Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>C(Cl)Cl.O>[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[N:13][C:5]=1[O:4][C:3]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:2]=1[F:1]
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1F
Reactant: NCc1ccccc1Cl
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1ccccc1Cl)c1cccnc1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.1 %

Procedure:
To a stirred solution of 2-(2,4-difluoro-phenoxy)-nicotinic acid (0.300 grams, 1.19 mmole) and NMM (0.133 grams, 1.31 mmole) in dry methylene chloride (15 ml) at −10° C. was added isobutyl chloroformate (0.202 grams, 1.31 mmole). After 20 minutes at −10° C. 2-chlorobenzylamine (0.202 grams, 1.43 mmole) was added and the mixture was allowed to warm to room temperature over night. The mixture was poured into water and extracted with ethyl acetate. The combined organics were washed with 1 N NaOH, water and brine, dried over MgSO4, filtered and concentrated to give a clear oil that was purified by chromatography on silica gel eluting with 30% ethyl acetate/hexane to give a solid. Recrystalization from ethyl acetate/hexane gave a solid (0.295 g). M.P. 122-124° C.; Anal. calcd. for C19H13N2O2F2Cl: C, 60.89; H, 3.50; N, 7.47. Found: C, 60.77; H, 3.44; N, 7.38.
Reaction SMILES: [CH2:1]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=C.I([O-])(=O)(=O)=[O:17].[Na+]>C1COCC1.O.CC(O)(C)C.O=[Os](=O)(=O)=O>[C:10]1([C:4]2([CH2:1][CH:2]=[O:17])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CCC1(c2ccccc2)CCCCC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: O=CCC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (1-allylcyclohexyl)benzene (210 mg, 1.048 mmol) in THF (5 mL) was added a solution of sodium periodate (538 mg, 2.52 mmol) in water (5.00 mL), and 0.105 ml of 2.5% OsO4 in t-BuOH, and the mixture was stirred at room temp for 18 hrs. It was extracted with EtOAc and washed with brine. The combined aqueous layers were back extracted with EtOAc and combined. Dried over Na2SO4 and evaporated to give an oily residue. 1H NMR (400 MHz, CCl3D) δ ppm 9.36 (2H, t, J=3.08 Hz), 7.18-7.42 (5H, m), 2.58 (2H, d, J=3.30 Hz), 1.34-1.81 (10H, m).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]([O:17]CC)=[O:16])[CH:3]=1.[OH-].[Na+]>C(O)C.C(OCC)(=O)C.O>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[C:4]([C:15]([OH:17])=[O:16])[CH:3]=1
Reactant: CCOC(=O)c1cc(C)n(CCc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)O)nn1CCc1ccccc1
Yield: 94.7 %

Procedure:
Ethyl 5-methyl-1-phenethylpyrazole-3-carboxylate (3.84 g, 14.9 mM) in ethanol (30 ml) with sodium hydroxide (0.6 g 14.9 mM) was stirred at room temperature for 3 days. The mixture was then diluted with ethyl acetate and water and the layers separated. The organic phase was further extracted with water. The combined aqueous extracts were acidified to pH 2.0 with 5M hydrochloric acid and extracted with dichloromethane. The organic extracts were dried (MgSO4) and evaporated to give the title compound (3.24 g, 95%); νmax (CH2Cl2) 1759 and 1699 cm-1 ; δH (CDCl3) 1.91 (3H, s), 3.16 (2H, t, J7 Hz), 4.31 (2H, t, J7 Hz), 6.54 (1H, s), 6.98-7.10 (2H, m), and 7.20-7.37 (3H, m).
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6](=[O:8])[O:5][C:3]1=O.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C1(C)C(C)=CC=CC=1>O>[CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6](=[O:8])[N:15]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:3]1=[O:5]
Reactant: Nc1ccncc1
Reactant: CC1(c2ccccc2)CC(=O)OC1=O
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1(c2ccccc2)CC(=O)N(c2ccncc2)C1=O
Reaction time: 7 h

