Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([CH3:13])[CH2:11][NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH:21]([S:24](Cl)(=[O:26])=[O:25])([CH3:23])[CH3:22]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([CH3:13])[CH2:11][NH:12][S:24]([CH:21]([CH3:23])[CH3:22])(=[O:26])=[O:25])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: C[C@@H](CN)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC[C@H](C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A 500 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer and an addition funnel is charged with (2R)-2-(4-nitrophenyl)propylamine (11.75 g, 65.21 mmol), methylene chloride (150.0 mL) and triethylamine (18.2 mL, 130.4 mmol). To this solution at 0° C. was added isopropylsulfonyl chloride (8.92 mL, 63.9 mmol) over a period of 20 minutes. Reaction was then stirred to room temperature overnight, then quenched with 1N HCl (150.0 mL). The lower organic layer is separated and dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford [(2R)-2-(4-nitrophenyl)propyl][(methylethyl)sulfonyl]amine (14.11 g, 97%) as an oil; 1H nmr (CDCl3, 300 MHz) δ 1.26 (d, 3H, J=6.7Hz), 1.31 (d, 6H), 3.06 (m, 1H), 3.30 (m, 1H), 4.25 (broad triplet, 1H), 7.38 (d, 2H), 8.10 (2H); 13C nmr (CDCl3, 300 MHz) δ 16.75, 18.95, 41.29, 50.15, 53.85, 124.22, 128.52, 151.26.
Reaction SMILES: [N+:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)([O-:3])=[O:2].[O:14]=O>C(O)(=O)C>[N+:1]([C:4]12[CH2:5][CH:6]3[CH2:12][CH:10]([CH2:9][C:8]([OH:14])([CH2:7]3)[CH2:13]1)[CH2:11]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])C12CC3CC(CC(C3)C1)C2
Reactant: O=O
Solvent: CC(=O)O
Product: O=[N+]([O-])C12CC3CC(CC(O)(C3)C1)C2
Yield: 48 %

Procedure:
To 25 ml of acetic acid were added 10 mmol of 1-nitroadamantane, 1 mmol of NHPI and 0.05 mmol of V(AA)3, and the resultant mixture was stirred in an oxygen atmosphere at a temperature of 75° C. for 8 hours. The analysis by gas chromatography revealed the formation of 1-nitro-3-adamantanol (yield: 48%) a 1-nitro-3,5-adamantanediol (yield:19%) and a 1-nitro-3,5,7-adamantanetriol (yield:2%), converted from 1-nitroadamantane at a conversion rate of 76%. These products were analyzed by mass spectrometric analysis.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11])(=O)C.O(C)[Na].Cl>CO>[OH:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11]
Reactant: CC(=O)OCCOCn1cc(C)c(=O)[nH]c1=O
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: Cc1cn(COCCO)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 1-[(2-acetoxyethoxy)methyl]thymine (4 g, 16 mmol) in CH3OH (100 mL) was added NaOCH3 in CH3OH (20 mL, 1N). After 2 hours of stirring at room temperature, 1N HCl was added to adjust the pH to 4.0. Methanol and water were removed under vacuum to obtain a solid. The solid was dissolved in CH3OH and crystallized by dropwise addition of CHCl3; it was used in the next reaction without further purification. Yield 76%; Wt. 2.5 g; mp 154°-156° C.; 1HNMR (DMSO-d6) 1.75 (s, CH3 C5 thymine), 3.55-3.75 (A2B2 pattern, O CH2 CH2 O), 5.10 (s, O CH2 N), 7.55 (s, H C6 thymine), 11.3 (s, HN thymine).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:20])([CH:17]([CH3:19])[CH3:18])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5].[CH3:21][N:22]=[C:23]=[O:24]>CN(C=O)C.C1COCC1>[CH3:20][C:3]([NH:2][C:23]([NH:22][CH3:21])=[O:24])([C:4](=[O:5])[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH:17]([CH3:18])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(C)(N)C(C)C)cc1
Reactant: CN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A solution of 2-amino-2,3-dimethyl-N-(p-tolylsulfonyl)butyramide hydrochloride (5 g, 15.58 mmols) dissolved in 50 mL of DMF under nitrogen is cooledto -30° C. Then 10 mL of methyl isocyanate in 10 mL of THF is added at such a rate that temperature is maintained at -30° C., and the reaction mixture is allowed to stir for two hours at -30° C. and then for 16 hours at room temperature.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:34])([F:33])[O:21][C:22]1[CH:23]=[C:24](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30](=[O:31])/[CH:29]=[CH:28]/[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:33])([F:34])[F:19])[CH:23]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1cccc(OC(F)(F)F)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3cccc(OC(F)(F)F)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(3-trifluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1Cl
Temperature: 0 °C

