Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([F:41])[C:27]=1[OH:42].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:25].[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([N:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]2)[CH:29]=[C:28]([F:41])[C:27]=1[OH:42]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](N(C)C)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure II, 1-{6-chloro-4-[trans-4-(dimethylamino)cyclohexyl amino)-1,5-naphthyridin-3-yl)ethanone (45 mg, 0.12 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (47 mg, 0.17 mmol) followed by formation of the dihydrochloride salt to afford the desired product (6.9 mg, 11%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.17 (s, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.00 (s, 1H), 7.91 (dd, J=11.4, 2.2 Hz, 1H), 5.69-5.59 (m, 1H), 3.52-3.45 (m, 1H), 2.92 (s, 6H), 2.76 (s, 3H), 2.63-2.56 (m, 2H), 2.33-2.26 (m, 2H), 1.89-1.71 (m, 4H). ESI MS m/z 457 [M+H]+; HPLC>99% (AUC), tR=9.32 min.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(O)C>[C:4]([C:3]1[CH:12]=[CH:13][C:14]([O:16][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:2]=1[OH:1])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CBr
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: COC(=O)COc1ccc(C(=O)c2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
A mixture of 15.0 g (70.0 mmol) of 2,4-dihydroxybenzophenone, 10.7 g (70 mmol) of methyl bromoacetate, 19.3 g (0.14 mol) of potassium carbonate, and 125 ml of N,N-dimethylformamide is stirred at 25° C. for 18 hours. The reaction mixture is partitioned between diethyl ether and 0.5 N hydrochloric acid. Solids are removed by filtration, and the filtrate is dried over magnesium sulfate and concentrated. The concentrate is partially dissolved in diethyl ether, and solids are removed by filtration. The solid material is recrystallized from dichloromethane: 2-propanol to afford 13.7 g (69% yield) of the title compound, a pale yellow solid, mp 131°-4° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C@H:5]1[C:21](=[O:22])[N:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C:8]2[C:9]3[CH:10]=[N:11][NH:12][C:13]=3[C:14]([C:16]([CH3:18])=[CH2:17])=[CH:15][C:7]=2[CH2:6]1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C@H:5]1[C:21](=[O:22])[N:20]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:19][C:8]2[C:9]3[CH:10]=[N:11][NH:12][C:13]=3[C:14]([CH:16]([CH3:18])[CH3:17])=[CH:15][C:7]=2[CH2:6]1
Reactant: C=C(C)c1cc2c(c3cn[nH]c13)CN(CC(C)(C)C)C(=O)[C@H](CC(=O)OC)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C[C@@H]1Cc2cc(C(C)C)c3[nH]ncc3c2CN(CC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
[(S)-9-(2,2-Dimethyl-propyl)-4-isopropenyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-acetic acid methyl ester (100 mg, 0.26 mmol) was dissolved in a mixture of ethyl acetate (5.0 mL) and methanol (5.0 mL). A catalytic amount of 10% palladium on carbon was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 50 psi of hydrogen gas. Reaction shook at room temperature for 1 hour. Mixture was filtered and the filtrate was concentrated to dryness. Title compound was obtained as brown residue in 90% yield. MS m/e (M+H)+=386.3.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH:19]([C:21]2[CH:26]=[C:25]([OH:27])[C:24]3[C:28]4[CH2:29][NH:30][CH2:31][CH2:32][C:33]=4[C:34]([CH3:37])([CH3:36])[O:35][C:23]=3[CH:22]=2)[CH3:20])=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH:19]([C:21]2[CH:26]=[C:25]([OH:27])[C:24]3[C:28]4[CH2:29][N:30]([CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4])[CH2:31][CH2:32][C:33]=4[C:34]([CH3:36])([CH3:37])[O:35][C:23]=3[CH:22]=2)[CH3:20])=[CH:12][CH:11]=1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: NC(=O)NC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 1.50 g. (0.011 mole) of chloroacetyl urea in 20 ml. of dimethylformamide was added dropwise to a stirred solution of 3.95 g. (0.01 mole) of 8-[5-(4-fluorophenyl)-2-pentyl]-10-hydroxy-5,5-dimethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine in 25 ml. of dimethylformamide and 1.11 g. (0.011 mole) of triethylamine. After stirring at room temperature for 22 hours, the mixture was diluted with 45 ml. of water and extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was recrystallized from acetonitrile, m.p. 133°-134°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])(=[O:22])=[O:21])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O-])=O.[H][H]>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])(=[O:22])=[O:21])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: [H][H]
Reactant: Cc1ccccc1S(=O)(=O)NC(=O)c1ccc2c(ccn2Cc2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1ccc2c(ccn2Cc2cccc(N)c2)c1

