Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:29])/[CH:21]([OH:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:30][CH3:31])[C:15]([CH3:32])=[C:14]2[C:10]=1[C:11](=[O:33])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:34]I>CC#N.[Ag]=O>[Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:29])/[CH:21]([O:28][CH3:34])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:30][CH3:31])[C:15]([CH3:32])=[C:14]2[C:10]=1[C:11](=[O:33])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(O)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Reactant: CI
Agent: O=[Ag]
Solvent: CC#N
Product: CCOC(=O)CC(OC)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Temperature: 25 °C
Yield: 60 %

Procedure:
Ethyl (E) 6-(1,3-dihydro-4-tert-butyldimethylsilyloxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3-hydroxy-4-methyl-4-hexenoate (974 mg) was dissolved in a 6:1 mixture of methyl iodide in CH3CN (25 ml). Silver oxide was then added (5.1 g) and the mixture heated at reflux for 24 hr. The mixture was cooled to room temperature and filtered through a bed of celite. The celite was washed with CHICl2 (80 ml) and ethyl acetate (80 ml). The combined organic layers were evaporated to dryness and the residue passed through a flash column (silica gel, hexanes-EtOAc 8:2) to afford 601 mg (60%) of ethyl (E) 6-(1,3-dihydro-4-tert-butyldimethylsilyloxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5yl)-3-methoxy-4-methyl-4-hexenoate the product as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.[F:19][C:20]([F:31])([F:30])[O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>O1CCCC1.[NH4+].[Cl-]>[CH:11]([C@H:4]1[C:3]([O:2][CH3:1])=[N:8][C@H:7]([CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[O:21][C:20]([F:19])([F:30])[F:31])[C:6]([O:9][CH3:10])=[N:5]1)([CH3:13])[CH3:12]
Reactant: COC1=N[C@@H](C(C)C)C(OC)=NC1
Reactant: FC(F)(F)Oc1ccccc1CBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC1=N[C@H](Cc2ccccc2OC(F)(F)F)C(OC)=N[C@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of (2S)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (7.2 g, 39.4 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C. A solution of n-butyllithium in hexanes (2.5 M, 18.9 mL, 47.2 mmol) was added dropwise, and stirring was continued for 15 minutes. 2-Trifluoromethoxybenzyl bromide (10.0 g, 39.4 mmol) was added, and the resulting mixture was maintained at −78° C. for 30 minutes, then allowed to slowly warm to room temperature. The reaction was then diluted with saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (100% hexanes) to give the desired product.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:30]=[C:29]3[C:25]([CH2:26][CH2:27][CH:28]3[OH:31])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:52]1[CH:53]=[C:54]([CH:61]=[CH:62][CH:63]=1)[O:55][CH2:56][C:57]([O:59][CH3:60])=[O:58]>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:30]=[C:29]3[C:25]([CH2:26][CH2:27][CH:28]3[O:31][C:52]3[CH:53]=[C:54]([CH:61]=[CH:62][CH:63]=3)[O:55][CH2:56][C:57]([O:59][CH3:60])=[O:58])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: OC1CCc2ccc(-c3cccc(F)c3)cc21
Reactant: COC(=O)COc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)COc1cccc(OC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Reaction time: 16 h
Yield: 48.4 %

Procedure:
Diisopropyl azodicarboxylate (57 mg, 0.28 mmol) was added to a solution of 6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-ol (55 mg, 0.24 mmol), triphenylphosphine (97 mg, 0.37 mmol), methyl 2-(3-hydroxyphenoxy)acetate (37 mg, 0.20 mmol) and dichloromethane (2 mL) in a 50 mL round bottom flask at room temperature. After stirring overnight for 16 hours, the resulting mixture was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with ethyl acetate (100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (4 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 38 mg (40%) of methyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenoxy)acetate.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@@H:10]([NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:9][CH:8]=[CH:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO.O>[CH2:15]([O:14][C:12]([NH:11][C@@H:10]1[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH:7]=[CH:8][CH2:9]1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H]1CC=CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(N[C@H]1CC=CC[C@H]1C(=O)O)OCc1ccccc1
Reaction time: 3 h
Yield: 83.6 %

Procedure:
A sample of (1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid methyl ester (91.4 g) was dissolved in MeOH (500 mL) prior to the dropwise addition of NaOH (25.3 g) in water (95 mL). After 3 h, the solution was partially concentrated and an Et2O/water mixture was added. The aqueous layer was separated and was acidified (pH 2) with concentrated HCl. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine before they were dried, filtered, and concentrated to give (1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid (72.7 g). MS found: (M+H)+=276.2.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:11].Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:16][CH2:15][CH2:14][CH2:13][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]([CH3:1])[C:3]1=[O:11]
Reactant: Cn1c(=O)[nH]c2ccccc21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCCl)c2ccccc21
Temperature: 65 °C
Yield: 84.7 %

