Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[K+].[CH2:17](I)[CH3:18].Cl>CS(C)=O.O>[CH2:17]([O:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])[CH3:18]
Reactant: CCI
Reactant: CC(C)C(O)(C(=O)O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(C(=O)O)(c1ccccc1)C(C)C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 2-hydroxy-3-methyl-2-phenylbutanoic acid (Compound (5), 30.0 g) in dimethyl sulfoxide (250 ml) was added 85% powdered potassium hydroxide (60 g) and the mixed solution was stirred for one hour. Under ice cooling, ethyl iodide (55 ml) was added and the resulting mixture was stirred at room temperature for 3 days. After the addition of water (100 ml), the resulting mixture was stirred at 80° C. for 6 hours. The reaction mixture was acidified with 1N hydrochloric acid, followed by extraction with ether. The ether layer was dried over anhydrous sodium sulfate and removed under reduced pressure. To the residue, hexane (200 ml) was added. After the resulting mixture was allowed to stand overnight, the crystals so precipitated were removed by filtration. The filtrate was removed under reduced pressure to obtain the title compound (27.0 g, 78.7%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([CH3:11])[C:3]=1[CH:12]1[C:16](=[O:17])[CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14][C:13]1=[O:25].C(N(C(C)C)C(C)C)C.Cl[C:36]([S:38][CH:39]([CH3:41])[CH3:40])=[O:37]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:16](=[O:17])[CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14][C:13]=1[O:25][C:36]([S:38][CH:39]([CH3:41])[CH3:40])=[O:37]
Reactant: CC#Cc1cc(C)c(C2C(=O)CC(Cc3ccccn3)C2=O)c(C)c1
Reactant: CC(C)SC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC#Cc1cc(C)c(C2=C(OC(=O)SC(C)C)CC(Cc3ccccn3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
To a solution of the 2-(2,6-dimethyl-4-prop-1-ynyl-phenyl)-4-(2-pyridylmethyl)cyclopentane-1,3-dione (0.100 g, 0.302 mmol) in dichloromethane (3.02 mL) was added N-ethyl-N-isopropyl-propan-2-amine (1.51 mmol, 0.265 mL). The reaction was then cooled in the freezer for 30 minutes before addition of S-isopropyl chlorothioformate (0.075 ml, 0.603 mmol), and then the reaction mixture was stirred overnight at room temperature. The reaction was then washed with water, dried and reduced in vacuo. The crude product was then purified by column chromatography, eluting with acetonitrile and dichloromethane, to give the desired product (23 mg, 18%). The product was characterised by HPLC, as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[NH:10][N:9]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[NH:10][N:9]=1
Reactant: O=[N+]([O-])c1ccc2c(-c3ccccc3Cl)n[nH]c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(-c3ccccc3Cl)n[nH]c2c1
Yield: 28.5 %

