Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[C:6]=2[N:7]=1.[CH3:28][C:29]1([CH3:46])[CH2:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([CH3:45])([CH3:44])[NH:30]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[CH:11]1([N:8]2[C:6]3[N:7]=[C:2]([C:33]4[CH2:32][C:31]([CH3:45])([CH3:44])[NH:30][C:29]([CH3:46])([CH3:28])[CH:34]=4)[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]4[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=4[CH3:25])=[O:16])[C:5]=3[CH:10]=[N:9]2)[CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2CCC2)c(=O)[nH]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 6-bromo-1-cyclobutyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) solution was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (80% yield). LCMS: 489.30 (M+1)+; HPLC: 95.97% (@ 254 nm) (Rt;5.425); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.89 (t, 1H), 8.31 (s, 1H), 7.79 (s, 1H), 6.81 (s, 1H), 5.89 (s, 1H), 5.52-5.44 (m, 1H), 4.37 (d, 2H, J=4.8 Hz), 2.73-2.63 (m, 2H), 2.43 (m, 4H), 2.22 (s, 3H), 2.12 (s, 3H), 1.94-1.88 (m, 2H), 1.24 (d, 6H, J=6 Hz), 1.15 (s, 6H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])([CH3:10])([CH3:9])[CH3:8].[CH2:18]([O:20][C:21](=[O:26])[CH:22]=[C:23](Cl)[CH3:24])[CH3:19]>O1CCCC1>[CH2:18]([O:20][C:21](=[O:26])/[CH:22]=[C:23](/[O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]([CH3:10])([CH3:8])[CH3:9])\[CH3:24])[CH3:19]
Reactant: CC(C)(C)c1ccccc1O
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccccc1C(C)(C)C
Temperature: 23 °C
Yield: 77.8 %

Procedure:
Potassium t-butoxide (11.3 g, 0.10 mol) was added to a stirred solution of 2-t-butyl-phenol (7.60 g, 0.05 mol) in tetrahydrofuran (40 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 7.50 g, 0.05 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2-t-butyl-phenoxy)-but-2-enoic acid ethyl ester (10.2 g, 77%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)#[N:19]>>[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])=[CH:22][CH:21]=1)#[N:19]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(C#N)cc4)cc23)CC1
Yield: 43.3 %

Procedure:
Beginning with 20.0 mg (0.087 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 38.0 mg (0.131 mMol) 4-cyanobenzoic acid, 13.5 mg (43.1%) of the title compound were recovered.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[Cl:22][C:23]1[S:27][C:26]([C:28]([C:30]2[N:31]([CH3:35])[CH:32]=[N:33][CH:34]=2)=[O:29])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[S:27][C:26]([C:28]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)([C:30]2[N:31]([CH3:35])[CH:32]=[N:33][CH:34]=2)[OH:29])=[CH:25][CH:24]=1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)s1
Reactant: COc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Product: COc1cccc(-c2cc(OC)nc3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc23)c1
Yield: 80.1 %

Procedure:
Following the same procedure as that described in example 1E, 6-bromo-4-(3-methoxy-phenyl)-2-methoxy-quinoline (1 g, 2.91 mmol) and (5-chloro-thiophen-2-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (0.78 g, 3.49 mmol) generated the title compound of 31A (1.147 g, 80.2% yield).