Procedure:
A mixture of 1-methyl-1H-benzo[d]imidazol-2(3H)-one (2 g, 13.5 mmol, 1 equiv), 1-bromo-3-chloropropane (3.98 ml, 40.5 mmol, 3 equiv), and potassium carbonate (2.79 g, 20.25 mmol, 1.5 equiv) in N,N-dimethylformamide was heated at 65° C. for 16 h. The reaction was cooled to ambient temperature and diluted with ethyl acetate. After being washed with water and brine, the organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified using the Biotage chromatography system (SNAP 100 g cartridge, Rf=0.6, gradient—10%-50% ethyl acetate/hexanes) to afford 1-(3-chloropropyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one as a clear oil (2.57 g, 85%); 1H NMR (400 MHz, DMSO-d6): δ 2.05-2.12 (m, 1H); 2.14-2.21 (m, 1H); 3.32 (s, 3H); 3.53 (t, 1H, J=6.8 and 6.4 Hz); 3.66 (t, 1H, J=6.4 Hz); 3.92-3.97 (m, 2H); 7.05-7.09 (m, 2H); 7.12-7.16 (m, 1H); 7.17-7.21 (m, 1H); MS for C11H13ClN2O m/z 226.07 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11](O)=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[CH:32]=[C:31]([Cl:33])[C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][C:28]=2[NH2:38])=[CH:22][CH:21]=1)(=O)C>>[Cl:33][C:31]1[C:30]([C:34]([F:35])([F:36])[F:37])=[CH:29][C:28]2[N:38]=[C:11]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[N:26]([C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][OH:17])=[CH:21][CH:22]=3)[C:27]=2[CH:32]=1
Reactant: CC(=O)OCCc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2N)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(NC(=O)OC(C)(C)C)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 339, step 3 & Example 1, step 5 from N-(tert-butoxycarbonyl)-alanine and 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino phenyl)ethyl acetate (Example 339, step 2).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:27]=[C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:1]([C:3]2[N:8]=[C:7]([CH2:9][CH2:10][P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: CCOP(=O)(CCc1cccc(C#N)n1)OCC
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(CCc1cccc(-c2nc(=O)c3ccccc3s2)n1)OCC
Yield: 52 %

Procedure:
Diethyl 2-(6-cyano-2-pyridyl)ethylphosphonate (0.80 g, 2.9 mmol) and methyl thiosalicylate (1.00 g, 5.9 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 5 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from diisopropyl ether-ethanol to give the titled compound (0.61 g, 50%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[C:19](Cl)=O>C1COCC1>[CH3:15][C:16]1[CH:24]=[C:23]([C:25]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:22]=[C:18]([CH3:19])[CH:17]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)cc(C)c3)nc2c1
Reaction time: 0.5 h

Procedure:
A mixture of 2-amino-4,6-dimethoxybenzamide (0.0700 g, 0.36 mmol) and 3,5-dimethylbenzoyl chloride (0.112 g, 0.65 mmol) in THF (5.0 mL) was placed in a microwave reactor at 80° C. for 30 min. The THF was removed under reduced pressure, and the residue was purified via CombiFlash chromatography to yield the expected amide. This material was used directly in the next step. A mixture of the amide and H2O/MeCN (2:1, 5.00 mL) was basified to pH 12 with 2 N NaOH and stirred at 80° C. for 16 h. The mixture was cooled and neutralized with 1 N HCl. The resulting precipitate was collected on a frit, washed with water (5.00 mL) and lyophilized to yield 2-(3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.0395 g, 31% over two steps) as a white solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 7.80 (s, 2H), 7.21 (s, 1H), 6.76 (d, J=2.24 Hz, 1H), 6.53 (d, J=2.21 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.35 (s, 6H); MS (APCI) m/z 311 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[C:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH:7]1[CH:6]=[C:5]2[C:10]([CH:1]=[C:2]([NH:22][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:3]=[CH:4]2)=[CH:9][CH:8]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: Nc1cccc2ccccc12
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: c1ccc2cc(Nc3cccc4ccccc34)ccc2c1
Reaction time: 3 h
Yield: 96 %