Procedure:
3-(2-Chloro-phenyl)-6-nitro-1H-indazole (8.82 g, 32.23 mmol) was dissolved in 400 mL EtOH and 120 mL water, and the mixture was heated to 85° C. with stirring. After stirring for 40 minutes, Fe (9.0 g, 161.15 mmol) and NH4Cl (8.62 g, 161.15 mmol) were added, and the reaction mixture was stirred for 16 hours at 85° C. The reactuion mixture was filtered through Whatman filter paper, and the filtrate was concentrated under reduced pressure. The resulting residue was partitioned between water and ethyl acetate, and the organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel (hexanes/EtOAc 0-50%) to give 2.24 g of 3-(2-Chloro-phenyl)-1H-indazol-6-ylamine, MS (M+H)=245.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[C:11]([Cl:20])[CH:10]=2)[C:5]([F:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]2[O:30][CH:29]([C:31]([O:33][CH3:34])=[O:32])[CH2:28][C:27]=2[CH:35]=1>>[Cl:20][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:21])=[CH:4][N:3]=[C:2]([NH:22][C:23]3[CH:24]=[CH:25][C:26]4[O:30][CH:29]([C:31]([O:33][CH3:34])=[O:32])[CH2:28][C:27]=4[CH:35]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][C:16]([F:19])([F:18])[F:17]
Reactant: Fc1cnc(Cl)nc1Nc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC(F)(F)F)c(Cl)c4)n3)ccc2O1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamine and 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to produce N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.99 (bs, 1H), 9.49 (bs, 1H), 8.18 (d, 1H, J=4.5 Hz), 8.08 (t, 1H, J=2.4 Hz), 7.81-7.74 (m, 1H), 7.49 (d, 1H, J=8.1 Hz), 7.42 (s, 1H), 7.20 (d, 1H, J=8.1 Hz), 6.78 (d, 1H, J=8.7 Hz), 5.36 (m, 1H), 3.80-3.47 (m, 4H), 3.20 (dd, 1H, J=6.0 and 16.5 Hz); LCMS: purity: 100%; MS (m/e): 500 (MH+).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:34]=C[C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:20]([CH:30]([CH3:32])[CH3:31])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].C(S(C1C=CC(CN)=[N:44]C=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C@@H:20]([CH:30]([CH3:31])[CH3:32])[C:17]3=[N:18][CH:19]=2)=[O:13])=[N:44][CH:34]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(CN)nc1
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)nc1
Reaction time: 0.02 h

Procedure:
Procedure same as that for tert-butyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate, using (5-(ethylsulfonyl)pyridin-2-yl)methanamine as a starting material. LC-MS tR=0.86 min in 1 min chromatography, MS (ESI) m/z 489.4 [M+H]+. 1H NMR (CDCl3, 400 MHz, mixture of rotamers): δ 9.06 (s, 1H), 8.96 (s, 1H), 8.20 (dd, J=2.0 Hz, 8.4 Hz, 1H), 8.05 (d, J=7.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 4.99 (m, 2H), 4.90 (m, 2H), 4.80 (d, J=15.2 Hz, 1H), 4.51 (m, 1H), 3.17 (q, J=7.6 Hz, 2H), 2.63-2.54 (m, 0.5H), 2.48-2.39 (m, 0.5H), 1.52 (s, 9H), 1.33 (t, J=7.6 Hz, 3H), 1.10 (d, J=7.2 Hz, 1.5H), 1.01 (d, J=6.8 Hz, 1.5H), 0.78 (d, J=6.8 Hz, 1.5H), 0.73 (d, J=7.2 Hz, 1.5H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([NH:22][C:23]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1)=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: CCCCN=C=O
Product: CCCCNC(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1

Procedure:
2-Amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane and butyl isocyanate were treated in the same manner as in Example 29 to obtain 2-(butylcarbamoyl) amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:7][CH2:6]2.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:19][C:20]([F:28])([F:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:7][CH2:6]2
Reactant: Oc1ccccc1C(F)(F)F
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(CCl)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NC1CCc2cc(COc3ccccc3C(F)(F)F)ccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A mixture of N-(5-(chloromethyl)-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (30 mg, 0.104 mmol), 2-(trifluoromethyl)phenol (16.90 mg, 0.104 mmol), and potassium carbonate (28.8 mg, 0.208 mmol) in N,N-dimethylformamide (1 mL) was stirred at 60° C. overnight. The reaction mixture was partitioned between aq. sat. NaHCO3 (4 mL) and DCM (4 mL), filtered over a phase separator, and the organic phase was concentrated by blow down. Purification by flash chromatography (0-60% EtOAc in Heptane) and freeze drying from acetonitrile/water gave the title compound as a white solid (24 mg, 55.7%). MS (ESI): m/z [M−H]− 412.0.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:67]=[CH:66][C:37]([C:38]([O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64]O)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:36][CH:35]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([C:38]([O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:37]2[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:67][CH:66]=2)=[CH:44][CH:43]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COc1ccc(C(OCCOCCOCCOCCO)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(OCCOCCOCCOCCON2C(=O)c3ccccc3C2=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 81.8 %

