Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[CH:14][N:13]=2)=[O:10])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].C([Sn](CCCC)(CCCC)[C:33]1[CH:38]=[CH:37][N:36]=[N:35][CH:34]=1)CCC>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.CN(C=O)C>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:38]=[CH:37][N:36]=[N:35][CH:34]=3)=[C:3]([C:24]([F:27])([F:26])[F:25])[CH:4]=2)=[N:13][CH:14]=1
Reactant: O=C(Cc1ccc(Br)c(C(F)(F)F)c1)Nc1ccc(-c2cnccn2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccnnc2)c(C(F)(F)F)c1)Nc1ccc(-c2cnccn2)cn1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a reaction tube containing 2-(4-bromo-3-(trifluoromethyl)phenyl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 118-1 (53 mg, 0.12 mmol), 4-(tributylstannyl)pyridazine (54 mg, 0.14 mmol) and Pd(PPh3)4 (14 mg, 0.012 mmol) under argon was added DMF (0.6 mL). The mixture was stirred at 120° C. for 10 hours. The crude product, which was a solution, was subjected directly for reverse phase HPLC to give N-(5-(pyrazin-2-yl)pyridin-2-yl)-2-(4-(pyridazin-4-yl)-3-(trifluoromethyl)phenyl)acetamide 118 as white solid. MS m/z 437.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.14 (s, 1H), 9.35 (dd, 2H), 9.31 (d, 1H), 9.27 (s, 1H), 9.12 (d, 1H), 8.72 (dd, 1H), 8.62 (d, 1H), 8.52 (dd, 1H), 8.23 (d, 1H), 7.95 (s, 1H), 7.82-7.75 (m, 2H), 7.52 (d, 1H), 4.00 (s, 2H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1)#[N:2].C[Si]([N:37]=[N+:38]=[N-:39])(C)C.C([Sn](=O)CCCC)CCC.C(O)CO>C1(C)C=CC=CC=1>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[C:11]3[C:10]([O:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][C:1]4[NH:39][N:38]=[N:37][N:2]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:16][C:17]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH:23]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCOCCC#N)c23)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: OCCO
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCOCCc4nnn[nH]4)c23)cc1

Procedure:
Stir 200 mg (0.47 mmol) 4-[3-(2-cyanoethoxy)propoxy]-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]-pyrimidine, 804 mg (7.0 mmol) trimethylsilylazide and 174 mg (0.70 mmol) di-n-butyltin oxide in 10 ml toluene overnight at 80° C. Concentrate the mixture by evaporation, take up the residue in water and acidify with dilute hydrochloric acid. Next, extract with methylene chloride. Wash the organic extracts with sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. Purify the residue that remains by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%→98% acetonitrile, 50-55 min 98% acetonitrile). To remove organotin compounds, dissolve the beige foam obtained in 10 ml toluene and add 1 ml ethylene glycol. After heating for 1 h under reflux, remove the solvent under vacuum. Dissolve the residue in methylene chloride, wash with dilute hydrochloric acid and with sodium chloride solution, dry, and concentrate by evaporation. Purification of the residue by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-34 min 5%→98% acetonitrile, 34-38 min 98% acetonitrile) gives 46 mg (21% of theor.) of the title compound as a beige foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:10]=3[N:9]=2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.CO.[C:26](Cl)(=O)C(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:26])=[O:18])[C:10]=3[N:9]=2)=[C:4]([C:20]([F:22])([F:23])[F:21])[CH:3]=1
Reactant: O=C(O)c1cccc2[nH]c(-c3ccc(Cl)cc3C(F)(F)F)nc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc2[nH]c(-c3ccc(Cl)cc3C(F)(F)F)nc12
Yield: 75 %