Reaction SMILES: [CH:1]([N:14]1[CH:19]=[C:18](I)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1>>[CH:1]([N:14]1[CH:19]=[C:18]([C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1I
Product: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1-c1cccnc1
Yield: 23.9 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 14 (Step 2), starting from 1-benzhydryl-5-iodo-pyrimidine-2,4-dione (0.81 g, 2 mmol) and 3-pyridylboronic acid (0.370 g, 3 mmol). The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 30:70) to afford the title compound (0.17 g, 24%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.14 (s, 1H), 7.20-7.24 (m, 4H), 7.29-7.33 (m, 2H), 7.36-7.46 (m, 6H), 7.93 (dt, J=8.1, 2.0 Hz, 1H), 8.41 (d, J=1.7 Hz, 1H), 8.45 (s, 1H), 8.52 (dd, J=4.9, 1.6 Hz, 1H). MS (ESI) m/z: 356 [M-H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=C(C(OC)=O)[CH:3]=1.S(=O)(=O)(O)O.[CH3:19][CH2:20][O:21][C:22]([CH3:24])=[O:23].[C:25]([O-])(O)=O.[Na+]>CC(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:24]([C:22]([O:21][CH:20]([CH3:25])[CH3:19])=[O:23])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: O=C([O-])O
Reactant: COC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4,5,6-trichloropicolinate (prepared as in Balko, T. W. et al. U.S. Pat. No. 6,784,137 B2, Aug. 31, 2004; 14.19 g, 59.0 mmol) was slurried in 2-propanol (150 mL) in a 250 mL round bottom flask equipped with a Dean-Stark trap and a reflux condenser. Sulfuric acid (98% H2SO4; 8.07 g, 82 mmol) was added, and the reaction mixture was heated to reflux. After 20 h at reflux, the majority of the 2-propanol (100 mL) was distilled overhead. The remaining reaction mixture solidified upon cooling to room temperature. The resulting solid was stirred with EtOAc (500 mL) and satd aq NaHCO3 (500 mL). The organic layer was separated, washed with satd aq NaCl, and then filtered through Celite. The organic extract was concentrated to 150 mL by rotary evaporation. Hexane (100 mL) was added, and the solution was stored at −20° C. overnight. Crystals were collected, washed with hexane and dried in air (7.58 g, mp 104.6-105.7° C.). A second crop was obtained by concentration of the filtrate to give a total of 10.36 g (65%): 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H, pyridine H), 5.16 (septet, J=6.3 Hz, 1H, CHMe2), 1.34 (d, J=6.3 Hz, 6H, CHMe2); 13C{1H} NMR (101 MHz, CDCl3) δ 161.9 (CO2R), 150.6, 145.9, 145.0, 133.1, 125.4 (C3), 70.7 (CHMe2), 21.7 (Me). Anal. Calcd for C9H8Cl3NO2: C, 40.26; H, 3.00; N, 5.22. Found: C, 40.25; H, 3.02; N, 5.22.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.C(N(CC)CC)C.ClC(OCC)=O.[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCOCC.C1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:32]1[CH2:33][CH2:34][N:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:30][CH2:31]1)=[O:9]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCCCCBr
Agent: CCOC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(CCCCCBr)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 25 g (0.128 mol) of 6-bromohexanoic acid and 12.7 g (0.125 mol) of triethylamine in 150 ml of ether was cooled (0°) and treated dropwise with 28.5 g (0.263 mol) of ethyl chloroformate. The reaction mixture was stirred for 1 hr and then filtered. To the cooled (0°) filtrate was added a solution of 21 g (0.129 mol) of N-phenylpiperazine in 50 ml of ether. The reaction mixture was then allowed to warm to room temperature for 30 min and was then washed once with 1 N NaOH solution and once with water. The dried (Na2SO4) organic layers were concentrated in vacuo to give a yellow oil which was dissolved in benzene and chromatographed on silica gel (500 g). The column was eluted with benzeneethyl acetate mixtures, the product appearing in the benzeneethyl acetate (8.5:1.5) mixtures. Evaporation of those combined mixtures gave 1-(6-bromohexanoyl)-4-phenylpiperazine.
