Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.C[Si](C)(C)[O:40][NH2:41]>C1COCC1>[OH:40][NH:41][C:13](=[O:15])[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)ON
Reactant: O=C(O)C=CCCCCc1ccccc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(C=CCCCCc1ccccc1)NO
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 52.9 %

Procedure:
7-Phenylhept-2-enoic acid (7 g; 34 mmol) is dissolved in dry THF and cooled to 0° C. Diphenylphosphinic chloride (ClP(O)Ph2) (7.1 mL; 37 mmol) is added followed by dropwise addition of triethylamine (4.7 mL; 34 mmol). After 45 min at 0° C., a mixture of O-(trimethylsilyl)hydroxylamine (TMSONH2) (4.3 g; 37 mmol) and triethylamine (4.7 mL; 34 mmol) is added dropwise at 0° C. The bath is removed and the reaction is allowed to stir at 20° C. for 2 hours. The reaction is then filtered and the solid is extracted with EtOAc (500 mL). The EtOAc is washed with 60 mL 1 N HCl, 50 mL brine and dried (MgSO4). The resulting solution is concentrated in vacuo to yield a white solid which is purified by tituration with Et2O to obtain 7-phenylhept-2-enoic acid hydroxyamide (3.9 g; 18 mmol). MS (EI) m/e 219 (M+). Anal. (C13H17NO2) C, H, N.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: OCc1ccccc1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1

Procedure:
A suspension of 103.2 g (0.8 mol) of (L)-pyroglutamic acid in 2.8 liters of toluene, 86.6 g (0.8 mol) of benzyl alcohol and 4.3 ml of sulfuric acid is heated under reflux for 7 to 8 hours in a 4 liter apparatus equipped with a good stirrer and a Dean-Stark attachment. TLC (A) is used to check that the benzyl alcohol has disappeared and the mixture is cooled and washed with 2×400 ml of water, 2×400 ml of a 2% solution of Na2CO3 and then 2×400 ml water. The toluene layer is dried over sodium sulfate and evaporated in vacuo and the residue is dried in vacuo in the presence of P2O5. This gives 70 to 75% of a pure product of Rf=0.5 (A) and melting point=48°-49° C. The product can also be distilled; boiling point=170°-5° C. (0.1 mm Hg).
Reaction SMILES: CC[O-].[Na+].[CH2:5]([O:7][C:8]([CH2:10][C:11]([CH3:17])([CH3:16])[CH:12](Br)[C:13]#[N:14])=[O:9])[CH3:6].O.Cl>C(O)C>[CH2:5]([O:7][C:8]([CH:10]1[C:11]([CH3:17])([CH3:16])[CH:12]1[C:13]#[N:14])=[O:9])[CH3:6]
Reactant: CCOC(=O)CC(C)(C)C(Br)C#N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1C(C#N)C1(C)C
Reaction time: 3 h
Yield: 69 %

