Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K+].[CH3:2][S:3][C:4]1[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([C:17]([O-:19])=O)=[CH:6][N:5]=1.[C:20]1([C:26]2[CH:31]=[C:30]([CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:29]=[CH:28][C:27]=2[NH2:40])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:20]1([C:26]2[CH:31]=[C:30]([CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[CH:29]=[CH:28][C:27]=2[NH:40][C:17]([C:7]2[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[C:4]([S:3][CH3:2])=[N:5][CH:6]=2)=[O:19])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1
Reactant: CSc1ncc(C(=O)[O-])n1COCC[Si](C)(C)C
Reactant: Nc1ccc(CCN2CCOCC2)cc1C1=CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C(=O)Nc2ccc(CCN3CCOCC3)cc2C2=CCCCC2)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture of 2-methylsulfanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carboxylate potassium salt (90 mg, 0.28 mmol)(as prepared in the previous step), 2-cyclohex-1-enyl-4-(2-morpholin-4-yl-ethyl)-phenylamine (81 mg, 0.28 mmol)(as prepared in Example 33, step (c)), PyBrOP (170 mg, 0.37 mmol), and DIEA (0.10 mL, 0.57 mmol) in 1.5 mL of DCM was stirred for 8 h at RT. The mixture was diluted with 20 mL of DCM and washed with NaHCO3 (2×30 mL) and brine (30 mL) and dried over Na2SO4. Flash chromatography of the residue on Si gel with 100% EtOAc gave the title compound as a white solid (107 mg, 70%). Mass spectrum (ESI, m/z): Calcd. for C29H44N4O3SSi, 557.3 (M+H). found 556.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH:19]([C:21]1[CH:22]=[C:23]([Cl:31])[C:24]([O:27][CH:28]([F:30])[F:29])=[N:25][CH:26]=1)[CH3:20]>>[Cl:31][C:23]1[CH:22]=[C:21]([CH:19]([N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])[CH3:20])[CH:26]=[N:25][C:24]=1[O:27][CH:28]([F:30])[F:29]
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: CC(Br)c1cnc(OC(F)F)c(Cl)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1C(C)c1cnc(OC(F)F)c(Cl)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 5-(1-bromoethyl)-3-chloro-2-(difluoromethoxy)pyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.89 min., [M+H]+: 441.23 g/mol; tR=0.91 min., [M+H]+: 441.22 g/mol (diastereomers).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:15][CH2:16][C:17]1[N:21]([CH2:22][CH2:23][CH3:24])[C:20]2[CH:25]=[CH:26][C:27]([CH2:29][O:30][Si:31]([CH3:37])([CH3:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][C:19]=2[N:18]=1)[CH2:13][CH3:14]>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([N:15]([CH2:12][CH2:13][CH3:14])[CH2:16][C:17]1[N:21]([CH2:22][CH2:23][CH3:24])[C:20]2[CH:25]=[CH:26][C:27]([CH2:29][O:30][Si:31]([CH3:36])([CH3:37])[C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:28][C:19]=2[N:18]=1)=[O:5]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: CCCNCc1nc2cc(CO[Si](C)(C)C(C)(C)C)ccc2n1CCC
Solvent: ClCCl
Product: CCCN(Cc1nc2cc(CO[Si](C)(C)C(C)(C)C)ccc2n1CCC)C(=O)c1cc(F)ccc1F
Yield: 74 %

Procedure:
2,5-difluorobenzoylchloride 1.5 eq is treated with 1.0 eq 1.25 g (3.3 mmole) of propyl({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl) amine in dichloromethane at room temperature for 1 hr. The reaction is quenched with 1 N NaOH and partitioned between dichloromethane and water. The organic layer is dried over anhydrous Na2SO4 and the solvent removed in vacuo. The residue is chromatographed (SiO2) with ethyl acetate to afford 74% of (2,5-difluorophenyl)-N-propyl-N-({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:18][CH:17]=2)=O)=[CH:7][CH:6]=1)=[O:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30].O>O1CCCC1>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[S:30][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)=[CH:17][CH:18]=1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCCOc1ccc(C(=O)CCC(=O)c2ccc(C(=O)OC)cc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C(=O)OC)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 146.4 %

