Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)([OH:36])[CH2:9][NH:10][C:11]2[N:19]=[C:18](Cl)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:21]2[CH2:25][C@H:24]([NH:26][C:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])=[O:28])[C@@H:23]([OH:34])[C@H:22]2[OH:35])=[CH:4][CH:3]=1.[C:44]([NH:51][C@@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1)([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].[I-].[Na+]>C(#N)C>[Cl:43][C:40]1[CH:39]=[CH:38][C:37]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([OH:36])[CH2:9][NH:10][C:11]2[N:19]=[C:18]([N:54]3[CH2:55][CH2:56][C@@H:52]([NH:51][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:53]3)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:21]2[CH2:25][C@H:24]([NH:26][C:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])=[O:28])[C@@H:23]([OH:34])[C@H:22]2[OH:35])=[CH:42][CH:41]=1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
A suspension of acetic acid ((1S,2R,3S,4R)-4-{6-[2,2-bis-(4-chloro-phenyl)-2-hydroxy-ethylamino]-2-chloro-purin-9-yl}-2,3-dihydroxy-cyclopentylcarbamoyl)-methyl ester (intermediate ZL; 1 equivalent) and (3R)-(+)-3-(Boc-amino)pyrrolidine (4 equivalents) in acetonitrile is treated with a catalytic amount of sodium iodide and then heated using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 160° C. After 1 hour, the solvent is removed in vacuo; purification by column chromatography/crystallisation affords the title compound.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:20]=[C:19]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cccc3ccccc23)c1
Reaction time: 24 h
Yield: 76 %

Procedure:
Under an argon gas atmosphere, 200.0 g (1.163 mol) of 1-naphthalene boronic acid, 329.0 g (1.163 mol) of 3-bromoiodobenzene, 26.9 g (23.3 mmol) of tetrakis(triphenylphosphine)palladium(0), 3.7 L of toluene and 1.74 L of 2M sodium carbonate solution were mixed, and stirred for 24 hours while being refluxed. After the reaction in the mixture was over, the mixture experienced filtration, through which aqueous phase thereof was eliminated. After organic phase thereof was cleansed by water and dried with magnesium sulfate, toluene was distilled away under reduced pressure. Residue thereof was refined by silica-gel column chromatography, such that 250 g of 1-(3-bromophenyl)naphthalene was obtained with an yield of 76%.
Reaction SMILES: CC[Mg+].[Br-].[C:5]1([C:11]#[CH:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:13]1([N:19]=[N+:20]=[N-:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[C:13]1([N:19]2[C:11]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:12][N:21]=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C#Cc1ccccc1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: c1ccc(-c2cnnn2-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
To a solution of EtMgBr in THF (1.0M, 11.9 mL) was added phenylacetylene (1.30 mL, 11.9 mmol) at room temperature. The reaction mixture was heated to 50° C. for 15 min. After cooling the mixture to room temperature, a solution of phenylazide (1.41 g, 11.9 mmol) in THF (4 mL) was added. The resulting solution was stirred at room temperature for 30 min, and then heated to 50° C. for 1 hour before quenching with saturated NH4Cl (10 mL). The layers was separated, and the aqueous layer was extracted with CH2Cl2 (10 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the 1,5-diphenyltriazole as a white solid (1.98 g, 75%). 1H NMR (CDCl3, 300 MHz) δ 7.86 (s, 1H), 7.44-7.30 (m, 8H), 7.23-7.20 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 137.6, 136.5, 133.4, 129.3, 129.2, 128.8, 128.5, 126.7, 125.1.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:13]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=4)=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:50]([O:54][CH3:55])(=[O:53])[CH:51]=[CH2:52].C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:55][O:54][C:50](=[O:53])[CH:51]=[CH:52][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:13]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=4)=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2nn3ccccc3c2-c2ccnc3cc(Br)ccc23)n1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc2c(-c3c(-c4cccc(C)n4)nn4ccccc34)ccnc2c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 27.7 %

