Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[C:4]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1>>[CH:10]12[O:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][N:8]([C:6]1[CH:5]=[C:4]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[N:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[CH:23][CH:24]=3)[N:7]=1)[CH2:9]2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CS(=O)(=O)Cc1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Product: CS(=O)(=O)Cc1cc(N2CC3CCC(C2)O3)nc(-c2ccc(N)cc2)n1

Procedure:
4-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)aniline was prepared by Suzuki coupling using the general method from scheme 2 for the preparation of 6 using 3-(2-chloro-6-(methylsulfonylmethyl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (43, 1.63 g, 5.13 mmoles) and 4-aminophenyl boronic acid pinacol ester (1.24 g, 5.64 mmoles) as starting materials. The crude product was purified by chromatography on silica gel (eluting with 0-3% methanol in dichloromethane) to provide the desired compound as a light yellow solid. Yield: 1.80 g (94%). HRMS; [M+H]+ Obs'd=375.1485, [M+H]+ Calc'd=375.1485
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:6]([CH:8]1[CH2:13][CH2:12][N:11](C(=O)C)[CH2:10][CH2:9]1)=[O:7]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[O:7])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)cc1OC
Agent: Cl
Product: COc1ccc(C(=O)C2CCNCC2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A solution of 1-[4-(3,4-dimethoxy-benzoyl)-piperidin-1-yl]-ethanone (0.50 g, 1.7 mmol) in 5 mL of 6 N HCl was stirred at reflux for 6 hours and then it was stirred at room temperature overnight. The solvent was removed in vacuo to yield the title compound (0.41 g, 1.65 mmol). MS (ESI) m/z 249.8 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 0.91 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][C:23](O)=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH2:22][C:23]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2OCC(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)COc3ccccc32)CC1

Procedure:
1-t-Butyloxycarbonyl-4-((2-carboxymethoxyphenyl)amino)piperidine (5.2 g, 15 mmol) from Step 3 was cyclized using the EDC/HOBT coupling procedure given in Step 5 of Example 1. 4-(1-tert-butyloxycarbonyl-4-piperidinyl)-(2H)-1,4-benzoxazin-3(4H)-one was obtained as a foam (86% yield).
Reaction SMILES: [F:1][C:2]([F:18])([S:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].ClC1C=CC=C(C(OO)=O)C=1.[OH2:30].[OH2:31].O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].O>C(Cl)Cl>[F:18][C:2]([F:1])([S:13]([CH2:14][CH2:15][CH2:16][OH:17])(=[O:31])=[O:30])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: OCCCSC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(CCCO)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 93.1 %

Procedure:
3-(Perfluorobutylthio)propanol (8.60 g, 27.6 mmol) prepared in Synthetic Example 1 was dissolved in methylene chloride (80 ml), and m-chloroperbenzoic acid (m-CPBA) (52 g, 232 mmol) was added at room temperature in two portions with stirring, the reaction vessel being equipped with a calcium chloride tube. The mixture was stirred at room temperature for 7 days. The reaction mixture was injected into a mixture of sodium thiosulfate pentahydrate (130 g) and water (200 ml), and stirred for 1 hour. Methylene chloride (100 mL) was added and an organic layer was removed and an aqueous layer was extracted with methylene chloride (50 ml). Organic layers were joined, washed with a 5% aqueous sodium hydrogen carbonate and with a saturated saline solution, and then dried over sodium sulfate. A filtrate after filtration was concentrated under reduced pressure. A residue was subjected to a silica gel column chromatography (eluting solvent:hexane-ethyl acetate (2/1)), and fractions having Rf value of 0.32 [Rf value (Thin Layer Chromatography (TLC))=(Migration distance of sample)/(Migration distance of eluting solvent)] were gathered, concentrated under reduced pressure and dried under vacuum to give crystalline 3-(perfluorobutylsulfonyl)propanol (8.79 g). Yield: 91.8%.
Reaction SMILES: O=S(Cl)Cl.[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1Cl)[C:11]([OH:13])=O)([O-:7])=[O:6].[CH3:21][OH:22]>>[N+:18]([C:15]1[CH:14]=[C:10]([CH2:11][OH:13])[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[C:16]=1[C:8]1[CH:9]=[CH:10][C:21]([OH:22])=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1-c1ccc(O)cc1
Reaction time: 15 h

