Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)[N:5]=[C:4]([NH2:21])[CH:3]=1.P([O-])([O-])([O-])=O.[C:27]([O-])(=O)[CH3:28].[Na+].ClCC=O>C(O)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[CH:12]=2)[N:5]2[CH:27]=[CH:28][N:21]=[C:4]2[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(N)cc(Cl)n2)cn1
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: O=CCCl
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(-c2nc(Cl)cc3nccn23)cn1
Temperature: 95 °C
Yield: 39.3 %

Procedure:
To a solution of 6-chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (2.750 g, 8.439 mmol) in 60 mL of 1:1 absolute ethanol: pH=7 phosphate buffer were added sodium acetate (1.385 g, 16.88 mmol) and 2-chloroacetaldehyde (1.905 mL, 14.77 mmol) and the reaction mixture was then fitted with a condenser and heated to 95° C. overnight. The reaction was not complete so sodium acetate (1.385 g, 16.88 mmol) and 2-chloroacetaldehyde (1.905 mL, 14.77 mmol) were added and the reaction mixture was heated to 95° C. for four hours. After this time the reaction was allowed to cool to ambient temperature and was then diluted with aqueous saturated sodium bicarbonate (50 mL) and extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with 30-45% ethyl acetate in hexanes (1 L) to afford the title compound (1.16 g, 3.315 mmol, 39.29% yield). MS (apci) m/z=350.1 (M+H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(Cl)Cl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:15][CH:14]=1
Reactant: Brc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
AlCl3 (128.8 g, 0.97 mol) was added by portions within 20 min to a suspension of succinic anhydride (44.3 g, 0.44 mol) and bromobenzene (100 ml, 0.99 mol) in DCM (500 ml) while the reaction flask was cooled in a water bath. After 1 h 30 min at RT, the reaction mixture was refluxed for 2 h. After cooling, the reaction medium was slowly poured into a mixture of ice (1.5 l) and concentrated HCl (100 ml). The precipitate was washed twice with water, with isopropanol, and finally with pentane. After drying 4-(4-bromophenyl)-4-oxobutyric acid was obtained as an off-white solid (86.4 g, mp=148° C.). 1H NMR (CDCl3): 7.85 (2H, d, J=8.5 Hz), 7.62 (2H, d, J=8.5 Hz), 3.28 (2H, t, J=6.5 Hz), 2.82 (2H, t, J=6.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:71]1[CH:76]=[CH:75][C:74](/[CH:77]=[CH:78]/[C:79]2([OH:85])[CH2:84][CH2:83][O:82][CH2:81][CH2:80]2)=[C:73]([CH3:86])[CH:72]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[C:57]([CH3:70])[CH:56]=1)[CH2:53][CH3:54])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:58]2[CH:59]=[CH:60][C:55]([C:52]([CH2:53][CH3:54])([C:71]3[CH:76]=[CH:75][C:74](/[CH:77]=[CH:78]/[C:79]4([OH:85])[CH2:84][CH2:83][O:82][CH2:81][CH2:80]4)=[C:73]([CH3:86])[CH:72]=3)[CH2:50][CH3:51])=[CH:56][C:57]=2[CH3:70])=[CH:7][CH:6]=1
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCOCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCOCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
(4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 37 mg, 0.162 mmol), palladium acetate (2.5 mg, 0.011 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (9.0 mg, 0.022 mmol), potassium phosphate (69 mg, 0.324 mmol) and water (0.2 mL) were added to a solution of 4-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-tetrahydro-pyran-4-ol (Example 131-(3); 54.6 mg, 0.108 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for two hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (27.6 mg, 49%).
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].Cl.N[CH2:11][C:12]1[S:16][C:15]([Cl:17])=[N:14][CH:13]=1>O>[CH3:1][O:2][C:3](=[N:4][N+:5]([O-:7])=[O:6])[NH:8][CH2:11][C:12]1[S:16][C:15]([Cl:17])=[N:14][CH:13]=1
Reactant: COC(=N)N[N+](=O)[O-]
Reactant: NCc1cnc(Cl)s1
Agent: Cl
Solvent: O
Product: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.4 %

Procedure:
To a mixture of O-methyl-N-nitroisourea (3.0 g, 0.0252 mol), 36% hydrochloric acid (2.2 ml), and water (50 ml) was added 5-aminomethyl-2-chlorothiazole (93% purity, 4.4 g, 0.0275 mol) at 20° C. This mixture was stirred at room temperature for 6 hours and then extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and concentrated to provide 3.5 g (55.4% yield) of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.
