Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:9][C:8](=[O:10])[N:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B.C1C[O:25]CC1.[OH-].[Na+].OO.Cl>C1COCC1.O>[C:11]([N:7]1[CH2:6][CH2:5][C:4]([CH2:1][CH2:2][CH2:3][OH:25])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:9][C:8]1=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: C=CCC1(c2ccccc2)CCN(C(C)(C)C)C(=O)O1
Reactant: C1CCOC1
Agent: B
Agent: Cl
Agent: OO
Solvent: O
Product: CC(C)(C)N1CCC(CCCO)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-allyl-3-tert-butyl-6-phenyl-1,3-oxazinan-2-one (400 mg, 1.46 mmol) in dry THF (10 mL) was added dropwise 1 M of BH3/THF (4.5 mL, 4.40 mmol) at 0° C. under N2. After stirring at rt for 2 h, the reaction mixture was cooled to 0° C. again, and water (0.1 mL), 3 M of aq NaOH solution (0.1 mL), and 30% H2O2 (0.3 mL) were added sequentially. After the mixture was stirred at rt for another 2 h, 1 N aq HCl (1.5 mL) was added. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC followed by preparative chiral HPLC to afford two isomers of 3-tert-butyl-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][NH:16][CH:17]=[O:18])=[N:11][CH:12]=1)=[O:2]>CO>[CH:1]([NH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][NH:16][CH:17]=[O:18])=[N:11][CH:12]=1)=[O:2]
Reactant: O=CNCC#Cc1ccc(C#CCNC=O)nc1
Solvent: CO
Product: O=CNCCCc1ccc(CCCNC=O)nc1
Reaction time: 5 h

Procedure:
A mixture of N-(3-{5-[3-(formamido)prop-1-ynyl]pyridin-2-yl}prop-2-ynyl)formamide (9-1) (28 g) and 5% Pd/Al2O3 (2.8 g) in methanol (350 mL) was hydrogenated at 40 psi at ambient temperature for 5 h. The mixture was filtered through Solka Floc. The filtrate was concentrated to afford 13-1 as an oil.
Reaction SMILES: C(N1CCC(=O)CC1)C1C=CC=CC=1.[F:15][C:16]([F:48])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:39][CH2:38][C:25]2([N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]([CH3:36])[NH:27][C:26]2=[O:37])[CH2:24][CH2:23]1)=[O:21].Cl[CH2:50][C:51]1[N:52]=[C:53]([CH3:56])[S:54][CH:55]=1>>[F:48][C:16]([F:15])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:23][CH2:24][C:25]2([N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:28]([CH3:36])[N:27]([CH2:50][C:51]3[N:52]=[C:53]([CH3:56])[S:54][CH:55]=3)[C:26]2=[O:37])[CH2:38][CH2:39]1)=[O:21]
Reactant: Cc1nc(CCl)cs1
Reactant: CC1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1
Agent: O=C1CCN(Cc2ccccc2)CC1
Product: Cc1nc(CN2C(=O)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)N(c3ccccc3)C2C)cs1

Procedure:
The title compound, MS: m/e=597.0 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one 1-benzyl-piperidin-4-one and 4-chloromethyl-2-methylthiazole.
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.[Cl:12][C:13]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:14]=1N.NC1C=CC=CC=1>CC#N>[CH2:3]([C:14]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=1[Cl:12])[CH:1]=[CH2:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: CC(C)(C)ON=O
Solvent: CC#N
Solvent: Nc1ccccc1
Solvent: C=CCBr
Product: C=CCc1ccc([N+](=O)[O-])cc1Cl
Temperature: 12 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 2-chloro-4-nitroaniline (518 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 11-13° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 23° C. for one hour. The volatile material in the reaction mixture was then removed at reduced pressure. Column chromatography (heptane-ethyl acetate 97:3) gave 497 mg (84%) allyl-2-chloro-4-nitrobenzene as a light yellow oil containing 5% of 2-chloro-4-nitrobromobenzene. This corresponds to 79% yield of allyl-2-chloro-4-nitrobenzene. 1H NMR (CDCl3, 400 MHz) δ 8.25, (d, 1H, J=2.4 Hz), 8.08, (dd, 1H, J=8.5, 2.3 Hz), 7.42, (d, 1H, J=8.5 Hz), 6.01-5.89, (m, 1H), 5.23-5.10, (m, 2H), 3.59, (d, 2H, J=6.5 Hz); 13C NMR (CDCl3, 100 MHz) δ 147.3, 145.9, 135.3, 134.0, 131.2, 125.0, 122.2, 118.5, 38.0; Anal HRMS Calcd. for C9H8ClNO2 (M): 197.0244. Found: 197.0247.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH:7]=[C:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[C:5]([N+:16]([O-])=O)[CH:4]=1.[H][H]>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[C:5]([CH:4]=1)[NH2:16]
Reactant: [H][H]
Reactant: COc1ccc(C=C2CCOCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CC2CCOCC2)c(N)c1
Reaction time: 7 h
Yield: 93.9 %

