Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-])=O.S.[Na]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: S
Agent: [Na]
Solvent: O
Product: Nc1cc(Cl)ccc1Cl

Procedure:
576 Parts of 2,5-dichloro-nitrobenzene and 300 parts of water were placed in a stirring apparatus and reacted in the same manner as described in Example 1 with 1,446 parts of a 36% sodium hydrogen sulfide solution at a temperature within the range of from 80° to 85°C. Then, the 2,5-dichloroaniline formed as by-product was separated by steam distillation. After cooling to 20°C 1,210 parts of sodium sulfite and 430 parts of xylene were successively added and the pH was adjusted at 6 at a temperature within the range of from 8° to 12°C during 3 to 4 hours with 550 parts of 30% hydrochloric acid while stirring. After precipitation and separation of the organic phase, the aqueous phase was stirred once with 174 parts of xylene. 4-Chloro-2-amino-thiophenol was isolated from the organic phase, combined by vacuum distillation.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOCC.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: O=Cc1ccc(Sc2ccc(Cl)cc2)cc1

Procedure:
A solution of 4-fluoro-benzaldehyde (1 eq), 4-chloro-benzenethiol (1.0 eq) and sodium carbonate (1.5 eq) in DMF (0.16 M) was heated at 100° C. for 3 h then 18 h at rt. The mixture was diluted with ether and water, the organic phase washed with brine and the solvents evaporated. The residue was purified by stirring vigorously in hexane-ether followed by filtration to give the title compound as a white solid.
Reaction SMILES: COC1[CH:4]=[C:5]2[C:14](=[CH:15]C=1)[CH:13](COS(C1C=CC(C)=CC=1)(=O)=O)[CH:12]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[CH3:37][Mg]Br.[O:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH2:14]([CH:13]1[CH:12]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[C:5]2[C:41]1=[CH:42][CH:43]=[C:44]([O:40][CH3:37])[CH:4]=2)[CH3:15]
Reactant: COc1ccc(C2C(COS(=O)(=O)c3ccc(C)cc3)c3ccc(OC)cc3C3CCCCC32)cc1
Reactant: C1CCOC1
Reactant: C[Mg]Br
Product: CCC1c2ccc(OC)cc2C2CCCCC2C1c1ccc(OC)cc1
Reaction time: 18 h
Yield: 81 %

Procedure:
Combine toluene-4-sulfonic acid 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-ylmethyl ester (0.151 g, 0.30 mmol), methyl magnesium bromide (0.46 mL, 1.40 mmol), Li2CuCl4 (150 uL), and tetrahydrofuran (3 mL), and stir under nitrogen atmosphere. After 18 hours, concentrate reaction under vacuum and flash chromatograph using 0% to 10% ethyl acetate/hexanes to yield the titled compound (0.085 g, 81%) as a white foam. TLC Rf=0.60 in 8:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.32 (s, 1H), 7.24 (d, 2H, J=8.4 Hz), 6.94 (m, 3H), 6.81 (dd, 1H, J=8.4, 2.6 Hz), 3.86 (m, 6H), 3.42 (m, 1H), 3.23 (s, 1H), 3.08 (dd, 1H, J=12.1, 3.3 Hz), 2.49 (d, 1H, J=13.7 Hz), 1.93 (m, 2H), 1.67 (m, 1H), 1.57 (m, 2H), 1.44 (d, 2H, J=8.8 Hz), 1.19 (m, 3H), 0.62 (t, 3H, J=7.3 Hz).
Reaction SMILES: CCO/C(/C)=[N:5]\[O:6][S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8].Cl(O)(=O)(=O)=O>O1CCOCC1>[C:11]1([CH3:18])[CH:12]=[C:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:10]=1[S:7]([O:6][NH2:5])(=[O:9])=[O:8]
Reactant: CCO/C(C)=N\OS(=O)(=O)c1c(C)cc(C)cc1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1COCCO1
Product: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Temperature: 0 °C