Procedure:
Combine 7-bromo-4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (0.15 g, 0.36 mmol), tri-o-tolylphosphine (0.38 g, 1.26 mmol), tribuytlamine (0.12 mL, 0.5 mmol), methyl acrylate (0.065 ml, 0.72 mmol), anhydrous toluene (3 mL), and DMF (1.5 mL). Bubble nitrogen gas through the solution for 20 minutes. Add palladium acetate (4.0 mg, 0.018 mmol). Heat the reaction mixture at 80° C. for 48 hours. Chromatograph the residue on silica gel (elute with 2% methanol/methylene chloride, then 4% methanol/methylene chloride). Further purification by preparative HPLC affords the title compound 42 mg (28%) as a yellowish solid.
Reaction SMILES: C(OC(=O)[N:7]([C:20]1[C:21]2[N:22]([CH:37]=[CH:38][N:39]=2)[C:23]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:29]=[C:28](F)[CH:27]=2)=[CH:24][N:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C.CC([O-:45])(C)C.[K+].Cl>C1COCC1.O>[F:33][C:32]([F:35])([F:34])[C:30]1[NH:29][C:28](=[O:45])[CH:27]=[C:26]([C:23]2[N:22]3[CH:37]=[CH:38][N:39]=[C:21]3[C:20]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[CH:10][CH:9]=3)=[N:25][CH:24]=2)[CH:31]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(-c2cc(F)nc(C(F)(F)F)c2)n2ccnc12
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1cc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)cc(C(F)(F)F)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.3 %

Procedure:
To a solution of [5-(2-fluoro-6-trifluoromethyl-pyridin-4-yl)imidazo[1,2-a]pyrazin-8-yl]-(4-morpholin-4-yl-phenyl)carbamic acid tert-butyl ester (92 mg, 0.12 mmol) in THF (0.5 mL) is added KOtBu (26 mg, 0.23 mmol) and the mixture is stirred at rt for 20 min. HCl (12 M aq., 0.1 mL) is added and the mixture is diluted with water (10 mL) and concentrated under reduced pressure. The residue is dissolved in THF (5 mL) and HCl (12 M aq., 0.5 mL) is added and the mixture is stirred at rt for 5 h. NaHCO3 (sat. aq.) is added until the pH is 7 and the mixture is extracted with DCM (3×10 mL). The extracts are dried over Na2SO4 and evaporated under reduced pressure to afford a pale orange solid. This is purified by preparative HPLC to afford the title compound as a yellow solid (9.5 mg). LCMS: Rt=1.04 min (100%), m/z (ESI) 457 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9](/[CH:12]=[N:13]/[OH:14])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[OH:14][N:13]=[C:12]([Cl:19])[C:9]1[C:8]([C:15]([F:17])([F:18])[F:16])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1
Reactant: O/N=C/c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: ON=C(Cl)c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (E)-5-phenyl-4-(trifluoromethyl)isoxazole-3-carbaldehyde oxime (step C, 0.360 g, 1.41 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature was added N-chlorosuccinimide (0.281 g, 2.11 mmol) in one portion. The resulting green, homogeneous reaction mixture was stirred at room temperature for 30 min. An additional 220 mg of NCS was added, and the reaction mixture was stirred for an additional 30 min. The reaction mixture was diluted with ethyl acetate (35 mL), washed with a 10% aqueous solution of lithium chloride (2×), and brine. The combined aqueous layers were extracted with ethyl acetate (35 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave a pale green solid which was triturated with ether and filtered. The white solid was rinsed with ether, and the filtrate was concentrated under reduced pressure and dried under reduced pressure overnight to give a quantitative yield of N-hydroxy-5-phenyl-4-(trifluoromethyl)isoxazole-3-carbimidoyl chloride as a green solid. The compound had an HPLC ret. time=2.72 min. (condition A); LC/MS M+1=291.0. 1H NMR (400 MHz, CDCl3) δ ppm 7.51-7.58 (m, 2H), 7.58-7.64 (m, 1H), 7.70 (d, J=7.48 Hz, 2H), 8.04 (s, 1H), and 9.69 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH2:17])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[C:1]([C:4]1[C:5]([NH:17][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)[nH]c(-c2ccccc2C)c1N
Reactant: O=Cc1ccc(Cl)cc1
Product: CC(=O)c1c(C)[nH]c(-c2ccccc2C)c1NCc1ccc(Cl)cc1