Procedure:
8.15 g (0.12 mol) of sodium ethylate in 30 ml of ethanol were added dropwise to a solution of 24.8 g (0.1 mol) of 3-bromo-3-cyano-2,2-dimethyl-propane-1-carboxylic acid ethyl ester in 50 ml of ethanol. The mixture was subsequently stirred at 50°-60° C. for 3 hours. 200 ml of water were then added and the reaction mixture was neutralized with HCl and extracted twice with 50 ml of methylene chloride each time. The combined methylene chloride extracts were washed twice with 50 ml of H2O each time, dried over Na2SO4 and then concentrated. The residue was fractionated. 11.5 (69% theory) of 2-cyano-3,3-dimethyl-cyclopropane-1-carboxylic acid ethyl ester were obtained in the form of a colorless oil of boiling point 68°-72° C./2 mm Hg.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1.CCN(C(C)C)C(C)C.Cl.[N:24]1([C:29](N)=[NH:30])C=CC=N1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:29]([NH2:30])=[NH:24])=[CH:7][CH:6]=1
Reactant: N=C(N)n1cccn1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC(=N)N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
The mixture of 4-Aminomethyl-benzoic acid methyl ester HCl (15.7 g, 77.8 mmol) in DMF (85.6 mL) and DIPEA (29.5 mL, 171.2 mmol) was stirred at rt for 10 min. Pyrazole-1-carboxamidine HCl (12.55 g, 85.6 mmol) was added to the reaction mixture and then stirred at rt for 4 h to give clear solution. The reaction mixture was evaporated to dryness under vacuum. Saturated NaHCO3 solution (35 mL) was added to give nice suspension. The suspension was filtered and the filter cake was washed with cold water. The mother liquid was evaporated to dryness and then filtered. The two solids were combined and re-suspended over distilled H2O (50 ml). The filter cake was then washed with minimum quantities of cold H2O and ether to give 12.32 g white crystalline solid intermediate 1 (77% yield, M+1:208 on MS).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([O:22]CC)=O.[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1.Cl>>[CH:25]1([NH:30][C:20]([C:3]2[C:4](=[O:19])[NH:5][C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[C:8]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=3)=[O:22])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Reactant: NC1CCCC1
Agent: Cl
Product: O=C(NC1CCCC1)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclopentylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.75 (1H, br), 8.24 (1H, s), 7.35 (1H, s), 7.32-7.20 (5H, m), 4.21 (1H, m, J=6.7 Hz), 4.04 (2H, s), 1.93-1.35 (8H, m); Anal. Calcd for C21H21N3O3.1.90 HCl: C, 58.29; H, 5.33; N, 9.71. Found: C, 58.31; H, 5.33; N, 9.85.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:20])[CH:5]=[C:6]2[C:11]=1[N:10]([C@@H:12]1[CH2:14][C@@H:13]1[F:15])[CH:9]=[C:8]([C:16]([OH:18])=[O:17])[C:7]2=[O:19].Br.Br.[C:24]12[CH2:31][NH:30][CH2:29][C:28]=1[CH2:27][NH:26][CH2:25]2.C1CCN2C(=NCCC2)CC1.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[C:3]([N:26]2[CH2:27][C:28]3[CH2:29][NH:30][CH2:31][C:24]=3[CH2:25]2)=[C:4]([F:20])[CH:5]=[C:6]2[C:11]=1[N:10]([C@@H:12]1[CH2:14][C@@H:13]1[F:15])[CH:9]=[C:8]([C:16]([OH:18])=[O:17])[C:7]2=[O:19]
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: C1NCC2=C1CNC2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Yield: 10.7 %

Procedure:
A solution of 318 mg of 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 544 mg of 3,7-diazabicyclo[3.3.0]oct-1(5) -ene dihydrobromide (JP-A-3-193779) and 2 ml of DBU in 20 ml of acetonitrile was heated under reflux for 15 hours. To the mixture was added 1N sodium hydroxide, and an insoluble material was removed by filtration. To the filtrate, was added hydrochloric acid till pH became 7.4, and the mixture was extracted by five 50 ml portions of chloroform. A combined organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was recrystallized from a mixture of ethanol and ammonia water to yield 43.7 mg of the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][CH3:20])=[CH:15][C:14]([C:21]([OH:23])=O)=[CH:13][CH:12]=3)=[O:5])[CH3:2].CN(C)C=O.S(Cl)([Cl:31])=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][CH3:20])=[CH:15][C:14]([C:21]([Cl:31])=[O:23])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)O)cc3c2c1CC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)Cl)cc3c2c1CC

Procedure:
590 mg of 3-ethoxycarbonyl-4-ethyl-β-carboline-6-carboxylic acid is refluxed in 6 ml of thionyl chloride with a drop of dimethylformamide for 2.5 hours. After evaporation and drying, 664 mg of 3-ethoxycarbonyl-4-ethyl-β-carboline-6-carboxylic acid chloride is obtained in the form of the hydrochloride.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1[C:22]2[NH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[C:12]([C:23]([OH:25])=O)[CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[CH:60]=2)[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[O:51]=[C:50]([N:52]1[CH2:53][CH2:54][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:66])[F:67])[CH:60]=2)[CH2:56][CH2:57]1)[CH2:49][NH:48][C:23]([C:12]1[CH:11]=[CH:10][C:22]2[NH:21][C:20]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:25]
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1ccc2[nH]c3ccccc3c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1ccc2[nH]c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 71.1 %