Procedure:
The starting material is prepared as follows: The mixture of 68.6 g of 2-methyl-2-phenylsuccinic anhydride, 34 g of 4-aminopyridine and 675 ml of xylene is refluxed on a water separator while stirring for 7 hours. It is cooled to 40°, filtered, cooled to 0° and filtered again. The second residue is recrystallized from isopropanol-hexane, to yield the 3-methyl-3-phenyl-1-(4-pyridyl)-pyrrolidin-2,5-dione melting at 90°-92°.
Reaction SMILES: C(C1C=CC=CC=1)C.[Cl-].[OH:10][CH2:11][CH2:12][NH+:13]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41].[C:43]([Cl:48])(=[O:47])[C:44]([CH3:46])=[CH2:45]>N1C=CC=CC=1>[Cl-:48].[C:43]([O:10][CH2:11][CH2:12][NH+:13]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])(=[O:47])[C:44]([CH3:46])=[CH2:45]
Reactant: CC(C)CCCCCCCCCCCCCCCC1N(Cc2ccccc2)CC[NH+]1CCO
Reactant: C=C(C)C(=O)Cl
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCc1ccccc1
Product: C=C(C)C(=O)OCC[NH+]1CCN(Cc2ccccc2)C1CCCCCCCCCCCCCCCC(C)C
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a 10 percent w/v ethylbenzene solution of 135 g of 1-(2-hydroxyethyl)-2-isostearyl-3-benzylimidazolinium chloride at 20° C. is added 1.1 molar equivalents (24.5 g) of pyridine followed by dropwise addition of 1.3 molar equivalents (38.3 g) of methacryloyl chloride. The solution is stirred for 4 hours at 20° C. followed by separation of the supernatant liquid and the ethylbenzene removed to give an oil of 1-(2-methacryloxyethyl)-2-isostearyl-3-benzylimidazolinium chloride.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:18][C:19]2[C:20]([NH:29][S:30]([C:33]3[CH:34]=[C:35]([NH:39][C:40](=[O:51])[C@@H:41]([NH:43]C(=O)OC(C)(C)C)[CH3:42])[CH:36]=[CH:37][CH:38]=3)(=[O:32])=[O:31])=[N:21][C:22]3[C:27]([N:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1>C(Cl)Cl>[ClH:1].[NH2:43][C@@H:41]([CH3:42])[C:40]([NH:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([S:30](=[O:31])(=[O:32])[NH:29][C:20]2[C:19]([NH:18][C:12]3[CH:11]=[C:10]([O:9][CH3:8])[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=3)=[N:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH:34]=1)=[O:51]
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c2)cc(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(NC(=O)[C@H](C)N)c2)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4 N HCl is dioxane (10 mL) was added to a solution of (S)-tert-butyl 1-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenylamino)-1-oxopropan-2-ylcarbamate (160 mg) and DCM (15 mL). The mixture was stirred at room temperature for 3 hours. The solvent decanted and ether added to the solid, ether decanted to gave 80 mg product as HCl salt. 1H NMR (400 MHz, CD3OD) δ 8.50-8.49 (t, 1H), 7.89-7.87 (m, 1H), 7.74-7.72 (m, 1H), 7.61-7.5 (m, 3H), 7.40-7.36 (m, 2H), 7.21-7.20 (d, 2H), 6.23-6.21 (t, 1H), 4.09-4.03 (q, 1H), 3.78 (s, 6H), 1.60-1.58 (d, 3H); MS (EI) m/z for C25H26N6O5S.HCl: 523.1 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1)#[N:8].ClCCl.Br[C:22]1[N:26]2[N:27]=[C:28]([N:31]3[CH2:35][CH2:34][C@H:33]([OH:36])[CH:32]3[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=3)[CH:29]=[CH:30][C:25]2=[N:24][CH:23]=1>O1CCOCC1.O>[F:43][C:39]1[CH:38]=[C:37]([CH:32]2[C@@H:33]([OH:36])[CH2:34][CH2:35][N:31]2[C:28]2[CH:29]=[CH:30][C:25]3[N:26]([C:22]([C:13]4[CH:14]=[C:9]([CH:10]=[CH:11][CH:12]=4)[C:7]#[N:8])=[CH:23][N:24]=3)[N:27]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: N#Cc1cccc(-c2cnc3ccc(N4CC[C@H](O)C4c4cccc(F)c4)nn23)c1