Procedure:
2-(4-Chloro-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid (54; 500 mg, 1.46 mmol) was suspended in CH2Cl2 (15 mL). Methanol (2 mL) was added to solubilize. To the reaction solution was added dropwise oxalyl chloride (130 μL, 1.46 mmol). After having stirred the reaction at room temperature overnight, the reaction was concentrated. The residue was taken up in EtOAc and washed successively with saturated NaHCO3 and then brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (EtOAc/pentane) afforded methyl 2-(4-chloro-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylate as an orange solid (structure not shown) (390 mg, yield: 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:30])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([C:27]([NH2:29])=O)[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:31]([F:34])([F:33])[F:32])=[N:10]2)=[CH:5][CH:4]=1.O=S(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:30])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([C:27]#[N:29])[CH2:25][CH2:26]5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:31]([F:34])([F:32])[F:33])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C(N)=O)CC4)cc2)CC3)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C#N)CC4)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
The product from Example 14 (22 mg, 0.047 mmol) was stirred in DMF (0.3 mL) at RT in a capped vial. SOCl2 (0.05 mL) was added. The mixture was stirred at RT for 1.5 h. LC-MS showed completion of the reaction. Prep LC-MS purification (35–98% CH3CN in H2O) provided the title compound (15 mg, yield, 71%). LC/MS(ESI+) 453.4 (M+H)+, tR=5.24 min. 1H NMR (acetone-d6) δ 7.50 (d, J=9.2 Hz, 2H), 7.39 (m, 4H), 6.97 (d, J=8.8 Hz, 2H), 4.18 (t, J=6.6 Hz, 2H), 3.84 (s, 3H), 3.17 (t, J=6.6 Hz, 2H), 1.71 (m, 2H), 1.48 (m, 2H) ppm. 19F NMR (acetone-d6) δ −77.16 ppm.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[N:18]1[CH:23]=CC=C[CH:19]=1.CNC.C1COCC1>C(Cl)Cl>[CH3:19][N:18]([CH3:23])[S:14]([C:12]1[S:13][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)=[CH:10][CH:11]=1)(=[O:16])=[O:15]
Reactant: c1ccncc1
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Cl)s2)n1
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CSc1nccc(-c2ccc(S(=O)(=O)N(C)C)s2)n1
Reaction time: 8 h
Yield: 74.9 %

Procedure:
A solution of 5-(2-methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonyl chloride (200 mg, 0.652 mmol) in 6 mL DCM was treated with pyridine (0.078 mL, 0.97 mmol) and 2 M dimethylamine/THF (0.485 mL, 0.97 mmol). The solution was stirred overnight. Additional 2 M dimethylamine/THF (0.400 mL, 0.8 mmol) was added and the reaction was stirred overnight. The mixture contained <5% starting material by LCMS. The mixture was washed 2× 1 N HCl, 1× brine and dried over Na2SO4. 5-(2-Methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonic acid dimethylamide (154 mg, 74.9%) was obtained as an off-white solid, >95% pure by LCMS. This material was taken to the next step. MS: m/z 316 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)=[CH:14][CH:13]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[O:23]=[C:20]1[CH2:21][CH2:22][CH:17]([CH2:16][C:15]2[CH:24]=[CH:25][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:13][CH:14]=2)[CH2:18][CH2:19]1
Reactant: O=C1CCC(Cc2ccc(OCCCCl)cc2)CC1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(Cc2ccc(OCCCN3CCCCC3)cc2)CC1

Procedure:
A suspension of potassium carbonate (369 mg) in a solution of 4-[4-(3-chloropropoxy)benzyl]cyclohexanone (250 mg) and piperidine (264 μL) in N,N-dimethylformamide (6 mL) is heated for three hours at a temperature close to 80° C., then for two days at a temperature close to 50° C. Solvent is evaporated and the residue partioned between ethyl acetate (10 mL) and water (10 mL). The organic phase is separated by decantation, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated under reduced pressure and purified by column chromatography using a gradient dichloromethane/methanol/ammonia from 99/1/0.1 to 98/2/0.2 to give 270 mg of 1-{3-[4-(4-oxocyclohex-1-yl)methylphenoxy]propyl}piperidine.
Reaction SMILES: [CH3:1][C:2]([N+:5]([O-:7])=O)([CH3:4])[CH3:3].C(O)(=O)C.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O>C(O)C.[Zn]>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[N+:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[O-:7]
Reactant: O=Cc1ccccn1
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[N+]([O-])=Cc1ccccn1
Temperature: 5 °C