Procedure:
144 parts of β-naphthol, 143 parts of α-naphthylamine and 10 parts of triphenyl phosphite are mixed. A homogeneous melt is formed at 120° C internal temperature. The elimination of water commences when the internal temperature reaches 230° C and has ended after 3 hours, at an internal temperature of 250° C. 18 parts of water have distilled off. 258 parts of 1,2'-dinaphthylamine, of melting point 106° - 108° C, are obtained by distillation at 239° C/0.1 mm Hg. This corresponds to a yield of 96% of theory.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][CH:8]([OH:10])[CH2:7][NH:6]1.Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14].[OH-].[Na+]>O.C1COCC1>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]
Reactant: C=CCOC(=O)Cl
Reactant: COC(=O)[C@@H]1CC(O)CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 4-hydroxyproline methyl ester hydrochloride (Rosen et al, Synthesis, 40, 1988) (60.4 mMol) in water (10 ml) and THF (20 ml), at 0° C., was added dropwise allyl chloroformate (70 mMol) in THF (20 ml). The solution was maintained at a slightly basic pH by the simultaneous addition of 4N sodium hydroxide (144 mMol). The mixture was stirred at 0° for 1 hour. The aqueous layer was separated and washed, twice, with dichloromethane (25 ml). The organic layers were combined, dried and evaporated to give N-allyloxycarbonyl hydroxyproline methyl ester as a pale yellow oil (86%): NMR (CDCl3) 2.2(m, 3H); 3.58(m, 2H); 3.73(2d, 3H); 4.54(m, 4H); 5.25(m, 2H); 5.9(m, 1H): M/S CI (M+H)+ =230.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][NH:2]1.[H-].[Na+].[CH3:14][O:15][C:16](=[O:25])[CH:17](Br)[CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.O>O1CCCC1>[CH3:14][O:15][C:16](=[O:25])[CH:17]([N:2]1[N:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])[CH2:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1[nH]ncc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc2ccccc2c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 65.1 %

Procedure:
A solution of 2H-phthalazin-1-one (1.33 g, 9.1 mmol) in tetrahydrofuran (45.5 mL, 0.2M) cooled to 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (437 mg, 10.9 mmol). The reaction was stirred at 0° C. for 5 min and then at 25° C. for 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 2.35 g, 10 mmol). The reaction was then warmed to 50° C. where it stirred overnight. At this time, the reaction was cooled to 25° C., poured into water (100 mL), and extracted with methylene chloride (3×100 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 80 g, 20-50% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(1-oxo-1H-phthalazin-2-yl)-propionic acid methyl ester (1.78 g, 61%) as a clear oil; ES+-HRMS m/e calcd for C17H20N2O3 [M+H+] 301.1547 found 301.1546.
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][C:9]2=[O:19])=[CH:5][C:4]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@:38]1([CH3:45])[C:42](O)=[O:43])=[O:36])([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(#N)C>[O:19]=[C:9]1[NH:10][C:11](=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]1[CH2:7][C:6]1[CH:20]=[CH:21][C:3]([F:2])=[C:4]([CH:5]=1)[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:42]([C@@:38]2([CH3:45])[CH2:39][CH2:40][CH2:41][N:37]2[C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])=[O:43])[CH2:26][CH2:25]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)O
Reactant: O=C(c1cc(Cn2c(=O)[nH]c(=O)c3ccccc32)ccc1F)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)N1CCN(C(=O)c2cc(Cn3c(=O)[nH]c(=O)c4ccccc43)ccc2F)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
1-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione hydrochloric acid (30b, 37 mg) was suspended in acetonitrile (1.5 mL), treated with (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (40a, 30 mg), HATU (47 mg), and Et3N (0.5 mL) sequentially. The reaction mixture was stirred at ambient temperature (25° C.) for 19 hrs. The reaction mixture was directly purified by flash chromatography with MeOH—CH2Cl2 (0-20% gradient elution) to afford the desired product, (R)-tert-butyl 2-(4-(5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoyl)piperazine-1-carbonyl)-2-methylpyrrolidine-1-carboxylate (40b) as the major fraction (colorless oil, 50 mg). MS (ESI): m/z=594 (M+H+)
Reaction SMILES: [CH2:1]1[NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3][CH2:2]1.[CH2:10]1[CH2:21][NH:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1.[P:22](O)([OH:24])[OH:23]>>[CH2:1]1[NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3][CH2:2]1.[CH2:7]([O:24][PH:22]([CH2:19][CH:18]=[CH2:17])=[O:23])[CH3:8].[CH2:18]1[CH2:17][NH:16][CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][CH2:21][NH:20][CH2:19]1
Reactant: OP(O)O
Agent: C1CNCCCNCCCNC1
Agent: C1CNCCNCCN1
Product: C=CC[PH](=O)OCC

Procedure:
It appears however that the HI3 salts of the monomethylenesulfonic acids of [9]aneN3 and [12]aneN3 can be used directly. When these triiodide salts are added to melted phosphorous acid at 80° C., at 25° C., HP(=O)Et(OEt), or HP(=O)(OEt)2, a very exothermic reaction occurs whereby the respective monomethylenephosphonate, the monomethylene(ethyl)- phosphinate ethyl ester and the monomethylenephosphonate diethyl ester of [9]aneN3 (FIGS. 31A, 31B, and 31C) and the monomethylenephosphonate diethyl ester and the monomethylene(ethyl)-phosphinate ethyl ester of [12]aneN3 (FIGS. 32A and 32B) are formed almost quantitatively within a few seconds.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]([CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:8].[C:35]([NH2:38])(=[O:37])[CH3:36]>O>[C:35]([NH:38][C:10]([CH:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:18][CH:19]=1)[C:7]([O:6][CH3:5])=[O:8])=[O:12])(=[O:37])[CH3:36]
Reactant: CC(N)=O
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)NC(C)=O
Temperature: 60 °C
Yield: 37.3 %

