Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:8][C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([C:4]([F:6])([F:5])[F:7])[C:2]([F:16])([F:17])[F:1])(=[O:28])=[O:27]
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
5.16 g (20 mmol) of 1,1,1,3,3,3-hexafluoro-2-p-tolylpropan-2-ol were dissolved in 50 ml of methylene chloride, and 2.8 g (28 mmol) of triethylamine were added. 3.2 g (22 mmol) of methanesulfonyl chloride were added dropwise, while stirring, to the solution cooled to 5° C. After warming up to room temperature, the mixture was allowed to stand overnight. The precipitated salt was filtered off and the organic solution was evaporated down. The subsequent chromatography (silica gel/methylene chloride) gave 4.8 g of 2-methanesulfonyloxy-2-p-tolyl-1,1,1,3,3,3-hexafluoropropane (pale yellow oil).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:15][CH3:16])[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=2[O:6]1)=[O:4].I[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=1[Cl:33]>>[Cl:33][C:23]1[CH:24]=[C:25]([O:28][C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:14][C:12]1[CH:11]=[CH:10][C:8]2[CH2:9][C:5]([CH2:15][CH3:16])([C:3]([OH:2])=[O:4])[O:6][C:7]=2[CH:13]=1
Reactant: CCC1(C(=O)OC)Cc2ccc(O)cc2O1
Reactant: FC(F)(F)Oc1ccc(OCCCI)c(Cl)c1
Product: CCC1(C(=O)O)Cc2ccc(OCCCOc3ccc(OC(F)(F)F)cc3Cl)cc2O1

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4, employing the phenol prepared in Step 2 and the iodide prepared in Example 3, Step 2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][Br:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(Br)c1CBr

Procedure:
To a solution of 1-bromo-2-methyl-3-nitrobenzene (50.0 g, 0.231 mol) in CCl4(500 mL) was added NBS (41.2 g, 0.231 mol) and BPO (6.51 g, 0.0231 mol), and the mixture was stirred at reflux for 1 h. Then the mixture was washed with 1 N HCl (300 mL*3), dried over Na2SO4, concentrated in vacuo. The residue was purified via chromatography (petrol ether) to give 1-bromo-2-(bromomethyl)-3-nitrobenzene.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 69% overall yield. FDMS m/e=366(M+of free base). α[D]589 =-10.45(c=0.61, methanol).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:12]([CH2:14][C:15]([OH:17])=[O:16])#[N:13].C([O-])(=O)C.[NH4+].C1C=CC=CC=1>N1C=CC=CC=1.Cl>[C:12]([C:14](=[CH:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)[C:15]([OH:17])=[O:16])#[N:13]
Reactant: N#CCC(=O)O
Reactant: O=Cc1ccc2c(c1)CCO2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: N#CC(=Cc1ccc2c(c1)CCO2)C(=O)O

Procedure:
39.5 g of 2,3-dihydro-5-benzofurancarbaldehyde (prepared according to the process described in J. Org. Chem. (1984), 49, p. 409), 22.7 g of 2-cyanoacetic acid and 4.08 g of ammonium acetate are mixed in 37 ml of pyridine and 210 ml of benzene The mixture is brought to reflux for 6 hours 30 minutes. The precipitate formed is isolated and then suspended in 600 ml of 6 N hydrochloric acid. The solid isolated is filtered off and washed with water and dried in the air.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:47])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]4[N:30]=[CH:31][CH:32]=[C:28]4[CH:27]=[C:26]([C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=5)[CH:36]=[CH:37][CH:38]=4)[N:25]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)(C)(C)C.[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>ClCCl>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]3[N:29]4[N:30]=[CH:31][CH:32]=[C:28]4[CH:27]=[C:26]([C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=5)[CH:36]=[CH:37][CH:38]=4)[N:25]=3)=[CH:21][CH:22]=2)=[O:47])=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2cccc(-c3cc4ccnn4c(Nc4ccc(NC(=O)c5ccc(CNC(=O)OC(C)(C)C)cc5)cc4)n3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cccc(-c3cc4ccnn4c(Nc4ccc(NC(=O)c5ccc(CN)cc5)cc4)n3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (4-{4-[5-(4′-methoxy-biphenyl-3-yl)-pyrazolo[1,5-c]pyrimidin-7-ylamino]-phenylcarbamoyl}-benzyl)-carbamic acid tertbutyl ester (0.124 g) and trifluoroacetic acid (TFA)(1.5 ml) in dichloromethane (7 ml) is stirred 3 h at ambient temperature. The reaction mixture is evaporated, coevaporated with toluene and dried at high vacuum. Crystals (0.136 g) are obtained in quantitative yield and a melting temperature at 235-240° C.
Reaction SMILES: [C:1]([N:5]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][CH2:25]Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:23][O:24][CH2:25][N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: COCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: COCN(C(=O)c1ccccc1)N(C(=O)c1ccccc1)C(C)(C)C
Reaction time: 3 h

