Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[CH:5][CH:4]=1)#[N:2].Cl.C(=O)([O-])[O-].[NH4+:34].[NH4+]>C(Cl)Cl.C(O)C>[ClH:28].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[CH:5][CH:4]=1)(=[NH:34])[NH2:2]
Reactant: Cc1cc(OCc2ccc(C#N)cc2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(OCc2ccc(C(=N)N)cc2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 147.6 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(4-cyanophenyl)methoxy]-5-methylphenyl ester (414 mg, 1.0 mmol), as prepared in the preceding step, in methylene chloride (10 mL) was added 37% HCl in ethanol (20 mL) at 0° C. The mixture was stirred at room temperature for 2 days. The solvent was evaporated and the residue was co-evaporated with methylene chloride several times. The residue was then dissolved in ethanol (20 mL) and ammonium carbonate (385 mg, 4.0 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was partitioned between methylene chloride and 10% K2CO3 (50 mL). The organic phase was washed with 50 mL of 10% K2CO3 and dried over K2CO3. The solvent was removed in vacuo. The residue was diluted with CH2Cl2, treated with HCl in methanol (30 mL), and concentrated. The residue was then purified by crystallization (methanol and ethyl acetate) to give the title compound as a white solid (345 mg, 74%). 1H-NMR (300 MHz, DMSO-d6) δ 2.21 (s, 3H), 5.16 (s, 2H), 6.53 (t, 2 H, J=9.3 Hz)), 6.86 (s, 1H), 7.55-7.62 (m, 3H), 7.82-7.89 (m, 4 H), 7.93 (d, 1H, J=4.0 Hz), 9.24 (br s, 2 H) and 9.44 (br s, 2 H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C21H19N2ClO4S: 431.1 (M+H). Found: 431.1.
Reaction SMILES: S(=O)(=O)(O)O.[P:6]([CH2:10][N:11](CC(O)=O)[CH2:12][C:13]([OH:15])=[O:14])([OH:9])([OH:8])=[O:7].OO>O>[P:6]([CH2:10][NH:11][CH2:12][C:13]([OH:15])=[O:14])([OH:9])([OH:8])=[O:7]
Reactant: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Temperature: 80 °C

Procedure:
Thirty-nine parts of water and 39 parts of concentrated sulfuric acid were charged into a suitable reaction vessel and then 20 parts of N-(phosphonomethyl) iminodiacetic acid added. The mixture was heated to 80°C. and then 277 parts of a 35% hydrogen peroxide solution was added over a period of from 61/2 to 7 hours while maintaining the temperature at 77°-81°C. During the addition of the hydrogen peroxide, 8 additional 20 part increments of N-(phosphonomethyl) iminodiacetic acid were added over a 4 hour period. The reaction was then heated at 80°C. with stirring until nuclear magnetic resonance spectral analysis showed that the reaction was essentially complete. The mixture was then cooled at 0°C. overnight, centrifuged, washed with a small amount of water and dried under vacuum to yield approximately 100 parts of N-phosphonomethyl glycine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:13][C:12]([OH:15])([CH3:14])[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87](O)=[O:88])=[O:72])([CH3:69])([CH3:68])[CH3:67]>C(Cl)Cl>[C:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:13][C:12]([OH:15])([CH3:14])[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][CH2:8]1)=[O:88])=[O:72])([CH3:69])([CH3:67])[CH3:68]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCN(C(=O)OC(C)(C)C)CC(C)(O)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCN(C(=O)OC(C)(C)C)CC(C)(O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 44, tert-butyl 6-hydroxy-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate (70 mg, 0.20 mmol) in MeOH (5 mL), was added 10% palladium on carbon (10 mg) and the mixture was stirred under an atmosphere of H2 (60 psi) for 16 hr. The mixture was filtered through Celite® and the solvent was removed under reduced pressure to afford tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate as an oil. To a solution of this amine in DCM (5 mL), DIPEA (0.1 mL, 9.6 mmol), PyBOP (0.16 g, 0.3 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (78 mg, 0.22 mmol) were added and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (30 mL) and washed with water (10 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave tert-butyl 4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate as a solid (122 mg). To this solid (122 mg, 0.18 mmol) in MeOH (1 mL), a solution of HCl (4 M in 1,4-dioxane, 3.2 mL, 12.9 mmol) was added and the resulting solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure and the crude residue was dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7 N ammonia in MeOH. Purification by preparative HPLC gave 190 as an off-white solid (40 mg, 44% over three steps). 