Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:33])[C:15]([C:28]([O:30]CC)=[O:29])=[CH:16][N:17]3[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[CH:12][C:11]=2[F:34])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O1CCOCC1>[C:1]1([S:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:33])[C:15]([C:28]([OH:30])=[O:29])=[CH:16][N:17]3[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[CH:12][C:11]=2[F:34])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(S(=O)(=O)c3ccccc3)c(F)cc2c1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(S(=O)(=O)c3ccccc3)c(F)cc2c1=O
Yield: 74.3 %

Procedure:
In 8.0 ml of dioxane was suspended 800 mg of ethyl 7-benzenesulfonyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine 3-carboxylate, and 4.9 ml of N hydrochloric acid was added thereto, after which the resulting mixture was subjected to reaction under reflux for 4 hours. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene-ethyl acetate (10:1 by volume)] to obtain 560 mg (yield 74.3% of 7-benzenesulfonyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8naphthyridine-3-carboxylic acid having a melting point of 252°-258° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:19][C:20]1[N:24]([CH2:25][CH2:26][CH3:27])[CH:23]=[N:22][CH:21]=1.O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:19][C:20]2[N:24]([CH2:25][CH2:26][CH3:27])[CH:23]=[N:22][CH:21]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCCn1cncc1CCl
Reactant: O=[N+]([O-])c1ccc(S)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1cncc1CSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 40 h
Yield: 70.7 %

Procedure:
2-mercapto-5-nitropyridine (2.3 g) was dissolved in DMF (47 ml), potassium carbonate (6.2 g) and 5-chloromethyl-1-propylimidazole hydrochloride (3.5 g) was added to the mixture, and the mixture was stirred for 40 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 5-nitro-2-[[(1-propylimidazol-5-yl)methyl]sulfanyl]pyridine (2.9 g).
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1>CN(C)C=O.O>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH2:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:3]3[C:2]([Br:1])=[C:6]([N+:7]([O-:9])=[O:8])[C:5]([Br:10])=[N:4]3)[CH:22]=2)[N:3]=1
Reactant: BrCc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Br)nn(Cc2cccc(Cn3nc(Br)c([N+](=O)[O-])c3Br)c2)c1Br
Reaction time: 0.83 h

Procedure:
13.54 g of 3,5-dibromo-4-nitropyrazole, 11.1 g potassium carbonate, 0.8 g of potassium iodide and 6.6 g α, α′-dibromo-m-xylene are heated to 100° C. in 40 ml of dimethyl formamide. After 50 minutes the reaction mixture is allowed to cool and poured into 400 ml water. The precipitate is filtered, washed with water and dried in vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16](OCC)=[O:17])=[C:5]2[OH:21].C(N(C(C)C)C(C)C)C.Cl.[NH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16]([NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:17])=[C:5]2[OH:21]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)cc(F)c2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)cc(F)c2C(C)(C)C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 23.8 %

Procedure:
Ethyl 6-chloro-8-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.75 g, 2398 μmol) was dissolved in 1,4-dioxane (4797 μL) and N-ethyl-N-isopropylpropan-2-amine (1253 μL, 7195 μmol). tert-Butyl 2-aminoacetate hydrochloride (603 mg, 3597 μmol) was added, and the reaction was stirred at 80° C. for 3 hours. The reaction was then diluted with 150 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 75 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (227 mg) as a white solid. MS (m/z)=420 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Cl:6].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[Cl-:6].[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: FC(F)(F)c1ccccc1CCl
Solvent: Cc1ccccc1C
Product: FC(F)(F)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 150 °C