Reaction SMILES: [Na+].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C@H:14]([CH3:18])[C:15]([O-:17])=[O:16])[CH:8]=[CH:7]2.Br[CH2:20][CH2:21][OH:22].CCOCC.CCCCCC>CN(C=O)C.C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C@H:14]([CH3:18])[C:15]([O:17][CH2:20][CH2:21][OH:22])=[O:16])[CH:8]=[CH:7]2
Reactant: COc1ccc2cc([C@H](C)C(=O)[O-])ccc2c1
Reactant: OCCBr
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OCCO)ccc2c1
Yield: 84.1 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid sodium salt (10.9 g, 43.2 mmol) and 2-bromoethanol (27.11 g, 0.22 mol) in DMF (150 mL) was heated to 80° C. for 3.5 hours. The excess 2-bromoethanol and DMF were evaporated under vacuum at 60° C. The resulted crude material was dissolved in CH2Cl2 (400 mL) and washed with water (400 mL), saturated NaHCO3 (100 mL), 3N HCl (100 mL), brine and dried over Na2SO4, filtered and concentrated. Trituration of the residue with ether/hexane gave the title compound as a white solid (9.97 g, 84% yield). m.p. 72-73° C. 1H NMR (300 MHz, CDCl3) δ 8.0-7.68 (m, 3H), 7.66-7.61 (m, 1H), 7.16-7.1 (m, 2H), 4.25-4.15 (m, 2H), 3.93 (s, 3H), 3.92 (q, J=7.2 Hz, 1H), 3.75-3.70 (m, 2H), 1.78 (br. t, 1H), 1.59 (d, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.7, 157.3, 135.2, 133.4, 129.9, 128.6, 126.9, 125.8, 125.6, 118.6, 105.3, 65.9, 60.3, 54.8, 45.0, 18.2. MS (API) m/z 275 (M+NH4)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(CO)cc1
Temperature: 60 °C
Yield: 87.5 %

Procedure:
Azide 5 (1.96 g, 12.0 mmol) and PPh3 (6.50 g, 24.8 mmol, 2.05 eq) were dissolved in THF (25 ml) and heated at 60° C. for 1 hour. Water (4.5 ml, 248 mmol, 20 eq) was added and the reaction was heated overnight. The solvent was evaporated and the residue obtained was purified by flash chromatography (eluent DCM to 4:1 DCM/methanol saturated with NH3) to yield 6 as a white solid (1.44 g, 10.5 mmol, 85%). Rf=0.05 (9:1, DCM/MeOH sat. NH3); νmax=cm−1; 1H NMR (300 MHz, CDCl3) δ=7.35 (d, 3J(H,H)=8.4 Hz, 2H, ArCH α to CH2NH2), 7.30 (d, 3J(H,H)=8.4 Hz, 2H, ArCH α to CH2OH), 4.67 (s, 2H, CH2OH), 3.85 (s, 2H, CH2NH2), 1.68 (bs, 3H, OH, NH2); 13C NMR (75 MHz, CDCl3) δ=142.6 (ArCCH2NH2), 139.6 (ArCCH2OH), 127.3 (ArCH), 127.2 (ArCH), 65.0 (CH2OH), 46.2 (CH2NH2); HRMS (ESI+): m/z calculated for C8H12NO [M+H]+: 138.0913, found 138.0933.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5](=[O:17])[CH2:4]1.CCN(CC)CC>C(Cl)Cl>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:6]2[C:5](=[O:17])[CH2:4][CH:3]([CH:2]=[O:1])[CH2:7]2)=[CH:14][CH:13]=1
Reactant: COc1ccc(CN2CC(CO)CC2=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CC(C=O)CC2=O)cc1
Temperature: 1 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
In a three necked flask, under argon, a solution 4-hydroxymethyl-1-(4-methoxy-benzyl)-pyrrolidin-2-one a2 (4.3 g, 0.018 mol) and Et3N (8.9 ml) in CH2Cl2 (25 ml) cooled down to −10° C. Pyridine-SO3 (10.1 g, 0.064 mol, 3.5 eq) is added by portions and the temperature raised up to 1° C. After 3 h at −10° C., the reaction is quenched with water (100 ml) and extracted with CH2Cl2 (3 times). The organic phase is washed with successively a 1M solution of KHSO4, water, brine, dried over MgSO4, filtered and evaporated in vacuo to give the crude aldehyde a3 (3.2 g, 87%). It is dried several times by azeotropic distillation with toluene and used as such in the next step.