Procedure:
In step 3-5, in a microwave vessel sodium carbonate (105 mg, 1.0 mmol), 3-cyano phenylboronic acid (200 mg, 1.36 mmol) and Pd(DPPF)-dichloride catalyst (1,1′ bis(diphenylsphosphino-ferrocene)-dichloropalladium (II) adduct with dichloromethane) (100 mg, 0.12 mmol) were added to a solution (3S)-1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-(3-fluorophenyl)pyrrolidin-3-ol (1.40 g, 0.36 mmol) and 4 mL of 1,4-dioxane/water (3:1). This solution was then subjected to the following microwave conditions using a laboratory microwave instrument (conditions: 150° C., 200 W max threshold, 20 atm. max pressure, 20 minute reaction time). The reaction mixture was purified directly with reverse phase C-18 HPLC (water/acetonitrile 90:10 to 10:90 gradient) to yield 3-(6-((3S)-2-(3-fluorophenyl)-3-hydroxypyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile (3-5) as a mixture of diastereomers. 1H NMR (400 MHz, D6 acetone) δ ppm 8.85 (br s, 1H), 8.40-8.03 (m, 3H), 7.90-7.22 (m, 5H), 7.10 (app d, J=5.5 Hz, 1H), 6.98 (app t, J=4.5 Hz, 1H), 5.25 (app d, J=4.5 Hz, 1H), 4.80 (app q, J=7.5 Hz, 1H), 4.30 (br s, 1H), 3.82-3.75 (m, 1H), 3.3-3.55 (m, 1H), 2.42-2.34 (m, 1H), 2.25-2.12 (m, 1H). LCMS observed m/z 400.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1Cl
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1sc2nc(-c3ccccn3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-dichlorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N+:19][O-:6])=[CH:16][CH:15]=1
Reactant: CN(C)c1ccc(C#N)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN(C)c1ccc(C#[N+][O-])cc1

Procedure:
A solution of 13.8 g of meta-chloroperoxybenzoic acid in 200 ml of methylene chloride was added dropwise to a solution of 11.7 g of para-dimethylaminobenzonitrile in 80 ml of methylene chloride at a temperature of from 0° C. to -5° C. over the course of two hours. When no more peroxide was detectable (negative Kl test), the solvent was evaporated on a rotary evaporator. This gave 25.7 g of the meta-chlorobenzoic acid salt of para-dimethylaminobenzonitrile N-oxide. Pure para-dimethylaminobenzonitrile N-oxide was isolated by chromatography on aluminum oxide. 9
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[CH:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1.Br[CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH:32]=[O:33])[CH2:28][CH2:27]1.C(N(CC)CC)C>CN(C)C=O>[CH2:2]([N:3]1[C:9]2[C:8](=[CH:13][C:12]([F:14])=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([CH:32]=[O:33])[CH2:28][CH2:27]4)[CH2:17][CH2:16]3)[CH:10]=2)[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:1]
Reactant: O=CN1CCC(CBr)CC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC4CCN(C=O)CC4)CC3)cc21
Temperature: 100 °C
Yield: 75 %

Procedure:
A mixture of norfloxacin (0.96 g, 3 mmol), 4-bromomethyl-1-formylpiperidine (1.26 g 6.1 mmol) and triethylamine (0.44 g, 0.6 mL, 4.3 mmol) in anhydrous dimethylformamide (15 mL) was heated at 100° C. for 2 hours. The solvent was removed under high vacuum and the residue was dissolved in methanol, filtered and precipitated by the addition of diethyl ether to give the product as a white solid (1.0 g, 75% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:7]1[C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=[C:2]([Cl:1])[CH:8]=1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1c(Br)cc(Cl)cc1[N+](=O)[O-]
Yield: 81 %