Procedure:
To a suspension of 1,1-dimethylnitroethane (545.5 mg, 5.29 mmol) and zinc (516.6 mg, 7.90 mmol) in ethanol (3.0 ml) was added acetic acid (950.1 mg, 15.8 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 20 minutes. After cooling the mixture to 5° C. again, 2-pyridinecarbaldehyde (283.9 mg, 2.65 mmol) was added dropwise to the mixture while stirring and stirred at room temperature overnight. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:10]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:10]=2)[N:3]=1
Reactant: CS(=O)(=O)c1cccc(-c2cc(Cl)nc(Cl)n2)c1
Reactant: C1COCCN1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccc(-c2cc(N3CCOCC3)nc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 38540 %

Procedure:
2,4-dichloro-6-(3-(methylsulfonyl)phenyl)pyrimidine (220 mg, 0.72 mmol, 1 eq) was dissolved in EtOH (5 mL) and DIEA was added (0.31 mL, 2.2 mmol, 3 eq). The reaction mixture was cooled to 0° C. and morpholine (94 mg, 1.1 μmol, 1.6 eq) was added. The reaction mixture was stirred at room temperature for 3 days. The ethanol was concentrated under reduced pressure and the residue was partitioned between EtOAc and sat. aq. NaHCO3. The organic layer was separated, washed with water and dried (Na2SO4). The residue was purified by column chromatography on silica gel (3% EtOAc/DCM to 40% EtOAc/DCM) to obtained the desired product (150 mg, 58%). LCMS (m/z): 302.8 (MH+), Rt: 1.51 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.CN([CH:17]=[O:18])C.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([CH:17]=[O:18])=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1cccc2c(C)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C=O)c2c(C)cccc12
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a well stirred solution of 1-methoxy-5-methylnaphthalene (above Step-3 intermediate) (7.0 g, 40.7 mmol) in toluene (8 mL) and DMF (4.7 mL, 61 mmol) at 0° C. was added, POCl3 (4.6 mL, 49.6 mmol) drop wise and the reaction mixture was stirred for 45 min at 0° C. and then refluxed for 2 h. The dark red solution was cooled to RT and poured into a mixture of ice (50 mL) and 10% aq. NaOH (100 mL) with stirring. The crude product was extracted with EtOAc (4×75 mL) and the combined organic layer was washed with 1 N HCl (3×50 mL), water (3×50 mL), brine, dried (Na2SO4) and filtered. The solvent was evaporated and the residue was washed with hexanes (2×15 mL) to afford the desired compound (6.4 g, 79%) as reddish brown solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9](=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].O>O1CCCC1>[OH:18][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH:20]1[CH2:24][CH2:23][O:22][C:19]1=[O:21]
Reactant: COc1cccc(C=O)c1
Reactant: CCOC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(O)C2CCOC2=O)c1
Reaction time: 0.5 h

Procedure:
To a solution of y-butyrolactone (3.0 g) in tetrahydrofuran (THF) (30 ml) was added lithium diisopropylamide (LDA) (28 ml, 1.5 M solution in cyclohexane) at −78° C. under N2, and then after 30 minutes, a solution of m-anisaldehyde (4.7 g) in THF (10 ml) was added in the solution. After being stirred for 2 hours at the same temperature, the solution was poured into the mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 3-[hydroxy(3-methoxyphenyl)methyl)-2-oxotetrahydrofuran (7.4 g).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3](O)[OH:4].[CH:8]1([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1C=CC=CC=1>[CH:8]1([C:14]([NH:16][CH:3]([OH:4])[C:2]([Cl:7])([Cl:6])[Cl:1])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC(=O)C1CCCCC1
Reactant: OC(O)C(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C(NC(O)C(Cl)(Cl)Cl)C1CCCCC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 80.9 %