Procedure:
Thionyl chloride (1.0 ml) was added to 2-methoxycarbonyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid (2.63 g, 6.43 mmol) obtained in Example 1, and the mixture was stirred with heating at 60° C. for 1 hr. Excess thionyl chloride was evaporated under reduced pressure and acetamide (504 mg, 8.54 mmol) was added to the residue. The mixture was stirred with heating at 120° C. for 30 min. Tetrahydrofuran-ethyl acetate (1:1, 100 ml) and water (50 ml) were added to the reaction mixture for partition. The organic layer was washed with saturated brine (50 ml), dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=1:1) to give the title compound (1.08 g, yield 34%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH3:30][NH:31][CH2:32][CH3:33]>>[CH2:32]([N:31]([CH3:30])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:33]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: CCNC
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(-c3ccccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-methylethanamine in step E. MS (ESI): predicted mass calcd. for C22H20FN5O2, 405.2
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=O)[CH2:17][CH2:16][CH2:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([CH2:25]P(=O)(OCC)OCC)#[N:24].[H-].[Na+].O>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[CH:25][C:23]#[N:24])[CH2:17][CH2:16][CH2:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCc2cc(OCCCCc3ccccc3)ccc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC=C1CCCc2cc(OCCCCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution of 6-(4-phenylbutoxy)-3,4-dihydronaphthalen-1(2H)-one (300 mg) in tetrahydrofuran (10 mL), diethyl cyanomethylphosphonate (199 mg) and sodium hydride (60%, 97.8 mg) were added, followed by stirring at room temperature for 24 hours. After adding water, the reaction, mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, concentrated and then purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to thereby give the title compound (E/Z mixture, 207 mg) having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:24])=[CH:4][C:5]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])=[N:6][CH:7]=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>CC(N(C)C)=O>[OH:24][C:3]1[CH:4]=[C:5]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[N:6]=[CH:7][C:2]=1[NH:1][C:25](=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)Cl
Reactant: Nc1cnc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1O
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1cnc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1O

Procedure:
A mixture of 4-{[(5-Amino-4-hydroxy-pyridin-2-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione (332 mg, 0.761 mmole), 6 mL of dimethylacetamide is stirred, then propionyl chloride (705 mg, 7.61 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, and then stirred overnight with a saturated aqueous sodium bicarbonate solution, the solid is filtered, washed well with water and dried to give a yellow solid, 46 mg, (11%); m.p. 210-18° C. dec; MS (ES+): m/z 492.9 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[CH2:17]([N:19]([CH2:36][CH3:37])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[NH:26][C:27]([CH:34]=O)=[C:28]2[C:33]=1[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:24])[CH3:18]>>[CH2:36]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[NH:26][C:27]([CH:34]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])=[C:28]2[C:33]=1[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:24])[CH3:37]
Reactant: CCN(CC)CCNC(=O)c1[nH]c(C=O)c2c1CCCC2
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Product: CCN(CC)CCNC(=O)c1[nH]c(C=C2C(=O)Nc3cc(-c4cccnc4)ccc32)c2c1CCCC2
Yield: 37.7 %

Procedure:
6-Pyridin-3-yl-1,3-dihydroindol-2-one (60 mg, 0.4 mmol) was condensed with 3-formyl-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid (2-diethylaminoethyl)amide (80 mg) to give 50 mg (38%) of the title compound as a reddish solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)[O:4][N:3]=1.Br[C:34]1[CH:46]=[CH:45][C:37]([CH2:38][C:39]2([C:42]([OH:44])=[O:43])[CH2:41][CH2:40]2)=[CH:36][CH:35]=1>>[OH:17][CH:7]([C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[C:18]1[CH:19]=[CH:20][C:21]([C:34]2[CH:46]=[CH:45][C:37]([CH2:38][C:39]3([C:42]([OH:44])=[O:43])[CH2:40][CH2:41]3)=[CH:36][CH:35]=2)=[CH:22][CH:23]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C1(Cc2ccc(Br)cc2)CC1
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1C(O)CCCc1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(CC4(C(=O)O)CC4)cc3)cc2)c1C(O)CCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-{3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-4-phenyl-butan-1-ol and 1-(4-bromo-benzyl)-cyclopropanecarboxylic acid.