Procedure:
A suspension of 1-(4-methoxycarbonylphenyl)-4-(4-n-pentyloxyphenyl) butane-1,4-dione (765 mg) and phosphorus pentasulfide (533 mg) in tetrahydrofuran (10 ml) was stirred for 6 hours at room temperature, poured into water and stirred for 1 hour. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give methyl 4-[5-(4-n-pentyloxyphenyl)thiophen-2-yl]benzoate (668 mg).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1C[O:34]CC1>>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([OH:34])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: COC(=O)C(O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of methyl 3-(4-tert-butyldimethylsilyloxyphenyl)propionate (5 g, 16.98 mmol) in THF (50 ml) at −78° C. was added dropwise potassium bis(trimethylsilyl)amide (0.5M in toluene, 34 ml, 17 mmol). The mixture was stirred at this temperature for 0.5 hours and treated with dropwise addition of a solution of trans-2-phenylsulfonyl-3-phenyloxaziridine (5.3 g, 20.38 mmol) in THF (30 ml). The mixture was stirred at −78° C. for 1 hour, quenched with aqueous ammonium chloride, warmed to room temperature and diluted with ethyl acetate. The organic phase was washed with aqueous ammonium chloride, brine, dried over sodium sulfate and concentrated in vacuo. Bulb-to-bulb distillation gave the title material (2 g, 38%) as a colorless oil (b.p. 115° C./0.025 mm Hg) which solidified upon standing.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH3:17][NH2:18]>C1COCC1>[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:18][CH3:17])=[CH:4][CH:5]=1)#[N:16]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C

Procedure:
62.1 g (228 mmol) 4-bromomethyl-2'-cyanobiphenyl (prepared according to . D. J. Carini et al., J. Med. Chem. 1992, 34, 2525) were dissolved in 3 l THF. After addition of 1.5 l of a 40% aqueous solution of methylamine the mixture was stirred over night at room temperature, and the THF distilled off in vacuo. The remaining aqueous layer was extracted with ethyl acetate, the extract dried by stirring over night with 0.4 nm mole sieve, and evaporated in vacuo. The title compound was obtained as a viscous oil, which was pure enough according to its 1H-NMR spectrum for further conversions,
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([CH3:33])[C:13](=[O:14])[N:12]([CH2:15][C:16]([NH:18][C@H:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[C:11](=[O:32])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:35][OH:36].C(N(CC)CC)C>C(O)C>[NH2:2][C:1](=[N:35][OH:36])[C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([CH3:33])[C:13](=[O:14])[N:12]([CH2:15][C:16]([NH:18][C@H:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[C:11](=[O:32])[NH:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CN1C(=O)N[C@@](C)(c2ccc(C#N)cc2)C1=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C[C@H](NC(=O)CN1C(=O)N[C@@](C)(c2ccc(C(N)=NO)cc2)C1=O)c1ccccc1

Procedure:
b 120 l of ethanol were initially introduced into a vessel. At room temperature, 12 kg (26.786 mol) of ethyl (S)-3-(2-((S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionate were added into the vessel, while stirring. 3.74 kg (53.813 mol) of hydroxylamine hydrochloride and 5.44 kg (7.45 l; 53.86 mol) of triethylamine were added. The reaction mixture was heated to reflux and stirred at 80° C. for 2 h. 90 l of ethanol were distilled off in vacuo at a bath temperature of 50° C. The remaining mixture was taken up in 220 l of ethyl acetate and this latter mixture was extracted three times with 50 l of water on each occasion. The ethyl acetate phase was evaporated down to 30 l in vacuo and at a bath temperature of 50° C. It was treated four times with 10 l of toluene on each occasion and evaporated to dryness.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:24](O)=[O:25])[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:32]>CN(C)C=O>[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:32][C:24](=[O:25])[C@H:12]([CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(NC(C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O
Yield: 21.2 %