Procedure:
214 g (1.1 mols) of o-trifluoromethylbenzyl chloride are initially introduced into the reaction vessel and are heated to about 150° C. A hot solution, at about 100° C., of 262 g (1 mol) of triphenylphosphine in 115 ml of xylene is added thereto, whilst stirring. Stirring is continued at 150° C. for a short time, the mixture is cooled to 20° C. and the crystal sludge is filtered off and washed with cyclohexane/methylene chloride (7:3). After drying at 170° C. and under 0.1 mm Hg, 412 g (90.2% of the theoretical yield) of o-trifluoromethylbenzyltriphenyl-phosphonium chloride are obtained.
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[C]=O.[H][H]>>[C:1]([O:4][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:5])(=[O:3])[CH3:2]
Reactant: COC(C)=O
Reactant: [H][H]
Agent: [C]=O
Product: CC(=O)OC(C)OC(C)=O

Procedure:
There are few literature or patent references regarding methods for producing ethylidene diacetate. Several of these references disclose methods wherein methyl acetate, carbon monoxide and hydrogen are reacted in tile presence of a homogeneous catalyst to produce ethylidene diacetate. While these methods which employ a homogeneous catalyst produce good selectivity and yield, all suffer from several significant disadvantages, including difficulties associated with separating and purifying the reaction products from the catalyst. Conventional homogeneous catalysts employed in these methods include complexes of group VIII transition metals, preferably rhodium, ruthenium, iridium, palladium and platinum. Japanese Pat. No. 51-115409 and European Pat. No. 0028474 disclose methods for producing ethylidene diacetate using a homogeneous rhodium catalyst. Japanese Pat. No. 54-98713 and British Patent No. 1,112,555 disclose methods for producing ethylidene diacetate using homogeneous palladium catalysts. All of these methods suffer from difficulties in separating and purifying the reaction products from the homogeneous catalyst. These prior methods require the use of a distillation process to separate the homogeneous catalyst from the reaction products. For example, the '474 European patent, which discloses a method having a yield of 75.3% ethylidene diacetate based on dimethyl acetate starting material, requires a distillation step to separate the homogeneous catalyst from the reaction products.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.Cl.[C:10](=[O:13])(O)[O-].[Na+].[C:15](#N)C>[Cu]I>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:10](=[O:13])[CH3:15])=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC#N
Reactant: O=C([O-])O
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Product: CC(=O)c1ccc(F)cn1
Temperature: 25 °C

Procedure:
2-Bromo-5-fluoropyridine (13.0 g, 73.9 mmol), copper(I) iodide (2.10 g, 11.1 mmol) and dichlorobis (triphenylphosphine) palladium(II) in anhydrous acetonitrile (100 ml) was added tributyl(1-ethoxyvinyl)atannane (27.5 ml, 81.3 mmol). The reaction was heated at reflux. After heating for 70 hours, 1.5 M aqueous HCl (20 ml) was added to quench the reaction and the mixture was heated at reflux for 1 hour. After cooling to room temperature, the reaction mixture was neutralized with saturated sodium bicarbonate and extracted with ether (3×100 ml). The combined organic layers were dried over dried over sodium sulfate, and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane-ether=5:1) to give the title compound as a clear oil [11.3 g (75% pure), 82%]. 1H NMR (400 MHz, CDCl3) 8.51 (d, J=3.2 Hz, 1H), 8.11 (dd, J=4.4 and 4.4 Hz, 1H), 7.51 (ddd, J=2.8, 3.2 and 2.8 Hz, 1H), 2.71 (s, 3H).
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[N:10]=[CH:11][CH:12]3[CH:17]([CH:18]=2)[N:16]([CH2:19][CH3:20])[C:15](=[O:21])[C:14]([C:22]2[C:23]([F:41])=[CH:24][C:25]([F:40])=[C:26]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=4[F:39])=[O:30])[CH:27]=2)=[CH:13]3)=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:33]1[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=1[NH:31][C:29]([NH:28][C:26]1[CH:27]=[C:22]([C:14]2[C:15](=[O:21])[N:16]([CH2:19][CH3:20])[CH:17]3[CH:12]([CH:13]=2)[CH:11]=[N:10][C:9]([NH:8][CH3:7])=[CH:18]3)[C:23]([F:41])=[CH:24][C:25]=1[F:40])=[O:30]
Reactant: CCN1C(=O)C(c2cc(NC(=O)Nc3cc(F)ccc3F)c(F)cc2F)=CC2C=NC(N(C)Cc3ccc(OC)cc3)=CC21
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)C(c2cc(NC(=O)Nc3cc(F)ccc3F)c(F)cc2F)=CC2C=NC(NC)=CC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A solution of 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(2,5-difluorophenyl)urea (0.129 g, 0.213 mmol) and anisole (0.233 mL, 2.130 mmol) in DCM (2 mL) was treated with TFA (2 mL, 26.0 mmol) and stirred at RT overnight. The mixture was concentrated to dryness, treated with EtOAc and satd. NaHCO3, stirred for 1 h and the resulting solid collected via filtration and dried to afford 1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea (84 mg, 81% yield). The material was suspended in MeCN (2 mL), treated with 0.5 N HCl (2.076 mL, 0.208 mmol), diluted with water (2 mL), frozen, lyophilized, triturated with Et2O and the resulting solid was collected via filtration and dried to yield 1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea hydrochloride (85 mg, 94% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.24 (s, 1H), 9.18 (s, 1H), 8.53 (s, 1H), 8.18 (t, 1H), 8.02-7.97 (m, 1H), 7.94 (s, 1H), 7.90 (br s, 1H), 7.42 (t, 1H), 7.32-7.26 (m, 1H), 6.84-6.80 (m, 1H), 6.48 (s, 1H), 4.19 (q, 2H), 2.94 (s, 3H), 1.21 (t, 3H); MS (ESI) m/z: 486.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[O-:16][C:17]#N.[K+].CO.O.C[N:24](C)[CH:25]=[O:26]>>[CH3:1][C:2]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:24][C:25](=[O:26])[O:16][CH3:17]
Reactant: N#C[O-]
Reactant: CN(C)C=O
Reactant: Cc1c(CBr)cccc1-c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)NCc1cccc(-c2ccccc2)c1C

