Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH2:35][CH2:36][C:37](=[O:40])[NH:38][N:39]=2)=[CH:30][CH:29]=1)N>>[O:40]=[C:37]1[NH:38][N:39]=[C:34]([C:31]2[CH:32]=[CH:33][C:28]([N:26]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:29][CH:30]=2)[CH2:35][CH2:36]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1ccc(C2=NNC(=O)CC2)cc1
Product: O=C1CCC(c2ccc(-n3nccc3-c3nn(-c4cccc(OC(F)(F)F)c4)ccc3=O)cc2)=NN1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 6-(4-hydrazino-phenyl)-4,5-dihydro-2H-pyridazin-3-one (described in Journal of Medicinal Chemistry (1990), 33(10), 2870-5) according to example 43 gave the desired product. MS: M=495.0 (M+H)+
Reaction SMILES: C(O)C.[CH2:4]([N:6]([CH2:32][CH3:33])[C:7](=[O:31])[CH:8]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:22]=2[F:30])[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:5].O.O.Cl[Sn]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH2:19][CH2:20][N:15]([CH:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:7]([N:6]([CH2:4][CH3:5])[CH2:32][CH3:33])=[O:31])[CH2:16][CH2:17]2)=[C:22]([F:30])[CH:23]=1
Reactant: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
A 500 mL, round-bottomed flask under a positive pressure of nitrogen was equipped with a magnetic stirrer and charged with absolute ethanol (150 mL) followed by N,N-diethyl-2-[4-(2-fluoro-4-nitro-phenyl)piperazin-1-yl]-2-phenyl-acetamide (5.6 g, 13.5 mmol). To this stirred solution was added in one portion, SnCl2.2H2O (9.1 g, 40.3 mmol) and the reaction mixture was placed in a pre-heated oil bath maintained at ˜85° C. for 8 h. The reaction mixture was cooled to ambient temperature and then concentrated on the rotary evaporator to yield a viscous orange-brown oil. To this oil was added saturated aqueous sodium carbonate solution (100 mL) and EtOAc (150 mL). The resulting biphasic suspension was stirred at ambient temperature for 0.5 h, then filtered through a pad of Celite®. The Celite® pad was washed with EtOAc (2×50 mL). The filtrates were combined and phases were separated. The aqueous layer was extracted with EtOAc (1×50 mL). The organic layers were pooled, and dried over anhydrous sodium sulfate, filtered and concentrated to yield the title compound as a reddish-brown oil, which was used in the next step without further purification.
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:7][C:8]1[C:9]([CH3:18])=[N:10][CH:11]=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[S:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([O:7][C:8]2[C:9]([CH3:18])=[N:10][CH:11]=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[S:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=S)c1cnc(C)c(O)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=S)c1cnc(C)c(OC2CCCC2)c1
Temperature: 60 °C

Procedure:
Cyclopentyl bromide (0.78 mL) is added to a stirred mixture of methyl 5-hydroxy-6-methylthionicotinoate (810 mg) and anhydrous potassium carbonate (1.8 g) in dry dimethylformamide (15 mL). The mixture is heated at 60±5° C. for 8 hours. After cooling the mixture is concentrated in vacuo and the residue partitioned between water and ethyl acetate. The ethyl acetate phase is isolated, washed with water and dried (MgSO4). The solvent is removed in vacuo to give methyl 5-cyclopentyloxy-6-methylthionicotinoate (920 mg) as a light brown oil. [Elemental analysis: —C, 58.41; H, 6.41; N, 5.24%. calculated: —C, 58.2; H, 6.44; N, 5.33%.].
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].CO[C:7]1[C:8](=[O:20])[C:9]2[C:14]([C:15](=[O:19])[C:16]=1[O:17][CH3:18])=[CH:13][CH:12]=[CH:11][CH:10]=2.[NH4+].[Cl-].[CH2:23]1[CH2:27]O[CH2:25][CH2:24]1>[Cl-].[Cl-].[Zn+2]>[CH3:18][O:17][C:16]1[C:15](=[O:19])[C:14]2[C:9]([C:8](=[O:20])[C:7]=1[CH2:25][CH2:24][CH2:23][CH2:27][CH2:9][CH2:8][CH2:7][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: C1CCOC1
Reactant: COC1=C(OC)C(=O)c2ccccc2C1=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [NH4+]
Product: CCCCCCCCCCCCC1=C(OC)C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 2.1 %