Procedure:
N'-t-butyl-N,N'-dibenzoylhydrazine (2 g, 0.007M) was stirred at room temperature in a two phase system of toluene-50% sodium hydroxide with 100 mg of phase transfer catalyst (tetra-n-butylammonium hydrogen sulfate). Methoxymethyl chloride (1.2 g, 0.015M) was added dropwise and the mixture was stirred 3 hours. The layers were separated and the toluene layer was washed several times with water (until the water washes were neutral). The toluene solution was dried over anhydrous magnesium sulfate and the toluene removed under vacuum to afford N-methoxymethyl-N'-t-butyl-N,N'-dibenzoylhydrazine as a thick oil.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH2:17][C:18]([OH:20])=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.ClC(OCC)=O.[CH3:27][NH:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCCC1>[CH3:27][N:28]([C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[C:18](=[O:20])[CH2:17][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: O=C(O)Cn1ccc2ccccc21
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)Cn1ccc2ccccc21)[C@@H]1CCCC[C@H]1N1CCCC1
Reaction time: 0.08 h
Yield: 29.5 %

Procedure:
Triethylamine (139 μl, 1 mmol) was added to a solution of 1H-indole-1-acetic acid (175 mg, 1 mmol) in tetrahydrofuran (10 ml) at -15° C. with vigorous stirring. Ethyl chloroformate (96 μl, 1 mmol) was added, and the mixture stirred for five minutes. A solution of trans-(±)-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine (182 mg, 1 mmol) in tetrahydrofuran (2 ml) was added, and stirring continued for 30 minutes at -15° C., then 30 minutes at room temperature. The reaction was evaporated to small volume, the residue dissolved in ethyl acetate (50 ml), and washed with saturated sodium biocarbonate solution (3×50 ml). The organic extract was drige (MgSO4), evaporated under reduced pressure, and recrystallized from diethyl ether/methylene chloride to yield the amide (100 mg, 32%); Vmax C=0 1635 cm-1.
Reaction SMILES: CC(O)C.[O:5]1[CH2:7][CH:6]1[CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.[NH3:18]>>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([O:9][CH2:8][CH:6]([OH:5])[CH2:7][NH2:18])=[CH:11][CH:12]=1)#[N:15]
Reactant: N#Cc1ccc(OCC2CO2)cc1
Reactant: N
Solvent: CC(C)O
Product: N#Cc1ccc(OCC(O)CN)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46 %

Procedure:
IPA (300 mL) was added to a stirred suspension of 4-(2-oxiranylmethoxy)benzonitrile (100 g; 571 mmol; see Example A above) in NH3 (500 mL; conc.), and the reaction mixture was stirred at rt. for 3 days. The precipitate was filtered off and the residue concentrated and recrystallized from MeCN to give the sub-title compound in a 46% yield.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])=[O:7].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[C:9]1=[O:17])(=[O:20])[CH3:19]
Reactant: O=C1Nc2ccccc2C1C(=O)c1ccco1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)C(C(=O)c2ccco2)c2ccccc21
Yield: 73 %

Procedure:
Acetylation of 3-(2-furoyl)-2-oxindole with acetic anhydride, substantially according to the procedure of Example 1, afforded a 73% yield of the title compound, m.p. 137.5°-138.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:10])[C:3]=1[C:20]([O:22]C)=O.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH2:31]>>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH3:10])[C:3]=1[C:20](=[O:22])[NH:31][CH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: NCc1ccccn1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)NCc1ccccn1

Procedure:
Same procedure as described in preparation 133a was used from (S)-methyl 3-bromo-1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (374 mg, 0.96 mmols) and pyridine-2-ylmethanamine (0.30 ml, 2.87 mmols). After reverse phase chromatography the title compound was obtained (74 mg, 17%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C@@H:7]([NH:13]C(OCC1C=CC=CC=1)=O)[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>CO.[Pd]>[C:1]([O:5][C:6](=[O:24])[C@@H:7]([NH2:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Temperature: 25 °C