Procedure:
To a solution of 25 ml of fuming nitric acid and 20 ml of sulfuric acid, 25 g of 2,4-dichlorobenzoic acid was gradually added. After completion of the heat generation, the reaction mixture was poured into ice water. Precipitated solid was washed with water and dried to obtain 23.0 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH3:11][C:12]([CH3:16])=[CH:13][CH:14]=O>N1C=CC=CC=1.C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[C:8]2[C:9]=1[O:10][C:12]([CH3:16])([CH3:11])[CH:13]=[CH:14]2
Reactant: CC(C)=CC=O
Reactant: O=Cc1ccc(O)c(O)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)C=Cc2cc(C=O)cc(O)c2O1

Procedure:
3,4-Dihydroxybenzaldehyde (2.3 g, 17 mmol) and 3-methylbut-2-enal (1 mL, 10 mmol) were dissolved in 3 mL of pyridine and refluxed overnight. Pyridine was evaporated under vacuum, and the crude reaction mixture was dissolved in methylene chloride. 9 (103 mg, 2.4%) was purified with silica gel chromatography with ethyl acetate/hexane (1/50). 1H NMR (CDCl3): δ 1.50 (s, 6H), 5.70 (d, J=10.1 Hz, 1H), 6.38 (d, J=10.1 Hz, 1H), 7.15 (d, J=2.14 Hz, 1H), 7.32 (d, J=1.83 Hz, 1H), 9.78 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH3:33])=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]([C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)[CH3:33])=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1CCCC1NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCCC1N(C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1665 g, 0.5 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 2-Methylamino-cyclopentanecarboxylic acid ethyl ester (0.0856 g, 0.5 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1003 g, 0.525 mmol). Then N-methylmorpholine (115 μL, 1.05 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-{[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-methyl-amino}-cyclopentanecarboxylic acid ethyl ester, as a yellow oil. LC-MS (ESI) calcd for C19H26N4O7S2 486.12, found 487.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[F:32][C:33]([F:46])([F:45])[O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:44][S:41]([C:38]3[CH:39]=[CH:40][C:35]([O:34][C:33]([F:32])([F:45])[F:46])=[CH:36][CH:37]=3)(=[O:42])=[O:43])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-[(trifluoromethyl)oxy]benzenesulfonamide: 1H-NMR (CDCl3) δ 7.98 (2H, d, J=9.1 Hz), 7.47-7.21 (11H, m), δ 12 (1H, br.s), 3.50-3.43 (2H, m), 2.85 (2H, t, J=6:5 Hz). 2.32 (3H, s), 2.23 (3H, s).
Reaction SMILES: [OH:1][C@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2>>[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Yield: 50 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 1 with (R)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 1f obtained from step 5 of Example 1 and 5-bromo-1,3-dihydro-indol-2-one as starting materials to give (R,Z)-2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 4 (24 mg, yield 50%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.[Na].[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1>CS(C)=O>[CH3:1][N:2]1[C:6](=[O:7])[N:5]([CH2:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([O:11][CH3:10])=[O:21])=[CH:14][CH:15]=2)[C:4](=[O:8])[NH:3]1
Reactant: Cn1[nH]c(=O)[nH]c1=O
Reactant: COC(=O)c1ccc(CCl)cc1
Agent: [Na]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Cn2c(=O)[nH]n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of 1-methyl-[1,2,4]triazolidine-3,5-dione (1.886 g, 0.0164 mol) and sodium hyhride (200 mg) in DMSO (5 mL) was added 4-chloromethyl-benzoic acid methyl ester (1.0 g, 0.0054 mol). The mixture was stirred at RT for overnight, quenched with H2O (100 mL), and extracted by CH2Cl2. The organic layer was washed with H2O, dried (Na2SO4) and concentrated in vacuo to yield methyl 4-((1-methyl-3,5-dioxo-1,2,4-triazolidin4-yl)methyl)benzoate (1.02 g, 72%). 1H NMR (CDCl3): 7.93 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 4.68 (s, 2H), 3.83 (s, 3H), 3.27 (s, 3H). MS (ESI) m/e: 264 (M++1)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[O:14][CH2:15][C:16]([F:19])([F:18])[F:17].[CH3:20][N:21]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:40].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH2:12]([S:9]([CH2:8][C:6]1[CH:5]=[CH:4][C:3]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:2]([C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:40])[N:21]([CH3:20])[CH:30]=2)[CH:7]=1)(=[O:11])=[O:10])[CH3:13]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Reactant: CCS(=O)(=O)Cc1ccc(OCC(F)(F)F)c(Br)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: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)Cc1ccc(OCC(F)(F)F)c(-c2cn(C)c(=O)c3ccccc23)c1
Temperature: 70 °C
Yield: 64.5 %