Procedure:
To 0.216 g (1.62 mmoles) of AlCl3 in 50 mL of THF was added 7.0 g (0.697 mmoles/g in THF, 4.88 mmoles) of dodecyl MgBr. This mixture was added dropwise to 1.27 g (9.34 mmoles) of ZnCl2 and 1.00 g (4.67 mmoles) of 2,3-dimethoxy-1,4-naphthoquinone in 50 mL of THF. The mixture was stirred overnight, poured into 100 mL of NH4Cl solution, extracted with 3×50 mL of ether, dried over MgSO4, filtered, and solvent was removed by rotary evaporation. The residue was chromatographed on silica gel eluted with toluene. Thus, 0.034 g (0.096 mmoles, 2.1%) of 2-methoxy-3-dodecylnaphthoquinone was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]1[CH:12]=[C:13]([C:21]([O:23][CH3:24])=[O:22])[C:14](=[CH:19][CH:20]=1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][C:11]2[CH:12]=[C:13]([C:21]([O:23][CH3:24])=[O:22])[C:14](=[CH:19][CH:20]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CBr)cc1C(=O)OC
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(CSc2cccc(Br)c2)cc1C(=O)OC
Reaction time: 2 h
Yield: 97.3 %

Procedure:
5 g (26 mmol) of 3-bromothiophenol and 9.2 g (32 mmol) of dimethyl 4-bromomethylphthalate are dissolved in 150 mL of 2-butanone. 4 g (29 mmol) of potassium carbonate are added and the mixture is brought to reflux and stirred for 2 h. The reaction medium is then filtered and concentrated under reduced pressure and the residue is purified by chromatography on a column of silica. A yellow oil (10 g) is obtained in a yield of 100%.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2O[CH:3]12.[C:16]1([C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][C:2]1([CH3:15])[CH:3]=[C:4]([N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: c1ccc(-c2ncc[nH]2)cc1
Product: CC1(C)C=C(n2ccnc2-c2ccccc2)c2cc(C#N)ccc2O1

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 2-phenyl-1H-imidazole as starting materials, the title compounds were prepared as white solids.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:12][C:13]1[C:18](B(O)O)=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.O.O1CCOCC1>[F:12][C:13]1[C:18]([C:2]2[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: COc1ncc(Br)c(OC)n1
Reactant: OB(O)c1cccnc1F
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: OBO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ncc(-c2cccnc2F)c(OC)n1
Temperature: 90 °C
Yield: 93.1 %

Procedure:
To a mixture of 5-bromo-2,4-bis(methyloxy)pyrimidine (Prep86, 3 g, 13.70 mmol), 2-fluoropyridine-3-boronic acid (1.930 g, 13.70 mmol) and Pd(PPh3)4 (0.791 g, 0.685 mmol), dry 1,4-Dioxane (45 ml) was added followed by potassium carbonate 1M solution (27.4 ml, 27.4 mmol). The mixture was degassed with Argon and then heated at 100° C. for 1 h (internal T˜90° C.). Then the mixture was cooled down to ambient, further 1 eq of boronic acid (1.930 g, 13.70 mmol) followed by 5 mol % of PdTetrakis (0.791 g, 0.685 mmol) were added and the mixture heated at 100° C. for two 2 h. The reaction mixture was cooled down to room temperature, taken up with water and AcOEt. The aqueous layer was back extracted with AcOEt. The combined organics were dried over Na2SO4 and evaporated to dryness. The crude material was purified by SiO2 flash chromatography eluting with Cy/EA 8/2 to get the title compound as white solid (3 g).
Reaction SMILES: O[CH2:2][C:3]1[CH2:4][N:5]([C:15](=[O:17])[CH3:16])[CH2:6][CH2:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O=S(Cl)[Cl:20]>C(Cl)Cl>[Cl:20][CH2:2][C:3]1[CH2:4][N:5]([C:15](=[O:17])[CH3:16])[CH2:6][CH2:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: CC(=O)N1CCC(c2ccccc2)=C(CO)C1
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ccccc2)=C(CCl)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-(3-(hydroxymethyl)-4-phenyl-5,6-dihydropyridin-1(2H)-yl)ethanone (88 mg, 0.38 mmol) in DCM (2 mL) was added SOCl2 (0.67 mL, 9.50 mmol) at 0° C. After stirring at 0° C. for 15 min, the solution was concentrated to remove SOCl2, dried under high vacuum to give 1-(5-(chloromethyl)-4-phenyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one as crude product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][N:12]=[CH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:32]([C:35]1[O:39][C:38]([C:40](Cl)=[O:41])=[CH:37][CH:36]=1)([O-:34])=[O:33]>C(OCC)(=O)C>[N+:32]([C:35]1[O:39][C:38]([C:40]([O:24][C:19]2[CH:18]=[CH:17][C:16]3[C:21](=[CH:22][CH:23]=[C:14]([CH:13]=[N:12][NH:11][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH:15]=3)[CH:20]=2)=[O:41])=[CH:37][CH:36]=1)([O-:34])=[O:33]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Reactant: O=C(NN=Cc1ccc2cc(O)ccc2c1)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NN=Cc1ccc2cc(OC(=O)c3ccc([N+](=O)[O-])o3)ccc2c1)OCc1ccccc1