1H NMR (400 MHz, d6-DMSO) δ 9.19 (s, 1H), 8.24 (s, 1H), 7.59-7.48 (m, 3H), 7.33-7.23 (m, 2H), 3.69 (s, 3H), 3.26-3.02 (m, 4H), 2.98-2.73 (m, 4H), 1.01 (s, 3H). Alkyl NH and OH not observed. LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][CH3:12].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:42][C:43]1([CH3:50])[C:47]([CH3:49])([CH3:48])[O:46][BH:45][O:44]1.C(N(CC)CC)C>O1CCOCC1.CC#N.CC#N.Cl[Pd]Cl>[CH2:11]([C:3]1[CH:4]=[C:5]([O:9][CH3:10])[C:6]([F:8])=[CH:7][C:2]=1[B:45]1[O:46][C:47]([CH3:49])([CH3:48])[C:43]([CH3:50])([CH3:42])[O:44]1)[CH3:12]
Reactant: CCc1cc(OC)c(F)cc1Br
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1cc(OC)c(F)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 110 °C
Yield: 63.8 %

Procedure:
To a solution of 1-bromo-2-ethyl-5-fluoro-4-methoxy-benzene (Preparation 12, 18.0 g, 77.2 mmol) in dioxane (100 mL) were added SPhos (4.12 g, 10.0 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (14.8 g, 116 mmol) and triethylamine (10.7 mL, 77.2 mmol). The reaction mixture was degassed with nitrogen prior to the addition of dichlorobis(acetonitrile)palladium (II) (801 mg, 3.09 mmol). The reaction mixture was then heated at 110° C. for 18 hours, cooled to room temperature and filtered through a pad of Celite, washing with EtOAc. The solvent was removed in vacuo and the residue was redissolved in EtOAc (30 mL) and washed with water (30 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was triturated with methanol and the resulting solid was collected by filtration to give the title compound as a beige solid (13.8 g) in a 64% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8]([N+:13]([O-])=O)=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[H][H].O>[Ni].C(O)C>[NH2:13][C:8]1[C:9]([F:12])=[C:10]([F:11])[C:2]([Cl:1])=[C:3]([F:16])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: O=C(O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Nc1c(F)c(F)c(Cl)c(F)c1C(=O)O

Procedure:
63.9 g (0.25 mol) of 3-chloro-2,4,5-trifluoro-6-nitrobenzoic acid and 15 g of Raney nickel are suspended in 450 ml of ethanol. Hydrogenation is carried out at 10°-15° C. under a hydrogen pressure of 5-10 bar until the uptake of hydrogen has ended. The crude reaction mixture is poured onto 1 l of water. The carboxylic acid which has precipitated is dissolved by addition of 10% strength sodium hydroxide solution. When the catalyst has been filtered off with suction, a pH of 2-3 is established by addition of half-concentrated hydrochloric acid. The precipitate is filtered off with suction, washed with water and dried over KOH in a desiccator.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]([CH:16]=1)=[N:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:7]=2[C:17]([OH:19])=[O:18].N1C=CC=CC=1.F[C:27]1[CH:32]=[CH:31][CH:30]=[C:29](F)[C:28]=1O>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]([CH:16]=1)=[N:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:7]=2[C:17]([O:19][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:18]
Reactant: COc1ccc2c(C(=O)O)c3ccccc3nc2c1
Reactant: Oc1c(F)cccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(C(=O)Oc3ccccc3)c3ccccc3nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-acridine-9-carboxylic acid (0.50 g) was suspended in 10 mL thionyl chloride (3-10 mL) and reaction mixture was refluxed for 3 h. The solvent was removed under reduced pressure to obtain a yellow solid which was dissolved in CH2Cl2 and pyridine (0.44 g) under argon. A solution of 2,6-difluorophenol (0.32 g) in CH2Cl2 was added dropwise. The solution was stirred overnight at room temperature then diluted with more CH2Cl2 (100 mL) and washed with water (3×50 mL) . The organic layer was dried over Na2SO4 and concentrated to obtain the product which was further purified by chromatography on silica gel (30% ethyl acetate/hexane) to yield the pure product as a creamy solid. 1H NMR (acetone-d6) δ 4.08 (s, 3H), 7.39-8.29 (m, 12H).