Procedure:
First, cyclohexyl-N-(2,2,2-trichloro-1-hydroxyethyl)carboxamide 3 was synthesized as follows. A mixture of chloral hydrate (9.0 g, 54,5 mmol) and cyclohexane carboxamide (5.0 g, 49.5 mmol) in dry benzene (30 ml) was heated at 80° C. in an oil bath. The initial suspension eventually became a clear solution (reaction time depends on the amount of starting materials, in this example it took about 6 hours). The mixture was stirred for an additional 30 minutes, then removed from the oil bath, and left at room temperature. Upon cooling, the crystalline solid formed was filtered and washed with hexanes to give the product cyclohexyl-N-(2,2,2-trichloro-1-hydroxyethyl)carboxamide 3 (11.0 g). NMR (1H, CDCl3): δ 6.23 (d, J=8.4 Hz, 1H), 5.9 (dd, 1H), 4.35 (broad s, 1H), 2.16 (t, 1H), 1.90-1.22 (m, 10H).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C([O:8][CH:9]=[C:10]([C:16](OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])C>[O-]CC.[Na+].C(O)C.ClCCl>[CH3:3][C:2]1[NH:4][C:9](=[O:8])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:5]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cnc(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.4 %

Procedure:
Acetamidine hydrochloride (37.16 g, 0.39 mole) was stirred in sodium ethoxide in ethanol (73 mL of a 21% solution, 0.20 mole) for 5 minutes. Diethyl ethoxymethylenemalonate (31.5 mL, 0.15 mole) was added, and the reaction mixture was refluxed for 5 h. The reaction mixture was allowed to cool to room temperature overnight, and diluted with dichloromethane (100 mL). The solution was filtered, washing the solid cake with dichloromethane. The filtrate was concentrated at reduced pressure. The residue was dissolved in dichloromethane (150 mL) and 2.0N HCl (30 mL). The pH of the aqueous layer was 1. The organic layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in hot dichloromethane (50 mL). Ethyl acetate was added (50 mL). The product precipitated. The solution was boiled for 5 minutes, cooled to room temperature, and hexanes were added (50 mL). The resulting crystals were filtered, then washed with ethyl acetate (20 mL) followed by hexanes (50 mL) to yield the title compound (7.22 g, 27%) as off-white crystals. Rf=0.27 (silica gel, 10% isopropanol in dichloromethane).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13])#[N:2].[Se](=O)=[O:15]>>[C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:15])[C:8]2=[O:13])#[N:2]
Reactant: N#Cc1cccc2c1CCCC2=O
Reactant: O=[Se]=O
Product: N#Cc1cccc2c1C=CC(=O)C2=O

Procedure:
Treatment of 5-cyano-1-tetralone with selenium dioxide as described in Reference Example 1A yielded the corresponding 5-cyano-[1,2]naphthoquinone, which was coupled with 2,3-diamino-benzoic acid, diacetate salt, as described to yield the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)[N:9]=[CH:8][C:7]=1[C:21]([NH:23][C:24]1[CH:25]=[N:26][C:27]([C:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=2)=[C:28]([CH3:30])[CH:29]=1)=[O:22].O>N1C=CC=CC=1>[C:1]([N:34]1[CH2:35][CH:36]=[C:31]([C:27]2[N:26]=[CH:25][C:24]([NH:23][C:21]([C:7]3[CH:8]=[N:9][N:10]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=4)[C:6]=3[CH3:5])=[O:22])=[CH:29][C:28]=2[CH3:30])[CH2:32][CH2:33]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N1CC=C(c2ncc(NC(=O)c3cnn(-c4ccc(C(F)(F)F)cn4)c3C)cc2C)CC1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Acetyl chloride (50 μl) was added to a solution of 5-methyl-N-[5-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (300 mg) described in Reference Example 170 in pyridine (3.4 ml), stirred at 40° C. for six hours. Acetyl chloride (50 μl) was added and stirred for two hours, and then, Acetyl chloride (50 μl) was added and stirred for six hours. Water was added to the reaction solution and the precipitated solid was washed with ethanol and water to give the titled compound (283 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:31])=[C:15]([N:18]4[CH2:22][CH2:21][CH:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]4)[CH:16]=3)[C:11](=[O:32])[N:10]([O:33]CC3C=CC=CC=3)[C:9]2=[O:41])=[CH:4][CH:3]=1>[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:31])=[C:15]([N:18]4[CH2:22][CH2:21][CH:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]4)[CH:16]=3)[C:11](=[O:32])[N:10]([OH:33])[C:9]2=[O:41])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2ccc(F)cc2)C1
Agent: [Pd]
Product: CC(C)(C)OC(=O)NC1CCN(c2cc3c(cc2F)c(=O)n(O)c(=O)n3-c2ccc(F)cc2)C1
Yield: 95.9 %