Procedure:
2.96 ml of SOCl2 is added at 0° C., under an inert atmosphere and dropwise to 10 g of 3,5-dinitro-4-chlorobenzoic acid (JANSSEN) in 150 ml of methanol and agitation is carried out under reflux of methanol for 2 hours then for 15 hours at ambient temperature. The reaction medium is poured into ice and precipitation of the product is observed. After drying, 10.3 g of expected product is obtained.
Reaction SMILES: CN(C=O)C.[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]([N:28]=[N+:29]=[N-:30])=[CH:16][C:15]=1[CH:31]([CH3:33])[CH3:32])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:34][O:35][C:36](=[O:54])[C:37]#[C:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([CH3:53])([CH3:52])[O:46][SiH2:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:41][CH:40]=1.CCOC(C)=O>O>[CH3:34][O:35][C:36]([C:37]1[N:30]=[N:29][N:28]([C:17]2[CH:16]=[C:15]([CH:31]([CH3:33])[CH3:32])[C:14]([O:13][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:19][C:18]=2[O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:38]=1[C:39]1[CH:40]=[CH:41][C:42]([C:45]([CH3:53])([CH3:52])[O:46][SiH2:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:43][CH:44]=1)=[O:54]
Reactant: COC(=O)C#Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1
Reactant: CC(C)c1cc(N=[N+]=[N-])c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nnn(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
A DMF solution (2.5 ml) containing 1,5-bis-benzyloxy-2-isopropyl-4-azido-benzene (373 mg, 1 mmol) and [4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-propynoic acid methyl ester (277 mg, 0.91 mmol) was degassed at RT by means of three vacuum-nitrogen cycles. [Cp*RuCl]4 (49 mg, 0.045 mmol) was then added and other three cycles were done. The reaction was stirred at RT until completion (monitored by TLC). AcOEt and water were then added. After standard work-up, the crude reaction mixture was purified by column chromatography (PE/AcOEt:60/40) to get the desired adduct as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:18]=[C:19]([NH:25][CH:26]=O)[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:18]=[C:19]([NH:25][CH3:26])[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(-c2nc3ccccc3n2Cc2ccccc2)cc(NC=O)c1=O
Solvent: C1CCOC1
Product: CNc1cc(-c2nc3ccccc3n2Cc2ccccc2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[5-(1-Benzyl-1H-benzoimidazol-2-yl)-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl]-formamide G1 (93.000 mg; 0.259 mmol) is suspended in THF (extra dry, 2.000 ml), borane-tetrahydrofuran complex (0.259 ml; 0.259 mmol) is added at 0° C. under argon. After 1 h stirring at RT, a second portion of borane-tetrahydrofuran complex (0.259 ml; 0.259 mmol) is added to the reaction mixture at 0° C. After an extra 1 h stirring at RT, a final third portion of borane-tetrahydrofuran complex (0.259 ml; 0.259 mmol) is added to the reaction mixture at 0° C. The mixture is stirred for 30 min at RT. The reaction mixture is quenched with water and extracted with 3×10 ml DCM. The combined organic layer is dried with Na2SO4, filtered and concentrated under reduced pressure. The residue is purified on silica chromatography Combiflash (Column: Redisep Rf, 12 g; gradient: cyclohexane/EtOAc=100%/0% to 0%/100%; flow rate=30 ml/min; 28 column volumes; detection wavelength: 254 nm). Product containing fractions are combined and concentrated under reduce pressure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:19]2[S:18](=[O:21])(=[O:20])[CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[NH:12][C:11]([CH3:22])=[C:10]1[C:23]([O:25][CH2:26][CH2:27][O:28][C:29](=[O:31])[CH3:30])=[O:24].C=O.[C:34]([BH3-])#N.[Na+].[OH-].[Na+]>C(#N)C.O.C(O)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:19]2[S:18](=[O:20])(=[O:21])[CH2:17][CH2:16][N:15]([CH3:34])[CH2:14][C:13]=2[NH:12][C:11]([CH3:22])=[C:10]1[C:23]([O:25][CH2:26][CH2:27][O:28][C:29](=[O:31])[CH3:30])=[O:24]
Reactant: CC(=O)OCCOC(=O)C1=C(C)NC2=C(C1c1cccc(Cl)c1Cl)S(=O)(=O)CCNC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCCOC(=O)C1=C(C)NC2=C(C1c1cccc(Cl)c1Cl)S(=O)(=O)CCN(C)C2
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A mixture of 2-acetoxyethyl 9-(2,3-dichlorophenyl) -1,1-dioxo-2,3,4,5,6,9-hexahydro-7-methyl-pyrido[2,3-f][1,4]thiazepine-8-carboxylate (0.880 g, 1.69 mmole) from Example 19, and 1 mL of 38% aqueous formaldehyde solution in 20 mL of acetonitrile was treated with sodium cyanoborohydride (0.070 g, 1.69 mmole). After stirring for 1 hour, 0.5 mL of acetic acid was added, and the reaction was stirred for another 2 hours. After the addition of 40 mL of water and adjustment of the pH to 9 with 6N sodium hydroxide, the reaction was extracted with 3×30 mL of chloroform. The combined organic extracts were dried with sodium sulfate, the solvent was removed under reduced pressure, and the residue was chromatographed (2% methanol, 0.1% ammonia in chloroform on silica gel) to obtain the title compound (0.743 g, 82%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:14][S:13][C:12]=2[CH:23]=1.Br[CH2:25][CH2:26][CH2:27][C:28]#[N:29]>C(#N)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([N:16]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])[CH2:18][CH2:17]3)=[CH:14][S:13][C:12]=2[CH:23]=1
Reactant: Fc1ccc2c(N3CCCNCC3)csc2c1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCCN1CCCN(c2csc3cc(F)ccc23)CC1
Yield: 42.8 %