Procedure:
N-hydroxyphthalimide (0.7 g, 4.3 mmol) and triphenylphosphine (1.1 g, 4.2 mmol) were added to a solution of 11-(4,4′-dimethoxytrityloxy)-3,6,9-trioxaundecanol (2.0 g, 4.0 mmol) in THF (60 mL). Diethylazodicarboxylate (DEAD, 0.7 mL, 3.6 mmol) was added dropwise and the stirring was continued overnight at ambient temperature. The reaction mixture was evaporated to an oil, applied onto a silica gel column, and eluted with a linear gradient from neat CH2Cl2 to a 97:3 (v/v) mixture of CH2Cl2 and MeOH. The purification was repeated to yield 2.1 g (80%) of the title compound.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[C:16](\[CH2:22][CH2:23][OH:24])/[C:17]([O:19]CC)=O)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.[OH-].[Na+]>C(O)C.O>[NH2:5][S:6]([C:9]1[CH:10]=[CH:11][C:12](/[C:15](=[C:16]2/[C:17](=[O:19])[O:24][CH2:23][CH2:22]/2)/[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[CH:13][CH:14]=1)(=[O:8])=[O:7]
Reactant: CCOC(=O)/C(CCO)=C(\c1ccc(F)cc1)c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(/C(=C2\CCOC2=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
Ethyl (E)-3-(4-t-butylaminosulphonylphenyl)-3-(4-fluorophenyl)-2-(2-hydroxyethyl)-2-propenoate (10 g), prepared in Example 59, is dissolved in 20 ml of ethanol, and a solution of 2 g of sodium hydroxide in 10 ml of water is added. The mixture is refluxed for 2 h. After evaporation to dryness, the residue is taken up with water, acidified with 1 N hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over magnesium sulphate and then evaporated under vacuum. The residue is added in portions to 500 ml of concentrated sulphuric acid. The mixture is stirred for 15 minutes at room temperature and then poured into iced water and the crystals formed are filtered off, washed with diethyl ether and then taken up with 100 ml of warm acetone. 50 ml of diethyl ether are added to the solution obtained and the crystals formed are filtered off and dried to give 6 g of (E)-3-[1-(4-aminosulphonylphenyl)-1-(4-fluorophenyl)methylidene]dihydrofuran-2-one in the form of crystals melting at 202° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:13])[C:6](=[O:12])[NH:7]2.[I:16]N1C(=O)CCC1=O>OS(O)(=O)=O>[I:16][C:9]1[CH:10]=[CH:11][C:3]([C:2]([F:1])([F:14])[F:15])=[C:4]2[C:8]=1[NH:7][C:6](=[O:12])[C:5]2=[O:13]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1Nc2cccc(C(F)(F)F)c2C1=O
Agent: O=S(=O)(O)O
Product: O=C1Nc2c(I)ccc(C(F)(F)F)c2C1=O
Temperature: 40 °C
Reaction time: 6 h
Yield: 41.5 %

Procedure:
A mixture of 4-trifluoromethylisatin (450 mg, 2.09 mmol) and N-iodosuccinimide (800 mg, 3.72 mmol) in conc. H2SO4 (5 mL) was stirred for 6 h at 40° C. and poured into crushed ice. The mixture was extracted with ethyl acetate and the extracts were washed with aqueous Na2SO3, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography with 3:1 hexane/ethyl acetate to give the title compound (296 mg, 42%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13](=[O:25])[NH:14][C:15]2[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:31][CH3:32].O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13](=[O:25])[N:14]([CH2:31][CH3:32])[C:15]2[CH:16]=[N:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(=O)Nc2ccc(C(F)(F)F)nc2)COC1(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCN(C(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccc(C(F)(F)F)nc1
Reaction time: 0.33 h
Yield: 70.5 %

