Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH2:13][N:14]([CH3:39])[C:15]([N:17]2[CH2:30][CH2:29][C@:20]3([NH:24][CH:23]([C:25]([O:27]C)=O)[CH2:22][CH2:21]3)[CH2:19][C@@H:18]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[NH3:44]>>[F:1][C:2]([F:40])([F:41])[C:3]1[CH:4]=[C:5]([CH2:13][N:14]([CH3:39])[C:15]([N:17]2[CH2:30][CH2:29][C@:20]3([NH:24][C@@H:23]([C:25]([NH2:44])=[O:27])[CH2:22][CH2:21]3)[CH2:19][C@@H:18]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)C1CC[C@@]2(CCN(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reactant: N
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@H](C(N)=O)N2)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 87 %

Procedure:
In a sealed tube a solution of methyl(5S,7R)-8-{[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 22, 63 mg, 0.107 mmol) in 7 N ammonia solution in MeOH (5 ml, 35.0 mmol) was shaken overnight. The solvent was evaporated to dryness and the crude was purified by flash-chromatography [Si cartridge (5 g), from 1:0 to 95:5 DCM/MeOH] to give the title compound (53.5 mg, 0.093 mmol, 87% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.95 (s, 1H) 7.61 (s, 2H) 7.24-7.32 (m, 1H) 7.15-7.24 (m, 1H) 6.98-7.05 (m, 1H) 6.92 (d, 1H) 6.79 (t, 1H) 4.65 (d, 1H) 4.36 (d, 1H) 4.15 (d, 1H) 3.44-3.59 (m, 1H) 3.38 (d, 1H) 2.93 (s, 3H) 2.75 (t, 1H) 2.65 (br. s., 1 H) 2.33 (s, 3H) 1.99-2.21 (m, 1H) 1.51-1.93 (m, 6H) 1.45 (t, 1H); HPLC: Rt 4.88 mins; MS: m/z=575 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=1O)=[O:17].C(N(CC)C(C)C)(C)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:25]1[CH:24]=[C:21]([C:22]#[N:23])[CH:20]=[CH:19][C:18]=1[CH:16]=[O:17])(=[O:5])=[O:4]
Reactant: N#Cc1ccc(C=O)c(O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.4 ml (14.27 mmol) of trifluoromethanesulfonic anhydride are added dropwise to a solution of 2 g (13.59 mmol) of 4-formyl-3-hydroxybenzonitrile and 2.5 ml (14.27 mmol) of N,N-diisopropylethylamine in 37 ml of anhydrous dichloromethane at 0° C. under an argon atmosphere. The reaction mixture is stirred at RT for 1 h, then diluted with 70 ml of dichloromethane and washed successively with 1 M hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic solution is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:1). 2.36 g (62% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH:4]([OH:6])[CH3:5].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Cl:15])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]>O>[Cl-:15].[N+:18]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:10]=1[O:9][CH3:8])[CH2:14][N+:2]([CH2:3][CH:4]([OH:6])[CH3:5])([CH3:7])[CH3:1])([O-:20])=[O:19]
Reactant: COc1ccc(CCl)cc1[N+](=O)[O-]
Reactant: CC(O)CN(C)C
Solvent: O
Product: COc1ccc(C[N+](C)(C)CC(C)O)cc1[N+](=O)[O-]
Product: [Cl-]

