μmol) and CuI (19.6 mg, 103 μmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 2.5 h. The reaction mixture was concentrated under high vacuum and the residue was purified by chromatography (80 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 30 min) to give N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (159 mg, 300 μmol, 58.2%) as an off-white solid. MS (M+Na)+=553 (>90% purity); 1H NMR (CDCl3) δ: 10.74 (br. s., 1H), 9.29 (s, 1H), 8.42 (s, 1H), 8.36 (d, J=2.3 Hz, 1H), 8.09 (s, 1H), 7.64 (d, J=9.1 Hz, 1H), 7.40 (dd, J=8.9, 2.1 Hz, 1H), 6.57 (t, J=74.0 Hz, 1H), 5.76 (s, 2H), 3.56-3.70 (m, 2H), 1.67 (s, 9H), 0.92-1.04 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH:9]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: NS(=O)(=O)c1ccc2occc2c1
Reactant: Cc1ccc(N=C=O)cc1
Product: Cc1ccc(NC(=O)NS(=O)(=O)c2ccc3occc3c2)cc1
Yield: 33.8 %

Procedure:
The 5-benzofuransulfonamide (5.74 mmol) and 4-methylphenylisocyanate (5.74 mmol) were reacted as described in Method B above to obtain a solid. This residue was purified by reverse phase chromatography with 50% acetonitrile in water with 1% acetic acid on a C18 column to obtain 0.64 g of the title product as a solid. 1H NMR (CD3SOCD3): κ10.35 (bs, 1 H), 8.74 (s, 1 H), 8.38 (d, J =3 Hz, 1 H), 8.20 (d, J =3 Hz, 1 H), 7.96 (dd, J =3, 9 Hz, 1 H), 7.86 (d, J =9 Hz, 1 H), 7.22 (d, J =9 Hz, 2 H), 7.20 (d, J =3 Hz, 1 H), 7.06 (d, J =9 Hz, 2 H), 2.22 (s, 3 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]([NH:15]C(=O)OC(C)(C)C)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:24].O1CCOCC1>C(Cl)Cl>[ClH:24].[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(Cc2ccccc2)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H]1CCCCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
To a solution of (S)-tert-butyl 1-benzyl-2-oxoazepan-3-ylcarbamate (340 mg, 1.07 mmol) in DCM (5 mL) was added solution of 4 M HCl in dioxane (0.243 mL, 0.971 mmol) at rt under argon. The reaction was allowed to stir at rt for 5 hr. The reaction mixture was concentrated and dried under vacuum to give (S)-3-amino-1-benzylazepan-2-one hydrochloride (210 mg, 0.962 mmol, 99% yield) as a white solid. Anal. Calcd. for C13H18N2O m/z 218.3. found: 219.3 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([OH:15])=[O:14])([CH3:3])[CH3:2].[CH3:16]O>S(=O)(=O)(O)O>[CH:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([O:15][CH3:16])=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2[nH]nc(C(=O)O)c2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1n[nH]c2ccc(C(C)C)cc12

Procedure:
A mixture of 5-isopropyl-1H-indazole-3-carboxylic acid (1.44 g) and conc. sulphuric acid (2 drops) in methanol (20 ml) was stirred under reflux for 1 day. After removal of solvent by evaporation, the resulting residue was dissolved with ethyl acetate. The ethyl acetate extract was washed successively with aqueous sodium hydrogen carbonate solution, water, and brine, and was dried over magnesium sulfate, and concentrated under reduced pressure to give methyl 5-isopropyl-1H-indazole-3-carboxylate (1.39 g).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=1Br.[CH3:25]N(C=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C[Sn](C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.C(N(CC)CC)C>[CH3:1][N:2]([CH3:24])[C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14]1[C:15]([CH3:25])=[CH:16][C:17]([Cl:21])=[CH:18][C:19]=1[F:20]
Reactant: CN(C)C=O
Reactant: CCc1ccc(Nc2c(F)cc(Cl)cc2Br)c(CC(=O)N(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Sn](C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1ccc(Nc2c(C)cc(Cl)cc2F)c(CC(=O)N(C)C)c1