Procedure:
The title compound from Step 5 (200 mg, 0.58 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (197 mg, 0.69 mmol), Pd(PPh3)4 (67 mg, 58.0 umol) and Na2CO3 (184 mg, 1.74 mmol) in dioxane (6 mL) and water (6 drops) was degassed and then heated to 70° C. for 18 hours under N2. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (PE:EA=5:1˜1:1) followed by prep-HPLC purification to afford the title compound (164.44 mg, 67%) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 8.52 (d, J=8.0 Hz, 1H), 7.58-7.48 (m, 3H), 7.40 (d, J=2.4 Hz, 1H), 7.22 (d, J=8.0, 1 H), 7.07 (t, J=8.0, 2 H), 4.30 (q, J=8.0 Hz, 2H), 4.23 (s, 2H), 3.67 (s, 3H), 2.98 (q, J=7.6 Hz, 2H), 1.43 (t, J=7.6 Hz, 3H). LCMS: 440.0 (M+1)+
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH:33]([CH3:35])[CH3:34])[CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH:33]([CH3:34])[CH3:35])[CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: CC(C)Oc1ccc2cc(C3(O)CCNCC3)ccc2c1
Product: CC(C)Oc1ccc2cc(C3(O)CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)ccc2c1
Yield: 69.5 %

Procedure:
Beginning with 0.099 gm (0.50 mMol) (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 0.150 gm (0.50 mMol) 4-hydroxy-4-(6-isopropoxynaphth-2-yl)piperidine, 0.165 gm (66%) of the title compound were recovered as a white solid by the procedure described in Example 9.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[NH2:21]>>[F:16][C:17]([F:29])([F:30])[C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=2)[CH:22]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:24]=1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCOC(=O)c1c(C)nc(SC)nc1Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 71.7 %

Procedure:
The title compound was prepared as described in Example 1d by starting from ethyl 4-chloro-6-methyl-2-(methyl thio)pyrimidine-5-carboxylate (1.2 g, 4.86 mmol) and 3,5-bis(trifluoromethyl)aniline (777 uL, 4.86 mmol) and continuing until the reaction yielded the brown solids, title compound ethyl 4-(3,5-bis(trifluoromethyl)phenylamino)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (1.53 g, 70.2%). MS m/z: 440.1 (M+1)+.
Reaction SMILES: C(O[C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1OC(=O)C)(=O)C.[O:17]=[C:18]1[CH:27]=[CH:26][C:25](=[O:28])[C:24]2[CH2:23][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:20][C:19]1=2>C1(C)C(C)=CC=CC=1>[O:17]=[C:18]1[C:27]2[C:26](=[CH:6][C:7]3[C:8]([CH:5]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:25](=[O:28])[C:24]2[CH2:23][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:20][C:19]1=2
Reactant: COC(=O)C1CCC2=C(C1)C(=O)C=CC2=O
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)C1CCC2=C(C1)C(=O)c1cc3ccccc3cc1C2=O
Yield: 81.2 %

Procedure:
A mixture of 240 mg (1.1 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 220 mg (1.0 mmol) of methyl rac-1,2,3,4,5,8-hexahydro-5,8-dioxonaphthalene-2-carboxylate in 20 ml of dry xylene was stirred and heated under reflux under an atmosphere of nitrogen for 18 hours. The solution was evaporated to dryness, the yellow residue was stirred with 100 ml of diethyl ether and the mixture was subsequently filtered to give 260 mg (81%) of methyl rac-1,2,3,4,5,12-hexahydro-5,12-dioxonaphthacene-2-carboxylate in the form of a bright yellow solid of melting point 173°-174° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[C:28]1[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=1)([OH:3])=[O:2].B(Br)(Br)Br.O>ClCCl>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:13]=[C:12]1[C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)([OH:3])=[O:2]
Reactant: COc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)n2CCCCCCCC(=O)O)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCCCCCCn1c(-c2ccc(O)cc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.2 %