Procedure:
The title compound (M.p. 167°-70° C) is prepared from 4-acetyl-3-amino-5-methyl-2-(o-tolyl)-pyrrole (m.p. 258° C), obtained substantially in the same way as compound A), by transforming into the corresponding p-chlorobenzylidene derivative (m.p. 215° C) by reaction with p-chlorobenzaldehyde and subsequent catalytic hydrogenation.
Reaction SMILES: O=[C:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[N:6]2[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]2[CH2:4][NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[S:29]=[C:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[N:6]2[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]2[CH2:4][NH:3]1
Reactant: CCOC(=O)c1ncn2c1CNC(=O)c1sccc1-2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncn2c1CNC(=S)c1sccc1-2
Yield: 132.1 %

Procedure:
4. 24.07 g of ethyl 5,6-dihydro-6-oxo-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate are suspended in 260 ml of toluene and treated with 22.73 g of Lawesson reagent. The mixture is heated to reflux temperature for 1.25 h., then cooled and filtered. The filter cake is dried. 21.78 g of ethyl 5,6-dihydro-6-thioxo-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[C:9]([C:20]([OH:22])=O)=[N:10][C:11]([O:18][CH3:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[NH2:23][CH2:24][CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27]>>[F:27][C:26]([F:29])([F:28])[CH:25]([OH:30])[CH2:24][NH:23][C:20]([C:9]1[C:8]([N:3]2[C:4]([CH3:7])=[CH:5][CH:6]=[C:2]2[CH3:1])=[CH:13][C:12]([C:14]([F:17])([F:15])[F:16])=[C:11]([O:18][CH3:19])[N:10]=1)=[O:22]
Reactant: COc1nc(C(=O)O)c(-n2c(C)ccc2C)cc1C(F)(F)F
Reactant: NCC(O)C(F)(F)F
Product: COc1nc(C(=O)NCC(O)C(F)(F)F)c(-n2c(C)ccc2C)cc1C(F)(F)F

Procedure:
This compound was prepared from 3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate D2) and 3-amino-1,1,1-trifluoropropan-2-ol analogously to Example 1; LC-MS Rt=1.50 mins [M+H]+ 426 (Method 2 minLC_v002).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:9]=[N:10][NH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])=[C:4]([N+:20]([O-])=O)[CH:3]=1>C(O)C.C(Cl)(Cl)Cl.O=[Pt]=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:9]=[N:10][NH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])=[C:4]([NH2:20])[CH:3]=1
Reactant: CCOC(=O)c1[nH]nnc1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1[nH]nnc1C(=O)c1ccc(Cl)cc1N
Reaction time: 19 h
Yield: 108.4 %