Procedure:
To a solution of 25.0 g (74.1 mmol) (S)-2-(benzyloxycarbonylamino)pentanedioic acid 1-tert.-butyl ester (prepared according to Liebigs Ann. Chem. 1961, 646, 127) in 500 ml dry methanol were added 2.5 g 10% Pd/C, and the mixture was stirred over night at room temperature under an atmosphere of hydrogen. The catalyst was removed by filtration through celite and the filtrate was concentrated under reduced pressure. The remaining solid title compound was purified by stirring with a small amount of ethanol, filtered with suction, and dried in vacuo. Another crop (1.7 g) was obtained after concentration of the mother liquid and stirring of the residue with ethyl acetate.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:25]C1N=C(F)N=C(F)N=1>ClCCl>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([F:25])=[O:18])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a mixture of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (3.00 g, 11.7 mmol) and pyridine (1.132 mL, 14.0 mmol) in dichloromethane (100 mL) at room temperature was added 2,4,6-trifluoro-1,3,5-triazine (cyanuric fluoride) (1.18 mL, 14.0 mmol). The reaction mixture was stirred at room temperature overnight, diluted with dichloromethane (300 mL), washed with an ice-cold solution of 0.5N aqueous hydrochloric acid (2×100 mL), and the organic layer was collected. The aqueous layer was back-extracted with dichloromethane (200 mL), and the combined organic layers were dried anhydrous sodium sulfate and concentrated to afford 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (2.91 g, 11.2 mmol, 96% yield) as a yellow, viscous oil. The product was found to react readily with methanol and on analysis was characterized as the methyl ester, which had an HPLC ret. time=2.56 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=272.3 (methyl ester).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:35]2[CH2:36][CH2:37][O:38][CH2:39][CH:40]=2)([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:35]3[CH2:36][CH2:37][O:38][CH2:39][CH:40]=3)([CH3:34])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC(C)(C)C2=CCOCC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1=CCOCC1
Yield: 99 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 129b (5.5 g, 9.29 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a dark solid (6 g, 99%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1(CO)[CH2:51][OH:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:51][OH:52])[CH2:32][O:31]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1F
Temperature: -10 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 4m (1.11 g, 1.46 mmol) was dissolved in 20 mL dichloromethane and cooled to −10° C., followed by addition of trifluoroacetic acid (0.23 mL, 3 mmol). The reaction mixture was warmed and stirred for 2 hours and partitioned after 20 mL saturated sodium bicarbonate solution were added. The aqueous phase was extracted with dichloromethane (20 mL×2). The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 4n (830 mg, colourless grease), yield: 78.3%. MS m/z (ESI): 742.3 [M+18].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:9]1[O:10][C:11]3([CH2:17][S:18][C:8]=1[C:7](=[O:22])[C:6]2=[O:23])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3.[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]2[CH2:33][O:32]2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]([OH:32])[CH2:33][N:14]2[CH2:15][CH2:16][C:11]3([O:10][C:9]4[C:19]5[C:5]([C:6](=[O:23])[C:7](=[O:22])[C:8]=4[S:18][CH2:17]3)=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=5)[CH2:12][CH2:13]2)=[CH:27][CH:26]=1
Reactant: Clc1ccc(OC[C@@H]2CO2)cc1
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCNCC2)CS1
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCN(C[C@H](O)COc3ccc(Cl)cc3)CC2)CS1