Procedure:
To a solution of 3.2 g of 6-(benzyloxycarbonylaminoiminomethyl)-2-naphthol in 40 ml of ethyl acetate, was added 1.2 g of triethylamine. To the resulting solution, while cooling in ice and stirring, was added 5-nitrofuran-2-carboxylic acid chloride. Thereafter the mixture was stirred overnight at room temperature. The precipitate was collected by filtration and washed with water to obtain 4.4 g of 6-(benzyloxycarbonylaminoiminomethyl)-2-naphthyl 5-nitrofuran-2-carboxylate, m.p.: 109°-112° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=[CH2:8].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.COC1C=CC(O)=CC=1>>[CH2:1]([N:3]([CH2:8][CH2:7][C:6]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH3:5])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CCNCC
Agent: COc1ccc(O)cc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: CCOC(=O)CCN(CC)CC
Yield: 96 %

Procedure:
The following materials were charged to the reaction vessel: anhydrous diethylamine (292 grams); ethyl acrylate (200 grams); phenothiazine (1.0 gram); and p-methoxyphenol (1.0 gram). This mixture was heated at reflux (about 56°-60° C.) for 24 hours. At the end of this period, unreacted amine was removed by distillation. The product was recovered at 80°-81° C. and 10 mm. mercury pressure in a yield of 96 percent. The product is designated herein as Amine Catalyst IX and has the formula, (C2H5)2N-Ch2CH2 -C(O)OC2H5, as verified analytically by infrared spectroscopy.
Reaction SMILES: [Li].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:15]([O-])=[CH:16][C:17](=O)[C:18]([O:20]CC)=[O:19])[CH:7]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:9]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([NH:54][NH2:55])[CH:49]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:15]2[N:54]([C:50]3[CH:49]=[N:48][CH:53]=[CH:52][CH:51]=3)[N:55]=[C:17]([C:18]([OH:20])=[O:19])[CH:16]=2)[CH:7]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:9]=1
Reactant: NNc1cccnc1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(OC)cc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: COc1cc(OC(F)(F)F)cc(-c2cc(C(=O)O)nn2-c2cccnc2)c1

Procedure:
500 mg (1.29 mmol) of the compound of Example 10A is reacted analogously to the synthesis of the compound of Example 20A with 207 mg (1.42 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 248 mg (51% of theory) of the title compound is obtained.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].[OH-].[Na+].[H][H]>[Pd].C(O)C>[F:18][C:15]([F:16])([F:17])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][C:7]1[CH:6]=[N:5][NH:4][C:3](=[O:19])[CH:2]=1
Reactant: [H][H]
Reactant: O=c1[nH]ncc(Cc2ccccc2C(F)(F)F)c1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1cc(Cc2ccccc2C(F)(F)F)cn[nH]1
Reaction time: 20 h
Yield: 79.7 %