Reaction SMILES: NC(N)=[O:3].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])(=[O:29])=[O:28])=[CH:23][N:22]=1.O>ClCCl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])(=[O:29])=[O:28])=[CH:23][N+:22]=1[O-:3]
Reactant: NC(N)=O
Reactant: O=S(=O)(c1ccc(Cl)nc1)c1ccccc1F
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)[n+]([O-])c1)c1ccccc1F
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Urea-hydrogen peroxide (0.36 g, 3.83 mmol) was suspended in dichloromethane (3 mL) and trifluoroacetic anhydride (0.77 g, 3.67 mmol) was added to form a clear solution. 2-Chloro-5-[(2-fluorophenyl)sulfonyl]pyridine (Example 1 Steps 1 and 2, 0.5 g, 1.84 mmol) in dichloromethane (1 mL) was added and the reaction stirred at room temperature under nitrogen for 7 hours. The mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium thiosulfate (×3). The combined aqueous layers were extracted once with ethyl acetate, then the combined organic layers washed again with sodium thiosulfate then with brine, dried over MgSO4 and concentrated in vacuo to give 2-chloro-5-[(2-fluorophenyl)sulfonyl]pyridine 1-oxide as a pale yellow solid (0.53 g, quant.). δH (500 MHz, d6 DMSO): 8.84 (1H, d, J=1.5 Hz), 8.08 (1H, td, J=7.5, 1.5 Hz), 8.03 (1H, d, J=8.6 Hz), 7.87–7.77 (2H, m), 7.51 (1H, q, J=8 Hz), 7.47 (1H, d, J=8.6 Hz); m/z (ES+) 288 [MH+].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O.C(Br)(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH3:20]
Reactant: BrC(Br)(Br)Br
Reactant: COCCOCOCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCOCOCCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
79.32 g of triphenylphosphine were added, whilst ice-cooling (at 5° to 8° C.), to a solution of 48.40 g of 5-(2-methoxyethoxy)methoxy-1-pentanol (prepared as described in Preparation 59) and 100.19 g of carbon tetrabromide dissolved in 500 ml of methylene chloride. The mixture was stirred at room temperature for 1 hour, after which the solvent was removed by evaporation under reduced pressure. Diethyl ether was then added to the resulting residue. The insoluble materials were filtered off, and the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 850 g of silica gel, and 57.87 g of the title compound were obtained, as a colorless oil, from those fractions eluted with a 1:9 by volume mixture of ethyl acetate and hexane.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[NH:13]1[CH2:18][CH2:17][CH2:16][N:15]=[C:14]1[SH:19].[I:20]I.[I-].[K+]>CO.O>[IH:20].[NH:15]1[CH2:16][CH2:17][CH2:18][N:13]=[C:14]1[S:19][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([OH:12])=[O:11]
Reactant: II
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: SC1=NCCCN1
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: I
Product: O=C(O)c1[nH]c2ccccc2c1SC1=NCCCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6.4 g indole-2-carboxylic acid in 25 ml methanol and 4.6 g 1,4,5,6-tetrahydro-2-pyrimidinethiol in 50 ml methanol is added to a well-stirred solution of 10.1 g iodine and 16.3 g potassium iodide in 50 ml water. The mixture is stirred at room temperature for 11/2 hours, and cooled. The crystalline product is filtered off. A second yield is obtained by concentrating the filtrate to a small volume and cooling. The combined product is recrystallised from hot water to give 3-(1,4,5,6-tetrahydro-2-pyrimidinylthio)-indole-2-carboxylic acid hydriodide melting at 252°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]2=[N:10]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:32]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:32])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]2=[N:10]1
Reactant: COc1ccc2nn(-c3cc(C)ccc3O)nc2c1
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2nn(-c3cc(CBr)ccc3O)nc2c1
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-5′-bromomethyphenyl)-5-methoxybenzotriazole was prepared from the bromination of 2-(2′-hydroxy-5′-methyphenyl)-5-methoxybenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 5.693 g (0.0223 mol) 2-(2′-hydroxy-5′-methyphenyl)-5-methoxybenzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml. 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-hydroxy-5′-methyphenyl-5-methoxybenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy-5′-bromomethyphenyl)-5-methoxybenzotriazole was 6.3 g (84%).