Procedure:
The process of Example 50 was repeated except that 715 mg (2.00 mmol) of N-benzyloxycarbonyl-(β-benzyl)-D,L-aspartic acid and 215 mg of L-phenylalanine methyl ester hydrochloride, 200 mg of Prolisin and 200 mg of the inhibitor were reacted. As a result, an 110 mg amount (yield of 21.2%) of N-benzyloxycarbonyl-(β-benzyl)-L-aspartyl-L-phenylalanine methyl ester having an [α]D22 = -12.8 (C=1.0 dimethylformamide) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]([OH:7])[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>O.C1(C)C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:1]2[CH2:6][CH:5]([OH:7])[CH2:4][N:3]([S:23]([C:20]3[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=3)(=[O:24])=[O:25])[CH2:2]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: OC1CNCNC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC(O)CN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of hexahydro-5-pyrimidinol (1.0 g, 9.8 mmol) and sodium carbonate (1.04 g, 9.8 mmol) in 10 mL of water in a 250 mL round bottom flask was stirred with a magnetic stir bar for 10 minutes. A solution of 4-nitrobenzenesulfonyl chloride (4.4 g, 19.8 mmol) in 10 mL of toluene was added dropwise over a period of 30 minutes. The reaction mixture formed a white suspended solid. A mixture of 100 mL of water and 20 mL of toluene was added to the reaction mixture and stirred overnight. The reaction mixture was filtered and the solid was washed with 100 mL of toluene, then with 100 mL of water. The solid was dried at room temperature under reduced pressure to give 4.4 g (95%) of crude product, hexahydro-1,3-bis(4-nitrobenzenesulfonyl)-5-pyrimidinol. [1H NMR (DMSO-d6): δ2.29 (s, 1H), 2.84, 3.47 {AB q of d, J=12.4(3.8) Hz, 12.4(7.9) Hz, 4H}, 3.30 (m, 1H), 4.46, 5.07 (AB q, J=12.5 Hz, 2H), 5.31 (s, 1H), 8.11, 8.41 (AB q, J=8.7 Hz, 8H); 13C NMR (DMSO-d6): δ50.0, 59.8, 60.6, 124.6, 128.9, 143.3, 150.1].
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][CH2:16][CH:17](O)[CH3:18]>O1CCCC1>[CH3:18][C:17]1[C:10]2[C:9](=[O:14])[CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][C:11]=2[NH:15][CH:16]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: CC(O)CN
Solvent: C1CCOC1
Product: Cc1c[nH]c2c1C(=O)CC(c1ccccc1)C2
Temperature: 150 °C
Reaction time: 4 h
Yield: 38.4 %

Procedure:
A mixture of 5-phenylcyclohexane-1,3-dione (5.0 g), 3-aminopropan-2-ol (2.6 g), molecular sieves 4A (30 g) and tetrahydrofuran (70 ml) was refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (130 ml). To the solution were added 2-bromomesitylene (5.3 g), tetrakistriphenylphosphine palladium (0.77 g) and potassium carbonate (7.3 g), and the mixture was stirred at 150° C. for 4 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane), and the resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 3-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (2.3 g).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([O:15][CH3:16])=[C:6]([C:11]([Cl:14])=[CH:12][CH:13]=1)[C:7]([NH:9][OH:10])=[O:8].Br[CH2:18][C:19]([OH:21])=[O:20].Cl>O.C(O)C>[Cl:3][C:4]1[C:5]([O:15][CH3:16])=[C:6]([C:11]([Cl:14])=[CH:12][CH:13]=1)[C:7]([NH:9][O:10][CH2:18][C:19]([OH:21])=[O:20])=[O:8]
Reactant: O=C(O)CBr
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1c(Cl)ccc(Cl)c1C(=O)NOCC(=O)O
Temperature: 25 °C

Procedure:
To a solution of 86.34 g. of sodium hydroxide in 1.2 W of water was added 900 ml. of 95% ethanol and 240 g. of 3,6-dichloro-2-methoxybenzohydroxamic acid. To aid dissolution, an additional 300 ml. 95% ethanol and 60 ml. H2O were added. A solution of 153.12 g. bromoacetic acid in 120 ml. of 95% ethanol was then added to the reaction mixture over 0.5 hours, followed by 60 ml. of water. The mixture was then heated to reflux for 3 hours, cooled to ambient temperature, and 150 ml. 20% HCl added. The reaction mixture was then extracted twice with ethyl acetate. The ethyl acetate solutions were combined, washed with brine, and dried over MgSO4 overnight, then filtered and solvent evaporated in vacuo. The residue was crystallized from chloroform to yield [(3,6dichloro-2methoxybenzoyl)aminooxy]acetic acid as a white solid in two crops (m.p. 145°-154° C.).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH:9](=O)[CH:10]([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[CH:10]([CH:12]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][O:1]1)([CH3:11])[CH3:9]
Reactant: CC(C)C=O
Reactant: CC(C)C[C@H](N)CO
Solvent: Cc1ccccc1
Product: CC(C)C[C@H]1COC(C(C)C)N1
Yield: 100.2 %