Procedure:
The nitrobenzylindole (Example 3) (2.7 g) was dissolved in methanol (125 ml) and ethyl acetate (125 ml), and 10% palladium on charcoal (0.5 g) added. The reaction mixture was hydrogenated in a Parr bottle at 50 p.s.i. with shaking until hydrogen uptake was complete (approximately 1 hour). The catalyst was filtered off through Celite and the solvent removed in vacuo to give N-[1-(3-aminobenzyl)indol-5-ylcarbonyl]-2-methylbenzene sulphonamide as a foam. This crude product was used in the next step without purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:4].[CH3:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3](=[O:4])[CH2:2][NH:1][C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=1)=[O:31]
Reactant: COc1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CN
Reactant: Cc1cccc(N=C=O)c1
Product: COc1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CNC(=O)Nc1cccc(C)c1
Yield: 49.2 %

Procedure:
Using a procedure similar to that described in Example 11, but starting with tert-butyl 2-[2-amino-N-(2-methoxyphenyl)acetamido]acetate (4.2 g) and 3-methylphenyl isocyanate (1.9 g), and after recrystallisation in ethyl acetate, tert-butyl 2-{N-(2-methoxyphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (3 g), m.p. 171° C., is obtained.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>CN(C=O)C>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[I:3])[C:14]=1[C:15]#[N:16]
Reactant: OCc1ccccc1I
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1ccccc1I
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
To a cold (ice water) suspension of sodium hydride (216 mg; 5.0 mmol) in anhydrous DMF (4 mL) is added a solution of 2-iodobenzyl alcohol (1.17 gm; 5.0 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 45 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (702 mg; 5.0 mmol) in anhydrous DMF (3 mL), and allowed to room temperature over 4 hours. The reaction mixture is poured into ice water with vigorous stirring and the resulting solid is filtered, washed with water, and dried under vacuum at 40° C. for 3 hours to give 1.40 grams of 2-fluoro-6-(2-iodobenzyloxy)-benzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(Br)c1
Reactant: C1=COCCC1
Agent: Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Brc1cccc(COC2CCCCO2)c1
Reaction time: 48 h

Procedure:
The alcohol of Step 1 (41.23 mmol), dihydropyran (12.5 mL, 137 mmol) and triphenylphosphine hydrobromide (725 mg, 2.11 mmol) were mixed together in 200 mL of CH2Cl2 and stirred for 2 days. The solvent was then evaporated and the title product was purified by flash chromatography on silica using EtOAc:toluene.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[N:7]=[C:8]([CH3:11])[S:9][CH:10]=1)([OH:3])=[O:2].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:19][CH2:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(CCC(=O)O)cs1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)CCc1csc(CBr)n1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a stirring solution of 4-carboxyethyl-2-methyl thiazole (30.3 g) in CCl4 (1L) was added NBS (37.7 g) and AIBN (2.2 g). The resulting mixture was refluxed and irradiated with UV light for 4 hours. The mixture was cooled to room temperature and filtered. The solution was flash chromatographed (CH2Cl2) to yield 36.6 g of a red oil. This material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([CH2:14]OS(C)(=O)=O)[C@@H:4]([C:20]([O:22][CH3:23])=[O:21])[O:3]1.[N-:25]=[N+:26]=[N-:27].[Na+].O>CN(C=O)C>[N:25]([CH2:14][C@@H:5]1[C@@H:4]([C:20]([O:22][CH3:23])=[O:21])[O:3][C:2]([CH3:24])([CH3:1])[N:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[N+:26]=[N-:27]
Reactant: COC(=O)[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1CN=[N+]=[N-]
Temperature: 70 °C
Yield: 31.3 %

