Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1.C1(C)C(C)=CC=CC=1>[C:22]1([NH:21][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Ic1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: Nc1cccc2ccccc12
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: c1ccc(-n2c3ccccc3c3cc(Nc4cccc5ccccc45)ccc32)cc1
Temperature: 90 °C
Yield: 79 %

Procedure:
Under nitrogen, 12 mL of dehydration xylene was added to a mixture of 3.7 g (10 mmol) of 3-iodo-9-phenylcarbazole, 1.6 g (5 mmol) of 1-aminonaphthalen, 60 mg (0.1 mmol) of bis(dibenzylideneacetone)palladium(0), 200 μL (0.5 mmol) of tri(t-butyl)phosphine (49 wt % hexane solution), 3 g (30 mmol) of t-butoxysodium (abbreviation: t-BuONa). This was stirred while heating at 90° C. under a nitrogen atmosphere for 7 hours. After the termination of the reaction, this suspension was added with about 200 mL of hot toluene and was filtered through florisil®, alumina, and celite. The obtained filtrate was concentrated and this residue was separated by silica gel column chromatography (toluene:hexane=1:1). When an obtained solid was recrystallized with a mixture of ethyl acetate and hexane, 1.5 g of 3-[N-(1-naphthyl)amino]-9-phenylcarbazole (PCN) that was a target substance and was cream-colored powder was obtained in a yield of 79% (Synthesis Scheme (g-1)).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:4]1)#[N:2].[OH-].[Na+]>[Ni].C(O)C>[NH2:2][CH2:1][CH:3]1[CH2:4][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(C#N)C2)C1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC(CN)C2)C1
Reaction time: 5 h

Procedure:
Raney nickel is added in catalytic amount to a solution of 0.27 g (1.14 mmol) of tert-butyl 2-cyano-6-azaspiro[3.4]octane-6-carboxylate (isomer 1a), obtained in step 8.1., in 10 mL of a 1N solution of sodium hydroxide in ethanol. The reaction medium is placed in a Parr flask under a hydrogen atmosphere (4 bar), at room temperature for 5 hours.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([CH3:8])=[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1)=O.[H-].[Na+].CI.O.CN(C)[CH:27]=[O:28]>>[CH:27]([C:6]1[S:7][C:3]([CH3:1])=[C:4]([CH2:5][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=1)=[O:28]
Reactant: CN(C)C=O
Reactant: Cc1sc(C=O)cc1NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cc1sc(C=O)cc1CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To a solution of benzyl (5-formyl-2-methyl-3-thienyl)carbamate (1.6 g) in N,N-dimethylformamide (20 mL) was slowly added sodium hydride (60%, oily, 0.3 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Methyl iodide (0.47 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give benzyl (5-formyl-2-methyl-3-thienyl)methylcarbamate (0.72 g, yield 43%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][OH:11])=[N:6][C:7]=1[O:8][CH3:9]>C(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:10]=[O:11])=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1nc(CO)ccc1Br
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1nc(C=O)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(5-Bromo-6-methoxypyridin-2-yl)methanol of preparation 77 (92 mg, 0.42 mmol) was dissolved in DCM (5 ml). MnO2 (477 mg, 5.49 mmol) was added. The reaction was stirred under nitrogen at room temperature for overnight. LCMS showed ˜30% of the starting material remained, and the reaction continued for another 5 hr at which time ˜15% of the starting material remained by LCMS. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. A brownish solid was obtained (69 mg) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:18][N:19]([S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=3)(=[O:39])=[O:38])[C:20](=[O:28])[N:21]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccn4)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and pyridine-2-sulfonyl chloride to give the title compound as a colorless solid. MS: 520.2 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH2:22][CH2:21][C:14]2[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=2[CH2:12]1.[CH:23]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:23]([C:26]1[CH:27]=[C:28]([NH:29][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH2:22][CH2:21][C:14]4[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=4[CH2:12]3)[CH:4]=2)[CH:30]=[CH:31][CH:32]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1cccc(N)c1