Procedure:
Proceeding in a manner similar to that described above in D-1a, 16 parts of 1-dimethylamino-2-propanol and 32 parts of 4-methoxy-3-nitrobenzyl chloride were interacted in 14 parts of water to obtain N-(3-nitro-4-methoxybenzyl)-N-(2-hydroxypropyl)-N,N-dimethylammonium chloride. The product was not isolated but was used directly in solution for reduction of the nitro group.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:16]=[CH:15][C:14]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][CH3:32])[CH:26]=1.O1CCCC1.C(N(CC)CC)C>O>[CH2:1]([NH:8][C:9](=[O:10])[N:31]([C:27]1[CH:26]=[C:25]([C:14]2[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:13]=2[O:12][CH3:11])[CH:30]=[CH:29][CH:28]=1)[CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CNc1cccc(-c2ccc(CCC(=O)OC)cc2OC)c1
Reactant: CCCCCCCN=C=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
540 μL (3.3 mmol, 2 eq) of heptyl isocyanate are added to a solution of 495 mg (1.65 mmol, 1 eq) of methyl 3-(2-methoxy-3′-methylaminobiphenyl-4-yl)propanoate in 10 mL of an 8/2 tetrahydrofuran/triethylamine mixture. The reaction mixture is stirred for 12 hours at room temperature. The reaction medium is hydrolyzed in water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 525 mg of methyl 3-[3′-(3-heptyl-1-methylureido)-2-methoxybiphenyl-4-yl]propanoate are obtained in oil form. Yield=72%
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:5]([O:13][CH2:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:21][CH2:20]2)=[N:6][CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1>CO.C(Cl)Cl.Cl[Ni]Cl>[NH2:10][C:8]1[CH:9]=[C:4]([CH3:3])[C:5]([O:13][CH2:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])[CH2:21][CH2:20]2)=[N:6][CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
To the solution of NiCl2 (Nickel (II) Chloride-hexahydrate, 1.03 g, 4.32 mmol) in 40 ml of methanol was added 150 mg of NaBH4 (it turned dark) at RT and the mixture stirred 5 minutes. Benzyl 4-((1R,2S)-2-{-[(3-methyl-5-nitropyridin-2-yl)oxy]ethyl}cyclopropyl)piperidine-1-carboxylate (1.90 g, 4.32 mmol) in 15 ml of DCM was added followed by the addition of another 116 mg of NaBH4 in 3 portions. The resulting mixture was then stirred for 40 minutes. The reaction was then diluted with DCM and filtered through a celite and silica gel pad. The filtrate was concentrated in vacuo and the residue was partitioned between saturated NaHCO3 aqueous solution and DCM. The organics were separated, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to afford the title compound as a crude product which was used for the next step. LC/MS (m/z): 410 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH:7]([CH2:11][CH3:12])[C:8]([NH2:10])=[O:9])[C:4](=[O:13])[CH2:3]1.[CH:14](OCC)(OCC)OCC.[N-:24]=[N+:25]=[N-:26].[Na+]>CC(O)=O>[O:13]=[C:4]1[CH2:3][CH:2]([N:1]2[CH:14]=[N:26][N:25]=[N:24]2)[CH2:6][N:5]1[CH:7]([CH2:11][CH3:12])[C:8]([NH2:10])=[O:9]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Reactant: CCC(C(N)=O)N1CC(N)CC1=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(C(N)=O)N1CC(n2cnnn2)CC1=O

Procedure:
Alternatively to §5.6, reaction of 2-[4-amino-2-oxo-1-pyrrolidinyl]butanamide with triethyl orthoformate, NaN3 and AcOH provided 2-[2-oxo-4-(1H-tetrazol-1-yl)-1-pyrrolidinyl]butanamide 67.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])([OH:13])=[O:12].[O-]CCCC.[K+]>CC(N(C)C)=O>[C:11]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([OH:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C(O)COc1ccccc1O
Agent: CCCC[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)COc1ccccc1Oc1ccc([N+](=O)[O-])cc1

Procedure:
4-nitro-fluorobenzene and 2-(carboxymethoxy)phenol were reacted together in DMA in the presence of potassium butoxide for 2 hours at 150° C. to yield 4-(2-(carboxymethoxy)phenoxy)nitrobenzene.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][N:6]([C:8](=[O:19])[CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:11])[CH3:7])C.[Li+].[OH-]>O.C1COCC1>[C:15]([O:14][C:12]([N:10]([CH3:11])[CH2:9][C:8]([N:6]([CH2:5][C:4]([OH:20])=[O:3])[CH3:7])=[O:19])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)CN(C)C(=O)CN(C)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CC(=O)O)C(=O)CN(C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 90 %