Procedure:
Compound XXXVII (0.30 g, 0.80 mmol) was dissolved in DMF (10 mL) followed by the addition of NBu4Br (0.092 g, 0.28 mmol) and then NaN3 (0.15 g, 2.32 mmol). The mixture was heated at 70° C. for 7 h. Water (30 mL) was added to the cooled reaction mixture and it was extracted with EtOAc (3×20 mL). The organic phase was separated, dried over Na2SO4 and evaporated. The residue was purified on a silica gel column (3:1 hexane/EtOAc→1:1 hexane/EtOAc) to yield (4R,5S)-3-tert-butyl 5-methyl 4-(azidomethyl)-2,2-dimethyloxazolidine-3,5-dicarboxylate XXXVIII (0.078 g, 0.25 mmol, 31%). ESIMS found for C13H22N4O5 m/z 337 (M+Na).
Reaction SMILES: C(N(CC)[C:4]1[CH:9]=CC=C[CH:5]=1)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[C:15]([O:32]CC#C)[CH:14]=1.[F-].[Cs+]>O>[Cl:12][C:13]1[C:14]2[CH:5]=[C:4]([CH3:9])[O:32][C:15]=2[C:16]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:17][CH:18]=1
Reactant: C#CCOc1cc(Cl)ccc1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Reactant: CCN(CC)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: Cc1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 185 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
200 ml of N,N-diethylaniline was added to 20.0 g (55.8 mmol) of 3-(4-chloro-2-propargyloxyphenyl)-1-methyl-6-trifluoromethyluracil and 17.0 g (112 mmol) of cesium fluoride, followed by stirring at 180 to 190° C. for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with a 10% hydrochloric acid aqueous solution, water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 7.0 g (yield: 35.0%) of the desired product as white crystals. Melting point: 206-207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:18][N:17]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[N+:26]([O-])=O)[CH2:16][CH:15]3[O:29][C:30](=[O:32])[CH3:31])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C(O)C>[NH2:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[N:17]1[CH2:18][CH:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)[CH:15]([O:29][C:30](=[O:32])[CH3:31])[CH2:16]1
Reactant: CC(=O)OC1CN(c2ccc(Cl)cc2[N+](=O)[O-])CC1N1CCN(C(=O)c2ccc(Cl)cc2)CC1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(=O)OC1CN(c2ccc(Cl)cc2N)CC1N1CCN(C(=O)c2ccc(Cl)cc2)CC1
Yield: 45.3 %

Procedure:
To a solution of acetic acid 4-[4-(4-chloro-benzoyl)-piperazin-1-yl]-1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl ester (140 mg, 0.31 mmol) in ethanol (1 mL), was added Pt (S) (28 mg, 20 weight %) and HCOONH4 (87 mg, 1.38 mmol). The mixture was stirred at reflux for 1 h. After cooling, the mixture was filtered through celite and concentrated to give the desired compound as a light purple oil (67 mg, 50% yield). MS: (ESI), M/Z, 477(M+1). Retention time: 2.28 min (FA-polar).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+]([O-])=O)=[C:8]([S:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH3:23][S-:24].[Na+].C(O)(=O)C>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:24][CH3:23])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cncc(Br)c2)c([N+](=O)[O-])s1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(S(=O)(=O)c2cncc(Br)c2)c(SC)s1

Procedure:
The procedure described in Example 27: step a was followed using 4-(5-Bromo-pyridine-3-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (151 mg, 0.37 mmol, Example 127: step c) and sodium thiomethoxide (1.0 M in EtOH, 26.3 mg, 0.37 mmol). The reaction was quenched with acetic acid (21 uL, 0.37 mol) and the solvents were removed in vacuo. The residue was then dissolved into EtOAc and washed with saturated NaHCO3 and brine solutions. The organic layer was dried Na2SO4) and removal of the solvents in vacuo was followed by purification by flash column chromatography SiO2 (30% EtOAc in hexanes) to yield the title compound. ESI-MS (m/z): Calcd. for C12H10BrNO4S3: 407.9 (M+1) found: 408.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:10](=[O:12])[C:9]2[CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][C:8]=2[N+:14]([O-:16])=[O:15])=[N:19][CH:20]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: Nc1ccc(Cl)cn1
Product: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cn2)c1