Procedure:
N,N-Dimethyl-5-ethyl-2-(2′-bromo-4′-chloro-6′-fluoroanilino)phenylacetamide (2.5 g, 6.0 mmol) is combined with DMF (10 ml), triethylamine (10 ml), tri-o-tolylphosphine (0.5 g, 1.6 mmol), tetramethyltin (4 ml, 5.16 g, 28.9 mmol) and palladium acetate (0.25 g, 1.1 mmol), and the mixture heated in a sealed tube for 3 days at 95°. The tube is allowed to cool and carefully opened. Water and ethyl acetate are added to the reaction and the mixture separated. The organic fraction is washed with a dilute NaCl solution (2×50 ml). The combined aqueous fractions are then washed with ethyl acetate and the combined organic fractions are then dried (magnesium sulfate). The material is absorbed onto a small amount of silica gel and purified by flash chromatography (on silica, ethyl acetate:hexanes, 1:4 to 1:1) to give N,N-dimethyl-5-ethyl-2-(4′-chloro-2′-fluoro-6′-methylanilino)phenylacetamide.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[O:18][C:19]([Br:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:32][C:33](=O)[NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]3=[O:47])=[CH:37][C:36]=2[F:48])=CC=1)([O-])=O>>[F:48][C:36]1[CH:37]=[C:38]([N:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]2=[O:47])[CH:39]=[CH:40][C:35]=1[NH:34][C:33]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[O:18][C:19]([Br:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:32]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NC[C@H]1CCNC1)c1ccc(Br)o1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1ccc(Br)o1

Procedure:
59.3 Using general method H, 5-bromo-furan-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(5-bromo-furan-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. White solid. MS 504.9 ([M+H]+)
Reaction SMILES: [Na].[O:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]#[N:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:18](OCCC(C)C)=[O:19].Cl>C(O)C>[OH:19][N:18]=[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:16]#[N:17]
Reactant: N#CCc1ccccc1Oc1ccccc1
Reactant: CC(C)CCON=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N#CC(=NO)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.1 %

Procedure:
To anhydrous ethanol (15 ml) was dissolved sodium (0.55 g, 0.024 mole) and a mixture of 2-phenoxyphenylacetonitrile (4.18 g, 0.02 mole) and anhydrous ethanol (3 ml) was added dropwise to the mixture below 0° C. over 7 minutes. isoamyl nitrite (3.51 g, 0.03 mole) was further added dropwise to the mixture below 0° C. over 10 minutes, followed by stirring at room temperature for 24 hours. After completion of the reaction, 5% hydrochloric acid was added to the reaction mixture, which was extracted with ether and dried over anhydrous magnesium sulfate. The crude product obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain α-hydroxyimino-2-phenoxyphenylacetonitrile (4.53 g, yield: 95.1%) as crystals having a low melting temperature.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH:15][C:16]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[N:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[N:24][CH:23]=4)[CH2:17][CH2:18]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: OC1(c2cncc3ccccc23)CCNCC1
Product: OC1(c2cncc3ccccc23)CCN(CCCOc2cccc3[nH]ccc23)CC1
Yield: 47.8 %

Procedure:
Beginning with 0.184 gm (0.88 mMol) 3-chloropropyl indol-4-yl ether and 0.200 gm (0.88 mMol) 4-hydroxy-4-(isoquinolin-4-yl)piperidine, 0.169 gm (48%) of the title compound were recovered as a light yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[CH:19]=1)(=[O:3])[CH3:2].[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1O)#[N:21].N1C=CC=CC=1>O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]([C:16]([O:18][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])=[O:17])=[CH:11][C:10]=2[CH:19]=1)(=[O:3])[CH3:2]
Reactant: N#Cc1ccccc1O
Reactant: CC(=O)OCc1ccc2oc(=O)c(C(=O)O)cc2c1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(=O)OCc1ccc2oc(=O)c(C(=O)Oc3ccccc3C#N)cc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the suspension of the acid chloride of 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid (4 mmol) obtained according to Pochet et al. (Bioorg. Med. Chem. 2000, 8, 1489) in anhydrous dioxane (10 mL) was added 2-cyanophenol (5 mmol) and pyridine (0.4 mL). After 12 h stirring at room temperature, the solvent was evaporated under vacuum and the residue was suspended in methanol. The resulting precipitate was collected by filtration, washed with methanol and dried. The solid was crystallyzed in ethyl acetate (40%); mp: 181-183° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.Cl[Sn:8]([CH3:11])([CH3:10])[CH3:9]>CCCCCC.C1COCC1>[CH3:1][N:2]1[C:6]([Sn:8]([CH3:11])([CH3:10])[CH3:9])=[CH:5][CH:4]=[N:3]1
Reactant: C[Sn](C)(C)Cl
Reactant: Cn1cccn1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1nccc1[Sn](C)(C)C
Temperature: 25 °C
Reaction time: 0.15 h
Yield: 100.4 %