Procedure:
4-(4-methoxy-2-nitrobenzylidene)tetrahydro-2H-pyran (1.8 g; 7.22 mmol; 1 eq) is dissolved in EtOH (100 mL) and palladium on charcoal (180 mg, 10%) is added at room temperature under argon. The solution is treated with hydrogen at atmospheric pressure. After 7 h at room temperature, the reaction is complete. The mixture is filtered through celite and the filtrate is concentrated under reduced pressure to afford 1.5 g (94%) of the title compound as an orange oil. 1H NMR (DMSO-d6) δ 6.72 (d, J=8.3 Hz, 1H), 6.18 (d, J=2.6 Hz, 1H), 6.04 (dd, J=8.3, 2.6 Hz, 1H), 4.82 (s, 2H), 3.82-3.77 (m, 2H), 3.62 (s, 3H), 3.19 (td, J=11.7, 1.8 Hz, 2H), 2.29 (d, J=6.8 Hz, 2H), 1.72-1.61 (m, 1H), 1.51-1.46 (m, 2H), 1.24-1.10 (m, 2H). HPLC (max plot) 88%; Rt 1.83 min LC/MS: (ES+): 222.4.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O.[C:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14](/[CH:15]=[CH:23]/[C:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[O:24])[CH:17]=1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1C=O
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 66 %

Procedure:
The title compound was prepared by condensing 5-(1H-indol-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-61A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Red solid, mp 210–212° C., 66% yield. 1H-NMR (Aceton-d6) δ 10.53 (br, s, 1H), 8.32 (s, 1H), 8.14–8.21 (m, 5H), 7.89 (d, J=15 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 7.38 (d, J=7 Hz, 1H), 6.97–7.07 (m, 3H), 6.87 (s, 1H), 4.07 (s, 3H), 4.02 (s, 3H), MS m/z=427 ([M]+). HMRS (EI) calcd. for C26H21NO5: 427.1420; found: 427.1435.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].[CH2:28]([S:31](Cl)(=[O:33])=[O:32])[CH2:29][CH3:30]>>[CH2:28]([S:31]([O:26][C:11]1[N:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=1[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:27])[NH:6]2)(=[O:33])=[O:32])[CH2:29][CH3:30]
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)Oc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(C)=O)=C(C)N2