Reaction SMILES: COC[O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[N:13][C:8]=2[S:7][C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20]([Li])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1.CCCCCC>[CH3:21][C:20]([C:12]1[CH:11]=[CH:10][C:9]2[C:5]([OH:4])=[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:7][C:8]=2[N:13]=1)([CH3:23])[CH3:22]
Reactant: COCOc1c(-c2ccccc2)sc2ncccc12
Reactant: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(O)c(-c3ccccc3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 2.72 g (10.0 mmol) of 3-methoxymethoxy-2-phenyl-7-azabenzothiophene in 20 mL of dry tetrahydrofuran was cooled to -78° C. To this was added 11 mL of a 1.0M solution of t-butyllithium in hexane and the solution was allowed to warm to room temperature. The solution was quenched with methanol and stirred in air for 60 minutes, then partitioned between ether and water. The aqueous layer was washed with two portions of ether and the combined extracts were washed with brine, dried, and concentrated to an oil. The oil was dissolved in 10 mL methanol and 10 mL of 2M HCl and stirred at room temperature for 24 hours. The solution was partitioned between ether and water and the ether layer dried and concentrated. Recrystallization from ether-hexane afforded 2.43 g (84%) of pale yellow needles, m.p. 181°-183° C.
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>O.C(OC)(C)(C)C.CN(C)C(=O)C>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:7]([N:19]3[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:15])[CH2:17][CH2:18]3)=[N:6][CH:5]=[CH:4][N:3]=2)=[CH:31][CH:30]=1
Reactant: Clc1nccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
Charge a reactor with 2,3-dichloropyrazine (73.6 g, 0.497 mol, 1.0 equiv), piperazine-1-carboxylic acid t-butyl ester (101.9 g, 0.547 mol, 1.1 equiv) and powdered potassium carbonate (164.8 g, 1.19 mol, 2.4 equiv). Add N,N-dimethylacetamide (1.1 L) and heat to 110° C. under nitrogen for 5 hr. Cool the reaction to room temperature, and add 4-fluorophenylboronic acid (83.4 g, 0.596 mol, 1.2 equiv), tetrakis(triphenyl-phosphine)palladium(0) (2.87 g, 2.5 mmol, 0.005 equiv) and water (442 mL). Heat the reaction to 110° C. under a nitrogen atmosphere for 5 hr. Cool the reaction to 60° C. and dilute with water (800 mL) and methyl t-butyl ether (1.0 L). Cool to room temperature and separate the resulting layers. Wash the organic layer with 200 mL of water, separate the layers, and concentrate to give 3-(4-fluorophenyl)-2-[4-(t-butyloxycarbonyl)piperazin-1-yl]pyrazine as a light yellow solid that is taken into the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[N:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1O)[C:12]([F:18])([F:17])[O:11][C:10]2([F:20])[F:19])=[O:5].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[N:23][CH:22]=[CH:21][C:3]=1[C:4]1[O:5][C:15]2[CH:14]=[C:13]3[C:12]([F:17])([F:18])[O:11][C:10]([F:19])([F:20])[C:9]3=[CH:8][C:7]=2[N:6]=1
Reactant: O=C(Nc1cc2c(cc1O)C(F)(F)OC2(F)F)c1ccncc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC1(F)OC(F)(F)c2cc3oc(-c4ccncc4Cl)nc3cc21
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
To a mixture of 0.68 g of 3-chloro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide, 8 ml of tetrahydrofuran and 0.55 g of triphenylphosphine, 0.90 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature, and the reaction mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.55 g of 2-(3-chloropyridin-4-yl)-5,5,7,7-tetrafluoro-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole (hereinafter, referred to as “active compound 86”).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[F:1][C:2]1[C:3]([NH:17][S:29]([CH3:28])(=[O:31])=[O:30])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(COc2ncc(F)c(N)n2)cc1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(COc2ncc(F)c(NS(C)(=O)=O)n2)cc1