Procedure:
In glacial acetic acid, 51.8 g (300 mmoles) of 4-chloro-2-nitroaniline was reacted with 57.5 g (360 mmoles) of bromine to give 61.6 g (243 mmoles) of 6-bromo-4-chloro-2-nitroaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15]([OH:17])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CCOCC1)C.FC(F)(F)C(O)=O.[Cl:61][C:62]([Cl:77])([Cl:76])[C:63]1[O:67][N:66]=[C:65]([N:68]2[CH2:73][CH2:72][CH:71]([CH2:74][NH2:75])[CH2:70][CH2:69]2)[N:64]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15]([NH:75][CH2:74][CH:71]1[CH2:72][CH2:73][N:68]([C:65]2[N:64]=[C:63]([C:62]([Cl:77])([Cl:76])[Cl:61])[O:67][N:66]=2)[CH2:69][CH2:70]1)=[O:17]
Reactant: Cc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Reactant: NCC1CCN(c2noc(C(Cl)(Cl)Cl)n2)CC1
Agent: CCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCC2CCN(c3noc(C(Cl)(Cl)Cl)n3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid (200 mg, 0.615 mmol) was dissolved in 5 ml DMF. After cooling to −15° C. HATU (257.34 mg, 0.676 mmol) and N-ethylmorpholine (283.3 mg, 2.46 mmol) were added. The mixture was stirred at 0° C. for 15 min. and 30 min. at room temperature. C-[1-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-piperidin-4-yl]-methylamine; compound with trifluoro-acetic acid (254.4 mg, 0.615 mmol) was added and the mixture stirred for 1 hour and evaporated under reduced pressure. The residue was dissolved in sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried with MgSO4 and evaporated. The crude material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:4][N:3]=1>C(O)(C(F)(F)F)=O.ClCCl>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:6]=3[S:10][CH:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2csc3c(-c4ccncc4)cnc(N)c23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2csc3c(-c4ccncc4)cnc(N)c23)cc1
Yield: 129 %

Procedure:
A solution of Example 121A (0.11 g, 0.263 mmol) in TFA (3 mL) and dichloromethane (1 mL) was stirred at room temperature for 30 minutes and concentrated under a stream of nitrogen. The residue was triturated from ethyl acetate/hexanes to provide 108 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 5.66 (s, 2H), 6.78 (d, J=8.14 Hz, 2H), 6.97 (s, 2H), 7.20 (d, J=8.48 Hz, 2H), 7.75 (s, 1H), 7.91 (d, J=6.44 Hz, 2H), 8.19 (s, 1H), 8.83 (d, J=6.44 Hz, 2H); MS (ESI(+)) m/e 319 (M+H)+.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([OH:27])=O.C(N(CC)CC)C.Cl.[CH2:36]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][CH2:51][CH2:52][C:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O>[CH2:36]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][CH2:51][CH2:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][C:25]([CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)=[O:27])=[CH:55][CH:54]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: Nc1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccccn1)Nc1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 68.1 %