Procedure:
3.57 g of 2-methyl-3-phenylbenzyl bromide, 1.66 g of potassium cyanate and 7.00 g of methanol in N,N-dimethylformamide (30 ml) were stirred at 80° C. for 5 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 2.01 g of methyl N-(2-methyl-3-phenylbenzyl)carbamate as colorless crystals. m.p. 91-94° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:38](=[O:43])[C:39]([O:41][CH3:42])=[O:40]>C(Cl)Cl>[O:43]=[C:38]([NH:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:3]=1)[C:39]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
2-(5-Aminopyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.200 g, 0.508 mmol) was dissolved in DCM (5 mL) and pyridine (0.0820 mL, 1.02 mmol) was added, followed by the addition of methyl 2-chloro-2-oxoacetate (0.0620 g, 0.508 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched by the addition of water (10 mL) and the mixture extracted with CH2Cl2 (4×10 mL). The combined organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 2-oxo-2-((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)amino)acetate (0.180 g, 70.2%). The residue was taken for the next step without further purification. LCMS Condition B-80: retention time 2.32 min, [M+1]=480.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.90 (s, 3H), 4.93 (d, J=4.7 Hz, 2H), 6.83 (d, J=2.8 Hz, 1H), 7.25-7.39 (m, 2H), 7.44-7.63 (m, 6H), 7.79 (td, J=7.7 Hz, J=1.8 Hz, 1H), 7.92 (d, J=2.8 Hz, 1H), 8.36-8.41 (m, 1H), 8.95-9.05 (m, 2H), 9.19 (d, J=1.8 Hz, 1H), 11.20 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[C:13]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:18]=[CH:17][C:16]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[Cl:1])=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: O=Cc1c(Cl)n(-c2ccc(-c3ccccc3)cc2)c2ccccc12
Yield: 52 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-biphenylboronic acid as described in Step 1 of Example 29 to afford 1-biphenyl-4-yl-2-chloro-1H-indole-3-carboxaldehyde (52% yield) as a yellow solid. ESI/MS 332 (M+H), RT 4.14 min; NMR 10.15 (1H, s); 8.23 (1H, d, J=9 Hz); 7.99 (2H, d, J=9 Hz); 7.82 (2H, d, J=9 Hz); 7.69 (7H, m); 7.54 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>C(Cl)Cl>[C:8]1([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a stirring solution of 4-aminobiphenyl (9.53 g, 56.3 mmol) and triethylamine (5.70 g, 56.3 mmol, 7.85 mL) in methylene chloride (60 mL), cooled to 0° C., was added slowly isobutyryl chloride (6.0 g, 56.3 mmol, 5.90 mL). After stirring at 0° C. for 1 h, the mixture was diluted with methylene chloride (120 mL) and washed with 1N NaOH and saturated brine, then dreid (MgSO4), filtered and concentrated. The residue was washed with ether and dried to provide the title compound as a pale yellow crystalline solid (9.83 g, 73%). 1HNMR (400 MHz, CDCl3 /CD3OD) δ7.58 (d, 2H), 7.50 (m, 4H), 7.40-7.25 (m, 3H), 2.55-2.49 (m, 1H), 1.18 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cu](C#N)[C:18]#[N:19]>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(I)c([N+](=O)[O-])c1O
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(C#N)c([N+](=O)[O-])c1O
Temperature: 110 °C