Procedure:
A pressure vial containing a mixture of 4-chloro-5-(2-trifluoromethyl-benzyl)-2H-pyridazin-3-one (328.1 mg, 1.1 mmol), ethanol (12.1 mL), and a 2N aqueous sodium hydroxide solution (0.61 mL) was treated with 10% palladium on carbon (121 mg). The reaction was then pressurized with hydrogen (50 psi), where it shook for 20 h. The resulting reaction mixture was removed from the hydrogenator and then filtered through a pad of diatomaceous earth, washing with ethanol. The filtrate was concentrated in vacuo to remove organics. The resulting residue was taken up in 90/10 methylene chloride/methanol (75 mL) and water (40 mL). The aqueous layer was acidified with a 2N aqueous hydrochloric acid solution to pH=1, and the layers were separated. The aqueous layer was then back extracted with a 90/10 methylene chloride/methanol solution (2×75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-(2-trifluoromethyl-benzyl)-2H-pyridazin-3-one (223 mg, 77%) as a yellow solid; ES+-HRMS m/e calcd for C12H9N2OF3 [M+H+] 255.0740, found 255.0740. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.05 (s, 2H), 6.28 (s, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.75 (d, J=2.1 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 12.96 (br. s., 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-])=O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(c1ccccc1)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: Nc1cc(C(=O)c2ccccc2)ccc1N1CCOCC1

Procedure:
A solution of 9.37 g. of 3-nitro-4-morpholinobenzophenone in 196 ml. of ethyl acetate is reduced as described in Examples 1 or 2. 8.26 g. of 3-amino-4-morpholinobenzophenone are obtained; m.p.: 138° C.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:7]=1[N:8]([CH3:11])[CH:9]=[O:10])(=[O:5])[CH3:4]>C(O)(=O)C.ClCCl>[Br:1][CH2:4][C:3]([C:6]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:7]=1[N:8]([CH3:11])[CH:9]=[O:10])=[O:5]
Reactant: BrBr
Reactant: COc1cc(C(C)=O)c(N(C)C=O)cc1OC
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(=O)CBr)c(N(C)C=O)cc1OC
Reaction time: 0.75 h

Procedure:
Bromine (1.57 ml) was added dropwise over a period of 5 minutes to a stirred solution of 2'-acetyl-4',5'-dimethoxy-N-methylformanilide (7.13 g) in glacial acetic acid (35 ml) at ambient temperature. The mixture was stirred for 45 minutes and then diluted with dichloromethane (350 ml) before washing with saturated aqueous sodium sulphite (175 ml) then aqueous sodium bicarbonate (1M, 350 ml). The mixture was dried over magnesium sulphate and the solvent was removed by evaporation to give crude 2'-(2-bromoacetyl)-4',5'-dimethoxy-N-methylformanilide.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:12]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](=[O:29])[C:19]2[C:14](=[CH:15][C:16]([Cl:30])=[CH:17][CH:18]=2)[N:13]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:7][C@@H:8]([C:12]1[N:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:20](=[O:29])[C:19]2[C:14](=[CH:15][C:16]([Cl:30])=[CH:17][CH:18]=2)[N:13]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)[C@@H](N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, nitrogen inlet, heating mantle and water condenser, is charged with 60 mL of toluene, 4.42 g (10 mmol) of (R)-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester (the compound of Formula 107 or 203 prepared, e.g., as described in Example 6.4 or 6.3), and 4.20 g of PTSA. The mixture is heated to reflux for 1 h, during which the evolution of gas is observed. Upon cessation of gas evolution, TLC analysis (hexanes/ethyl acetate 7:3) indicates complete reaction. The mixture is cooled to room temperature, initially forms an oil that separates at the bottom of the flask and quickly solidifies into a brown solid. Toluene is decanted and 50 mL of saturated potassium bicarbonate (room temperature) is added to the solid with stirring followed by the addition of 25 mL of water. The resulting white solid is collected by filtration to afford the title compound of Formula 301, (R)-2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-quinazolin-4-one.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[CH3:15][N:6]1[C:5]2[CH:7]=[C:8]([F:12])[C:9]([F:11])=[CH:10][C:4]=2[N:3]=[C:2]1[CH3:1]
Reactant: CI
Reactant: Cc1nc2cc(F)c(F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(F)c(F)cc2n1C

Procedure:
Using the alkylation procedure of Preparation A-2, 3.6 g of 2-methyl-5,6-difluorobenzimidazole, 1.03 g of 50% sodium hydride and 1.33 ml of methyl iodide in 40 ml of dimethylformamide gave 1.1 g of the desired product as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[C:32]([O:31][C:29](=[O:30])[CH2:28][N:16]1[C:15]2[CH:14]=[CH:13][C:12]([Cl:20])=[C:11]([O:10][C:8]3[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=3)[C:19]=2[N:18]=[N:17]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1nnc2c(Oc3cc(Cl)cc(C#N)c3)c(Cl)ccc21