Procedure:
A suspension of PtO2 (541.6 mg) in ethanol (50 mL) was shaken under hydrogen (40 psi) in a PARR™ hydrogenator for 19 hours. A solution of ethyl 4-(4-chloro-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate (1.014 g, 3.124 mmol) in chloroform (10 mL)/ethanol (200 mL) was then added to the reaction mixture and shaking on the PARR™ hydrogenator at 51 psi was continued. After 3 hours the reaction mixture was filtered through a pad of CELITE™, washing with ethanol. The filtrate was concentrated under vacuum (0.3 torr) to afford 0.998 g (108%) of crude title compound as a bright yellow foam.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[Br:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[F:9])=[C:15]([CH:19]=1)[C:16]([O:18][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9])=[O:17]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1F)c1cc(Br)ccc1OCc1ccccc1F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Neat 1-(bromomethyl)-2-fluorobenzene (1533 mg, 8.11 mmol) was added over 1 min to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (800 mg, 3.69 mmol) and potassium carbonate (1274 mg, 9.22 mmol) in acetone (60 ml) in air at room temperature. The reaction mixture was stirred at 70° C. overnight. The reaction mixture was filtered. The filtrate was evaporated and the residue was dissolved in diethyl ether (30 ml) and evaporated again. The residue was dried in vacuo to yield the title compound as a white solid. 1.74 g.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:15][CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32]I>>[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32][O:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C@:5]([CH2:15][CH3:16])([C:3]([OH:2])=[O:4])[CH2:9][C:8]=2[CH:10]=1
Reactant: CCC1(C(=O)OC)Cc2cc(O)ccc2O1
Reactant: FC(F)(F)Cc1ccc(OCCCI)c(Cl)c1
Product: CC[C@@]1(C(=O)O)Cc2cc(OCCCOc3ccc(CC(F)(F)F)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4, employing the chiral phenol prepared in Example 10, Step 2 and the iodide prepared in Step 2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[C:31](=[O:32])[C:30]([CH3:34])([CH3:33])[NH:29][C:28]1=[O:35]>>[F:25][C:4]1[CH:3]=[C:2]([N:29]2[C:30]([CH3:34])([CH3:33])[C:31](=[O:32])[N:27]([CH3:26])[C:28]2=[O:35])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Reactant: CN1C(=O)NC(C)(C)C1=O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4(C)C)cc3F)CC2)nc1C
Yield: 13.9 %

Procedure:
Using (4-bromo-2-fluorophenyl) [4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (163 mg) described in Preparation Example 128 and 3,5,5-trimethylimidazolidine-2,4-dione (63 mg) described in Preparation Example 218 and by the reaction and treatment in the same manner as in Example 536, the title compound (26 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>C(Cl)(Cl)Cl.C(#N)C>[NH:11]1[CH:15]=[N:14][C:13]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)=[N:12]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1nc[nH]n1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: N#Cc1ccc(Cc2nc[nH]n2)cc1

Procedure:
A solution containing alpha-bromo-4-tolunitrile (19.6 g) and 1,2,4-triazole (30.5 g) in a mixture of chloroform (250 mL) and acetonitrile (50 mL) is stirred at reflux for 15 hours. The solution is cooled and washed with 3% aqueous sodium bicarbonate (200 mL) and the organic solution is then dried (MgSO4) and evaporated. The residue is chromatographed on silica gel (300 g). Elution with chloroform/isopropanol (10:1) affords 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile, m.p.77°-79° which forms a hydrochloride salt, m.p. 200°-205° when its solution in ethyl acetate is treated with ethereal HCl.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:5]=1[O:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([O-])=O>CO.[Pd]>[N:9]1([CH2:8][CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:4]=2[NH2:1])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1OCCN1CCCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1OCCN1CCCC1

Procedure:
To a solution of 1-[2-(2-Nitro-4-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine (1.70 g, 5.59 mmol) in dry MeOH (56 mL) was added Pd/C (10%, 350 mg). H2 gas was bubbled through the solution, which was then stirred vigorously under an atmosphere of H2. After completion of the reaction by LCMS, the mixture was filtered through celite and concentrated to affod the desired product as a yellow/orange oil. MS (M+H)+=275; Calc'd 274.29 for C13H17F3N2O.
Reaction SMILES: N1CCCCC1.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].Cl>N1C=CC=CC=1>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=[CH:15][C:16]([OH:18])=[O:17]
Reactant: O=Cc1cccs1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccs1
Yield: 90.1 %

Procedure:
Piperidine (2.45 g, 0.056 mol) was added drop wise over a period of 10 min to a stirred solution of thiophene-2-carbaldehyde (4.00 g, 0.036 mol) and malonic acid (1.00 g, 0.18 mol) in pyridine (40 mL) at 0° C. and the resulting reaction mixture was refluxed for 2 h. The reaction mixture was poured into 2N HCl (100 mL) and the precipitated solid filtered. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 3-(2-thienyl)prop-2-enoic acid (5.00 g, 92%) as a solid.
Reaction SMILES: [C:1]([C:9]1[O:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.[OH-].[K+].Cl>O.C(O)CO>[CH2:1]([C:9]1[O:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)o1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: O=C(O)c1ccc(Cc2ccccc2)o1
Temperature: 160 °C
Yield: 63.6 %