Procedure:
To a stirred solution of (R)-2,2-dimethyl-4-(6-trifluoromethyl-pyridin-3-ylcarbamoyl)-oxazolidine-3-carboxylic acid tert-butyl ester (0.20 g, 0.51 mmol) in dimethylsulfoxide (4 ml) under an argon atmosphere was added sodium hydride (0.028 g, 0.59 mmol) and the mixture was stirred for 20 min. Iodoethane (0.05 ml, 0.61 mmol) was added and the mixture was stirred overnight at room temperature. Water (20 ml) was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4) and filtered. After removal of the solvent the residue was purified by column chromatography (SiO2, heptane/EtOAc=1:1) to yield a light yellow oil (0.15 g, 70%), MS (ISP): 418.2 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[N:26]=3)=[CH:21][CH:20]=2)[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:38]1([OH:43])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:38]1([O:43][C:2]2[N:3]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[N:26]=4)=[CH:21][CH:20]=3)[N:4]=[C:5]3[C:10]=2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]3[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Reactant: OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(OC3CCCC3)n(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Temperature: 150 °C

Procedure:
3-chloro-2-(4-(6-fluoropyridin-2-yl)benzyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (20 mg, 0.045 mmol), cesium carbonate (22 mg, 0.068 mmol) and cyclopentanol (0.3 mL) are placed in a Biotage microwave vial. The vial is sealed, and then heated in a Biotage microwave instrument at 150° C. for 4 h. The reaction mixture is purified with a semi-preparative HPLC to give 10.4 mg of pure product as pale yellow solids (Purity: 97.7%). MS (ESI) m/z 492.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([C:12](=[CH2:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[OH-:20].[Na+].OO.Cl>C1COCC1.O>[CH3:19][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][OH:20])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: C=C(CCCCC)c1ccc2c(c1)SCCC2(C)C
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(CO)c1ccc2c(c1)SCCC2(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4,4-dimethyl-7-(1-methylene-hexyl)-thiochroman (0.939 g, 3.42 mmole) in 15 mL of THF at 0° C., was treated with 3.42 mL of 1M BH3.THF complex. The reaction mixture was stirred at room temperature for three hours and then cooled to 0° C. The mixture was treated successively with 0.59 mL of water, 0.67 mL of 3M sodium hydroxide and 0.67 mL of 30% hydrogen peroxide. The reaction mixture was stirred at room temperature for two hours and then diluted with 20 mL of water. The pH was adjusted to 4.0 with 10% HCl and then extracted with three 25 mL portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow oil. The product was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to yield 0.532 g of 2-(4,4-dimethyl-thiochroman-7-yl)-heptan-1-ol as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH:11]1([C:14](Cl)=O)[CH2:13][CH2:12]1>O1CCOCC1.CN(C)C=O>[CH:11]1([C:14]2[N:1]=[C:2]3[N:3]=[C:4]([CH3:10])[CH:5]=[C:6]([OH:9])[N:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc(=O)n(N)c(N)n1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1cc(O)n2nc(C3CC3)nc2n1

Procedure:
To a solution of Intermediate 1 (0.5 g, 3.57 mmol) in a mixture of 1,4-dioxane (4 mL) and N,N-dimethylformamide (1 mL), cyclopropanecarbonyl chloride (ALDRICH, 0.49 mL, 5.35 mmol) was added and the resulting mixture was heated under reflux overnight. The reaction was then concentrated under vacuum yielding a pale yellow solid which was purified by flash chromatography (Si, eluting with DCM:MeOH mixtures, gradient from 100:0% to 90:10%) to yield a beige solid which was re-purified by flash chromatography (Si, eluting with DCM:MeOH mixtures from 100:0 to 85:15%). The title compound was obtained as a white solid.
Reaction SMILES: O=[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[C@@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C.Cl.[NH2:38][OH:39].C([O-])(=O)C.[Na+]>O>[N:38](=[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[C@@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:39]
Reactant: COc1ccccc1CN[C@H]1CCCN(CCCC(=O)c2ccccc2)[C@H]1c1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1CN[C@H]1CCCN(CCCC(=NO)c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Under a nitrogen atmosphere in a round bottom flask were placed 445 mg (1 mmol) of (2S,3S)-1-(4-oxo-4-phenylbut-1-yl)-3-(2methoxybenzylamino)-2-phenylpiperidine and 6 ml of ethanol. To the system were added 209 mg (3.2 mmol) of hydroxylamine hydrochloride and 417 mg (5 mmol) of sodium acetate in 6 ml of H2O, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and partitioned between chloroform and water. The layers were separated, and the aqueous phase was extracted two times with chloroform. The combined organic extracts were dried (sodium sulfate) and concentrated to 368 mg of gold oil. The crude product was purified by flash column chromatography using 7% in chloroform as the eluant to obtain 174 mg of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11]1>C1C=CC=CC=1>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:17])=[O:5]
Reactant: O=C1CCCC(=O)O1
Reactant: Nc1ccccc1C=O
Solvent: c1ccccc1
Product: O=Cc1ccccc1NC(=O)CCCC(=O)O
Yield: 91.9 %