Procedure:
A mixture of methyl 5-chloro-2-hydroxy-4-iodo-3-nitrobenzoate (5.00 g, 14.0 mmol) and copper cyanide (1.9 g, 21 mmol) in N,N-dimethylformamide (25 mL) was heated at 110° C. for 2 hours. After cooling to room temperature, the mixture was quenched with 1 N HCl and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate and then evaporated to dryness under reduced pressure. The residue was used directly in the next step (3.6 g, 100%).
Reaction SMILES: [O:1]=[C:2]1[C@@H:6](OS(C)(=O)=O)[CH2:5][CH2:4][NH:3]1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[CH:16][C:15]=1[CH3:28].CCN(C(C)C)C(C)C>C(#N)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]2[CH2:27][CH2:26][N:25]([C@@H:6]3[CH2:5][CH2:4][NH:3][C:2]3=[O:1])[CH2:24][CH2:23]2)=[O:21])=[CH:16][C:15]=1[CH3:28]
Reactant: CS(=O)(=O)O[C@H]1CCNC1=O
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)C2CCN([C@@H]3CCNC3=O)CC2)cc1C
Temperature: 85 °C
Yield: 67.4 %

Procedure:
In a 1 L round bottom flask was added methanesulfonic acid (S)-2-oxo-pyrrolidin-3-yl ester (prepared according to procedure in Eur. Pat. Appl., 257602, 2 Mar. 1988) (18.75 mmol, 3.36 g) and (4-methoxy-3-methyl-phenyl)-piperidin-4-yl-methanone (18.75 mmol, 4.37 g) in DIEA (75 mmol, 13.1 mL) and acetonitrile (100 mL). The reaction mixture was heated at 85° C. for 4 hours. The reaction was evaporated under a vacuum and silica gel flash column chromatography was performed on the remaining residue eluting with ethyl acetate to 20% MeOH/ethyl acetate to provide the title compound as a white solid (4 g, 67.4% yield). Calculated for C18H24N2O3 MS=316.4036. found MS (ESI) m/e 317.1863 (M+H+); 1H NMR (400 MHz, MeOD) δ ppm 1.69-1.89 (m, 4H) 2.08-2.21 (m, 1H) 2.24-2.30 (m, 1H) 2.44-2.56 (m, 1H) 2.73-2.84 (m, 1H) 2.84-2.92 (m, 1H) 3.08-3.17 (m, 1H) 3.30-3.42 (m, 6H) 3.45-3.54 (m, 1H) 3.90 (s, 3H) 6.95-7.04 (m, 1H) 7.72-7.81 (m, 1H) 7.83-7.90 (m, 1H); analytical RP-HPLC retention time=4.67 min.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:20]=[N:21][C:22](Cl)=[C:23]([CH3:25])[CH:24]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][N:30]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([C:33]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=4)=[N:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(Cl)c(C)c3)nc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(-c4ccnc(C)c4)c(C)c3)nc2)CC1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To the mixture of N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(6-chloro-5-methylpyridin-3-yl)acetamide 148-1 (80 mg, 0.21 mmol) and 2-methyl-4-(tributylstannyl)pyridine 148-2 (75 mg, 0.21 mmol) in DMF (1.5 mL) was added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 0.18 mmol). The reaction was stirred at 110° C. for 20 hours. After cooling down to room temperature, the reaction mixture was purified by reverse-phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2′,3-dimethyl-2,4′-bipyridin-5-yl)acetamide 148 as off-white solid. MS m/z 445.