Procedure:
The title compound is prepared in analogy to example 10 from 50 mg (0.13 mmol) of 3-acetyl-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-4,6-dihydro-1,6-naphthyridin-5(1H)-one and 17 μl (0.15 mmol) of propanesulfonyl chloride. 46 mg (71% of theory) of the product are obtained as a pale yellow solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([F:36])[CH:30]=1.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48]>C1(C)C=CC=CC=1.C(O)C>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48].[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([NH:49][C:50]([NH:33][C:32]1[CH:34]=[CH:35][C:29]([O:28][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=3)[N:22]=[CH:21][CH:20]=2)=[CH:30][C:31]=1[F:36])=[S:51])=[O:48]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: COc1ccc(C(=O)Cl)c(OC)c1
Agent: COc1ccc(C(=O)N=C=S)c(OC)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
2,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (54 mg, yield 67%). Mass spectrometry value (ESI-MS, m/z): 538 (M++1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.C([N-]C(C)C)(C)C.[Li+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH:8]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCc2cc(OC)c(OC)cc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
3,4-Dihydro-6,7-dimethoxy-1(2H)-naphthalenone (10.0 g) was dissolved in tetrahydrofuran (200 ml), and thereto was added dropwise a 2M solution of lithium diisopropylamide in tetrahydrofuran (37 ml) at -70° C. The mixture was stirred for 30 minutes, and thereto was added dropwise ethyl bromoacetate (10.5 g) at -70° C. The mixture was stirred at the same temperature for two hours, and then stirred at 20° C. overnight. The reaction mixture was poured into ice-water, and extracted with diethyl ether. The ether layer was washed successively with water, 10% hydrochloric acid and 10% aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The resultant was concentrated under reduced pressure to remove the solvent to give ethyl 1,2,3,4-tetrahydro-6,7-dimethoxy-1-oxo-2-naphthaleneacetate (12.0 g) as an oily product.
Reaction SMILES: FC(F)(F)S([O:6][CH2:7][CH:8]([F:10])[F:9])(=O)=O.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31]3=[N:32][CH:33]=[C:34](O)[CH:35]=[C:30]3[N:29]([CH2:37][CH3:38])[C:28]2=[O:39])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Cl-].[Ca+2]>CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[C:31]3=[N:32][CH:33]=[C:34]([O:6][CH2:7][CH:8]([F:10])[F:9])[CH:35]=[C:30]3[N:29]([CH2:37][CH3:38])[C:28]2=[O:39])=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(O)cc21
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(OCC(F)F)cc21
Yield: 85.2 %

Procedure:
2,2-Difluoroethyl trifluoromethanesulfonate (213 mg) was added to a solution of 3-[4-(benzyloxy)phenyl]-1-ethyl-6-hydroxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg) and potassium carbonate (229 mg) in DMF (5 mL) at room temperature. The mixture was stirred at ambient temperature under a dry atmosphere (CaCl2 tube) for 3 h. The mixture was quenched with water at room temperature and extracted with AcOEt. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 15%-50% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-6-(2,2-difluoroethoxy)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (301 mg) as colorless oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][N:13]([CH:15]([C:30]([O:32][CH3:33])=[O:31])[C:16]3[CH:21]=[CH:20][C:19]([O:22]CC4C=CC=CC=4)=[CH:18][CH:17]=3)[C:12]2=[O:34])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][N:13]([CH:15]([C:30]([O:32][CH3:33])=[O:31])[C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[C:12]2=[O:34])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(c1ccc(OCc2ccccc2)cc1)N1CC(NC(=O)Cc2ccccc2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(c1ccc(O)cc1)N1CC(NC(=O)Cc2ccccc2)C1=O
Yield: 71.1 %

Procedure:
3-(2-Phenylacetamido)-1-(α-methoxycarbonyl-4-benzyloxybenzyl)-2-azetidinone (70 mg) was dissolved in absolute ethanol (10 ml), and to the solution, there was added 10% palladium on carbon (30 mg). The mixture was subjected to catalytic reduction in a stream of hydrogen gas at ordinary temperature and ordinary atmospheric pressure. After a calculated volume of the hydrogen gas was absorbed into the mixture in the course of 3 hours, the catalyst was removed by filtration to give a filtrate, which was evaporated to dryness under reduced pressure. The resultant residue was treated with diethyl ether to give 3-(2-phenylacetamido)-1-(α-methoxycarbonyl-4-hydroxybenzyl)-2-azetidinone (40 mg), mp 171.5° to 175° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:25]=[CH:24][C:18]2[CH:19]=[C:20]([CH:22]=O)[O:21][C:17]=2[CH:16]=1.[O:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32].N1CCCC1.C(O)C>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:25]=[CH:24][C:18]2[CH:19]=[C:20]([CH2:22][CH:30]3[O:26][C:27](=[O:32])[NH:28][C:29]3=[O:31])[O:21][C:17]=2[CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(C=O)oc2c1
Reactant: O=C1COC(=O)N1
Solvent: CCO
Solvent: C1CCNC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CC3OC(=O)NC3=O)oc2c1
Yield: 6.6 %