Procedure:
Diphenylphosphoryl azide (0.46 ml) was added dropwise to a stirred suspension of 2-pyridylacetic acid (0.367 g) and triethylamine (0.3 ml) in N,N-dimethylformamide (10 ml) maintained at 0° C. A suspension of 4-[3-(2-benzyloxyphenyl)propyl]benzeneamine hydrochloride (0.75 g) in N,N-dimethylformamide (10 ml) containing triethylamine (0.9 ml) was added rapidly to the reaction mixture. Stirring was continued at ambient temperature for 16 hours and the reaction mixture was concentrated to small volume. The residue was partitioned between water and diethyl ether. The diethyl ether extract was washed once each with saturated aqueous sodium bicarbonate (20 ml) and brine (20 ml) and dried. The gum obtained on removal of the solvent was subjected to chromatography on silica (Merck 9385) eluted with a mixture of ethyl acetate and hexane (1:1 v/v). The gum obtained was triturated with ether at 0° C. to give 4-[3-(2-benzyloxy-phenyl)propyl]-N-(2-pyridylmethylcarbonyl)benzeneamine (m.p. 61°-2° C.; yield 0.63 g 68%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[C:7]12([CH2:17][NH:18][C:19](=[O:28])[C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Br)[CH:21]=3)[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2>CN1CCCC1=O>[C:7]12([CH2:17][NH:18][C:19](=[O:28])[C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([O:5][CH2:4][CH2:3][OH:6])[CH:21]=3)[CH2:8][CH:9]3[CH2:10][CH:11]([CH2:12][CH:13]([CH2:15]3)[CH2:14]1)[CH2:16]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ncc1Cl
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCO)ncc1Cl
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 0.080 g) was added to ethylene glycol (3 ml) and the resulting suspension stirred under an atmosphere of nitrogen for 30 minutes. To this mixture was added a solution of N-(1-adamantylmethyl)-2-bromo-5-chloroisonicotinamide (Example 1(ii)) (0.192 g) in anhydrous N-methyl-2-pyrrolidinone (1 ml). The stirring bar was removed and the resulting solution heated in a MARS microwave for 15 minutes (300 Watts, 150° C.). The mixture was cooled and poured into water (50 ml) and extracted into is ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (2×10 ml), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate:isohexane (1:1) to afford the sub-titled compound (0.092 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[C:34]([NH:38]O)([CH3:37])([CH3:36])[CH3:35].O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][NH:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)NO
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.4 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione (400 mg, 1.37 mmol) (compound of Example 9) and 1,1′-carbonyldiimidazole (334 mg, 2.06 mmol) in N,N-dimethylformamide (16 mL) was stirred for 1 hour. In one portion, N-tert-butylhydroxylamine hydrochloride (516 mg, 4.11 mmol) was added and the solution was stirred for 17 hours at room temperature. To the resulting solution was added water (20 mL). The insoluble material was filtered and washed with hot methanol (3×20 mL) to give the title compound (300 mg, 61% yield, m.p. 258° C.).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][CH2:12][NH:11][C@@H:10]1[C@@H:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=1[CH3:26])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:36](Cl)(Cl)=[O:37]>C(Cl)Cl.C1(C)C=CC=CC=1>[O:8]([C@@H:9]1[C@@H:10]2[N:11]([C:36](=[O:37])[N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=3[CH3:26])[C@H:14]2[CH3:15])[CH2:12][CH2:13]1)[Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(N[C@@H](C)[C@H]2NCC[C@@H]2O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(N2C(=O)N3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude 61I (˜1.81 mmol) in CH2Cl2 (10 mL) was added i-Pr2NEt (2 mL) followed by 20% phosgene in toluene (2.5 mL) dropwise. The reaction was stirred at rt overnight. Reaction was extracted with EtOAc (50 mL) which was washed twice with 1N HCl and then saturated NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. Purification by flash chromatography (silica gel, 0 to 10% EtOAc in hexane) provided the title compound (369 mg): MS (ES) m/z 420.23 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([CH:6]=[C:7]([CH3:21])[C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([Cl:20])=[CH:12][CH:11]=1)[NH2:5].[F:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:25]=1[C:26]([N:28]=[C:29]=[O:30])=[O:27]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:5][C:29]([NH:28][C:26](=[O:27])[C:25]2[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:24]=2[F:23])=[O:30])[CH:6]=[C:7]([CH3:21])[C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([Cl:20])=[CH:12][CH:11]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Cc1cc(N)c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(=O)c2c(F)cccc2F)c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
Into a solution containing 3.0 grams (9.0 mmol) of 3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethylaniline prepared in Part B of Example I in 25 milliliters of toluene which solution was warmed to a temperature of 50° .C and placed under a nitrogen atmosphere was slowly added a solution containing 2.5 grams (13.5 mmol) of 2.6-difluorobenzoyl isocyanate in 5 milliters of toluene. After stirring for one hour at a temperature of 50° C. the reaction mixture was cooled to room temperature, placed in an ice bath. and filtered through a Buchner funnel. The collected solid was dried under a vacuum at a temperature of 50° C. to afford 2.89 grams of 1-[3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethylphenyl]-3-(2,6-difluorobenzoyl)urea as a white powder havin a melting point of 187° C. Elemental analysis of the white powder indicated the following:
Reaction SMILES: [N:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:1][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1
Reactant: O=NN1CCN(Cc2cccs2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NN1CCN(Cc2cccs2)CC1
Reaction time: 3 h
Yield: 97.7 %

Procedure:
A solution of N-nitroso-N'-2-thenylpiperazine (3.0 g, 0.014 mole) in anhydrous freshly distilled tetrahydrofurane (30 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (1.5 g excess) under nitrogen in anhydrous tetrahydrofuran (150 ml) at 60°-65° C. After addition, stirring was continued for 3 hours. Work-up via cooling, controlled addition of water (1.5 ml), 10% sodium hydroxide (2.25 ml) and water (3.75 ml) followed by filtration, drying over potassium carbonate, filtration and evaporation in vacuo gave N-amino-N'-2-thenyl-piperazine (2.7 g, 96%) as an almost colourless oil, used without further purification,