Procedure:
A suspension of {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid ethyl ester (12.3 g, 42.7 mmol) and LiOH (8.9 g, 214 mmol) in H2O (20 mL) and THF (100 mL) was stirred overnight. Volatile solvent was removed under vacuum and the residue was extracted with ether (2×100 mL). The aqueous phase was acidified to pH 3 with dilute HCl solution, and then extracted with CH2Cl2 (2×300 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to give {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid as a colorless oil (10 g, 90%). 1H NMR (CDCl3) δ 7.17 (br s, 1H), 4.14-4.04 (m, 4H), 3.04-2.88 (m, 6H), 1.45-1.41 (m, 9H); ESI-MS 282.9 m/z (M+Na+).
Reaction SMILES: [O:1]1[CH:9]2[CH:2]1[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]2.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.O>C(Cl)Cl>[CH2:10]([NH:17][C@@H:2]1[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][C@H:9]1[OH:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: C1=CCCC2OC2CC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: ClCCl
Product: O[C@@H]1CCC=CCC[C@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To a stirred solution of 5,6-epoxycyclooctene III (10.0 g, 0.081 mol) in dry CH2Cl2 (100 ml) kept under nitrogen atmosphere, benzylamine (10.35 g, 0.097 mol) and Ytterbium(III) trifluoromethanesulfonate (4.96 g, 0.008 mol) were added and the mixture was stirred for 24 hrs at room temperature. Extractive work-up of the reaction mixture with water and CH2Cl2 gave the title product as a white solid (yield 83%). m.p.: 70-71° C., b.p:140° C./1 mm Hg. 1H NMR (CDCl3): δ 7.59-7.56 (m, 2H, ArH), 7.38-7.35 (m, 3H, ArH), 5.64-5.44 (m, 2H, CH=CH), 5.42-5.00 (bs, D2O exchangeable, OH) 4.07 (AB syst, 2H, J=12.57 Hz, PhCH2), 3.75-3.65 (m, 1H, CHOH), 3.00-3.15 (m, 1H, CHNH--), 2.35-2.02 (m, 6H), 1.95-1.42 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][C:13]([C:19]([OH:21])=[O:20])=[CH:12]3)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C>C(O)C.[Pd]>[N:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][C:13]([C:19]([OH:21])=[O:20])=[CH:12]3)=[CH:7][CH:2]=1
Reactant: O=C(O)c1cnc2ccc(Oc3ccnc(Cl)c3)cc2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)c1cnc2ccc(Oc3ccncc3)cc2c1
Temperature: 25 °C

Procedure:
To a mixture of 6-[(2-chloropyridin-4-yl)oxy]quinoline-3-carboxylic acid (Int-31, 0.358 g, 1.19 mmol) and palladium (10% on carbon 0.07 g) in ethanol (5 mL) was added triethylamine (1 mL, 7.2 mol). The reaction flask was carefully evacuated and backfilled with an atmosphere of hydrogen from a balloon. After stirring at room temperature under hydrogen over night the flask was carefully purged with nitrogen and the suspension filtered through Celite. The filtrate was concentrated and used as obtained in the following step. LC-MS: (FA) ES+ 267.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH3:10])=[N:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=[O:4].[OH-].[K+].O>C(O)C>[CH3:10][C:8]1[S:9][C:5]([C:3]([OH:4])=[O:2])=[C:6]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:7]=1
Reactant: COC(=O)c1sc(C)nc1-c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc(C)sc2C(=O)O)cc1

Procedure:
2-Methyl-4-p-tolyl-thiazole-5-carboxylic acid methyl ester (2.67 mmol) and solid KOH (5.35 mmol) were dissolved in ethanol (1.04 mL) and water (0.26 mL) and heated under reflux for 3 hours. After cooling, the solvent was evaporated under reduced pressure and ice water was added to the residue, followed by washing with hexane. The aqueous layer was acidified with 1N aq. HCl and the crystals thus precipitated were collected by filtration, washed with water and then dried to provide 2-methyl-4-p-tolyl-thiazole-5-carboxylic acid. LC-MS: tR=0.83 min; [m+H]+=234.02.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[C:12](=O)([O-:14])[O-:13].[K+].[K+].C(=O)=O>>[NH2:1][C:5]1[CH:6]=[C:7]([C:12]([OH:14])=[O:13])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C=O
Agent: [K+]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 185 °C
Yield: 35 %

Procedure:
p-Acetaminophenol 15 g, and potassium carbonate 37.5 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 3.0 MPa and heated to 185° C., maintained for 14 hours, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve potassium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the yield is 35%.
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH2:8])[C:4]([CH3:7])=[CH:5][CH:6]=1.N1C=CC=CC=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(OCC)(=O)C.C(Cl)Cl>[CH3:1][C:2]1[N:3]([NH:8][C:17](=[O:18])[CH2:16][Cl:15])[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1N
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C)n1NC(=O)CCl
Reaction time: 8 h
Yield: 54.9 %