Reaction SMILES: [F:1][C:2]1([F:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=2[O:3]1.[C:17]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[F:16][C:2]1([F:1])[C:7](=[O:8])[N:6]([CH3:17])[C:5]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=2[O:3]1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2OC1(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C(F)(F)Oc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C

Procedure:
To a stirred suspension of 2,2-difluoro-7-nitro-4H-1,4-benzoxazin-3-one (WO 99/40094, 2.16 g, 9.38 mmol) in DMF (10 mL) is added K2CO3 (1.94 g, 14.07 mmol) followed by addition of MeI (0.87 mL, 14.07 mmol). The resulting solution is stirred over night at room temperature. To this reaction mixture is added water (50 mL), and the resulting solution is extracted with EtOAc (50 mL×3). The combined organic phases are washed with water (50 mL) and saline (50 mL), dried over Na2SO4 and concentrated under reduced pressure to give the title compound that is purified by passing through a short silica gel column with EtOAc (1.3 g, 57%), 1H NMR (300 MHz, DMSO) δ 8.25-8.17 (m, 2H), 7.62 (d, 1H), 3.47 (s, 3H).
Reaction SMILES: [C:1]([S:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:14][N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[C:1]([S:9][CH2:10][C:11]([CH:17]1[CH2:18][C:19](=[O:20])[N:15]([OH:14])[C:16]1=[O:21])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CSC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C(SCC(=O)C1CC(=O)N(O)C1=O)c1ccccc1
Temperature: 4 °C
Reaction time: 12 h
Yield: 78.5 %

Procedure:
To a stirring solution of (9.20 g, 46.9 mmoles) benzoylmercaptoacetic acid and (5.41 g, 46.9 mmoles) N-hydroxysuccinimide in (100 mL) dioxane was added a solution of (9.70 g, 47 mmoles) dicyclohexylcarbodiimide in (40 mL) dioxane. The reaction was stirred 12 hours followed by cooling to 4° C., filtering, and rotavapping off the dioxane to a white solid. The solid was triturated with cold isopropanol, filtered, and dried in vacuo yielding 10.8 g, 78% benzoylmercaptoacetyl-N-hydroxysuccinimide. 200 mg was recrystallized from 500 mg in hot ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:11]([CH2:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O[N:33]1[C:37]2[N:38]=CC=C[C:36]=2[N:35]=[N:34]1.C([N:45](CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:11]([CH2:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:38][CH2:37][C:36]4[NH:45][N:33]=[N:34][N:35]=4)=[O:29])=[CH:25][CH:24]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(-c2cc(-c3cc(Cl)cc(Cl)c3)nn2Cc2ccc(C(=O)O)cc2)cc1
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2cc(-c3cc(Cl)cc(Cl)c3)nn2Cc2ccc(C(=O)NCc3nnn[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from example 73 step D (100 mg, 0.22 mmol) in 1:1 DMF/DCM (0.54 mL) was added 1-hydroxy-7-azabenzo-triazole (35 mg, 0.264 mmol), N,N-diisopropylethyl amine (92 μL, 0.53 mmol) amino methyl tetrazole (26 mg, 0.26 mmol) and 1-(3-(Dimethylamino)propyl-3-ethyl carbodiimide hydrochloride (51 mg, 0.26 mmol). The reaction was left stirring at room temperature for 18 hours. The reaction was diluted with DCM, washed with 1N HCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (Gilson) to give the title compound. 1H NMR (DMSO, 500 MHz): δ 9.21 (t, J=5.3 Hz, 1H), 7.88 (d, J=2.1 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H), 7.56 (t, J=2.1 Hz, 1H), 7.39 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.3 Hz, 2H), 7.12 (s, 1H), 7.04 (d, J=8.7 Hz, 2H), 5.49 (s, 2H), 4.74 (d, J=5.4 Hz, 2H), 3.79 (s, 3H). LC-MS: 3.82 min; (M+H)=534.1.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[ClH:21].[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:24]=3)=[O:30])=[CH:14][CH:13]=2)=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Nc1ncc2[nH]cnc2n1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Cl