Reactant: CSc1ncc2c(n1)CCN(c1cc(C(=O)O)ccc1C)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc2c(n1)CCN(c1cc(C(=O)Nc3cccc(C(C)C)c3)ccc1C)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-methyl-3-[2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]benzoic acid (67 mg, 0.212 mmol), 3-isopropylaniline (0.03 ml, 0.212 mmol) and N,N′-diisopropylethylamine (0.18 ml, 1.06 mmol) in DMF (1.0 ml) was treated with HATU (89 mg, 0.233 mmol). After stirring at room temperature for 1.5 hours, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with sat′d NaCl (aq.), dried (MgSO4), filtered, and concentrated. Trituration of the residue with cold MeOH yielded the title compound as a white, crystalline solid (50 mg, 55%).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][C:17]([CH3:23])=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:11])[CH3:8].Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>ClCCl>[CH:28]([O:27][C:25]([N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([CH3:23])[N:16]=2)[C:21](=[O:22])[C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])=[CH:13]1)=[O:26])([CH3:30])[CH3:29]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOC(=O)c1c[nH]c2nc(C)ccc2c1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(C(=O)OC(C)C)c2nc(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Add pyridine (2.43 ml, 30.0 mmol) to a suspension of 7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (2.32 g, 10.0 mmol) in dichloromethane (100 ml), and then add isopropyl chloroformate (1.0 N in toluene, 30.0 ml). Stir the reaction mixture at room temperature overnight. Wash with brine (3×100 ml). Separate the organic layer, dry over Na2SO4, filter, and concentrate. Purify using silica gel column chromatography (gradient eluent, 0-60% ethyl acetate in hexane) to provide 7-methyl-4-oxo-4H-[1,8]naphthyridine-1,3-dicarboxylic acid 3-ethyl ester 1-isopropyl ester (1.31 g, 41%). MS (ES+): 319 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].CN[CH:15]1[CH2:20][CH2:19]C[CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[CH:3]1([N:2]([CH:4]=[N:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[OH:12])[CH3:1])[CH2:19][CH2:20][CH2:15][CH2:16][CH2:17]1
Reactant: CN(C)C=Nc1ccncc1O
Reactant: CNC1CCCCC1
Solvent: Cc1ccccc1
Product: CN(C=Nc1ccncc1O)C1CCCCC1
Yield: 83.8 %

Procedure:
A mixture of 4-[[(dimethylamino)methylene]amino]-3-pyridinol (5.00 g), N-methylcyclohexylamine (5.20 g), and anhydrous toluene (50 mL) was heated at reflux under nitrogen for 17 hours. The solution was concentrated under reduced pressure and the crude product chromatographed on silica gel (10% methanol in dichloromethane) to afford 5.92 g of solid. Recrystallization from ethyl acetate/hexanes afforded 4.90 g of crystalline material, m.p. 127°-129° C.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:14]([OH:16])=O)=[C:6]2[C:10]=1[CH:9]1[C:11]([CH3:13])([CH3:12])[CH:8]1[CH2:7]2)[CH3:2].[Li][CH3:18]>C(OCC)C>[CH2:1]([C:3]1[S:4][C:5]([C:14](=[O:16])[CH3:18])=[C:6]2[C:10]=1[C@@H:9]1[C:11]([CH3:12])([CH3:13])[C@@H:8]1[CH2:7]2)[CH3:2]
Reactant: [Li]C
Reactant: CCc1sc(C(=O)O)c2c1C1C(C2)C1(C)C
Solvent: CCOCC
Product: CCc1sc(C(C)=O)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 1 h

Procedure:
To a solution of rac-(1aS,5aR)-2-ethyl-1,1-dimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (5.9 g, 25.0 mmol) in diethyl ether (420 mL) MeLi (30 mL, 1.6 M solution in diethyl ether) is added at rt. The mixture is stirred at rt for 30 min before another portion of MeLi (6 mL) is added. Stirring is continued at rt for 1 h. The mixture is poured onto ice/water, the organic layer is separated, washed with 1 N aq. NaOH and brine, dried over Na2SO4, and filtered. The solvent is removed in vacuo and the crude product is purified by CC on silica gel eluting with hexane:EA 9:1 to give rac-1-((1aS,5aR)-2-ethyl-1,1-dimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-ethanone (3.7 g) as a pale yellow oil; LC-MS: tR=1.07 min, [M+1]+=235.31, 1H NMR (CDCl3): δ 2.98 (dd, J=5.9, 18.8 HZ, 1H), 2.83-2.70 (m, 3H), 2.40 (s, 3H), 1.94-1.87 (m, 2H), 1.27 (t, J=7.6 Hz, 3H), 1.12 (s, 3H), 0.71 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]([CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)[CH3:24])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C[C@H]1CC[C@H](C(=O)O)CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solutionoof 20.3 g (0.07 mol) of trans-4-(N-benzyloxycarbonyl-aminomethyl)cyclohexanecarboxylic acid in 380 ml of dimethylformamide is treated at 15°-20° under argon with 0.21 mol of sodium hydride (9.35 g of a 55% dispersion in mineral oil) and thereupon stirred at room temperature for a further 30 minutes. A solution of 17.5 ml (0.28 mol) of methyl iodide in 20 ml of dimethylformamide is added thereto at 25°-30° within 20 minutes and the mixture is stirred at 70° for a further 1 hour. After concentration under reduced pressure the residue is partitioned between water and methylene chloride. The organic phase is evaporated and the residual oil is dissolved in a mixture of 350 ml of ethanol and 350 ml of 1N sodium hydroxide solution. The mixture is heated to reflux for 1 hour, cooled and poured into 700 ml of ice-water The solution is extracted with ethyl acetate and then acidified with 6N hydrochloric acid. The liberated acid is extracted with methylene chloride and the extract is dried over sodium sulphate and evaporated. The residual oil is chromatographed on 270 g of silica gel with a mixture of methylene chloride/ethyl acetate (4:1) as the elution agent. There are obtained 13.6 g (64%) of trans-4-(N-benzyloxycarbonyl-N-methyl-aminomethyl)cyclohexanecarboxylic acid as a thick oil.