Procedure:
Add potassium carbonate (39.3 g, 284 mmol) to a solution of 1-(6-fluoro-benzo[b]thiophen-3-yl)-[1,4]diazepane (Example 4) (23.7 g, 95 mmol) and 4-bromobutyronitrile (21.0 g, 142 mmol) in acetonitrile (400 mL) and stir the mixture under reflux for 10 h. Filter the mixture, evaporate the solvent, and dissolve the residue in ethyl acetate (EtOAc). Wash with water and saturated sodium chloride solution, and dry the organic phase over MgSO4. Evaporate the solvent under vacuum, and purify the crude product by column chromatography (EtOAc/MeOH 9:1) to give 12.9 g of a yellow oil LC/MS, (LiChrospher 5μ, RP-18, 250 mm
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:16].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]([Cl:28])=[CH:25][CH2:26]Cl>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:16][CH2:26][CH:25]=[C:24]([Cl:28])[Cl:23]
Reactant: Oc1ccc(Sc2ccc(Cl)cc2)cc1Br
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1ccc(Sc2ccc(Cl)cc2)cc1Br
Temperature: 0 °C
Yield: 78.1 %

Procedure:
To a mixture of 0.59 g of 2-bromo-4-(4-chlorophenylthio)phenol, 0.28 g of potassium carbonate and 20 ml of N,N-dimethylformamide, a solution prepared by dissolving 0.30 g of 1,1,3-trichloropropene in 5 ml of N,N-dimethylformamide was added dropwise at room temperature with stirring. After the mixture was stirred at room temperature for 6 hours, the reaction solution was poured into ice-water, and extracted twice with 50 ml of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel column chromatography to give 0.62 g of 2-bromo-4-(4-chlorophenylthio)-1-(3,3-dichloro-2-propenyloxy)benzene, yield 78%; nD25.0 1.6514.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][CH:19]2[O:21][CH2:20]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Temperature: 100 °C
Yield: 77.7 %

Procedure:
1-(4-Nitrophenoxy)-2,3-epoxypropane was prepared by an analogous method to that described by Zhen-Zhong Lui et. al. in Synthetic Communications (1994), 24, 833–838. 4-Nitrophenol (4.0 g), anhydrous potassium carbonate (8.0 g) and tetrabutylammonium bromide (0.4 g) were mixed with epibromohydrin (10 ml). The reaction mixture was heated at 100° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was evaporated to dryness and the residue was codistilled twice with toluene. The resulting oil was purified by column chromatography and eluted with ethanol (1.0%):dichloromethane to yield on evaporation an oil that crystallised (4.36 g, 77.7% yield). NMR (CDCl3): 2.78 (m, 1H), 2.95 (m, 1H), 3.38 (m, 1H), 4.02 (dd, 1H), 4.38 (dd, 1H), 7.00 (d, 2H), 8.20 (d, 2H); m/z 196 [MH]+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:24]([O:26][CH:27]1[CH:34]2[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:36][CH:28]1[CH2:29]3)[CH2:33]2)=[O:25].C(Cl)Cl.Cl>>[C:9]([O:8][C:7]([NH:6][CH2:5][CH:3]1[CH2:4][N:1]([C:24]([O:26][CH:27]2[CH:28]3[CH2:36][CH:32]4[CH2:31][CH:30]([CH2:35][CH:34]2[CH2:33]4)[CH2:29]3)=[O:25])[CH2:2]1)=[O:13])([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCC1CNC1
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Reaction time: 0.08 h
Yield: 23 %