Procedure:
Butylithium (2.5M in hexane, 9.75 ml, 24.4 mmol) was added to a stirred solution of 1-methylpyrazole (2.0 g. 24.4 mmol) in THF (30 ml) at -78° C. After 0.15 hours, a solution of chlorotrimethylstannane (4.85 g, 24.4 mmol) was added dropwise and the mixture allowed to warm to room temperature. The mixture was evaporated under reduced pressure and the residue partitioned between ether (50 ml) and water (50 ml). The ether layer was dried (MgSO4) and evaporated to yield the title compound as colourless oil (6.0 g, quantitative), which was characterised by 1H-NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]1=[O:9].CC(C)CC(O)C>[Ru]>[CH3:7][C:4]1([CH3:8])[CH:5]([OH:6])[C:2]([CH3:10])([CH3:1])[CH:3]1[OH:9]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Agent: [Ru]
Solvent: CC(C)CC(C)O
Product: CC1(C)C(O)C(C)(C)C1O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A 2 liter Parr autoclave was charged with 100 grams of 2,2,4,4-tetramethylcyclobutane-1,3-dione, 300 grams of 4-methyl-2-pentanol, and 50 grams of 2% ruthenium on alumina (surface area=10 m2/g, purchased from BASF Catalysts). The autoclave was pressure purged three times with nitrogen and three times with hydrogen, and the pressure was increased to 3.5 MPa (500 psig) with hydrogen. The autoclave was heated to 100° C. with stirring at approximately 1300 rpm and held for 6 hours at 3.5 MPa (500 psig). Analysis of the product by gas chromatography indicated that complete conversion of the 2,2,4,4-tetramethylcyclobutane-1,3-dione was obtained with 99.5% selectivity to 2,2,4,4-tetramethycyclobutane-1,3-diol with a cis:trans ratio of 1.54:1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([C:14]2[N:18]([CH3:19])[C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[C:9]([F:22])[CH:8]=1.Cl>N1C=CC=CC=1>[C:20]([C:17]1[N:18]([CH3:19])[C:14]([C:10]2[C:9]([F:22])=[CH:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][C:11]=2[F:13])=[CH:15][CH:16]=1)#[N:21]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1c(F)cc(N)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c(C#N)ccc1-c1c(F)cc(NS(C)(=O)=O)cc1F
Temperature: 50 °C
Yield: 44.9 %

Procedure:
A mixture of methanesulfonyl chloride (0.046 mL, 0.66 mmol) and 5-(4-amino-2,6-difluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.100 g, 0.429 mmol) in pyridine (1.5 mL) was heated to 50° C. for 4 hours. The reaction mixture was acidified with 1N HCl solution and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/acetone, 97/3) to afford the title compound (0.060 g, 45%).
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][C:6]#[N:7])[CH3:2].C([Li])CCC.[C:13]1([CH2:23][CH2:24][CH2:25]I)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(Cl)Cl>O1CCCC1>[CH2:1]([O:3][CH:4]=[C:5]([C:6]#[N:7])[CH2:25][CH2:24][CH2:23][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCOC=CC#N
Reactant: ICCCc1cccc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC=C(C#N)CCCc1cccc2ccccc12
Temperature: 25 °C
Yield: 26.9 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 1.5 mL (0.014 mole) of 3-ethoxyacrylonitrile in 45 mL of tetrahydrofuran was cooled to about -110° C., and 6.2 mL (0.015 mole) of 2.5M n- butyllithium in hexanes was added dropwise at a rate to keep the reaction mixture temperature below -65° C. Upon completion of addition, the reaction mixture was stirred for about ten minutes, and then a solution of 4.0 grams (0.014 mole) of 3-(naphth-1-yl)propyl iodide in 15 mL of tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was stirred at about -78° C. for two hours. After this time the reaction mixture was allowed to warm to ambient temperature as it stirred for about 16 hours. The reaction mixture was concentrated under reduced pressure, yielding a dark residual oil. The oil was passed through a short column of silica gel using methylene chloride as the eluant. The eluate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 2:1 methylene chloride and petroleum ether. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.0 gram of 1-ethoxy-2-cyano-5-(naphth-1-yl)-1-pentene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][N:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)=[CH:32][CH:31]=1)[OH:29]>C(Cl)Cl>[CH3:22][N:23]1[CH:27]=[CH:26][N:25]=[C:24]1[C:28]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)=[CH:34][CH:35]=1)=[O:29]
Reactant: Cn1ccnc1C(O)c1ccc(OC2CCCCO2)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cn1ccnc1C(=O)c1ccc(OC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 76.9 %