Procedure:
3-chloro-5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (500 mg, 1.64 mmol) and cesium carbonate (534 mg, 1.64 mmol) were suspended in DMF (5 mL) under N2. To this was added tert-butyl bromoacetate (336 mg, 1.72 mmol) After 1 hour, the reaction was quenched with saturated aqueous ammonium chloride (5 mL), diluted with water and the mixture extracted with ethyl acetate (2×25 mL). The combined organic fractions were washed with water (3×25 mL) and dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by automated column chromatography on silica gel (40 g) eluting with 0-15% EtOAc/hexanes to give the title product. LRMS (M+1)=418.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([N:17]4C=C[N:19]=[CH:18]4)=[O:16])=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.[CH3:25][O:26][CH2:27]C(=NO)N>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][N:19]=[C:18]([CH2:25][O:26][CH3:27])[N:17]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: COCC(N)=NO
Reactant: CN1Cc2c(C(=O)n3ccnc3)ncn2-c2ccc(F)cc2C1=O
Solvent: CN(C)C=O
Product: COCc1noc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)n1
Reaction time: 8 h

Procedure:
A mixture of 6.50 g (20 mmol) of 1-[[8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]carbonyl]imidazole, 50 ml of N,N-dimethylformamide and 2.10 g (20 mmol) of methoxyacetamidoxime is stirred at 100° overnight. After evaporation of the solvent the residue is dissolved in methylene chloride and washed with water. The organic solution is dried over magnesium sulphate and evaporated. By chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from methylene chloride and ethyl acetate there is obtained 8-fluoro-4,5-dihydro-3-(3-methoxymethyl-1,2,4-oxadiazol-5-yl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 192°-194°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:3][CH:4]=3)[NH:9][C:10]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a suspension of 2-(4-aminophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole (80 mg, 0.24 mmol) [See Ex. 28 above] and triethylamine (0.12 mL, 0.86 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (55 mL, 0.72 mmol). After stirring at rt for 1 h, the mixture was poured into aqueous NaHCO3 and extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 2-10% MeOH/CHCl3 to afford the title compound as a tan solid (35 mg, 36%): ESMS (m/z): 409 (M++H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:22][CH:21]=1>C(O)CCC>[N:28]1[CH:27]=[CH:26][C:25]([O:24][C:23]2[CH:31]=[CH:32][C:20]([NH:19][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]([CH2:12][C:13]4[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=4)=[N:4][N:3]=3)=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: Nc1ccc(Oc2ccncc2)cc1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Solvent: CCCCO
Product: c1ccc2c(Nc3ccc(Oc4ccncc4)cc3)nnc(Cc3ccncc3)c2c1
Temperature: 130 °C
Reaction time: 18 h
Yield: 39.8 %

Procedure:
A mixture of 1-chloro-4-(4-pyridylmethyl)phthalazine (for preparation see Novartis patent WO98135958, 11.02.98) (0.540 g, 2.11 mmol) and 4-(4-aminophenoxy)pyridine (1.18 g, 6.33 mmol) in anhydrous 1-butanol (8.4 mL) was stirred under argon at 130° C. for 18 h. The reaction mixture was quenched with saturated aqueous potassium carbonate (˜50 mL) and then extracted with dichloromethane (3×100 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography in 7:11:2 v/v acetone-dichloromethane-methanol provided the title compound as an oil (0.340 g, 0.84 mmol, 40% yield). 1H-NMR (DMSO-d6) 9.26 (s, 1H), 8.58 (d, J=8.3, 1H), 8.41 to 8.44 (m, 4H), 8.10 (d, J=8.2, 11H), 7.90 to 8.03 (m, 4H), 7.30 (d, J=5.9, 2H), 7.17 (d, J=9.2, 2H), 6.91 (d, J=5.8, 2H), 4.56 (s, 2H); MS ES 406 (M+H)+, calc. 405; TLC (1:7:12 v/v methanol-acetone-dichloromethane) Rf=0.08.