Procedure:
A vial was charged with tert-butyl azetidin-3-ylmethylcarbamate (25 mg, 0.12 mmol), i-Pr2NEt (31 μL, 0.17 mmol) and a flea stir bar. A solution of 2-adamantyl chloroformate in CH2Cl2 (1.5 mL, 17 mg mL−1, 0.12 mmol) was added. The mixture was stirred overnight at rt. A 10-mL ChemElut cartridge (Varian Inc. catalog number 12198007) was wetted with 5% aq HCl (5 mL) and allowed to stand for 5 min. The reaction mixture was applied to the cartridge and eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford the title compound (10 mg, 23%). 1H NMR (CDCl3) δ 1.42 (s, 9H), 1.5-2.0 (14H), 2.76 (m, 1H), 3.35 (m, 2H), 3.67 (m, 2H), 4.03 (m, 2H), 4.68 (m, 1H), 4.78 (s, 1H); LC-MS Method 1 tR=2.08 min, m/z=387, 365, 309.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](I)=[CH:6][CH:7]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(N(C(C)C)CC)(C)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: Clc1ccc(I)nn1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1ccc(Cl)nn1
Temperature: 111 °C
Yield: 8.2 %

Procedure:
A suspension of 3-chloro-6-iodopyridazine (2.4 g, 10 mmol), ethyl acrylate (4.4 mL, 40 mmol), palladium(II) acetate (90 mg, 0.40 mmol) and tri(o-tolyl)phosphine (366 mg, 1.20 mmol) in DMF (10 mL) and diisopropylethyl amine (5 mL) was stirred with heating (111° C. oil-bath) for 3.5 h, cooled to room temperature, diluted with H2O (50 mL) and extracted with EtOAc (300 mL). The extract was washed (brine) and dried. After solvent removal at reduced pressure, the residue was chromatographed (14% to 20% EtOAc/hexane) to give 174 mg (8%) of ethyl(E)-3-(3-chloro-6-pyridazinyl)-2-propenoate as a brown solid, mp 106-110° C. IR 2928, 1715, 1186 cm−1; 1H NMR (CDCl3) δ 1.38 (t, J=7.5 Hz, 3H, CH2CH3), 4.33 (q, J=7.5 Hz, 2H, CH2CH3), 7.98 (d, J=16.2 Hz, 1H, CH═CHCO), 7.57 (d, J=8.4 Hz, 1H, 4-ArH), 7.63 (d, J=8.4 Hz, 1H, 5-ArH), 7.86 ppm (d, J=16.2 Hz, 1H, CH═CHCO). HRMS calcd C9H9ClN2O2 [M+H]+ 213.0425. found 213.0431.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].CC(O)=O>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:20])[C:9]([N:11]2[C@@H:15]([CH:16]([CH3:17])[CH3:18])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)Cc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](C)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of (4S)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one (1.07 g, 3.81 mmol) in dry THF (30 mL) at −78° C. under argon, was added dropwise 1.0M solution of NaHMDS in THF (4.20 mL, 4.20 mmol) over a period of 10 min. After stirring at −78° C. for 1 h, Mel (1.19 mL, 19.1 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 1 h and −40° C. for 2 h, quenched with HOAc (11.4 mmol) in ether (20 mL), filtered over celite. The filtrate was concentrated in vacuo and the residue was dissolved in CH2Cl2 (50 mL) and washed with H2O following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (5%–10% EtOAc in hexane) to give 0.68 g (2.30 mmol, 60%) of (4S)-3-[(2S)-2-(4-chlorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCl3) δ 7.30–7.23 (m, 4H), 5.11 (q, 1H, J=7.9 Hz), 4.35 (quintet, 1H, J=3.7 Hz), 4.16–4.09 (m, 2H), 2.46–2.36 (m, 1H), 1.49 (d, 3H, J=7.3 Hz), 0.91 (apparent t, 6H, J=6.9 Hz); ESMS m/e: 296.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)([CH3:8])[C:3]([O:5]CC)=[O:4].O[Li].O.Cl>C1COCC1.O>[CH3:8][C:2]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 50 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Ethyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propanoate (4.60 g, 16.7 mmol) was dissolved in THF/water (2:1, 30 mL). LiOH.H2O (1.40 g, 33.3 mmol) was added and the mixture was stirred at 50° C. for 3 h. The mixture was made acidic by the careful addition of 3N HCl. The product was extracted with ethylacetate and the combined organic phases were washed with brine and dried over magnesium sulfate to give 2-methyl-2-(5-nitro-1H-indol-2-yl)propanoic acid (4.15 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[N+:11]([O-])=O.Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[NH2:11]
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1F
Agent: Cl
Solvent: O
Product: COc1cc(Cl)c(N)cc1F
Temperature: 55 °C
Yield: 186.7 %