Procedure:
The product of Example 1 (13.2 g) and pyridine (9.48 g) were stripped in ethyl acetate (200 ml) at room temperature with dropwise addition of 13.56 g chloroacetyl chloride. The mixture was stirred overnight, stripped, dissolved in methylene chloride, washed with water, dried and stripped. The residue was chromatographed in a silica gel (325 g) column (chloroform elution), to yield the title product (12.27 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.[Cl:23][CH2:24][CH2:25][N:26]=[C:27]=[O:28]>C1COCC1>[Cl:23][CH2:24][CH2:25][NH:26][C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:6][CH:7]=1)=[O:28]
Reactant: O=C=NCCCl
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Solvent: C1CCOC1
Product: CCn1c(-c2ccc(NC(=O)NCCCl)cc2)c(C#N)c2ccc(OC)cc21
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (50 mg, 0.172 mmol) in THF (2 mL) is added 2-chloroethyl isocyanate (22 uL, 0.258 mmol) at room temperature. After stirring overnight at reflux, the reaction mixture is concentrated in vacuo and the residue is diluted with ethyl acetate. The resulting semi-solid is triturated with hexane and the precipitate collected is collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford (62 mg, 91%) of 1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[C:5]([O:8][C@H:9]1[C@H:14]([N:15]=[C:16]=[S:17])[C@@H:13]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]([O:22][C:23](=[O:25])[CH3:24])[C@@H:11]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:10]1)(=[O:7])[CH3:6].C(N(CC)CC)C>C(#N)C>[C:5]([O:8][C@H:9]1[C@H:14]([NH:15][C:16]([NH:4][O:3][CH3:2])=[S:17])[C@@H:13]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]([O:22][C:23](=[O:25])[CH3:24])[C@@H:11]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:10]1)(=[O:7])[CH3:6]
Reactant: CON
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CONC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a suspension of methoxyamine hydrochloride (180 mg, 2.16 mmol) in acetonitrile (7 mL) was added (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (560 mg, 1.44 mmol) followed by triethylamine (300 μL., 2.16 mmol). The mixture was stirred at room temperature for 2 h. Solvents were removed by concentration. The residue was purified by flash chromatography on silica gel (hexane/EtOAc 1:1) to give (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-methoxythioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white solid (545 mg, 87% yield). 1H NMR (500 MHz, CDCl3) δ 2.05 (s, 3H), 2.09 (s, 3H), 2.10 (s, 6H), 2.13 (s, 3H), 3.67 (s, 3H), 3.82-3.85 (m, 1H), 4.15 (dd, 1H, J=2.5, 12.5 Hz), 4.28 (dd, 1H, J=4.5, 12.5 Hz), 5.03 (dd, 1H, J=10.0, 13.0 Hz), 5.20-5.30 (m, 2H), 5.84 (d, 1H, J=8.5 Hz), 7.01 (d, 1H, J=10.0 Hz).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[O:23][CH3:24])=O)(C)(C)C.[N+:25]([O-])([OH:27])=[O:26].C(Cl)(Cl)Cl>O>[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:23][CH3:24])=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:21]([N+:25]([O-:27])=[O:26])[CH:22]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OCCCNC(=O)OC(C)(C)C)c(OC)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OC)c(OCCCN)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
The ester 198 (4.0 g, 11.8 mmol) was added in small portions to a stirred solution of 70% HNO3 (2 mL acid/g of substrate) at room temperature and the reaction mixture was allowed to stir overnight. After 16 hours TLC (CHCl3) revealed the complete loss of starting material. The reaction mixture was cooled in an ice bath, and 15 g of iced water was added, precipitating the product. The precipitate was collected by vacuum filtration and washed with small amount of iced water. The filtrate was cooled and a second crop of precipitate was collected by vacuum filtration and washed with iced water. The combined precipitate was dried in vacuo to provide compound 199 as a yellow solid, which was not purified further, but used directly in the subsequent reaction (2.3 g, 70%). mp=101-103° C.; 1H-NMR (CDCl3/DMSO-d6, 270 MHz): δ 2.31 (m, 2H, H2′), 3.20 (br, 2H, H3′), 3.95 (s, 3H, OCH3 ether), 3.98 (s, 3H, OCH3ester), 4.24 (t, 2H, J=5.95 Hz, H1′), 7.11 (s, 1H, H6), 7.49 (s, 1H, H3), 8.21 (s, 3H, NH); 13C-NMR (CDCl3, 68.7 MHz): δ 26.5 (C2′), 37.0 (C3′), 53.0 (OCH3ester), 56.0 (OCH3ether), 66.7 (C1′), 108.3 (C3), 111.0 (C6), 121.6 (Carom), 140.9 (C2), 149.3 (Carom), 152.6 (Carom), 166.8 (C═O); Ms (E/I) m/z (relative intensity): 284 (M+., 90), 237 (70), 227 (93), 196 (47), 181 (38), 137 (100), 122 (81), 93 (52), 79 (44); HRMS (E/I) exact mass calcd for C12H17N2O6: m/e 284.1008, obsd m/e 284.1018; IR (Nujol®) n: (cm−1) 3472, 2937, 2911, 2855, 1733, 1532, 1516, 1462, 1377, 1292, 1224, 1143, 1052, 884, 812, 792, 773, 756, 724, 646.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1.[CH3:20][S:21]SC.CCOCC>C1COCC1>[Cl:6][C:7]1[C:8]([S:21][CH3:20])=[C:9]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CC1(C)COC(c2cccc(Cl)c2)=N1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1c(Cl)cccc1C1=NC(C)(C)CO1
Temperature: -65 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
n-Butyllithium (2.5M in hexane, 4.2 ml) was added to a solution of 2-(3-chlorophenyl)-4,4-dimethyloxazoline (2 g) in THF while maintaining the temperature below -45° C. The mixture was stirred at -65° C. for 3 hours. Dimethyl disulphide (1.0 g) was added and the mixture was stirred at -65° C. for 2.5 hours and allowed to warm to room temperature. Ether was added and the mixture was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-(3-chloro-2-methylsulphenylphenyl)-4,4-dimethyloxazoline (2.35 g) as a yellow oil NMR (CDCl3) 2.0(s,6H) 3.0(s,3H) 4.65(s,2H) 7.5-8.1(m,3H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:12])[CH2:10][CH3:11].[Br:15]Br>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:10]([CH3:11])[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:13])([F:14])[F:1])=[O:12]
Reactant: BrBr
Reactant: CCC(=O)c1ccccc1C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)C(=O)c1ccccc1C(F)(F)F
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a solution of 2′-trifluoromethyl-propiophenone (10 g, 48 mmol) in carbon tetrachloride (50 ml) was added a solution of bromine (2.72 mL, 52.8 mmol) in carbon tetrachloride (20 mL) dropwise. After the addition was complete, stirring was continued for another 2h. The solution was washed with satd NaHCO3 and water, dried (anhyd Na2SO4) and concentrated under reduced pressure to give 2-bromo-1-(2-trifluoromethyl-phenyl)-propan-1-one as an oil (12.8 g, 95%), which was used in the next step without purification. 1H-NMR (CDCl3): δ 7.73 (m, 2H), 7.58-7.67 (m, 2H), 4.96 (q, 1H), 1.90 (d, 3H). To a solution of 2′-trifluoromethyl-propiophenone (10 g, 48 mmol) in carbon tetrachloride (50 ml) was added a solution of bromine (2.72 mL, 52.8 mmol) in carbon tetrachloride (20 m
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([Sn](CCCC)(CCCC)C=C)[CH2:10]CC.[Li+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:7]1[C:2]([CH:9]=[CH2:10])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cccnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1ncccc1Br
Temperature: 100 °C
Yield: 53.4 %

Procedure:
A solution of 2,3-dibromopyridine (2.0 g, 8.44 mmol) in DMF (10 mL) was treated with tributyl(vinyl)tin (2.94 g, 9.29 mmol), LiCl (1.07 g, 25.32 mmol), and PdCl2(PPh3)2 (0.296 g, 0.422 mmol). The reaction mixture was heated at 100° C. for 18 hours. The mixture was extracted with hexanes (3×50 mL). The combined hexane layers were extracted with 1N HCl. The aqueous layer was neutralized with 1N NaOH, extracted with hexanes, and the extracts were dried (MgSO4), filtered, and concentrated to provide the desired product as a yellowish oil (0.83 g, 53% yield). MS m/z 184(MH+); 1H NMR (300 MHz, CD3OD) δ 5.53 (dd, J=10.80, 2.01 Hz, 1H), 6.33 (dd, J=16.83, 1.83 Hz, 1H), 7.08–7.26 (m, 2H), 7.96 (dd, J=8.05, 1.46 Hz, 1H), 8.44 (dd, J=4.76, 1.46 Hz, 1H); 13C NMR (300 MHz, CD3OD) δ 121.9, 122.4, 125.7, 134.9, 142.8, 149.5, 154.5.