Procedure:
A mixture of 6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofurancarbaldehyde (1.70 g), 2,4-oxazolidinedione (1.55 g), pyrrolidine (0.365 g) and ethanol (40 ml) was heated under refluxing conditions for 3 hours. The reaction mixture was poured over water; the resulting crystals were collected by filtration. The crystals were dissolved in tetrahydrofuran (100 ml); after palladium-carbon (0.40 g) was added, the mixture was subjected to catalytic reduction at room temperature under an atmospheric pressure of 1 atm. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography. From the fraction eluted with methanolchloroform (2:98, v/v), crystals of 5-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofuranylmethyl]-2,4-oxazolidinedione (0.14 g, 6.6%) were obtained, which was then recrystallized from dichloromethane-methanol to yield colorless prisms having a melting point of 172° to 173° C.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.O.[NH2:19][NH2:20]>C(O)C>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:19][NH2:20])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: NN
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CCO
Solvent: O
Product: NNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
1.181 g (5.00 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was placed into a 25 ml flask equipped with a magnetic stirring bar. About 5 ml absolute ethanol was added and then 2.50 g (50.00 mmol) of hydrazine hydrate was added and the solution was stirred at room temperature in a closed flask. A large amount of precipitate formed after about 30 minutes and the solution was allowed to stand overnight. The solution was filtered by vacuum and the white solid was washed with ethanol and then with ether. Upon drying, 0.890 g of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid hydrazide (AIT-0056) as a white solid was obtained. Yield: 80%.
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:16][NH:17]C(OC(C)(C)C)=O)[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CCOC(C)=O>[C:1]1([S:7]([NH:10][C@@H:11]([CH2:16][NH2:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of 23-8 (0.35 g, 0.98 mmol) in EtOAc (5 mL) was cooled to -40° C. and saturated with HCl gas. The solution was warmed to 0° C. for 2 h, then concentrated to give 23-9 as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1>C(Cl)Cl.C1(C)C(S(O)(=O)=O)=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:9]2)=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: Oc1ccc(I)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Product: Ic1ccc(OC2CCCCO2)cc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
To a stirred solution of 4-iodophenol (11.0 g, 50 mmol) in CH2Cl2 (50 ml) cooled with an ice bath, dihydropyran (5.0 g, 60 mmol) was added dropwise over 10 min at 0° C. to 5° C. After the solution became clear, toluenesulfonic acid (TsOH′ 10 mg) was added. The solution was stirred at 20° C. for 15 min. Then it was quenched by addition of NaHCO3 (1 g) and 3 drops of water, and after stirring for 5 min at 20° C., the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with petroleum ether as eluent to give 14.0 g (92%) of 1 as colorless crystal; mp 66° C.; δH(CDCl3, 300 MHz): 7.55 (d, J=8.3, 2H, Ar—H), 6.83 (d, J=8.4, 2H, Ar—H), 5.37 (t, J=3.1, 1H, OCHO), 3.86 (m, 1H, THP), 3.59 (m, 1H, THP), 1.87˜1.58 (m, 6H, THP).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[C:18]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[N:19][O:20][C:21]=2[CH3:22])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[Cl:29][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:30])[C:23]=1[C:18]1[C:17]([CH2:16][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[C:21]([CH3:22])[O:20][N:19]=1
Reactant: COC(=O)COc1ccc(SCc2c(-c3c(Cl)cccc3Cl)noc2C)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1CSc1ccc(OCC(=O)O)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 88A. mp 151-152° C.; IR (KBr) cm−1: 3084, 1743, 1430, 1277, 1245, 1106; 400 MHz 1H NMR (DMSO-d6): δ 12.97 (br(s), 1H), 7.47-7.70 (m, 3H), 6.90 (d, 1H, J=8.5 Hz), 6.52 (d, 1H, J=8.5 Hz), 4.63 (s, 2H), 3.58 (s, 2H), 2.75 (t, 2H, J=7.6 Hz), 2.65 (t, 2H, J=7.6 Hz), 2.07 (s, 3H), 1.89 (pentet, 2H) MS m/z 464 (M+1). Anal. Calc'd for C22H19Cl2NO4S: C, 56.90; H, 4.12; N, 3.02. found: C, 56.51; H, 3.96; N, 2.95.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:15](=[O:31])[NH:16][C@@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:30])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C@H:40]1[CH2:46][CH2:45][S:44][C@H:43]2[CH2:47][CH2:48][C@@H:49]([C:51]([F:54])([F:53])[F:52])[CH2:50][N:42]2[C:41]1=[O:55]>>[CH2:32]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:39][C@H:40]1[CH2:46][CH2:45][S:44][C@H:43]2[CH2:47][CH2:48][C@@H:49]([C:51]([F:52])([F:54])[F:53])[CH2:50][N:42]2[C:41]1=[O:55])=[O:10])[C:15]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]1=[O:30])=[O:31])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N[C@H]1CCS[C@H]2CC[C@@H](C(F)(F)F)CN2C1=O
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@@H]1CCCCN(c2ccccc2)C1=O)Cc1ccccc1
Product: O=C(N[C@H]1CCCCN(c2ccccc2)C1=O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@H]1CCS[C@H]2CC[C@@H](C(F)(F)F)CN2C1=O)Cc1ccccc1