Procedure:
Using the General Method 6A, the reaction of 10% Pd/C (0.075 g) with 1-(4-fluorophenyl)-6-fluoro-3-benzyloxy-7-(3-t-butoxycarbonylamino-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione (Example N-1, 0.225 g, 0.4 mmol) afforded 0.182 g of 1-(4-fluorophenyl)-6-fluoro-3-hydroxy-7-(3-t-butoxycarbonylamino-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24]>C1COCC1>[Cl:19][C:20]1[CH:21]=[C:22]([CH:23]([OH:24])[CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15])[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of diisopropyl amine (12.4 mL, 88.2 mmol) in THF (50 mL) at −78° C. was added n-butyllithium (35.3 mL, 88.2 mmol). The reaction mixture was stirred at −78° C. for 30 min, at which time ethyl acetate was added (16.1 mL, 163.2 mmol). After 1 h, 3-chlorobenzaldehyde was added and the reaction mixture was allowed to warm to room temperature over 2 h. The reaction mixture was quenched with aqueous saturated NH4Cl (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was rinsed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford yellow oil. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1:4) to afford ethyl 3-(3-chloro-phenyl)-3-hydroxy-propionate as a yellow oil (10.0 g, 99.0%). 1H NMR (400 MHz, d-DMSO): δ 7.43-7.30 (m, 4H), 5.66 (d, 1H), 5.01-4.95 (q, 1H), 4.14-4.04 (m, 2H), 2.71-2.58 (m, 2H), 1.24-1.17 (t, 3H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:3); Rf=0.50.
Reaction SMILES: [C:1](=[S:3])=S.[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[CH2:8][NH2:9])[CH3:5]>O1CCCC1>[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[CH2:8][N:9]=[C:1]=[S:3])[CH3:5]
Reactant: S=C=S
Reactant: CCOC(CN)OCC
Solvent: C1CCOC1
Product: CCOC(CN=C=S)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 120 ml of carbon disulfide and 60.6 g of dicyclohexycarbodiimide in 300 ml of tetrahydrofuran is cooled to -8° with an ice/salt mixture. Thereupon, 39.9 g of aminoacetaldehyde diethyl acetal are added dropwise while stirring so that the temperature of the reaction mixture does not exceed -5° (approximately 1 hour). The mixture is then warmed slowly to room temperature while stirring (approximately 2 hours) and left to stand overnight. The resulting precipitate (dicyclohexylthiourea) is then removed by filtration and washed thoroughly with n-hexane. The filtrate is concentrated in a vacuum and the separated dicyclohexylthiourea is again removed by filtration and washed with n-hexane. This procedure is repeated until dicyclohexylthiourea no longer separates upon concentration. Finally, the filtrate is freed completely from solvents. The residue is distilled at 11 Torr (bath temperature 130°-134°), whereby there is obtained 2,2-diethoxyethyl isothiocyanate in the form of a colorless oil; b.p. 100°/11 Torr.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[O:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][N:37]=2)[CH2:32][CH2:31]1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:39]3[CH:38]=[N:37][C:36]([N:33]4[CH2:32][CH2:31][O:30][CH2:35][CH2:34]4)=[CH:41][CH:40]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1ccc(N2CCOCC2)nc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(N3CCOCC3)nc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 2-morpholino-5-pyridine boronic acid. The title compound was obtained in 7% yield as yellow solid. MS (m/e): 568.4 (MH+, 100%).