Procedure:
1-(7-Carboxyheptyl)-2-(4-methoxyphenyl)-4,5-diphenyl-imidazole (2.5 g) was added, in portions over 40 minutes, to a solution of boron tribromide (2.17 ml) in anhydrous dichloromethane (40 ml). The reaction was stirred at room temperature for 5 h, cooled and water (50 ml) was carefully added. The organic layer was removed and the aqueous layer was washed with dichloromethane (3×75 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with a dichloro-methane:methanol gradient and recrystallisation from ethanol/water and acetonitrile gave 1-(7-carboxy-heptyl)-2-(4-hydroxyphenyI)-4,5-diphenyl-imidazole (0.49 g, 20%) as a white solid, m.p. 171°-172° . Further material was obtained from the mother liquors (0.79 g, 33%) m.p. 167°. Found C: 76.85; H, 6.65; N, 6.20%; C29H30N2O3 requires: C, 76.63; H, 6.65; N, 6.16%;
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]=[CH:8]1.C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:25][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:16])([CH3:17])[CH3:1])[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Into a flask containing methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (4.0 g; 15.6 mmol) in CCl4 (100 ml), catalytic AIBN, NBS (3.1 g, 17.1 mmol) were added and stirred at 65° C. for 3 h. The reaction mixture was quenched with aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography. Yield 3.5 g. 1H-NMR (400 MHz; DMSO-d6): δ 0.04 (s, 9H), 0.84 (t, 2H), 3.53 (t, 2H), 3.75 (s, 3H), 5.30 (s, 2H), 8.25 (s, 1H). LC-MS: [M+1]=335.01.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.ClC1C=CC(NC(=O)[NH:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([O:31][C:32]3[CH:40]=[CH:39][C:35](C(O)=O)=[CH:34][CH:33]=3)[CH2:27][CH2:26]2)=CC=1C(F)(F)F>>[CH3:7][NH:10][C:11](=[O:12])[C:39]1[CH:35]=[CH:34][CH:33]=[C:32]([O:31][C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=3)=[O:12])=[CH:30][CH:29]=2)[CH:40]=1
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N[C@H]1CC[C@H](Oc2ccc(C(=O)O)cc2)CC1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Product: CNC(=O)c1cccc(Oc2ccc(NC(=O)Nc3ccc(OC(F)(F)F)cc3)cc2)c1
Yield: 70 %

Procedure:
Compound 2576 was prepared in 70% yield from 4-(trifluoromethoxy)phenyl isocyanate using the procedure detailed for compound 2221 in Example 4. 1H NMR (300 MHz, DMSO-d6): δ 8.75 (q, J=5 Hz, 1H), 8.45 (d, J=6 Hz, 1H), 7.33 (d, J=3 Hz, 1H), 7.07 (dd, J=6 and 3 Hz, 1H), 6.86 (d, J=9 Hz, 2H), 6.64 (d, J=9 Hz, 2H), 5.19 (br s, 2H), 2.77 (d, J=5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[O:25])[N:3]=[CH:4]2)=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccncc1
Reactant: NC(=O)c1c(N)ncn1Cc1ccc(F)cc1
Product: NC(=O)c1c(NC(=O)c2ccncc2)ncn1Cc1ccc(F)cc1
Yield: 65 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 19, using 2.0 g (8.5 mmol) of 4-amino-1-(4-fluorobenzyl)-5-imidazolecarboxamide which was prepared in the same manner as in Example 58 and isonicotinic acid instead of cyclopentylacetic acid to obtain 1.87 g of 1-(4-fluorobenzyl)-4-(4-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 65%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([NH:28][OH:29])[CH2:19][CH2:20][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])C>C1COCC1.C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH:18]([N:28]([OH:29])[CH:30]=[O:32])[CH2:19][CH2:20][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)(=[O:15])=[O:16])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ccc(Br)cc2)CC1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CN(O)C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To a stirred solution of N-[1-([4-(4-bromophenyl)piperazino]sulfonylmethyl)-4-pyrimidin-2-ylbutyl]hydroxylamine (497 mg, 1.0 mmol) in THF (5.0 ml) and formic acid (2.5 ml), cooled to 0° C., was added a preformed mixture of acetic anhydride (566 μl, 6.0 mmol) and formic acid (2.0 ml). The mixture was stirred at 0° C. for 1 hour and allowed to come to room temperature. The solvents were removed by rotary evaporation and the residue purified by chromatography (50 g Silica Bond Elute, eluent 0→15% Methanol/Dichloromethane), pure fractions evaporated, and crystallised from hot ethyl acetate to give N-[1-([4-(4-bromophenyl)piperazino]sulfonylmethyl)-4-pyrimidin-2-ylbutyl]-N-hydroxyformamide as a white crystalline powder (262 mg, 51%).