Reaction SMILES: [CH2:1](/[C:3](/[C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[CH:4]\[CH3:5])[CH3:2].C(/C(/C1C2NC(=O)NC=2C=CC=1)=C/C)C.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:1]([CH:3]([C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: C/C=C(\CC)c1cccc2[nH]c(=O)[nH]c12
Agent: [Pd]
Agent: C/C=C(/CC)c1cccc2[nH]c(=O)[nH]c12
Agent: O=C[O-]
Solvent: CCO
Product: CCC(CC)c1cccc2[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a suspension of a mixture of 4-[(1E)-1-ethylprop-1-en-1-yl]-1,3-dihydro-2H-benzimidazol-2-one and 4-[(1Z)-1-ethylprop-1-en-1-yl]-1,3-dihydro-2H-benzimidazol-2-one (329 mg, 1.63 mmol) and ammonium formate (820 mg, 13.0 mmol) in ethanol (3 mL) was added 10% palladium on carbon (50% wet; 120 mg), and the mixture was stirred at room temperature for 15 hours. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate (X1). The organic layer was washed with brine (X1), dried over sodium sulfate and concentrated in vacuo to give 354 mg (>99%) of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:25][CH2:26][CH3:27])[N:14]([CH2:15][CH2:16][CH2:17][O:18][NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)CC>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:25][CH2:26][CH3:27])[N:14]([CH2:15][CH2:16][CH2:17][O:18][NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCONC(=O)C(C)C
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCONC(=O)C(C)C
Temperature: 100 °C

Procedure:
Under a nitrogen atmosphere, N-[3-(4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propoxy]-2-methylpropanamide (300 mg, 0.67 mmol), phenylboronic acid (123 mg, 1.01 mmol), a solution of palladium (II) acetate (1.5 mg, 0.0067 mmol) in hot toluene (0.2 mL), triphenylphosphine (5.3 mg, 0.02 mmol), and 2 M aqueous sodium carbonate (0.4 mL, 0.8 mmol) were combined in 5:1 n-propanol:water (1.44 mL). The solution was placed under vacuum and back-filled with nitrogen gas three times and then heated at 100° C. for 16 hours. Additional phenylboronic acid (123 mg, 1.01 mmol), palladium (II) acetate (1.5 mg, 0.0067 mmol), and triphenylphosphine (5.3 mg, 0.02 mmol) were added, and the reaction was heated at 100° C. overnight. Again, additional phenylboronic acid (123 mg, 1.01 mmol), palladium (II) acetate (1.5 mg, 0.0067 mmol), and triphenylphosphine (5.3 mg, 0.02 mmol) were added, plus 2 M aqueous sodium carbonate (0.4 mL, 0.8 mmol), and the reaction was heated at 100° C. overnight. After cooling to room temperature, the reaction mixture was diluted with chloroform (60 mL) and washed with water (2×10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-35% CMA in chloroform) followed by recrystallization from acetonitrile. The final product was isolated and dried under vacuum at 100° C. to yield N-[3-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propoxy]-2-methylpropanamide as a white powder, mp 169.0-171.0° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]I)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH2:18]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]>CC#N>[CH2:18]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:13][C@@H:12]([CH3:15])[CH2:11][N:6]2[C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=3[O:9][CH2:8][C:7]2=[O:10])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Reactant: CCCCC1CCNCC1
Solvent: CC#N
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)COc3cc(F)ccc32)CC1
Yield: 63.7 %

Procedure:
A microwave vial was charged with (S)-7-fluoro-4-(3-Iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF20) (0.274 g, 0.78 mmol) and 4-butylpiperidine (0.226 g, 1.60 mmol) in MeCN (4 mL) and sealed. After microwave irradiation, 100° C., 60 min, the reaction mixture was purified by cation exchange CC followed by flash CC (SiO2; CH2Cl2/MeOH 50:1) to give the title compound (112KK04) (0.180 g, 63%). 1H NMR (CD3OD) δ 7.24-7.21 (m, 1H), 6.81-6.76 (m, 2H), 4.60 (ABq, J=17.4 Hz, J=15.1 Hz, CH2), 3.98 (dd, J=14.3 Hz, J=5.9 Hz, 1H), 3.87 (dd, J=14.3 Hz, J=7.6 Hz, 1H), 2.86 (d, J=11.0 Hz, 1H), 2.73 (d, J=9.8 Hz, 1H), 2.28-2.23 (m, 1H), 2.16-2.08 (m, 2H), 1.93-1.81 (m, 2H), 1.79-1.62 (m 2H), 1.32-1.13 (m, 9H), 0.93-0.88 (m, 2 CH3); 13C NMR (CD3OD) δ 166.1, 160.3 (d, J=242.3 Hz), 148.1 (d, J=11.9 Hz), 126.4 (d, J=2.9 Hz), 117.8 (d, J=9.4 Hz), 109.9 (d, J=22.9 Hz), 105.7 (d, J=26.1 Hz), 68.6, 65.1, 56.3, 55.4, 46.6, 37.5, 37.0, 33.6, 33.4, 30.1, 29.9, 24.0, 17.2, 14.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:31]=1[C:32](Cl)=[O:33]>C1COCC1>[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:31]=1[C:32](=[O:33])[CH:13]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([F:11])([F:10])[F:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)Cc1ccc(C(F)(F)F)c(OC)c1
Reactant: COc1ccc(OC)c(C(=O)Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)c1cc(OC)ccc1OC)c1ccc(C(F)(F)F)c(OC)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of methyl 2-(3-methoxy-4-(trifluoromethyl)phenyl)acetate (18.6 g, 75 mmol) in anhydrous THF (250 mL) at −78° C., LiHMDS (1.0 M in THF, 79 mL, 79 mmol) was added dropwise under N2. The resulting mixture was stirred at −78° C. for 30 minutes, and a solution of 2,5-dimethoxybenzoyl chloride (15.9 g, 78 mmol; intermediate in Intermediate 1) in anhydrous THF (50 mL) was added dropwise. The reaction mixture was stirred for another 1 h at −78° C., quenched with saturated aqueous NH4Cl (100 mL), and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (30.1 g). 1H NMR (DMSO-d6): δ 7.50 (d, 1H), 7.34 (d, 1H), 7.09-7.07 (m, 1H), 6.94-6.87 (m, 3H), 5.71 (s, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.77 (s, 3H), 3.65 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][S:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)Cc3ccccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 72 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and (2-chlorophenyl)methanesulfonyl chloride, the title compound (yield 72%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [Na].[CH3:2][CH:3]([SH:6])[CH2:4][CH3:5].Cl[C:8]1[C:16]2[NH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[C:11]([N+:21]([O-:23])=[O:22])=[CH:10][C:9]=1[N+:24]([O-:26])=[O:25].O>C(O)C>[CH:3]([S:6][C:8]1[C:16]2[NH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[N:13][C:12]=2[C:11]([N+:21]([O-:23])=[O:22])=[CH:10][C:9]=1[N+:24]([O-:26])=[O:25])([CH2:4][CH3:5])[CH3:2]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1Cl
Reactant: CCC(C)S
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCC(C)Sc1c([N+](=O)[O-])cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
In 200 milliliters of ethanol, 1 gram of sodium (0.04 mole) was reacted with 3.6 grams of 2-butanethiol (0.04 mole). The mixture was stirred for one-half hour. Then 4-chloro-5,7-dinitro-2-trifluoromethylbenzimidazole (6.2 grams; 0.02 mole) was added, and the resulting reaction mixture was stirred overnight, poured into water, acidified, and filtered to separate the desired 4-sec-butylthio-5,7-dinitro-2-trifluoromethylbenzimidazole. It was recrystallized twice from a mixture of benzene and an aliphatic hydrocarbon fraction boiling at 60°-80° C., m.p., 111°-15° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Cl)nc(CBr)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(2-chloro-6-methyl-4-(trifluoromethyl)pyridine (10.0 g, 51 mmol), N-bromosuccinimide (10.9 g, 61 mmol), and 2,2′-azobis(2-methylpropionitrile) (164 mg, 1 mmol) were combined in carbon tetrachloride (200 mL) and heated to reflux. After 16 h, the reaction mixture was cooled to 0° C. and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (100% hexanes) to produce 9.1 g (70%) as a light yellow oil. 1H-NMR (CDCl3, 400 MHz) δ 7.59 (s, 1H), 7.47 (s, 1H), 4.52 (s, 2H).