Procedure:
An adaptation of the method described in WO 96/01826 was used. To a solution of ethyl O-mesitylsulfonylacetohydroxamate 7 (1.7 g, 6.0 mmol) in 1,4-dioxane (10 mL) cooled in an ice bath (freezes at 8-9° C.) was added 70% perchloric acid (7.5 mL) dropwise over 15 minutes, maintaining internal temperature below 15° C. The mixture was then diluted with ice water (100 mL) to precipitate the product O-(mesitylsulfonyl)hydroxylamine 8 which was filtered off, washed thoroughly with water, and immediately dissolved in chloroform (10 mL) while still wet (CAUTION! 8 is explosive when dry!). The organic layer was separated and was passed through a plug of Na2SO4 in a fritted syringe to remove water. The so obtained solution of O-(mesitylsulfonyl)hydroxylamine 8 was added dropwise to a solution of 2-amino-4,6-dimethylpyridine 9 (0.611 g, 5.00 mmol) in chloroform (10 mL) cooled in an ice bath. The mixture was then warmed to room temperature and was stirred for 2 hours to effect conversion to intermediate 10. Into the reaction mixture was then added 1,1′-thiocarbonyldimidazole 11 (1.16 g, 6.5 mmol) and the resulting mixture was stirred at 40° C. overnight. Volatiles were evaporated and the residue was chromatographed on silica gel (gradient elution with heptane:ethyl acetate 100:0→0:100) to yield imidazole-1-carbothioic acid (2-imino-4,6-dimethyl-2H-pyridin-1-yl)-amide 12 as an off-white solid (0.50 g, 40%) containing a minor amount of residual imidazole. 1H NMR (500 MHz, DMSO-d6): δ7.88 (s, 1H), 7.64 (s, 1H), 7.42 (br s, 2H), 6.93 (s, 1H), 6.69 (s, 1H), 6.67 (s, 1H), 2.28 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:11][C:41]([C:37]2[CH:36]=[C:35]3[C:40](=[CH:39][CH:38]=2)[N:32]([CH2:31][C:28]2[CH:27]=[CH:26][C:25]([C:20]4[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:30][CH:29]=2)[C:33]([CH3:45])=[C:34]3[CH3:44])=[O:42])([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1ccc(Br)cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC(C)(C)c3ccc(Br)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the 2-(4-bromophenyl)propan-2-amine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 595/597 [M+H]+.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:24])=[O:23])=[CH:20][CH:19]=1>>[ClH:24].[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([F:17])=[CH:19][CH:20]=3)=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1
Product: Cl
Product: O=C(Nc1ccc(N2CCN3CCC2CC3)cc1)c1ccc(F)cc1

Procedure:
Was prepared by Method G from 4-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-phenylamine and 4-fluorobenzoyl chloride. Mp. >270° C. (decomp.).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C:4]([NH:7][CH2:8][CH:9]([OH:28])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[C:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)([CH3:6])[CH3:5]>C(O)C>[CH3:6][C:4]([NH:7][CH2:8][CH:9]([OH:28])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[C:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:1])=[CH:22][CH:21]=1)([CH3:3])[CH3:5]
Reactant: CC(C)(C)NCC(O)COc1ccccc1C#Cc1ccc(C#N)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)NCC(O)COc1ccccc1C#Cc1ccc(C(N)=O)cc1
Yield: 71.8 %

Procedure:
A solution of 11.5 ml (31.5 mmoles) of 3N NaOH solution was added to a solution of 5.8 g (15.3 m moles) of 4-[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenylethynyl]benzonitrile, the product of Example 14 in 50 ml of 95% ethanol. The mixture was heated under reflux for 30 min. The solution of 25 ml of 95% ethanol and 5.0 ml of 3N aqueous NaOH was added. The mixture was heated under reflux for 15 min. The solution was cooled and the solid collected by filtration. The solid was recrystallized from 95% ethanol to give 4.38 g of 4-[[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenyl]ethynyl]benzamide, mp 199°-201° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:15](O)[CH3:16]>OS(O)(=O)=O>[CH2:15]([O:13][C:12](=[O:14])[CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH2:1])[S:3][C:4]=2[CH:10]=1)[CH3:16]
Reactant: CCO
Reactant: Nc1nc2ccc(CC(=O)O)cc2s1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc2nc(N)sc2c1