Procedure:
A solution of (1S)-1-(hydroxymethyl)-3-methylbutylamine (Method B1b; 152 g, 1.3 mol) and isobutyraldehyde (118 mL, 1.3 mol, 1.0 equiv.) in toluene (1.5 L) was heated at the reflux temp. until the theoretical amount of water had been collected in a Dean-Stark trap (23.4 mL). The reaction mixture was concentrated by distillation to approximately 700 mL. The resulting mixture was cooled to room temp. and was concentrated under reduced pressure to a constant weight to give (4S)-2-isopropyl-4-isobutyl-1,3-oxazolidine as a pale yellow oil (223 g, 100%): 1H NMR (CDCl3) δ0.88-0.99 (m, 12H), 1.18-1.35 (m, 1H), 1.42-1.56 (m, 1H), 1.61-1.79 (m, 4H), 3.08 (t, J=7.4 Hz 1H), 3.20-3.34 (m, 1H), 3.85 (t, J=7.4 Hz, 1H), 4.18 (dd, J=7.3, 3.4 Hz, 1H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:49])[CH2:30][CH2:31][C:32]([N:34]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)=[O:33]>>[CH3:49][N:29]([CH3:28])[CH2:30][CH2:31][C:32]([N:34]([C:35]1[CH:36]=[CH:37][C:38]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:8]3[C:7]\2=[CH:12][CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:40]=1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:33]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C)CCC(=O)N(Cc1ccccc1)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(Cc2ccccc2)C(=O)CCN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-((2-dimethylamino-ethyl)-carbonyl)-N-benzyl-p-phenylenediamine Rf value: 0.1 (silica gel, methylene chloride/methanol=10:1) C31H34N4O4
Reaction SMILES: [N+]([O-])(O)=O.[C:5]12([OH:15])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.C12([C:26]([OH:28])=[O:27])CC3CC(CC(C3)C1)C2>>[OH:15][C:5]12[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][C:7]([C:26]([OH:28])=[O:27])([CH2:13]3)[CH2:6]1)[CH2:14]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: OC12CC3CC(CC(C3)C1)C2
Solvent: O=[N+]([O-])O
Product: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Yield: 75.2 %

Procedure:
The same operations as conducted in Example 1 were repeated, except that the reaction mixture temperature after dropwise addition of nitric acid was set to 50° C. In the first carboxylation reaction step, the conversion of 1-adamantanol was found to be 99.0% and 1-adamantane carboxylic acid was generated in a reaction yield of 97%. In the second oxidation reaction step, the conversion of 1-adamantane carboxylic acid was found to be 99% and white crystals of 3-hydroxy adamantane-1-carboxylic acid (28.3 g, yield: 75.2%) were obtained.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][C:26](F)=[C:25]([Br:30])[CH:24]=3)=[O:22])=[C:19]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:33][CH:32]=3)[S:18][C:17]=2[CH:45]=1.O>CN(C=O)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:3][CH2:4][CH2:5][N:6]4[CH2:10][CH2:9][CH2:8][CH2:7]4)=[C:25]([Br:30])[CH:24]=3)=[O:22])=[C:19]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]4[CH2:41][CH2:42][CH2:43][CH2:44]4)=[CH:33][CH:32]=3)[S:18][C:17]=2[CH:45]=1
Reactant: OCCN1CCCC1
Reactant: COc1ccc2c(C(=O)c3ccc(F)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCC4)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reaction time: 0.08 h
Yield: 10 %