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.57 (s, 1H), 8.49 (d, 1H), 8.40 (d, 1H), 7.98 (d, 1H), 7.87 (d, 1H), 7.64 (d, 1H), 7.42 (s, 1H), 7.36-7.34 (m, 2H), 3.70 (s, 2H), 3.50 (b, 4H), 3.09 (t, 2H), 3.02 (t, 2H), 2.49 (s, 3H), 2.28 (s, 3H), 1.97 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[NH:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:14]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32].C([O-])([O-])=O.[K+].[K+].O>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[N:18]([CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[C:31](=[O:33])[CH3:32])[N:14]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2cc3cnn(C4CCCCO4)c3cc2NC2CCOCC2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(c1cc2c(cnn2C2CCCCO2)cc1OCc1ccccc1)C1CCOCC1
Yield: 82.4 %

Procedure:
To a solution of 5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-amine (1.87 g, 4.59 mmol) in THF (30 mL) is added acetyl chloride (0.39 mL, 5.48 mmol) and K2CO3 (760 mg, 5.50 mmol). After the reaction mixture is heated to reflux for 30 min, H2O (20 mL) and EtOAc (30 mL) are added. The organic phase is separated, washed with saturated aqueous NH4Cl, dried and concentrated to give the product (1.7 g, 82.4% yield). MS (m/z): 450.2 (M+H).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[N:9]([CH3:21])[C:10](=[O:20])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)[N:13]=2)[CH2:6][CH2:5][N:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH2:3]1.[Cl-].[OH:31][NH3+:32].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:31][NH:32][C:26](=[NH:27])[C:25]1[CH:28]=[CH:29][C:22]([N:4]2[CH2:5][CH2:6][N:7]([C:8]3[N:9]([CH3:21])[C:10](=[O:20])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][N:15]=4)[N:13]=3)[C@H:2]([CH3:1])[CH2:3]2)=[CH:23][CH:24]=1
Reactant: C[C@@H]1CN(c2ccc(C#N)cc2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@@H]1CN(c2ccc(C(=N)NO)cc2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-[(3R)-3-methyl-4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-piperazin-1-yl]-benzonitrile (1.50 mg, 3.87 mmol) in ethanol (8.0 ml) and water (4.0 ml) was added hydroxylammonium chloride (807 mg, 11.6 mmol) and sodium carbonate (2.05 g, 19.4 mmol), and the reaction mixture was stirred for 2 hours under reflux. The solution was partitioned between water and chloroform, and the organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting solid was used for next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][Cl:18]>>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[CH:3][C:4]1=[O:12]
Reactant: O=c1cc(O)c2ccccc2[nH]1
Reactant: ClCCCCBr
Product: O=c1cc(O)c2ccccc2n1CCCCCl
Yield: 107.2 %

Procedure:
Analogously to the procedure described in Example I, reaction of 4-hydroxy-1H-quinolin-2-one (24.82 mmol, 4.00 g, prepared according to Monatsh. Chem. 1965, 96, 418) and bromo-4-chlorobutane (29.78 mmol, 5.11 g) afforded 6.70 g of the title compound which is contaminated with reactant. The mixture thus obtained was used in the next step without further purification.