Procedure:
Using a similar procedure to that described in Example 8-A, 5-methoxycarbonyl-2-nitrobenzoic acid (20 g, 89 mmol) and 2-amino-5-chloropyridine (11 g, 85 mmol) afforded, after recrystallization from toluene, 23.6 g (83%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[F:8][C:9]([F:27])([F:26])[C:10]1[C:15]([CH:16]([C:18]2[C:19]([O:24][CH3:25])=[N:20][CH:21]=[N:22][CH:23]=2)[OH:17])=[CH:14][N:13]=[CH:12][N:11]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[F:27][C:9]([F:8])([F:26])[C:10]1[C:15]([CH:16]([C:18]2[C:19]([O:24][CH3:25])=[N:20][CH:21]=[N:22][CH:23]=2)[O:17][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[CH:14][N:13]=[CH:12][N:11]=1
Reactant: COc1ncncc1C(O)c1cncnc1C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ncncc1C(OC(=O)C(C)(C)C)c1cncnc1C(F)(F)F
Yield: 80.1 %

Procedure:
Trimethylacetyl chloride (36 μl, 35.1 mg, 0.28 mmol, 3.2 equivalent) was added via syringe to a solution of 1-(4-trifluoromethylpyrimidin-5-yl)-1-(4-methoxypyrimidin-5-yl)methanol (25.1 mg, 0.0877 mmol), triethylamine (70 μl, 50.5 mg, 0.50 mmol, 5.7 equivalents) and dimethylaminopyridine (DMAP) (cat.) in toluene (5 ml) and the solution heated to reflux for 2 hours. The solution was cooled, diluted with NaHCO3 (sat.), and extracted with EtOAc (3 times). The combined extracts were washed with brine (sat.), dried (MgSO4), filtered and concentrated in vacuo. Preparative thin layer chromatography (SiO2 ; hexane/EtOAc, 1:1) gave 26 mg of 1-(4-trifluoromethylpyrimidin-5-yl)-1-(4-methoxypyrimidin-5-yl)-1-trimethylacetoxymethane as a solid.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].N1C=CC=CC=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[C:12]([O:5][CH2:4][CH:2]1[O:3][CH2:1]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCC1CO1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OCC1CO1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
A mixture containing 14.8 g (0.2 mole) of glycidol, 150 ml of anhydrous ether, 16 g (0.4 mole) of pyridine and 28 g (0.2 mole) of benzoyl chloride was stirred at room temperature for 2 hours. The mixture was filtered and the ether was evaporated to leave an oil. This oil was distilled to give 21 g (60%) of colorless oil: b.p. 92° C./0.5 mm Hg. The NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].[CH3:12][C:13]1[CH:14]=[C:15]([CH:38]=[C:39]([CH3:41])[CH:40]=1)[C:16]([N:18]1[CH2:23][CH2:22][C@@H:21]([N:24]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]2)[CH2:20][C@@H:19]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:17].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([O:30][CH:27]1[CH2:28][CH2:29][N:24]([C@@H:21]2[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]3[CH:14]=[C:13]([CH3:12])[CH:40]=[C:39]([CH3:41])[CH:38]=3)[C@@H:19]([CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:20]2)[CH2:25][CH2:26]1)=[O:6]
Reactant: Cc1cc(C)cc(C(=O)N2CC[C@@H](N3CCC(O)CC3)C[C@@H]2Cc2ccccc2)c1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(C(=O)N2CC[C@@H](N3CCC(OC(=O)c4cc(Cl)cc(Cl)c4)CC3)C[C@@H]2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.3 %

Procedure:
3,5-Dichlorobenzoyl chloride (1 g) was added to a mixture of compound 31 (2 g) and triethylamine (0.5 g) in CH2Cl2 (25 ml) and the mixture was stirred at RT for 1 hour. The mixture was washed with water. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and their solvent evaporated. The residue was dried, yielding 0.34 g (11.7%) of (±)-trans-1-[1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinyl]-4-piperidinyl 3,5-dichloro-benzoate (compound 33, mp. 83.3° C.).
Reaction SMILES: CO[CH:3](OC)[CH2:4][Br:5].Br.O.[Br:10][C:11]1[C:12]([NH2:18])=[N:13][CH:14]=[C:15](Br)[N:16]=1>CN(C=O)C>[Br:5][C:4]1[N:16]=[C:11]([Br:10])[C:12]2[N:18]([CH:15]=[CH:14][N:13]=2)[CH:3]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: COC(CBr)OC
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cn2ccnc2c(Br)n1
Reaction time: 12 h
Yield: 81.3 %