Procedure:
A solution of (2-amino-benzothiazol-6-yl)-acetic acid (0.61 mmol, as prepared by Meyer et al. in J. Med. Chem. 1997, 40, 1060) in absolute ethanol (10 mL) was treated with 3 drops of concentrated H2SO4 and ca. 1 g of dry 4A molecular sieves, and heated to reflux for 3 d. The reaction was concentrated to dryness in vacuo, partitioned between CH2Cl2 and saturated aqueous NaHCO3, filtered, and phases separated. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo giving the title compound as a yellow solid. 1H NMR (CDCl3) δ 7.50 (1H, m), 7.41 (1H, d, J=8.3 Hz), 7.20 (1H, dd, J=8.2 Hz, 1.9 Hz), 4.15 (2H, q, J=7.2 Hz), 3.65 (2H, s), 3.42 (4H, s [NH2+H2O]), 1.26 (3H, t, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][NH:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][N:25]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:24]1
Reactant: CC1CNCC1CN
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC1CN
Temperature: 25 °C
Reaction time: 7 h
Yield: 33 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.6 g), anhydrous acetonitrile (5 ml), 3-aminomethyl-4-methylpyrrolidine (0.27 g) and 1,8-diazabicyclo[5,4,0]-7-undecene (DBU; 0.3 g) was refluxed for an hour and then stirred at room temperature for 7 hours. The resulting precipitate was collected by filtration and recrystallized from chloroform-methanol-concentrated aqueous ammonia (10:10:1) to give the title compound (0.26 g) as colorless prisms, mp 235°-238° C.
Reaction SMILES: [C:1]1(=[CH:6][C:7](=[O:9])[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CC(=O)C)CCCC=1.[C:19]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:20][C:21]([CH3:23])=O>CCCCCCC.C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:23][C:21]1[CH:20]([C:19]([O:25][CH2:26][CH3:27])=[O:24])[C:1]2([CH2:6][C:7](=[O:9])[CH:8]=1)[CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)C=C1CCCC1
Agent: CC(=O)CC1=CCCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CCCCCCC
Product: CCOC(=O)C1C(C)=CC(=O)CC12CCCC2
Yield: 12.1 %

Procedure:
A mixture of 1-cyclopentylidenepropan-2-one/1-cyclopentenylpropan-2-one (25:75, 100 g, 0.805 mol), ethyl acetoacetate (105 g, 0.805 mol), and zinc chloride (16.5 g, 0.12 mol) in heptane (100 ml) and benzene (100 ml) was refluxed for 6 days using a Dean-Stark apparatus. The resulting mixture was cooled, washed with water (250 ml), with a 5% aqueous solution of NaHCO3 (250 ml), with water, dried (MgSO4) and concentrated. Vigreux-Distillation (0.1 mbar, bath temperature 150° C., head temp. 106-130° C.) of the crude product (174 g) followed by FC (SiO2, hexane/MTBE 10:1 to 5:1) gave ethyl 7-methyl-9-oxospiro[4.5]dec-7-ene-6-carboxylate (23 g, 12%).
Reaction SMILES: [Cl:1]C[N:3]=[C:4]=[O:5].F[C:7]1[C:8](=O)[NH:9][C:10](=O)[NH:11][CH:12]=1>N1C=CC=CC=1>[Cl-:1].[NH:11]1[CH:12]=[CH:7][CH:8]=[N:9][CH:10]1[C:4]([NH2:3])=[O:5]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C=NCCl
Solvent: c1ccncc1
Product: NC(=O)C1N=CC=CN1
Product: [Cl-]
Yield: 97.1 %

Procedure:
Chloromethyl isocyanate (10.6 g, 116 mmol) and 5-fluorouracil (7.56 g, 58.2 mmol) were added into pyridine (100 ml). Then, the mixture was stirred and reacted under reflux for 15 minutes. After cooling the reactant, the obtained crystals were washed with pyridine, and then toluene, and vacuum-dried. 5-Fluoro-3,4-dihydro-2,4-dioxo-N-pyridiniomethyl-1(2H-pyrimidinecarboxamide chloride (17.0 g, 56.5 mmol) was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].CN(C=O)C.[H-].[Na+].Br[CH2:18][CH:19]=[CH2:20]>O>[CH2:20]([O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 3-hydroxy-2,2-dimethylpropanoate (5.59 g, 1 eq.) and DMF (42 ml) at 0° C. was slowly added NaH (60% in mineral oil, 1.69 g, 1 eq.). After 30 min, 3-bromoprop-1-ene (5.12 g, 1 eq.) was added. The reaction mixture was warmed to room temperature and stirred overnight. Water was carefully added. The resulting mixture was extracted with EtOAc, dried over MgSO4 and concentrated to yield a light-yellow oil to be used in the next step without purification.
Reaction SMILES: C(OC(=O)C)(=O)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[N:15][N:16]2[CH2:20][C:19](O)([CH3:21])[N:18]([N:23]=[CH:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:17]2=[O:31])[CH:9]=1.[OH-].[Na+]>C(O)(=O)C>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[N:15][N:16]2[CH:20]=[C:19]([CH3:21])[N:18]([N:23]=[CH:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:17]2=[O:31])[CH:9]=1
Reactant: CC1(O)CN(N=Cc2cccnc2)C(=O)N1N=Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1cn(N=Cc2cccnc2)c(=O)n1N=Cc1cccnc1
Temperature: 0 °C