Reaction SMILES: [C:1]1([C@@H:7]2[NH:10][C:9](=[O:11])[C@@H:8]2[O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:29]([N:10]1[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:8]([O:12][Si:13]([CH2:16][CH3:17])([CH2:18][CH3:19])[CH2:14][CH3:15])[C:9]1=[O:11])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@H]1c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@H]1C(=O)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Reaction time: 0.08 h

Procedure:
To a stirred solution of (3R, 4S)-4-phenyl-3-triethylsilyloxy-2-azetidinone (LXXII) (1.000 g, 3.601 mmol) in dry CH2Cl2 (25 mL) was added N,N-diisopropylethylamine (0.689 mL, 3.961 mmol, 1.1 equiv) at 0° C. under an argon atmosphere. The solution was stirred for 5 min followed by the addition of benzoyl chloride (0.459 mL, 3.961 mmol, 1.1 equiv) and 4-dimethylaminopyridine (96.5 mg, 0.790 mmol, 0.20 equiv). The reaction mixture was stirred at room temperature for 1 h, then it was diluted with ethyl acetate (25 mL). The resulting solution was washed with brine, 10% NaHCO3, 10% HCl solution, dried (MgSO4), and concentrated to give a crude compound as an oil. The compound was further purified by silica gel flash chromatography (being eluted with 15% ethyl acetate in hexanes) which afforded 1.04 g (Y: 80%) of 8.07-8.00 (m, 2H) 7.59-7.45 (m, 3H) 7.37-7.31 (m, 5H) 5.41 (d, J=6.1 Hz, 1H) 0.83-0.77 (m, 9H) 0.54-0.42 (m, 6H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][B-](F)(F)F)=[O:22])([CH3:19])([CH3:18])[CH3:17].[K+].C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([CH2:25][CH2:24][NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCC[B-](F)(F)F
Reactant: COc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cncc(CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
A 20 mL vial equipped with a septum cap and stir bar was charged with cesium carbonate (977 mg, 3.00 mmol), 3-bromo-5-methoxypyridine (188 mg, 1.00 mmol), potassium[2-(tert-butoxycarbonylamino)ethyl]trifluoroborate (301 mg, 1.20 mmol), di-(1-adamantyl)-n-butylphosphine (35.8 mg, 0.100 mmol) and palladium (II) acetate (11.2 mg, 0.050 mmol). Toluene (3 mL) and water (2 mL) were added, and the vial was purged with nitrogen gas and sealed. The mixture was stirred vigorously at 80° C. for 24 h, cooled to room temperature and the aqueous layer was removed. The organic layer was dried with sodium sulfate and the crude product solution was purified by silica gel chromatography (0-10% MeOH in DCM) to provide tert-butyl (2-(5-methoxypyridin-3-yl)ethyl)carbamate as a colorless syrup (153 mg, 0.606 mmol, 61%). 1H NMR (CDCl3, 500 MHz): δ (ppm) 8.21 (d, J=6.14 Hz, 1H), 8.09 (d, J=1.58 Hz, 1H), 6.98-7.16 (m, 1H), 4.53-4.90 (m, 1H), 3.87 (s, 3H), 3.33-3.47 (m, 2H), 2.82 (t, J=6.78 Hz, 2H), 1.46 ppm (s, 9H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][C:27](=[O:28])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCBr)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCC(=O)c2ccccc2)CC1
Yield: 37 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (7 g) and 4-bromo-1-phenyl-1-butanone (4.93 g) were reacted and treated in the same manner as in Example 172 to give 3.1 g of 4-amino-5-chloro-2-methoxy-N-((1-(4-oxo-4-phenylbutyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23](O)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH3:26][C:27]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)[CH2:35][CH2:34]1)([CH3:32])[C:28]([O:30][CH3:31])=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:39]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:48]=[CH:49][C:50]([C:53]([F:55])([F:56])[F:54])=[CH:51][CH:52]=3)=[CH:43][CH:42]=2)[CH:36]2[CH2:37][CH2:38][N:33]([C:27]([CH3:26])([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[CH2:34][CH2:35]2)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2ccccc21