Procedure:
A mixture of 5.0 g (30 mmol) of bromoacetaldehyde dimethyl acetal 1.0 ml of concentrated aqueous HBr solution and 4.0 ml of distilled water was brought to reflux for 1 h. After reaction, the mixture was alkalinized and extracted with ether. This organic phase was added to a solution of 1.0 g (4.0 mmol) of 3,5-dibromopyrazin-2-amine in 2 ml of DMF. The ether was removed and the mixture was stirred under a stream of nitrogen for 12 h. After reaction, the DMF was removed and the residue was dissolved in 5 ml of anhydrous ethanol and then it was brought to reflux for 1 h. The alcohol was then removed and the residue was dissolved in water, alkalinized with Na2CO3 and extracted with dichloromethane. After chromatography with alumina column (eluted with ether), 900 mg (yield: 82%) of 6,8-dibromoimidazo[1,2-a]pyrazine was obtained. ESI-MS (M+H+): 278.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]3([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH2:17][O:16]3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:26][NH:27][CH3:28]>C1COCC1>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)([OH:16])[CH2:17][N:27]([CH3:28])[CH3:26])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC2(c3ccncc3)CO2)CCN(C)C1
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(O)(CN(C)C)c2ccncc2)CCN(C)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2,8-Dimethyl-5-((2-(pyridin-4-yl)oxiran-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.3 mmol) was added to 2M dimethyl amine solution in THF (5 mL) and the reaction mixture was allowed to stir at 60° C. overnight. The progress of reaction was monitored by LCMS. The solvent was removed under reduced pressure to obtain a crude oily product that was purified by reverse phase HPLC to afford 5 mg of 1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(dimethylamino)-2-(pyridin-4-yl)propan-2-ol as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.58 (d, 2H), 7.81 (m, 2H), 7.18 (d, 1H), 7.05 (m, 1H), 6.91 (m, 1H), 4.63 (m, 1H), 4.51 (s, 2H), 4.27 (d, 1H), 4.18 (m, 2H), 3.58 (m, 2H), 3.48 (m, 1H), 3.1 (s, 6H), 2.89 (m, 1H), 2.8 (s, 3H), 2.35 (s, 3H). Separation by chiral HPLC provides enantiomers II-259a-b.
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[CH2:20]([Li])CCC.CI>C1COCC1>[F:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[C:3]1[C:2]([CH3:20])=[C:6]([C:7]([F:10])([F:9])[F:8])[N:5]([CH3:11])[N:4]=1
Reactant: [Li]CCCC
Reactant: Cn1nc(-c2cc(F)ccc2F)c(Br)c1C(F)(F)F
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(-c2cc(F)ccc2F)nn(C)c1C(F)(F)F
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A solution of 10 g of 4-bromo-3-(2,5-difluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole in 250 mL anhydrous THF was cooled to -78° C. and stirred with an overhead stirrer. The cold solution was treated with 12 mL of 2.5M n-butyllithium in hexanes never allowing the temperature to exceed -70° C. After stirring for 5 minutes, 1.9 mL of methyl iodide was added quickly. The cooling bath was removed and the solution allowed to warm to room temperature. The solution was diluted with diethyl ether and the combined organic extracts were washed twice with brine, dried over anhydrous magnesium sulfate and concd in vacuo. Chromatographic purification (silica, 5% ethyl acetate in hexanes) gave 5.8 g (72.4%) of 3-(2,5-difluorophenyl)-1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazole as an oil; 1HNMR (CDCl3) δ 2.0 (quintet, 3H, J=2.1 Hz), 3.9 (d, 3H, J=1.2 Hz), 6.9-7.1 (m, 3H). Anal. Calcd for C13H9F5N2: C, 52.18; H, 3.28; N, 10.14. Found: C, 52.20; H, 3.30; N, 10.11.