Procedure:
2-aminobenzaldehyde (2.87 g) and glutaric anhydride (3.26 g) were dissolved in benzene (60 ml) and the mixture was heated to reflux for 10.5 hours. Benzene was removed and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1- ethyl acetate) to obtain 5.12 g of 4-(N-(2-formylphenyl)carbamoyl)butanoic acid. Yield: 93%.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[Cl:40][C:41]1[C:42]([F:50])=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[NH2:32][C:4]1[S:3][C:2]([C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([Cl:40])[C:42]=2[F:50])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1cccc(Cl)c1F
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(Cl)c3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-chloro-2-fluorophenyl)boronic acid gave 338. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.47-8.06 (m, 1H), 7.86 (s, 1H), 7.66-7.55 (m, 1H), 7.52 (s, 2H), 7.30 (t, J=8.1 Hz, 1H), 4.83 (dd, J=10.5, 3.6 Hz, 1H), 4.58-4.37 (m, 1H), 4.36-4.22 (m, 1H), 4.18-3.97 (m, 1H), 3.76 (s, 3H), 2.10-2.00 (m, 1H), 1.89-1.60 (m, 4H). LCMS (ES+) m/z 483 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][C:17]1[N:21]=[C:20]([CH3:22])[NH:19][N:18]=1>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:18]2[C:17]([CH3:16])=[N:21][C:20]([CH3:22])=[N:19]2)[N:3]=[C:4]([CH3:9])[N:5]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Cc1n[nH]c(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 4,6-dichloro-2-methylpyrimidine (1-1) (5.00 g, 30.7 mmol) and cesium carbonate (15.0 g, 46 mmol) in DMF (250 mL) at 0° C. was added a solution of 3,5-dimethyl-1H-1,2,4-triazole (2.98 g, 30.7 mmol) in DMF (50 mL) via a dropping funnel over 1 h. The reaction was then warmed to room temperature and stirred for 1 h. The reaction was quenched by addition of water (500 mL) and extracted with ethyl acetate (3×400 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-30% EtOAc/hexanes) to afford 4-chloro-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine (1-2) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 2.91 (s, 3H), 2.72 (s, 3H), 2.41 (s, 3H); MS m/z=224 (M+H).
Reaction SMILES: [N+]([C:4]1[C:9]([CH3:10])=[CH:8][N+:7]([O-])=[CH:6][C:5]=1[CH3:12])([O-])=O.P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1>[Br:14][C:4]1[C:9]([CH3:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH3:12]
Reactant: Cc1c[n+]([O-])cc(C)c1[N+](=O)[O-]
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: Cc1cncc(C)c1Br
Yield: 31.4 %

Procedure:
By proceeding in a similar manner to the procedure contained in J.Chem.Soc., 1956, page 771 but using 4-nitro-3,5-dimethylpyridine-N-oxide (23.06 g), phosphorous tribromide (111.47 g) in toluene (50 ml) there was prepared the title compound (8 g) as a yellow oil.