Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH3:27])[C:6]1[C:7]2[CH2:15][C:14](=[O:16])[N:13]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4].[O:28]=P(Cl)(Cl)Cl.C(N(CC)CC)C.CNC>C(#N)C>[CH2:1]([N:5]([CH2:26][CH3:27])[C:6]1[C:7]2[C:15](=[O:28])[C:14](=[O:16])[N:13]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCN(CC)c1nc(C)nc2c1CC(=O)N2c1c(C)cc(C)cc1C
Agent: CNC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCN(CC)c1nc(C)nc2c1C(=O)C(=O)N2c1c(C)cc(C)cc1C

Procedure:
To a solution of 4-(butyl-ethyl-amino)-2-methyl-7-(2,4,6-trimethyphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (76 mg, 0.207 mmol), POCl3 (0.039 ml, 0.415 mmol), triethylamine (0.059 ml), and dimethylamine (1 ml) in 2 ml acetonitrile was heated at reflux for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a brown form (105 mg). After silica gel column chromatography, the title compound was isolated as a yellow glass (10 mg). 1H NMR (CDCl3) δ 7.00 (s, 2H), 3.95–4.15 (m, 2H), 3.65–3.85 (m, 2H), 2.38 (s, 3H), 2.32 (s, 3H), 2.10 (s, 6H), 1.55–1.75 (m, 2H), 1.35–1.55 (m, 2H), 1.25 (t, 3H), 1.00 (t, 3H) ppm.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=[C:4]([Cl:14])[CH:3]=1.[CH3:15][C:16]1[N:20]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[N:18][C:17]=1[CH:40]=[O:41]>>[Cl:14][C:4]1[CH:3]=[C:2]([CH:40]([C:17]2[N:18]=[CH:19][N:20]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:16]=2[CH3:15])[OH:41])[C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=1
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)OCc2cc(Cl)cc(Br)c2O1
Product: Cc1c(C(O)c2cc(Cl)cc3c2OC(C)(C)OC3)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 50 %

Procedure:
Starting from 8-bromo-6-chloro-2,2-dimethyl-4H-1,3-benzodioxin and 5-methyl-1-triphenylmethyl-1H-imidazole-4-carboxaldehyde. The addition of the organomagnesium compound is carried out at 0° C. Yield: 50% of theory;
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH2:11][OH:12])=[CH:9][N:8](CO)[C:5]2=[N:6][CH:7]=1.[OH:15]S(O)(=O)=O>CC(C)=O.O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:12])=[O:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: OCc1cn(CO)c2ncc(Br)nc12
Reactant: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1c[nH]c2ncc(Br)nc12
Temperature: 40 °C
Reaction time: 16 h
Yield: 107.3 %

Procedure:
To a stirred solution of (2-bromo-7-hydroxymethyl-pyrrolo[2,3-b]pyrazin-5-yl)-methanol (0.525 g, 2.03 mmol) in 200 mL of acetone at 40° C. was added a solution of CrO3 (0.832 g, 8.32 mmol) and H2SO4 (1.32 g, 13.4 mmol) in water (3 ml). Then the reaction was stirred at 40° C. for 16 hours then filtered through Celite. The filtrate was evaporated at 40° C. under reduced pressure to give 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.527 g) as an off-white solid. LCMS: (M+H)+=264; 1H NMR (300 MHz, DMSO-d6): δ 13.04 (s, 1H), 8.53 (s, 1H), 8.45 (s, 1H), 5.63 (s, 1H).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])=[O:40])=[CH:35][CH:34]=1>>[CH:1]1([CH:7]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:40])=[CH:37][CH:38]=2)[C:9]2[C:10]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC(c1cn(-c2ccc(C(F)(F)F)cn2)nc1CCc1ccccc1)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: O=C(O)CCNC(=O)c1ccc(NC(c2cn(-c3ccc(C(F)(F)F)cn3)nc2CCc2ccccc2)C2CCCCC2)cc1
Yield: 27.7 %