Procedure:
11.2 g of acetic anhydride are added to a suspension of 32.4 g of 1,3-bis(pyridin-3-ylmethyleneamino)-4-hydroxy-4-methylimidazolidin-2-one in 75 ml of acetic acid. The reaction mixture is then heated to 50°. After 3 hours the reaction mixture is cooled to 20°, then poured onto 800 ml of ice-water and neutralised with 30% sodium hydroxide solution. The aqueous phase is then extracted three times with 200 ml of methylene chloride each time. The organic phase is dried with magnesium sulfate, filtered and concentrated by evaporation. The residue is stirred with ether. The crystals are filtered off with suction and dried. 28.2 g of the title compound having a melting point of 176°-178° are thus obtained.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=3)[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1)C(=O)O
Yield: 27 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole, the title compound was obtained in 27% yield as a yellow solid. MS: (M+H)+ 473.2.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.C(N(CC)CC)C.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)Cl>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)[C:47](=[O:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N(Cc1ccc(CNCc2ccccn2)cc1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 118.6 %

Procedure:
To a pre-cooled (ice bath) solution of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (201 mg, 0.37 mmol) and triethylamine (80 μl, 0.55 mmol) in anhydrous CH2Cl2 (4 mL) was added a solution of benzoylchloride (54 μl, 0.46 mmol) in anhydrous CH2Cl2 (0.5 mL) and the reaction mixture was allowed to stir at room temperature for 18 hours and then concentrated. The residue was diluted with ethylacetate (300 mL), washed with sat. aqueous NaHCO3 then brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (1.5×20 cm, 50:50 EtOAc/CH2Cl2) to give the desired amide (203 mg, 85%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([C:14]#[CH:15])=[CH:13][C:8]=2[C:7](=[O:16])[N:6]([CH3:17])[C:5]2[CH:18]=[CH:19][CH:20]=[N:21][C:4]1=2)[CH3:2].Br[C:23]1[S:24][CH:25]=[CH:26][N:27]=1>>[N:21]1[C:4]2[C:5](=[N:6][C:7](=[O:16])[C:8]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]=3[N:3]=2)[CH:18]=[CH:19][CH:20]=1.[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:13][C:8]=2[C:7](=[O:16])[N:6]([CH3:17])[C:5]2[CH:18]=[CH:19][CH:20]=[N:21][C:4]1=2)[CH3:2]
Reactant: Brc1nccs1
Reactant: C#Cc1cnc2c(c1)C(=O)N(C)c1cccnc1N2CC
Product: CCN1c2ncc(CCc3nccs3)cc2C(=O)N(C)c2cccnc21
Product: O=c1nc2cccnc2nc2ncccc12

Procedure:
5,11-Dihydro-11-ethyl-5-methyl-8-(2-thiazolyl)ethynyl-(-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.15 g) was prepared from 5,11-dihydro-11-ethyl-8-ethynyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 2-bromothiazole by a procedure analogous to that described in Example 51b. Hydrogenation as described in Example 42b afforded 26 mg of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([Br:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH:12]1[C:21]2[C:16](=[C:17]([CH2:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1>>[Br:11][C:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([NH:1][C:23](=[O:24])[CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[CH:15]=[CH:14][N:13]=[CH:12]3)[S:3][CH:4]=1
Reactant: O=C(O)Cc1cccc2cnccc12
Reactant: COC(=O)c1c(Br)csc1N
Product: COC(=O)c1c(Br)csc1NC(=O)Cc1cccc2cnccc12