Procedure:
DIPEA (137 mg, 1.0 mmol) was added to a stirred solution of to a stirred solution of 9H-carbazole-3-carboxylic acid (50 mg, 0.23 mmol) in DMF (4 mL) followed by HOBt (35 mg, 0.26 mmol) and EDCI (116 mg, 0.59 mmol). After 2 minutes, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (88 mg, 0.26 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water and the precipitate was filtered. The solid obtained was purified by recrystallisation from a mixture of 10% ethyl acetate in hexane and 50% MeOH in H2O to afford 81 mg (69.23% Yield) of 9H-carbazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 496, 91.03%. 1H NMR (300 MHz, DMSO-d6): δ 11.6 (s, 1H), 8.8 (s, 1H), 8.6 (t, 1H), 8.1 (d, 1H), 8.0 (d, 1H), 7.6 (d, 2H), 7.46 (t, 1H), 7.36 (t, 2H), 7.24 (t, 1H), 4.9 (b, 1H), 4.3 (d, 3H), 4.0 (d, 2H), 3.5 (d, 2H), 2.1 (t, 2H), 1.7 (d, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:8])[NH2:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[CH3:13]N(C=O)C>O1CCCC1>[C:1]([O:5][C:6](=[O:8])[NH:7][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(N)=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
(1S,2S)-3-(tert-butyl-diphenyl-silanyloxy)-1-furan-2-yl-2-methyl-propyl)-carbamic acid tert-butyl ester 2.5.1a (3.9 g, 7.9 mmol, 1.0 equiv) was added to a suspension of 60% sodium hydride (0.94 g, 23.5 mmol, 3.0 equiv) in dry tetrahydrofuran (30 mL) at 0° C. under nitrogen. After stirring at 0° C. for 15 min, to this solution was added methyl iodide (3.7 g, 16.0 mL, 26.0 mmol, 3.3 eqiuv) and DMF (3 mL). The reaction mixture was then stirred at room temperature for 3 hours. The reaction was quenched with sat. ammonium chloride aq. solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give obtain (1S,2S)-3-(tert-Butyl-diphenyl-silanyloxy)-1-furan-2-yl-2-methyl-propyl)-methyl-carbamic acid tert-butyl ester (4.0 g, 100%). 1H NMR (400 MHz, CDCl3) 0.84 (m, 3H); 1.00 (s, 9H); 1.50 (s, 9H); 2.33 (m, 1H); 2.71 (m, 3H); 3.47 (m, 3H); 5.26 (m, 1H); 6.09 (m, 1H); 5.93 (s, 1H); 6.16 (m, 1H); 6.26 (m, 1H)
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][C@@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:26].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](O)=[O:34].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:15]1([CH2:14][C@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:12][C:11]2[CH:10]=[CH:9][C:8]3[C:7](=[O:26])[CH2:6][CH2:5][CH2:4][C:3]=3[C:2]=2[NH:1][C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[O:34])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O)c1ccccn1
Reaction time: 48 h
Yield: 81.9 %