Procedure:
1-Chloro-4-fluoro-5-methoxy-2-nitro-benzene (16.3 g, 79.3 mmol) and Sn granules (29.1 g, 246 mmol) were suspended in water (200 mL). Concentrated HCl (79 mL, 952 mmol) was added dropwise over 20 min. The resulting mixture was heated to 55° C. for 3 h. The solution was cooled to room temperature and carefully quenched with 1 N NaOH. The thick mixture was filtered through celite eluting the ethyl acetate to give a clear solution which was extracted with ethyl acetate. The ethyl acetate layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give 26 g (80%) of 2-chloro-5-fluoro-4-methoxyaniline: Crude 1H NMR (400 MHz, CDCl3): δ 6.88 (d, J=8.3 Hz, 1H), 6.57 (d, J=12.2 Hz, 1H), 3.79 (s, 3H), 3.77 (br s, 2H). The crude material was pure enough to carry on to the next step.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[S:10](=[O:12])(=[O:11])[N:9]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH2:8][C:7]1=[O:23].[C:30]([O:34][C:35](=[O:44])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42]O)=[CH:38][CH:37]=1)([CH3:33])([CH3:32])[CH3:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:30]([O:34][C:35]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][O:20][C:18](=[O:19])[C:17]2[CH:16]=[CH:15][C:14]([CH2:13][N:9]3[CH2:8][C:7](=[O:23])[NH:6][S:10]3(=[O:11])=[O:12])=[CH:22][CH:21]=2)=[CH:38][CH:37]=1)=[O:44])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)c1ccc(CO)cc1
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)O)cc3)S2(=O)=O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(COC(=O)c2ccc(CN3CC(=O)NS3(=O)=O)cc2)cc1
Temperature: 5 °C
Reaction time: 16 h

Procedure:
A solution of the title B compound, 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid (84 mg, 0.2 mmol) and 4-hydroxymethyl-benzoic acid t-butyl ester (42 mg, 0.2 mmol) in CH2Cl2 (3 mL) is treated with DMAP (12 mg, 0.1 mmol) and the reaction is cooled to 5° C. EDCl (39 mg, 0.2 mmol) is then added and the reaction is stirred for 16 h. The mixture is concentrated and partioned between EtOAc and 1N aqueous HCl. The organic solution is washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4 and concentrated to give 4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4-t-butoxycarbonyl-benzyl ester as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH2:16][O:15][C:14]2=[O:26])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:27]C1C=C(C=C(F)C=1F)C=O>>[O:26]=[C:14]1[N:13]([C:11]([O:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:12])[C@@H:17]([C:18]2[CH:23]=[C:22]([F:27])[C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:16][O:15]1
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: O=C1OC[C@H](c2cc(F)c(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Following the procedure for the synthesis of 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester, 3,4,5-triflourobenzaldehyde yielded the desired product. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, 2H, J=9.0 Hz), 7.31 (d, 2H, J=9.0 Hz), 7.11-7.02 (m, 2H), 5.37 (dd, 1H, J=4.1, 9.0 Hz), 4.81 (apparent t, 1H, J=9.0 Hz), 4.33 (dd, 1H, J=4.1, 9.0 Hz); Anal. Calc. for C16H9F3N2O6: C, 50.27; H, 2.37; N, 7.33. Found: C, 50.56; H, 2.50; N, 7.49.