Procedure:
Sodium hydride (95 mg of a 60% suspension in mineral oil; 2.4 mmol) was suspended in 22 mL of DMF in a flame-dried, argon-filled flask and stirred for about 5 min. 1-(2-Hydroxyethyl)pyrrolidine (0.23 mL; 2.0 mmol) was added and the mixture was stirred for 15 min. 3-Bromo-4-fluorophenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone in 3 mL of DMF was then added. The mixture was stirred for 4 h at room temperature, then poured into water (25 mL), and extracted with EtOAc (4×25 mL). The combined organics were washed with brine and dried over magnesium sulfate. The title compound (135 mg; 10% yield) was isolated by flash chromatography on silica gel eluting with a gradient of EtOAc(100-90%)/Et3N(0-5%)/MeOH(0-5%).
Reaction SMILES: [CH3:1][CH2:2][CH2-:3].[Mg+2].[Br-].[F:6][C:7]1[CH:32]=[CH:31][C:10]2[S:11][C:12]([C:15]3[N:19]4[N:20]=[C:21]([CH3:29])[CH:22]=[C:23]([C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[C:18]4=[N:17][C:16]=3[CH3:30])=[C:13]([CH3:14])[C:9]=2[CH:8]=1>C1COCC1>[F:6][C:7]1[CH:32]=[CH:31][C:10]2[S:11][C:12]([C:15]3[N:19]4[N:20]=[C:21]([CH3:29])[CH:22]=[C:23]([C:24]([OH:28])([CH2:1][CH2:2][CH3:3])[CH2:25][CH2:26][CH3:27])[C:18]4=[N:17][C:16]=3[CH3:30])=[C:13]([CH3:14])[C:9]=2[CH:8]=1
Reactant: [CH2-]CC
Reactant: CCCC(=O)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCCC(O)(CCC)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
N-Propylmagnesium bromide (0.601 g, 4.09 mmol) is added dropwise to a solution of 1-[3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-8-yl]-butan-1-one (1.08 g, 2.72 mmol) in THF (27 mL) at 0° C. The reaction is stirred at room temperature overnight. The mixture is quenched with ammonium chloride, extracted with ethylacetate, dried over sodium sulfate, filtered, and concentrated to dryness. The crude is purified by ISCO (5% EtOAc/Hexane) to give the title compound (280 mg, 24%). 1H NMR (CDCl3): δ 7.8 (dd, J=4.8, 8.5 Hz, 1H), 7.5 (dd, J=2.5, 9.7 Hz, 1H), 7.2 (m, 1H), 6.7 (s, 1H), 6.4 (s, 1H), 2.6 (s, 3H), 2.5 (s, 3H), 2.3 (s, 3H), 2.0 (m, 3H), 1.5 (m, 1H), 1.3 (m, 4H), 0.9 (t, J=7.3, 6H) ppm. Mass spectrum (m/e): 426 (M+1).
Reaction SMILES: [F:1][C:2]1[C:12]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:27](Br)[C:28]#[CH:29].O>CN(C=O)C>[F:1][C:2]1[C:12]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=2)=[CH:11][C:5]2[N:6]([CH2:29][C:28]#[CH:27])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2cc(F)c(-c3ccc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
0.3 g (0.87 mmol) of 3-(7-fluoro-2,3-dihydro-1,4-benzoxazin-3-on-6-yl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 1 ml of DMF, and 0.04 g (1 mmol) of 60% sodium hydride was added under cooling with ice, followed by stirring at room temperature for 15 minutes. Then, 0.12 g (1 mmol) of propargyl bromide was added thereto. The mixture was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 0.24 g (yield: 72%) of the desired product. Melting point: 166-168° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([O:9][C:3]2[CH:4]=[CH:5][C:6]([NH2:8])=[CH:7][C:2]=2[F:1])[CH:14]=[CH:13][N:12]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(O)c(F)c1
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Yield: 55.9 %

Procedure:
Using a procedure analogous to Example A2, 2-fluoro-4-aminophenol (2.6 g, 24 mmol) and 2,4-dichloropyridine (2.88 g, 20 mol) were combined to provide 4-(2-chloropyridin-4-yloxy)-3-fluoro-phenylamine (3.2 g, 67% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=5.6 Hz, 1H), 6.99 (m, 1H), 6.90 (m, 2H), 6.50 (d, J=1.6 Hz, 1H), 6.41 (d, J=10.4 Hz, 1H), 5.51 (s, 2H); MS (ESI) m/z: 239.1 (M+H+).