Procedure:
To a solution of 5-amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (150 mg, 0.432 mmol), picolinic acid (64 mg, 0.518 mmol) and HOBT (73 mg, 0.540 mmol) in DMF (4 mL) was added N-methylmorpholine (62 μL, 0.562 mmol) followed by EDCI HCl (108 mg, 0.562 mmol). After 2 days, the DMF was removed under reduced pressure. The residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O and brine, dried over Na2SO4 and concentrated to give a brown oil. Purification by chromatography (3-5% MeOH/CH2Cl2) afforded the title compound as a tan foam (160 mg, 0.354 mmol, 82%). The structure was confirmed by NMR and mass spectrometry. MS m/z 453 (M++H).
Reaction SMILES: C([O:8][C:9]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:11]([C:12]([NH:14][C:15]2[NH:19][N:18]=[N:17][N:16]=2)=[O:13])[CH:10]=1)C1C=CC=CC=1.CN(CCO)C.[H][H]>CN(C)C=O.[Pd]>[OH:8][C:9]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:11]([C:12]([NH:14][C:15]2[NH:19][N:18]=[N:17][N:16]=2)=[O:13])[CH:10]=1
Reactant: O=C(Nc1nnn[nH]1)c1cc(OCc2ccccc2)c2ccccc2n1
Reactant: [H][H]
Agent: [Pd]
Agent: CN(C)CCO
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1cc(O)c2ccccc2n1

Procedure:
4-Benzyloxy-N(1H-tetrazol-5-yl)quinaldamide (1.5 g) and dimethylaminoethanol (0.5 ml) in dimethylformamide (20 ml) were shaken with hydrogen at atmospheric pressure and room temperature in the presence of 10% palladium on charcoal catalyst (0.15 g). When uptake of hydrogen had ceased, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in water (50 ml) and the solution was acidified with dilute hydrochloric acid. The solid was collected, and crystallised from aqueous dimethylformamide and dried, m.p. 281° (d).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([I:13])=[C:7]([CH2:9][C:10]([OH:12])=[O:11])[CH:8]=1.[CH3:16][CH:17](O)[CH3:18]>OS(O)(=O)=O>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([I:13])=[C:7]([CH2:9][C:10]([O:12][CH:17]([CH3:18])[CH3:16])=[O:11])[CH:8]=1
Reactant: O=C(O)Cc1cc(C(F)(F)F)ccc1I
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)Cc1cc(C(F)(F)F)ccc1I

Procedure:
5-Trifluoromethyl-2-iodophenylacetic acid (30 g, 91 mmol) is dissolved in 2-propanol (250 mL), a catalytic amount (4 drops) of concentrated H2SO4 added and the solution is stirred and heated to reflux temperature for 12 hours. Solvents are removed by rotary evaporator and the residual oil is purified using flash chromatography (1:4 EtOAc/hexanes) to give isopropyl 5-trifluoromethyl-2-iodophenylacetate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2O[CH:12]=[C:13]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:14](=[O:24])[C:15]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])=[CH:4][CH:3]=1.C(O)C.[CH3:36][O:37][CH:38]([O:41][CH3:42])[CH2:39][NH2:40]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:40]([CH2:39][CH:38]([O:41][CH3:42])[O:37][CH3:36])[CH:12]=[C:13]([C:25](=[O:30])[C:26]([CH3:27])([CH3:28])[CH3:29])[C:14](=[O:24])[C:15]=2[O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:9])=[CH:31][CH:32]=1
Reactant: CC(C)(C)C(=O)c1coc(C(=O)NCc2ccc(F)cc2)c(OCc2ccccc2)c1=O
Reactant: COC(CN)OC
Solvent: CCO
Solvent: C1CCOC1
Product: COC(Cn1cc(C(=O)C(C)(C)C)c(=O)c(OCc2ccccc2)c1C(=O)NCc1ccc(F)cc1)OC
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To a solution of 3-benzyloxy-5-(2,2-dimethylpropionyl)-4-oxo-4H-pyran-2-carboxylic acid 4-fluorobenzylamide (0.13 g) in tetrahydrofuran (0.5 ml)-ethanol (0.5 ml) was added aminoacetaldehyde dimethyl acetal (0.033 ml) and the mixture was stirred at 70° C. for 3 days. After cooling to room temperature, the solvent was evaporated to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethylpropionyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 4-fluorobenzylamide (157 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[S:13][C:12]([C:14]#[C:15][C@H:16]([N:18]([OH:22])[C:19]([NH2:21])=[O:20])[CH3:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.FC1C=CC(CC2SC(C#C[C@H](N(O)C(N)=O)C)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[S:13][C:12](/[CH:14]=[CH:15]\[C@H:16]([N:18]([OH:22])[C:19]([NH2:21])=[O:20])[CH3:17])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](C#Cc1ccc(Cc2ccc(Cl)cc2)s1)N(O)C(N)=O
Agent: C[C@H](C#Cc1ccc(Cc2ccc(F)cc2)s1)N(O)C(N)=O
Product: C[C@H](/C=C\c1ccc(Cc2ccc(Cl)cc2)s1)N(O)C(N)=O