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:30][C@H:31]([P:33](=[O:36])([OH:35])[OH:34])[CH3:32])=[O:29])[CH2:25][CH2:26][CH3:27])=[O:22])=O)C1C=CC=CC=1>>[NH2:19][CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:30][C@H:31]([P:33](=[O:34])([OH:36])[OH:35])[CH3:32])=[O:29])[CH2:25][CH2:26][CH3:27])=[O:22]
Reactant: CCC[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: CCC[C@H](NC(=O)CN)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 5(A)(iii), from the monobenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-glycyl-L-norvalyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(glycyl-L-norvalylamino)-ethylphosphonic acid of melting point 265°-267° C. (decomposition); [α]D20 =-74.2°; [α]36520 =-271° (c=0.49% in water).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])[CH:5]=1)([O-])=O.[OH:16][C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][CH:23]([C:27]([OH:29])=[O:28])[CH2:24]2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:13]1([C:11]([NH:10][C:6]2[CH:5]=[C:4]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH2:21][CH2:22][CH:23]([C:27]([OH:29])=[O:28])[CH2:24]4)=[CH:19][CH:18]=3)[CH:9]=[CH:8][N:7]=2)=[O:12])[CH2:15][CH2:14]1
Reactant: O=C(Nc1cc([N+](=O)[O-])ccn1)C1CC1
Reactant: O=C(O)C1CCc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)C1CCc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cc2C1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A mixture of N-(4-nitropyridin-2-yl)cyclopropanecarboxamide (2.75 g, 13.3 mmol), 7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (2.55 g, 13.3 mmol) and Cs2CO3.(13.0 g, 39.8 mmol) in DMF (40 mL) was heated at 80° C. for 18 h. The reaction mixture was cooled to rt and concentrated. The residue was acidified to approximately pH 3 by the addition of 1N HCl. The precipitate was filtered and washed with water then hexane and dried under vacuum to provide 7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (4.08 g, 87.2%) as a beige solid. LCMS: (FA) ES+ 353.2, ES− 351.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17]CC3C=CC=CC=3)=[CH:13][C:12]=2[O:25][CH3:26])[CH:8]=[C:7]([C:27]([O:29][CH3:30])=[O:28])[N:6]=1)=[O:4]>C(O)C.[Pd]>[CH3:30][O:29][C:27]([C:7]1[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[O:25][CH3:26])[CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]=1)=[O:28]
Reactant: COC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2OC)cc(C(=O)OC)n1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(-c2ccc(O)cc2OC)cc(C(=O)OC)n1
Yield: 8.9 %

Procedure:
To a solution of 7 g (0.174 mole) of the diester 23 in 200 ml of ethanol was added 1.0 g of 10% Pd/C. The container for the resulting suspension was evacuated and filled with H2 (repeated three times) and kept under a positive atomosphere by means of a hydrogen-filled rubber bladder for 60 hours with very rapid stirring. The mixture was then filtered to remove catalyst and the solvent was removed from the filtrate by rotary evaporation. The resulting oil was dried in vacuo yielding after several hours (4.9 g) 89% of the desired phenol 24 as a solid.