Procedure:
5-Benzoylfuran-2-carboxylic acid [420 mg.; Knoppova et al. Collect. Czech. Chem. Commun. 42, 3175-9 (1977), Chem. Abs. 88, 169842d] was combined with 10 ml. of hydrazine, 1.5 g. of potassium hydroxide and 10 ml. of ethylene glycol and heated for 1.5 hours in an oil bath maintained at 160° C. The mixture was cooled in an ice-water bath, diluted with water and acidified with conc. hydrochloric acid. Filtration gave 5-benzylfuran-2-carboxylic acid (250 mg., m/e 202).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]=[CH:9][C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.Cl.Cl.[NH2:17][NH2:18]>N>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[CH:8]=[CH:9][C:10](=[O:11])[NH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)C=CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: N
Product: O=c1ccc(-c2ccc(F)cc2)n[nH]1
Yield: 93.7 %

Procedure:
3-(4'-Fluorobenzoyl)-acrylic acid (9.7 g, 0.04996 mol) was dissolved in 50 ml of concentrated aqueous ammonia solution, and the solution was allowed to stand for a few days, without a cover. The solution was first rendered neutral by adding hydrochloric acid (concentrated, 30 ml), a further 20 ml of concentrated hydrochloric acid were then added, followed by hydrazine hydrochloride (4.1 g, 0.06 mol), after which the mixture was refluxed for 8 hours. After cooling, the solid product which had precipitated was isolated, washed with water and dried to constant weight. 3-(4'-Fluorophenyl)-6-pyridazinone of m.p.=265°-267° C., 8.9 g, 0.04680 mol, were obtained, which corresponds to a yield of 93.7% of theory.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1ncc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Reactant: C1COCCN1
Product: O=C(Cn1ncc(OCc2ccccc2)cc1=O)c1ccc(CN2CCOCC2)cc1

Procedure:
5-Benzyloxy-2-[2-(4-morpholin-4-ylmethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared as example 1.1b from 90 mg (0.22 mmol) 5-benzyloxy-2-[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 17b) and 76 μL (0.87 mmol) morpholine.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:27]([Cu])#[N:28].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.6 %

Procedure:
A mixture of 1-bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (624 mg, 1.5 mmol; prepared as shown in Scheme 2, and according to US 2004/0254215 A1, 1H NMR (CDCl3): δ=11.89 (s, 1H), 8.35 (d, 1H), 7.63 (d, 1H), 7.08 to 7.52 (m, 6H), 4.47 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H)), CuCN (271 mg, 3 mmol) and dimethylformamide (6 mL) was refluxed with stirring under nitrogen for 15 min. After cooling to ambient temperature the mixture was diluted with ethyl acetate (100 mL). The resulting suspension was filtered through a pad of celite. The filtrate was washed with water (2×250 mL), and dried over MgSO4 before silica gel was added. Subsequently, the mixture was concentrated in vacuo. The residue was added on top of a short column filled with silica gel. Elution with dichloromethane gave the title compound as a white solid (313 mg); MS-(−)-ion: M−1=361.2.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18].OC1C=CC(CO)=CC=1>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18]
Reactant: ClCc1ccc2ccccc2n1
Reactant: OCc1cccc(O)c1
Agent: OCc1ccc(O)cc1
Product: OCc1cccc(OCc2ccc3ccccc3n2)c1
Yield: 85 %

Procedure:
The procedure from Example 6, part A was used except 2-(chloromethyl)quinoline was substituted for 7chloro-(2-chloromethyl)quinoline and 3-hydroxybenzyl alcohol was substituted for 4-hydroxybenzyl alcohol. The intermediate was obtained in 85% yield: mp 82°-86° C.