Procedure:
The desired compound is prepared according to the method of Example 1, step 5, except substituting (R)-N-{3-[5-(4-chlorophenylmethyl)thien-2-yl]-1-methyl-2-propynyl}-N-hydroxyurea, prepared as in step 4, for (R)-N-{3-[5-(4-fluorophenylmethyl)thien-2-yl]-1-methyl-2-propynyl}-N-hydroxyurea.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:4]=[C:5]([CH:9]([NH:11][C:12](=[O:19])[CH2:13][CH:14]2[CH2:18][CH2:17]CC2)[CH3:10])[C:6](=[O:8])[N:7]=1.[CH2:27](O)C>CCOCC>[NH2:1][C:2]1[N:3]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:4]=[C:5]([CH:9]([NH:11][C:12](=[O:19])[CH2:13][CH2:14][CH:18]([CH3:17])[CH3:27])[CH3:10])[C:6](=[O:8])[N:7]=1
Reactant: CC(NC(=O)CC1CCCC1)c1nn(Cc2ccccc2)c(N)nc1=O
Reactant: CCO
Solvent: CCOCC
Product: CC(C)CCC(=O)NC(C)c1nn(Cc2ccccc2)c(N)nc1=O

Procedure:
N-[1-(3-amino-2-benzyl-2,5-dihydro-5-oxo-as-triazin-6-yl)ethyl]-cyclopentylacetamide, m.p. 195°-196.5° (from a mixture of ethanol and ether).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:13])=[C:9]([CH2:11]O)[N:10]=2)[CH:7]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:16][CH2:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]2[C:8]=1[CH3:13]
Reactant: Cc1c(CO)nc2ccc(I)cn12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1c(CCl)nc2ccc(I)cn12
Reaction time: 4 h

Procedure:
To a stirred solution of (6-iodo-3-methylimidazo[1,2-a]pyridin-2-yl)methanol (200 mg) in DCM (2 ml) was added thionyl chloride (56 μl) at room temperature, and the mixture was stirred for 4 h. Additional thionyl chloride (125 μl) was added to the reaction mixture, and the mixture was stirred for further 3 h. The reaction mixture was diluted with DCM, and washed with saturated NaHCO3 solution. The DCM layer was separated, dried over Na2SO4 and concentrated in vacuo to give the title compound (150 mg) as a yellow solid.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH2:12][CH3:13])[C:9](=[S:14])[C:8]2[CH:15]=[CH:16][CH:17]=[N:18][C:7]=2[O:6]1.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH3:21])[CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH2:12][CH3:13])[C:9](=[S:14])[C:8]2[CH:15]=[CH:16][CH:17]=[N:18][C:7]=2[O:6]1
Reactant: CNC
Reactant: CCN1CC(CCCl)Oc2ncccc2C1=S
Agent: Cl
Product: CCN1CC(CCN(C)C)Oc2ncccc2C1=S
Temperature: 25 °C
Reaction time: 144 h