Procedure:
Pyridinium dichromate (36 g, 95.7 mmol) was added to a solution of 9.1 (21 g, 72.7 mmol) in DCM (100 mL) at 0° C. in several portions. The mixture was stirred at 0° C. for 1 hour and at room temperature for 6 hours. Silica gel (75 g) was added to the reaction mixture, and the resulting slurry was filtered through a pad of silica gel. The solid was washed with DCM (200 mL). The filtrate was washed with water and saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give an oily residue, which was flash chromatographed (silica gel, 0-30% EtOAc in hexane) to afford ketone 9.2 as yellow solid (16 g). 1H NMR (500 MHz) (CDCl3) δ 8.33-8.35 (m, 2H); 7.10-7.29 (m, 4H); 5.56 (t, J=3.0 Hz, 1H); 4.08 (s, 3H); 3.85-3.90 (m, 1H); 3.61-3.65 (m, 1H); 2.03 (m, 1H); 1.90-1.91 (m, 2H); 1.69-1.74 (m, 2H); 1.61-1.64 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])[CH:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:3]=1
Reactant: CCOC(=O)CCCCNc1cc(C)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccnc(NCCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
Ethyl 5-[N-(4-methylpyridin-2-yl)amino]pentanoate (16.7 g, 70.7 mmol, obtainable in accordance with Example 3a)) was dissolved in methanol (20 ml), 2N aqueous NaOH (71 ml, 141 mmol) was added, and the mixture was stirred overnight at room temperature. The solvent was then removed, and the resultant solid was extracted thoroughly with CHCl3 (500 ml) and an excess of DIPEA. The filtrate was evaporated and dried, giving a colourless solid (3.92 g, 18.8 mmol, 27%).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:21]([C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32])(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:38][C:36]1[CH:37]=[C:29]2[C:30](=[CH:34][CH:35]=1)[C:31](=[O:32])[N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1)[C:4]([C:3](=[O:2])[CH2:17][CH2:18][CH2:19][CH3:20])=[C:21]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCC(O)CNCc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Product: CCCCC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1

Procedure:
In the same manner as in Example 452, Step 2, the title compound was synthesized from 4-[(2-hydroxyhexylamino)methyl]benzenesulfonamide hydrochloride and 2-benzoyl-4-chlorobenzoic acid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]([C:13]1[CH:17]=[C:16]([Cl:18])[S:15][C:14]=1Cl)(=[O:12])[CH3:11].O>CN(C=O)C.[Cu]I>[C:10]([C:13]1[CH:17]=[C:16]([Cl:18])[S:15][C:14]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1cc(Cl)sc1Cl
Reactant: Oc1ccccc1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Cl)sc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 66.9 %

Procedure:
A mixture of phenol (1.22 g, 13 mM) and NaH (60% oil dispersion, 0.52 g, 13 mM) in DMF (25 mL) was stirred for 40 minutes at room temperature. 3-Acetyl-2,5-dichlorothiophene (1.95 g, 10 mM) and copper (I) iodide (50 mg) was added to the above mixture, and the resulting mixture was heated at 130° C. for 1.5 hours. After cooling, the mixture was poured into water. The whole was extracted with ethyl acetate-hexane (1:1, 200 mL×1, 100 mL×1), and the combined organic layers washed with water, brine, dried over MgSO4, and concentrated in vacuo. Chromatographic purification eluting with ethyl acetate-hexane (1:20) provided the subtitle compound (1.69 g. 67% yield) as a brown oil.