Reaction time: 0.33 h
Yield: 25.4 %

Procedure:
To a solution of 5-fluoro-2-(4-methylbenzyloxy)pyrimidin-4-ylamine (0.100 g, 0.43 mmol) in anhydrous THF (4 mL) was added LiHMDS (1.07 mL of 1.0M, 1.07 mmol) dropwise at room temperature, and the resulting orange solution was stirred for 20 min. Methanesulfonyl chloride (0.108 g, 0.94 mmol) was added in one portion and the turbid, light orange solution was stirred for 60 min. The reaction was quenched with brine (5 mL) and the THF phase was separated. The aq. phase was extracted w/ EtOAc (5 mL), and the organics were combined, dried over Na2SO4, filtered, and concentrated to an orange gummy residue. The residue was purified by flash chromatography (SiO2, 0→100% EtOac/hexanes) to give 0.034 g (26%) of the title compound as a white solid: mp 145-148° C.; 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.33 (d, J=7.9 Hz, 2H), 7.17 (d, J=7.9 Hz, 2H), 5.35 (s, 2H), 3.37 (s, 3H), 2.35 (s, 3H); HPLC-MS (ESI) m/z 312 (M+H)+, 310 (M−H)−.
Reaction SMILES: C(S)C.[H-].[Na+].C[O:7][C:8]1[CH:33]=[CH:32][C:11]([C:12]([C:14]2[CH2:15][CH2:16][C:17]3[C:22]([C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:21][CH:20]=[C:19]([O:30]C)[CH:18]=3)=[O:13])=[CH:10][CH:9]=1.Cl>CN(C=O)C>[OH:7][C:8]1[CH:33]=[CH:32][C:11]([C:12]([C:14]2[CH2:15][CH2:16][C:17]3[C:22]([C:23]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:21][CH:20]=[C:19]([OH:30])[CH:18]=3)=[O:13])=[CH:10][CH:9]=1
Reactant: COc1ccc(C(=O)C2=C(c3ccccc3)c3ccc(OC)cc3CC2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: O=C(C1=C(c2ccccc2)c2ccc(O)cc2CC1)c1ccc(O)cc1
Temperature: 60 °C

Procedure:
To 300 ml. of DMF were added under nitrogen and with ice bath cooling, 9.3 gms. of ethyl mercaptan. To the mixture then were added 7.2 gms. of 50 percent sodium hydride-oil mixture. The mixture represents 0.15 mole of sodium hydride. To the resulting mixture then were added 11.1 gms. (0.03 mole) of the product from Example 4. The mixture was heated at 60° C. for 1 hour. Analysis of the reaction mixture by TLC indicated the presence of starting material plus another component, probably the mono-hydroxy compound. The temperature of the reaction mixture was raised to 110° C., and this temperature was maintained for 1 hour. TLC showed no starting material; however, the presence of two components was noted. The reaction mixture therefore was heated for an additional 1 hour at 125° C. after which a single spot was noted by TLC analysis. The reaction mixture then was acidified by addition of cold 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The ethyl acetate was washed with water and evaporated. The resulting residue was recrystallized from a mixture of methanol and acetone to give 8 g. of the title compound, m.p. 205°-207° C.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:26][C@H:27]([C:29]([NH:31][C@@H:32]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH:33]([OH:40])[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[O:30])[CH3:28].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:11][CH:12]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13]([NH:26][C@H:27]([C:29]([NH:31][C@@H:32]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH:33]([OH:40])[C:34]([O:36][CH:37]([CH3:38])[CH3:39])=[O:35])=[O:30])[CH3:28])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)N)C(O)C(=O)OC(C)C