Procedure:
2-(2-Chloroethyl)-4-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-thione hydrochloride, 5.00 g (0.016 mole) was added to 20 ml of anhydrous dimethylamine. The reaction flask was sealed tightly and stirred at room temperature for 6 days. The flask was opened after cooling to 0° C. and dimethylamine allowed to evaporate at room temperature. The residue was taken up in chloroform (100 ml) and washed with dilute aqueous sodium hydroxide (1×30 ml). The chloroform layer was dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residual oil was dissolved in hot cyclohexane. Upon cooling, 1.76 g (39.4%) of light yellow crystals were collected, m.p. 73° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([O:24][C:25]([F:28])([F:27])[F:26])[CH:8]=[C:9]2[C:14]=1[O:13][CH:12]([C:15]([F:18])([F:17])[F:16])[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10]2)#[C:2][CH2:3][CH3:4]>C(O)C.[Pd]>[CH2:1]([C:5]1[CH:6]=[C:7]([O:24][C:25]([F:28])([F:26])[F:27])[CH:8]=[C:9]2[C:14]=1[O:13][CH:12]([C:15]([F:16])([F:17])[F:18])[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCC#Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Agent: [Pd]
Solvent: CCO
Product: CCCCc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Reaction time: 1.5 h
Yield: 68 %

Procedure:
A mixture of ethyl 8-but-1-ynyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 21q, Step 1 (450 mg, 1.10 mmole) and 10% Pd/C (45 mg) in absolute ethanol was hydrogenated at 30 psi for 1.5 h. The catalyst was removed by filtration and the solvent was removed in vacuo to give 310 mg (68% yield) of the product as a yellow crystalline solid: EIHRMS m/z 412.1099 (M+, C18H18F6O4, Calc'd 412.1109).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@@H:12]([OH:13])[CH2:11][CH2:10][C:9]=2[C:14]([O:16]C)=[O:15])=[CH:4][CH:3]=1.C1COCC1.OS([O-])(=O)=O.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@@H:12]([OH:13])[CH2:11][CH2:10][C@H:9]2[C:14]([OH:16])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(c2ccc(F)cc2)[C@@H](O)CC1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CC[C@H](O)[C@H]1c1ccc(F)cc1
Temperature: -48 °C
Reaction time: 0.5 h

Procedure:
To a toluene stream containing methyl (3S)-2-(4-fluorophenyl)-3-hydroxycyclopent-1-enecarboxylate in 21 L toluene was added 12 Liters of dry THF and the reaction mixture was cooled to −48° C. To the cooled solution was added drop-wise over 45 min 3.8 Liters (13.46 mol) of 70% Red-A1 in toluene. The reaction mixture was allowed to warm to −25° C. over 2.5 h and was added to a solution of 21 L of 2M NaHSO4. The mixture was stirred for 30 min and the layers separated. The toluene layer was then washed with 15 L of water. The toluene layer was then azeotropically dried (50° C., 25 inHg) to a final volume of 21 L (KF 130 ug/mL) and used in the next step. To the toluene solution was added 820 mL (3.6 mol) of 25 wt % NaOMe in MeOH at 50° C. and the mixture heated to 75° C. for 1 h. The mixture was then cooled to 50° C. and 17 L of water, 1 L of MeOH, and 4.5 L of 6N NaOH was added. The mixture was stirred at 20–25° C. overnight. The layers were separated, and the toluene layer discarded. The aqueous layer was then washed with 15 L of MTBE and the MTBE layer discarded. The aqueous layer was then made acidic with conc. HCl (2.1 L, pH 1). The mixture was extracted with 40 L of IPAC. The IPAC layer containing the product (1.35 kg, 69% assay) was then treated with 500 g of Darco for 30 min at 25° C. and filtered over a pad of solka floc, rinsing the pad with and additional 5 L of IPAC. The IPAC solution was then azeotropically dried (45° C., 25 inHg) to a final volume of 15 L (KF<200) and cooled to 20° C. To the IPAC solution was added 3.04 L of n-heptane and the mixture seeded with 5 g of (1R,2R,3S)-2-(4-fluorophenyl)-3-hydroxycyclopentane-1-carboxylic acid. After a good seed bed had been formed (30 min) the rest of the n-heptane (40.4 L) was added drop-wise over 1 hour. The slurry was cooled to 10° C. and filtered. The cake was washed with 2 L of 5:1 n-heptane/IPAC and then with 1 L of heptane. The cake was then dried under vacuum/N2 sweep at 20–25° C. overnight to provide (1R,2R,3S)-2-(4-fluorophenyl)-3-hydroxycyclopentane-1-carboxylic acid as a colorless solid.