Procedure:
Using cyclohexyl{3-(2-phenylethyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.50 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.28 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.20 g, 28%) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: OCCCBr
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(-c2ccccn2)sc2ccc(OCCCO)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.3 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.40 g, 1.5 mmol), 3-bromo-1-propanol (0.66 g, 4.7 mmol) and potassium carbonate (0.43 g, 3.1 mmol) and DMF (10 ml) was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water and extracted with a mixture solvent of ethyl acetate and ethanol. The extract was washed with water and dried. The solvent was evaporated. The obtained crystals were recrystallized from ethanol-hexane to give the titled compound (0.27 g, 54%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:4][N:3]=1.[C:12]([C:14]1[CH:29]=[CH:28][C:17]([CH:18]=[C:19]([C:25](=O)[CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1)#[N:13].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:12]([C:14]1[CH:29]=[CH:28][C:17]([CH:18]2[N:3]3[N:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=[C:2]3[NH:1][C:25]([CH3:26])=[C:19]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1)#[N:13]
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Reactant: CCOC(=O)c1nc(N)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2nc(C(=O)OCC)nn2C1c1ccc(C#N)cc1
Temperature: 55 °C
Reaction time: 6 h

Procedure:
Under an atmosphere of argon, ethyl 3-amino-1H-1,2,4-triazole-5-carboxylate (700 mg, 4.4 mmol) and ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (1.18 g, 4.9 mmol, 1.1 eq.) were dissolved in DMF (5 ml), and solid sodium bicarbonate (1.86 g, 22.1 mmol, 5 eq.) was added. The mixture was stirred at 55° C. for 6 h. The mixture was then filtered, and the DMF from the filtrate was distilled off under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (1.3 g, 80% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:35])([F:34])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:34])([F:33])[F:35])[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:28]([F:30])([F:31])[F:29])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of ethyl 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoate (400 mg, 0.75 mmol, 1.00 equiv) in methanol (5 mL), a solution of sodium hydroxide (400 mg) in water (5 mL). The resulting solution was stirred for 2 h at 50° C. The pH value of the solution was adjusted to 5 with hydrogen chloride (2 mol/L). The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 380 mg (crude) of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoic acid as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](S(C)=O)[N:3]=1.[CH3:19][C:20]1[C:21]([CH2:27][OH:28])=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([O:28][CH2:27][C:21]2[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[CH:23][N:22]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2cc(Br)co2)c1C#N
Reactant: Cc1cnc(CO)c(C)c1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cnc(COc2nc(N)nc(-c3cc(Br)co3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-(4-bromo-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 3,5-dimethyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 402 (M{81Br}+H+, 100), 400 (M{79Br}+H+, 95).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](Cl)=[O:7].[NH2:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[CH:29]=[C:28]([CH2:30][CH3:31])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[CH2:19][C@@H:18]1[O:32][CH2:33][CH3:34]>>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([NH:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[CH:29]=[C:28]([CH2:30][CH3:31])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[CH2:19][C@@H:18]1[O:32][CH2:33][CH3:34])=[O:7]
Reactant: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CN
Reactant: CC(Oc1ccc(Cl)cc1Cl)C(=O)Cl
Product: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CNC(=O)C(C)Oc1ccc(Cl)cc1Cl

Procedure:
In an analogous manner, from 2(RS)-(2,4-dichlorophenoxy)propionyl chloride (prepared from the acid) and 5'-amino-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine, there was obtained 5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine of melting point 121°-124° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].S(O[CH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1)(=O)(=O)C>CC(N(C)C)=O>[C:46]([O:45][C:43]([N:40]1[CH2:41][CH2:42][CH:37]([CH2:36][O:17][C:11]2[CH:10]=[C:9]3[C:14]([C:5]([O:4][C:3]4[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:2]=4[F:1])=[CH:6][CH:7]=[N:8]3)=[CH:13][C:12]=2[O:15][CH3:16])[CH2:38][CH2:39]1)=[O:44])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To a solution of the 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-hydroxyquinoline (609 mg, 1.8 mmol) in DMA (9 mL) was added K2CO3 (1.24 g, 9.0 mmol) and N-Boc-4-piperidinemethanol mesylate (732 mg, 2.5 mmol). The mixture was then stirred at 80° C. for 2.5 h. After it was cooled to rt, the mixture was loaded directly to a Biotage column, and eluted with solvents (hexanes:EtOAc=1:3). The resulting product, 4-[4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester, was obtained as a solid (556 mg, 56%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10].[OH-].[Na+].[N:22]1([CH2:28][CH2:29]Cl)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1C=CC=CC=1.C(#N)C>[N:22]1([CH2:28][CH2:29][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9]([C:11]2[C:12]3[CH:13]=[CH:14][NH:15][C:16]=3[CH:17]=[CH:18][CH:19]=2)=[O:10])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(Nc1ccccc1O)c1cccc2[nH]ccc12
Reactant: ClCCN1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccccc1OCCN1CCCCC1)c1cccc2[nH]ccc12
Yield: 83.3 %