Reactant: COC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3ccc(F)cc3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A mixture of [2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C3) (100 mg, 1 equiv), methyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B1) (130 mg, 1.03 equiv), DIPEA (0.1 ml, 2 equiv), acetonitrile (2 ml) and HATU (130 mg, 1.4 equiv) was stirred at room temperature for 1 h, then evaporated and redissolved in acetonitrile. Purification by reverse phase HPLC (Preparative Method B) gave methyl 2-[4-({[2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetyl} {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate (126 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[C:12]([B:13]([OH:15])[OH:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:21][N:20]=1.CC(O)CC>CCCCCC>[C:29]1([C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]([NH:1][C:2]3[CH:17]=[CH:16][C:5]([O:6][C:7]4[C:12]([B:13]([OH:15])[OH:14])=[CH:11][CH:10]=[CH:9][N:8]=4)=[CH:4][CH:3]=3)=[N:20][N:21]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Nc1ccc(Oc2ncccc2B(O)O)cc1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Solvent: CCCCCC
Solvent: CCC(C)O
Product: OB(O)c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
2-(4-Aminophenoxy)pyridin-3-ylboronic acid (478 mg, 2.08 mmol), 1-chloro-4-phenylphthalazine (500 mg, 2.08 mmol) and butan-2-ol (4.16 ml, 2.08 mmol) were placed in a sealed tube. The reaction vessel was sealed and the mixture heated to 100° C. After 1 h 45 min, the reaction was cooled to rt. Hexane was added and the precipitated tan solid was filtered off with hexanes. LCMS of the solids indicated product, 2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-ylboronic acid. MS Calculated for C25H19BN4O: [M]+=434. Found: [M+1]+=435.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH2:9][CH3:10])[S:6][C:7]=1[CH3:8].[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH2:9]([C:5]1[S:6][C:7]([CH3:8])=[C:3]([CH2:2][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[N:4]=1)[CH3:10]
Reactant: CCc1nc(CCl)c(C)s1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1nc(CC)sc1C)OCC
Temperature: 160 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A mixture of 4-chloromethyl-2-ethyl-5-methyl-1,3-thiazole (3.2 g) and triethyl phosphite (6.7 g) was stirred at 160° C. for 16 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2-1:1, v/v) to give diethyl [(2-ethyl-5-methyl-1,3-thiazol-4-yl)methyl]phosphonate as a colorless oil (4.9 g, yield 97%).
Reaction SMILES: [NH2-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15](=O)[CH2:16][CH2:17][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:19][C:13]=3[O:12][N:11]=2)=[CH:6][CH:5]=1.[Cl-].[NH4+].O1CCC[CH2:28]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15](=[CH2:28])[CH2:16][CH2:17][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:19][C:13]=3[O:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)C1CCC(=O)c2c(-c3ccc(Cl)cc3)noc2C1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Product: C=C1CCC(C(=O)OC)Cc2onc(-c3ccc(Cl)cc3)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.65 g of a mixture of methyltriphenylphosphonium bromide and sodium amide (approximately 6.3 mmol of each component) was stirred under nitrogen and 16 ml of dry tetrahydrofuran were added. After stirring at room temperature for 15 minutes, the mixture was cooled in ice and a solution of 1.85 g (5.79 mmol) of methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-oxo-4H-cyclohept[d]isoxazole-7-carboxylate in 11 ml of dry tetrahydrofuran was added dropwise. The mixture was stirred in the cold for 0.5 hour and then at room temperature for 3 hours. The mixture was treated with 10 ml of saturated aqueous ammonium chloride solution and then partially evaporated. The aqueous phase was extracted three-times with dichloromethane and the combined organic phases were dried over magnesium sulfate and evaporated. The residue was triturated with diethyl ether. The solid was filtered off and washed with diethyl ether and the filtrate was evaporated. The residue was chromatographed on silica gel using 50% ethyl acetate/hexane for the elution. There were obtained 1.06 g of methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methylene-4H-cyclohept[d]isoxazole-7-carboxylate of melting point 113°-114° C.