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-2-oxo-1-phenylazepan-3-yl)-N6-((4S,8R,10aS)-5-oxo-8-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 24 (15 mg, 0.029 mmol) and Intermediate 61 (9.4 mg, 0.035 mmol) to give a white solid (14 mg, 63% yield). Anal. Calcd. for C42H49F3N4O4S m/z 762.4. found: 763.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.45-7.02 (m, 15H), 5.24 (t, 1H), 5.02-4.90 (m, 1H), 4.79 (dd, J=9.4, 7.0 Hz, 1H), 4.48 (dd, J=13.3, 4.4 Hz, 1H), 3.94 (dd, J=16.1, 12.3 Hz, 1H), 3.60 (d, J=15.1 Hz, 1H), 3.11-3.00 (m, 1H), 2.93-2.68 (m, 5H), 2.52 (ddd, J=14.4, 6.0, 2.9 Hz, 1H), 2.48-2.21 (m, 4H), 2.17-1.46 (m, 13H), 1.42-1.09 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.[C:9]([O-])(=[O:11])[CH3:10].[K+].C(OC(=O)C)(=O)C>CCOC(C)=O>[CH3:1][N:2]1[C:6]([NH:7][C:9](=[O:11])[CH3:10])=[CH:5][C:4]([CH3:8])=[N:3]1
Reactant: CC(=O)[O-]
Reactant: Cc1cc(N)n(C)n1
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(C)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
A suspension of 2,5-dimethylpyrazol-3-amine (1 g, 9.00 mmol), potassium acetate (0.971 g, 9.90 mmol) and acetic anhydride (1.002 mL, 9.00 mmol) in EtOAc (25 mL) was stirred at 25° C. overnight. Silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford N-(2,5-dimethylpyrazol-3-yl)acetamide (1.400 g, 102%) as a pale yellow oil. Mass spectrum: MH+ 154 Sodium hydride (0.385 g, 9.14 mmol) was added to N-(2,5-dimethylpyrazol-3-yl)acetamide (1.4 g, 9.14 mmol) dissolved in THF (20 mL) under nitrogen. The resulting light suspension was stirred at 35° C. for 30 minutes then 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (1.338 g, 4.35 mmol) was added. DMF (2 mL) was added and the mixture was stirred at 80° C. for 18 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL). Lithium hydroxide hydrate (0.548 g, 13.06 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with EtOAc and water, the phases were separated and the organic phase washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (40 g) eluting with 0 to 50% EtOAc in DCM. After collection of the fractions and evaporation of the solvents, the resulting solid was triturated in petroleum ether, collected by filtration, washed with petroleum ether and dried to a constant weight to afford N-(2,5-dimethylpyrazol-3-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (900 mg, 54.1%) as an off-white solid.