Procedure:
3 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide in 50 ml of benzene, 25 ml of acetonitrile and 50 ml of a 5N aqueous solution of sodium hydroxide were heated to 60° C. for 3 hours with stirring under an inert atmosphere with 0.4 g of 2-tetrabutylammonium hydrogenosulfate and 2.2 g of 2-piperidino-1-chloroethane. After cooling, decanting, extracting with ethyl acetate and purifying by chromatography over silica (eluent: ethyl acetate-triethylamine, 9-1), 3.6 g of N-[2-[2-(1-piperidinyl)ethoxy]phenyl]-1H-indol-4-carboxamide were obtained.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][C:7]([C:10]2[CH:31]=[CH:30][C:13]3[C:14]4[N:18]([CH2:19][CH2:20][O:21][C:12]=3[CH:11]=2)[CH:17]=[C:16]([C:22]2[N:23]([CH:27]([CH3:29])[CH3:28])[N:24]=[CH:25][N:26]=2)[N:15]=4)=[C:6]([C:32]([NH2:34])=[O:33])[CH2:5]1)([CH3:3])[CH3:2]>[Pt](=O)=O>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:31]=[CH:30][C:13]3[C:14]4[N:18]([CH:17]=[C:16]([C:22]5[N:23]([CH:27]([CH3:29])[CH3:28])[N:24]=[CH:25][N:26]=5)[N:15]=4)[CH2:19][CH2:20][O:21][C:12]=3[CH:11]=2)[CH:6]([C:32]([NH2:34])=[O:33])[CH2:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)N1CCC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)=C(C(N)=O)C1
Agent: O=[Pt]=O
Product: CC(C)N1CCC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)C(C(N)=O)C1
Temperature: 50 °C
Yield: 52.3 %

Procedure:
To a solution of 1-isopropyl-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid amide (153 mg, 0.33 mmol) in IMS (denatured ethanol) (10 mL) was added platinum (IV) oxide (15 mg, 0.06 mmol). The reaction mixture was heated at 50° C. under an atmosphere of hydrogen. The reaction mixture was cooled to RT, filtered through Celite® and the filtrate concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 10 to 20% methanol in DCM) to give 403 (80 mg, 52%). LCMS: RT=2.61 min, [M+H]+=464. 1H NMR 400 MHz (DMSO-d6) δ: 8.38 (1H, d, J=8.33 Hz), 8.15 (1H, s), 8.04 (1H, s), 7.04 (1H, dd, J=8.35, 1.82 Hz), 6.89 (1H, d, J=1.72 Hz), 5.86 (1H, m), 4.57-4.48 (4H, m), 3.57 (2H, t, J=12.74 Hz), 3.42 (1H, m), 3.31 (1H, m), 3.25 (1H, m), 3.22 (1H, m), 3.04 (1H, s), 2.60 (1H, d, J=13.63 Hz), 1.96 (1H, s), 1.50 (6H, dd, J=6.59, 3.63 Hz), 1.30 (3H, d, J=6.70 Hz), 1.22 (3H, d, J=6.70 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].CCOCC>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14]
Reactant: Brc1cccc2[nH]ccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a solution of the indole of Step 1 (8.9 g, 45 mmol) in DMF (150 mL) at 0° C. was added portionwise NaH (2.2 g, 55 mmol, 60% in oil). The reaction mixture was stirred for 30 minutes at 0° C. and triisopropylsilyl chloride (10.5 g, 55 mmol) was added. The reaction mixture was stirred for 30 minutes and 400 mL of Et2O was added. The reaction was quenched with saturated aqueous NH4Cl and extracted with Et2O. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 100% Hexanes to provide 16 g of the title compound as a white solid.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:13][N:12]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: ON=C1CCc2ccccc21

Procedure:
A mixture of 1-indanone (100 g), hydroxylamine HCl (183 g), potassium carbonate (183 g), methanol (1700 ml) and water (170 ml) was heated at reflux for 18 hours, then cooled and poured into water. The title compound was filtered, washed with water and air-dried.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:24]=[C:21]1[N:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH2:23][CH2:22]1
Reactant: CCOC(=O)CCCCCCBr
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NC(=O)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCN1C(=O)CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21