Procedure:
This compound was prepared from methyl 2-amino-4-bromothiophene-3-carboxylate and 2-(isoquinolin-5-yl)acetic acid using protocol A. Method[1], MS(ESI) 404.9 [M+H], Retention time=1.678 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]23)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][N:20]=1.C([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)#N>>[CH3:17][O:18][C:19]1[N:24]=[CH:23][C:22]([C:30]2[CH:35]=[CH:34][C:33]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:12][CH2:11][C@@H:10]5[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]45)=[CH:4][CH:3]=3)=[CH:32][CH:31]=2)=[CH:21][N:20]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: CN1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: COc1ncc(-c2ccc(-c3ccc(N4CC[C@@H]5CN(C)C[C@@H]54)cc3)cc2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 7D, substituting the product of Example 41A for the product of Example 7C and substituting 2-methoxy-pyrimidine-5-boronic acid for 4-cyanophenylboronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.76 (s, 2H) 7.66 (d, J=8.54 Hz, 2H) 7.53 (dd, J=11.75, 8.70 Hz, 4H) 6.67 (d, J=8.85 Hz, 2H) 4.13-4.22 (m, 1H) 4.07 (s, 3H) 3.53-3.61 (m, 1H) 3.26-3.35 (m, 1H) 2.91-3.03 (m, 1H) 2.71-2.77 (m, 1H) 2.48-2.67 (m, 3H) 2.33 (s, 3H) 2.13-2.25 (m, 1H) 1.90-2.01 (m, 1H). MS: (M+H)+=387.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[N:4]([CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[N:3]=1.C([Mg]Cl)(C)C.[CH2:23]([Sn:27]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])Cl)[CH2:24][CH2:25][CH3:26]>C1COCC1>[CH3:16][N:15]([CH3:17])[CH2:14][CH2:13][CH2:12][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=2)[C:2]([Sn:27]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:23][CH2:24][CH2:25][CH3:26])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccc2c(I)nn(CCCN(C)C)c2c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(CCCN(C)C)c2cc(C)ccc12
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 197.5 %

Procedure:
A solution of 3-(3-iodo-6-methyl-1H-indazol1-yl)-N,N-dimethylpropan-1-amine (400 mg, 1.2 mmol) in 20 mL of dry THF was cooled to −20° C. under nitrogen atmosphere, then isopropylmagnesium chloride (1.2 mL, 2.4 mmol, 2M in THF) was added and stirred for 15 min at −20° C. Then tributylchlorostannane (0.7 mL, 2.4 mmol) was added and allowed to warm to room temperature. The reaction was cooled in an ice bath and quenched with saturated ammonium chloride solution, product extracted with ethyl acetate (3×50 mL), combined organics dried with sodium sulfate and concentrated to give N,N-dimethyl-3-(6-methyl-3-(tributylstannyl)-1H-indazol-1-yl)propan-1-amine (1.2 g, crude) as an oil which was used in the next step directly without further purification.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=[O:24])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C>[F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[NH:15][C:14]2=[O:24])=[C:11]([N+:25]([O-:27])=[O:26])[C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc2N1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=C1COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c([N+](=O)[O-])c2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[7-Fluoro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-6-trifluoromethyl-2,4-(1H, 3H)-pyrimidinedione (7.0 g) was added by portion to a mixture of acetic acid (30 ml) and fuming nitric acid (90 ml) at 0° C. After stirring for 1 hr at room temperature, the solution was mixed with ice-water (200 ml) and then extracted with ethyl acetate (60 ml×3). The organic layers were combined and washed with water (20 ml×2) and brine (20 ml), dried over sodium sulfate. After filtration and evaporation, the residue was recrystallized from methylene chloride (8.3 g).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH:11]1([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1COCC1.ClCCl>[CH:20]1([NH:19][C:18](=[N:17][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:8][N:7]=[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: ON=C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C1CCC(=NOC(=NC2CCCCC2)NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.3 %

Procedure:
To a solution of cyclohexanone oxime (5.65 g, 0.05 mol) in dry THF (30 ml) is added finely powdered NaOH (0.2 g) and dicyclohexylcarbodiimide (11.34 g, 0.055 mol). The mixture is then stirred 5 h at room temperature under argon. The turbid mixture is thereafter diluted with dichloromethane (25 ml), filtered and evaporated under reduced pressure. The residue is stirred 10 minutes with acetonitrile (30 ml), the acetonitrile phase is then discarded, the oily residue is dissolved in dichloromethane (30 ml), filtered and evaporated to afford 14.27 g of the title compound as a slightly yellow liquid.