Reactant: O=C(O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12)C(O)C(=O)OC(C)C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a solution of 79 mg of 2-(1-naphthylmethyl)-3-morpholinocarbonylpropionic acid and 90 mg of isopropyl (2RS, 3S)-3-(L-alanyl)amino-2-hydroxy-5-methylhexanoate hydrochloride in 5ml of N,N-dimethylformamide were added 0.062 ml of diphenylphosphoryl azide and 0.110 ml of triethylamine under ice-cooling, and the mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol = 5/1 by volume: Rf2 =0.70) to obtain 19 mg of isopropyl (2RS, 3S)-3-{N-[2-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-L-alanyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:10].[K+].[OH2:12]>CO>[CH3:3][C:2]1([CH3:9])[O:12][C@@H:5]([CH2:6][O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:4][O:10]1
Reactant: N#Cc1ccc(O)cc1
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: CO
Product: CC1(C)OC[C@H](COc2ccc(C#N)cc2)O1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
A solution of 4-hydroxy benzonitrile (55 g) in methanol (100 ml) was treated with potassium hydroxide (29 g) in water (30 ml) and evaporated at reduced pressure. The remaining potassium salt was dissolved in dry dimethylformamide (75 ml) and (4R)-2,2-dimethyl-4 - methanesulfonyloxymethyl-1,3-dioxolane, 82.2 g, was add stirring at 110° C. for 20 h, allowed to cool and distributed between ether and water. The aqueous phase was extracted three times with ether, the combined ether phases washed three times with 10% aqueous potassium hydroxide and twice with water, dried over anhydrous sodium sulfate and evaporated. Yield 77 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])[C:4](=[O:17])[CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[N:7]([CH3:18])[C:6](=[O:8])[N:5]([CH2:9][CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])[C:4](=[O:17])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCCCC(CC)Cn1c(=O)cc(Cl)[nH]c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCC(CC)Cn1c(=O)cc(Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a solution containing 20 g of 6-chloro-3-(2-ethylhexyl)uracil thus obtained in 50 ml of dimethylformamide was added 11 g of potassium carbonate and then 12.1 g of methyl iodide was added thereto, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was filtered, the filtrate was poured into water and extracted twice with 100 ml of chloroform. The organic phase was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The chloroform was distilled off under reduced pressure to obtain 21 g of 6-chloro-3-(2-ethylhexyl)-1-methyluracil as an oily product.
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C([Cl:13])=O>CN(C=O)C>[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4]([Cl:13])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CC(F)=C(F)F
Solvent: CN(C)C=O
Product: O=C(Cl)CC(F)=C(F)F

Procedure:
Reaction of 3,4,4-trifiuoro-3-butenoic acid (IV) with oxalyl chloride in the presence of DMF as a catalyst without any solvent to give 3,4,4-trifluoro-3-butenoyl chloride (V).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.[F:18][C:19]1[CH:20]=[C:21]2[C@:28]3([C:32](=[O:33])[NH:31][C:30](=[O:34])[NH:29]3)[CH2:27][C@@H:26]([C:35](Cl)=[O:36])[O:25][C:22]2=[CH:23][CH:24]=1>>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:7]1[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][NH:1][C:35]([C@@H:26]2[CH2:27][C@@:28]3([C:32](=[O:33])[NH:31][C:30](=[O:34])[NH:29]3)[C:21]3[C:22](=[CH:23][CH:24]=[C:19]([F:18])[CH:20]=3)[O:25]2)=[O:36])[CH2:9][CH2:8]1
Reactant: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)Cl)Oc3ccc(F)cc32)N1
Reactant: COc1ccccc1N1CCN(CCN)CC1
Product: COc1ccccc1N1CCN(CCNC(=O)[C@@H]2C[C@]3(NC(=O)NC3=O)c3cc(F)ccc3O2)CC1

Procedure:
This compound was prepared by the similar procedure as in the case of Example 8, excepting that 4-(2-aminoethyl)-1-(2-methoxyphenyl)pyperazine and (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride (Reference Example 1) were employed.