Procedure:
A yellow solution of 2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one (step 1) (1.0 g, 3.04 mmol) and ethyl 7-bromoheptanoate (1.440 g, 6.07 mmol) in DMF (20 ml), under a nitrogen atmosphere, was treated with potassium carbonate (2.098 g, 15.18 mmol) and the resultant suspension was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc (×2). The extracts were washed with water (×2) and brine, dried (MgSO4) and evaporated under vacuum to a brown oil. The crude material was purified by chromatography on silica eluting with 0-100% EtOAc/iso-hexane to afford the title compound as a pale solid;
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c(Cl)cnn(Cc2ccccc2)c1=O
Reactant: OB(O)c1ccc(Cl)cc1
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
Solvent: O
Product: COc1c(-c2ccc(Cl)cc2)cnn(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 82.4 %

Procedure:
To a stirred solution of 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one (20.0 g, 79.8 mmol) in toluene (500 mL) was added Pd(PPh3)4 (5.5 g, 4.76 mmol) under an atmosphere of argon. 4-Chlorophenylboronic acid (18.7 g, 119.6 mmol) was added subsequently. Under vigorous stirring, Na2CO3 (33.8 g, 318.9 mmol) pre-dissolved in water (90 mL) was added to the suspension. A stream of argon was bubbled through this suspension for 10 min. After this time, the flask was placed in an oil bath preheated at 120° C. The reaction was refluxed for 3 h. After this time, the reaction was cooled to RT The reaction mixture was then poured into water (200 mL). The layers were separated and the aqueous mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with water (2×200 mL) followed by saturated aqueous NaCl (2×100 mL). The organic layer was then concentrated under reduced pressure to obtain crude product. This crude product was purified by silica gel column chromatography eluting with 8% EtOAc/hexanes to give the title compound, 2-benzyl-5-(4-chlorophenyl)-4-methoxypyridazin-3(2H)-one, (21.5 g, 82%) as a white solid. HPLC: 3.79 min; M+H=327. 1H NMR (CDCl3, 500 MHz): δ 7.76 (1H, s), 7.48 (2H, d, J=10.0 Hz), 7.40-7.45 (4H, m), 7.28-7.36 (3H, m), 5.35 (2H, s), 4.10 (3H, s).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:18]1[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[C:21]([CH3:43])[CH:22]2[Si:28]([CH:31]1[C:39]2[C:34](=[C:35](Br)[C:36]([CH3:40])=[CH:37][CH:38]=2)[CH:33]=[C:32]1[CH3:42])([CH3:30])[CH3:29]>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:18]2[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[C:21]([CH3:43])[CH:22]3[Si:28]([CH:31]2[C:39]3[C:34](=[C:35]([C:5]4[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=[C:3]([C:2]([F:1])([F:16])[F:15])[CH:4]=4)[C:36]([CH3:40])=[CH:37][CH:38]=3)[CH:33]=[C:32]2[CH3:42])([CH3:30])[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC(F)(F)c1cc([Mg]Br)cc(C(F)(F)F)c1
Reactant: CC1=Cc2c(ccc(C)c2Br)C1[Si](C)(C)C1C(C)=Cc2c1ccc(C)c2Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=Cc2c(ccc(C)c2-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1[Si](C)(C)C1C(C)=Cc2c1ccc(C)c2-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
In an argon atmosphere, to a solution of 15 mL of THF with 29.0 ml of 0.5 M ZnCl2 (14.5 mmol) in THF, 13.0 ml of 1.0 M 3,5-bis(trifluoromethyl) phenylmagnesium bromide (13.0 mmol) in THF was added at ambient temperature. This mixture was stirred for 1 hour, and, then, 10.0 ml of 0.02 M Pd(PtBu3)2 (0.20 mmol, 4 mol. %) in THF and 2.51 g (5.0 mmol) of 2 were added. The resulting mixture was stirred for 5 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 30 mm, l 100 mm; eluent: hexanes). Yield 3.65 g (95%) of white solid of ca. 1 to 1 mixture of rac- and meso-compounds.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10]Br.[C:12]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:22][CH2:23]1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: Clc1cccc(Cl)c1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NC1CCN(CCc2c(Cl)cccc2Cl)CC1)c1ccccc1
Yield: 41.1 %

Procedure:
2-(2,6-Dichlorophenyl)ethyl bromide (674 mg.) was reacted with 4-benzamidopiperidine (547 mg.) in the presence of anhydrous potassium carbonate (736 mg.) following the procedure of Example 12 to give the title compound as the hydrochloride (412 mg.) m.p. 285.7° C. after crystallisation from ethanolic hydrogen chloride and ether. (Found: C, 58.0; H, 5.6; N, 6.7. C20 22Cl2N2O. HCl requires C, 58.05; H, 5.6; N, 6.8%).