Procedure:
Compound 205 was synthesized using 8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=189-191° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.73 (d, J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (dd, J=1.5, 6.8 Hz, 3H), 6.98 (d, J=3.5 Hz, 1H), 4.90 (d, J=4.7 Hz, 1H), 4.05-3.92 (m, 2H), 3.87 (s, 3H), 3.05 (s, 2H), 2.86-2.74 (m, 2H), 2.55-2.38 (m, 4H), 2.01-1.93 (m, 2H), 1.86-1.73 (m, 2H). LCMS: 516 [M+H].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=1.Cl.[C@H:14]12[CH2:20][C@H:17]([NH:18][CH2:19]1)[CH2:16][O:15]2.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[Cl:8][C:6]1[N:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=[C:2]([N:18]2[CH2:19][C@@H:14]3[CH2:20][C@H:17]2[CH2:16][O:15]3)[CH:7]=1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1nc(Cl)cc(N2C[C@@H]3C[C@H]2CO3)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of 4,6-dichloro-2-methylsulfonyl-pyrimidine (3.41 g, 15 mmol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (2.03 g, 15.0 mmol) in N,N-dimethylacetamide (40.5 mL), was added N,N-diisopropylethylamine (6.60 mL). The resulting mixture was stirred at room temperature. After 30 min, the reaction mixture was concentrated to a solid. The crude material was purified by column chromatography using an 80 g column, with a gradient of 0% to 100% ethyl acetate in heptane. The combined fractions containing product were concentrated under reduced pressure to provide (1S,4S)-5-(6-chloro-2-methylsulfonyl-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (3.03 g). 1H NMR (400 MHz, Chloroform-d) δ 6.30 (s, 1H), 3.98-3.81 (m, 3H), 3.45-3.35 (m, 2H), 3.28 (s, 3H), 2.16-1.98 (m, 2H), 1.95-1.86 (m, 1H).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2([CH2:15][CH2:14][C:13](=[O:16])[C:12]3[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=3[NH:10]2)[CH2:6][CH2:5]1)(=O)C>Cl.[OH-].[Na+]>[NH:4]1[CH2:9][CH2:8][C:7]2([CH2:15][CH2:14][C:13](=[O:16])[C:12]3[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=3[NH:10]2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCC2(CCC(=O)c3ccccc3N2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCC2(CCNCC2)Nc2ccccc21
Temperature: 85 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
Acetate 10 (20 mg, 0.072 mmoles) was dissolved in 2 N HCl (0.31 mL) and heated to 85° C. After 3 h, the reaction mixture was diluted with 5 N NaOH to a pH˜11 and extracted with CH2Cl2 (3×3 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford 11(16.2 mg, 0.071 mmoles, 96%) as a colorless oil. 1H NMR (CDCl3) δ7.83 (1H, dd, J=1.7, 7.6 Hz), 7.32 (1H, ddd, J=2.2, 8.1, 9.1 Hz), 6.93 (1H, m), 6.77 (1H, d, J=7.9 Hz), 3.76 (1H, d, J=7.9 Hz), 3.98 (1H, s), 2.83 (6H, m), 1.31 (2H, m), 1.64 (5H, m); IR (thin film, NaCl) 3290, 2964, 1716, 1664, 1422 cm−1; LRMS: M+=230.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]([C:15](OCC)=[O:16])=[O:14])=[C:4]([N+:20]([O-:22])=O)[CH:3]=1.CN(C)C=O.N>O1CCCC1.[Pd]>[OH:22][N:20]1[C:4]2[CH:3]=[CH:2][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]=2[NH:12][C:13](=[O:14])[C:15]1=[O:16]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Br)c2ccccc12
Agent: [Pd]
Agent: N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1[nH]c2c3ccccc3ccc2n(O)c1=O
Yield: 64.4 %

Procedure:
A solution of 0.5 g (1.36 mmol) 4-bromo-1-ethoxalylamino-2-nitronaphthalene in 30 ml tetrahydrofuran was added 10 ml dimethylformamide and 0.7 ml 25% aqueous ammonia. The mixture was hydrogenated at atm. pressure by using 50 mg 5% Pd-C as a catalyst. The precipitated product was filtered off and washed with tetrahydrofuran. The filter cake was washed several times with 5% aqueous potassium hydroxide. Acidification of the filtrate with 4N hydrochloric acid and recrystallization (dimethylformamide-water) of the precipitated product gave 0.2 g (65%) 4-hydroxy-benzo[f]quinoxaline-2,3(1H,4H)-dione. M.p. 270° C. decomp. 1H-NMR (DMSO-d6 : 12.1 (1H, broad s), 8.6 (1H, m), 7.7 (5H, m). MS (m/e): 228 (M+, 90%).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=[CH:9][CH:10]=1)=[NH:4].C(N(C(C)C)CC)(C)C.[C:28]([CH2:32][CH2:33][C:34](Cl)=[O:35])([O:30][CH3:31])=[O:29]>C1COCC1>[C:14]([O:13][C:12]([NH:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]([NH:2][O:1][C:34](=[O:35])[CH2:33][CH2:32][C:28]([O:30][CH3:31])=[O:29])=[NH:4])=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=N)NO)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)ONC(=N)c1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 50-mL, one-neck, round bottomed flask equipped with a magnetic stirrer and a digital thermometer was charged with tert-butyl [3-(N-hydroxycarbamimidoyl)phenyl]carbamate (5.56 g, 22.1 mmol), diisopropylethylamine (4.29 g, 33.2 mmol) and THF (25 mL). The reaction mixture was then cooled to 0° C. in an ice/salt bath. 3-Carbomethoxypropionyl chloride (3.99 g, 26.6 mmol) was then added dropwise to the reaction mixture. Once the addition was complete, the cooling bath was removed and the mixture stirred at room temperature for an additional 3 h. The reaction was then concentrated under reduced pressure, the residue dissolved in ethyl acetate (60 mL), and the resulting solution washed with 2 M aqueous potassium carbonate solution (2×60 mL). Drying over sodium sulfate, filtration and concentration under reduced pressure afforded a quantitative yield of 3-tert-butyloxycarbonylamino-N-(3-carbomethoxypropionyloxy)benzamidine as a white solid that was used directly. 1H NMR (CDCl3) δ (ppm) 7.71 (s, 1H), 7.50 (m, 2H,), 7.33 (m, 2H), 6.58 (bs, 1H), 5.19 (bs, 2H), 3.71 (s, 3H), 2.83 (m, 2H), 2.75 (m, 2H), 1.52 (s, 9H).