Product: Nc1ncc2ncn(-c3ccc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3)c2n1

Procedure:
The title compound can be synthesized from 2-aminopurine, 4-fluoronitrobenzene and 4-chloro-3-(trifluoromethyl)phenyl isocyanate by the same methods as in Examples 29 and 30.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Br:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([Br:15])=[CH:8][N:7]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1.O>[Br:5][C:6]1[C:11]2[CH:1]=[CH:2][NH:12][C:10]=2[C:9]([Br:15])=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ncc1Br
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Brc1ncc(Br)c2[nH]ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Vinyl magnesium bromide (44 ml, 1M in THF) was added to dry THF (40 ml) and the solution was cooled to 0° C. under an atmosphere of nitrogen. A solution of 2,5-dibromo-4-nitropyridine (prepared by the method of: Lee, Bang-Lin; Yamamoto, Takakazu, Macromolecules (1999), 32(5) 1375-1382.) (3.53 g) in THF (80 ml) was added dropwise over 40 mins at 0° C. The mixture was stirred at room temperature for 1 hr then cooled to 0° C. and a saturated solution of ammonium chloride (60 ml) was added. The mixture was stirred at room temperature for 15 min then added to a mixture of ethyl acetate (200 ml) and water (200 ml). The organic layer washed with water and evaporated. The residue was dissolved in a mixture of methanol (20 ml) and conc hydrochloric acid (0.5 ml). After standing at room temp for 30 mins the solution was evaporated and the residue added to ethyl acetate (50 ml) and water (50 ml) and made basic with sodium hydroxide. The organic layer washed with water (2×50 ml) then brine, dried (MgSO4) and evaporated. The residue was triturated with ether (20 ml) to give a solid which was filtered off. The filtrate was evaporated and triturated with ether to afford a second crop which on combination with the above gave the title compound (0.97 g). The filtrate was evaporated and dissolved in DCM and purified with Biotage chromatography eluting with DCM/Et2O 20:1 and evaporated to give white solid (0.38 g)
Reaction SMILES: C[Mg+].[Br-].[C:4]1(C)C=CC=CC=1.C1COCC1.[Cl:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([CH:27]=[CH:28][C:29]3[CH:30]=[C:31]([C@H:35]([OH:48])[CH2:36][CH2:37][C:38]4[CH:47]=[CH:46][CH:45]=[CH:44][C:39]=4[C:40]([O:42]C)=O)[CH:32]=[CH:33][CH:34]=3)=[N:24]2)=[CH:19][CH:18]=1.CO>C1COCC1.O>[C:40]([C:39]1[CH:44]=[CH:45][CH:46]=[CH:47][C:38]=1[CH2:37][CH2:36][C@H:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH:28]=[CH:27][C:23]2[CH:22]=[CH:21][C:20]3[C:25](=[CH:26][C:17]([Cl:16])=[CH:18][CH:19]=3)[N:24]=2)[CH:30]=1)[OH:48])(=[O:42])[CH3:4]
Reactant: COC(=O)c1ccccc1CC[C@@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: Cc1ccccc1
Agent: C[Mg+]
Agent: [Br-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1ccccc1CC[C@@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
At 0° C., a 1.5M MeMgBr solution in toluene:THF 1:1 (130 mL, 195 mmol) was added dropwise to a solution of the hydroxyester of Step 3 (11.04 g, 24.1 mmol) (dried in EtOAc and stripped with toluene to remove the H2O) and MeOH (2.0 mL, 49.4 mmol) in 240 mL of anhydrous THF. The reaction mixture was stirred at r.t. for 2.5 h and was then poured into ice cold 25% NH4OAc. The product was extracted into EtOAc, dried over Na2SO4 and purified by flash chromatography on silica with EtOAc:toluene 10:90 and 15:85. [α]D : +23.8° (c=1.04, CHCl3).