Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][N:8]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5]C)=O.[CH3:20][C:21]([Mg]Cl)([CH3:24])[CH2:22][CH3:23]>C1COCC1>[CH3:20][C:21]([CH3:24])([CH2:22][CH3:23])[C:3](=[O:5])[C:2]([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][N:8]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:1]
Reactant: COC(=O)C(=O)C1CCCNN1Cc1ccccc1
Reactant: CCC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)C(=O)C1CCCNN1Cc1ccccc1
Reaction time: 5 h
Yield: 69 %

Procedure:
A solution of methyl 2-oxo-2-[2-benzylperhydropyridazinyl]acetate (9.0 g, 29.4 mmol) in 30 ml dry THF was cooled to −78° C. and treated with 35 ml of 1.0 M solution of 1,1-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at for 5 hours, the mixture was poured into saturated. ammonium chloride (150 ml) and extracted into ethyl acetate. The organic layer was washed with water, dried and concentrated. The crude material was purified by silica gel column, eluting with 10% ethyl acetate in hexane, to obtain 7.0 g product (69% yield) as clear oil. 1H NMR (CDCl3, 400 MHz): δ 0.76 (t, 3H, J=7.0); 1.06 (s, 6H); 1.69 (m, 6H); 2.80 (m, 1H); 3.15 (m, 1H), 4.03 (m, 1H); 4.13 (m, 1H), 5.18 (m, 2H), 7.36 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: BrCCCOc1ccc(Br)cc1
Temperature: 60 °C
Yield: 36.8 %

Procedure:
A suspension of 4-bromophenol (10.0 g, 58 mmol), 1,3-dibromopropane (14.0 g, 69.4 mmol) and potassium carbonate (16.0 g, 116 mmol) in DMF/THF (1:1, 200 mL) was heated to 60° C. over night. The reaction was poured into water and extracted with ether (2×200 mL). The organic layers were combined and washed with water (4×200 mL) and brine (2×200 mL). The organic layer was dried (Na2SO4), filtered and concentrated. Upon concentration a white solid precipitated, the solid was removed by filtration. The filtrate was concentrated and purified by flash column chromatography on an Anaolgix SF65-200 g column (hexanes/ethyl acetate 95:5) to afford the title compound as clear oil (6.28 g, 37%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.24-2.42 (m, 2H) 3.50-3.64 (m, 2H) 4.08 (t, J=5.66 Hz, 2H) 6.74-6.86 (m, 2H) 6.75-6.84 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH:15]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Fc1ccc(CN2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
Morpholine (0.96 mL) and acetic acid (0.57 mL) are added to a solution of 3-bromo-4-fluorobenzaldehyde (2.03 g) in dichloroethane (40 mL). Sodium triacetoxyborohydride (3.18 g) is added in portions over an hour, and the reaction is stirred at room temperature for 18 hours. The reaction is quenched with a 1 N solution of NaOH (10 mL) and diluted with CH2Cl2 (100 mL). The organic layer is washed with 1 N NaOH (3×35 mL). The aqueous layers are back-extracted with CH2Cl2 (20 mL). The combined organic layers are extracted with 0.1 N HCl (6×25 mL). The combined aqueous layers are basified (pH=12) with 2 N NaOH, and the product is extracted with CH2Cl2 (6×25 mL). The combined organic layers are washed with brine (20 mL) and dried (MgSO4). The solution is concentrated in vacuo to afford 2.23 g (82%) of the title compound as a clear, colorless oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]1[CH2:11][CH2:10][CH:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8][CH2:7]1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C(OCC)C>C(Cl)Cl>[NH2:12][CH:9]1[CH2:10][CH2:11][CH:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)NC1CCC(NS(C)(=O)=O)CC1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NC1CCC(N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 154.9 %

Procedure:
1,1-Dimethylethyl {4-[(methylsulfonyl)amino]cyclohexyl}carbamate (0.922 g, 3.15 mmol) was dissolved in DCM (50 mL). TFA was added (2.429 mL, 31.5 mmol) and the reaction allowed to stir at rt for 1 h. Evaporated off the volatiles and added DCM (50 mL) followed by evaporation of volatiles. The DCM addition/evaporation was repeated several times to give a maroon semi-solid. The residual semi-solid was treated with diethyl ether (10 mL) after which the suspension was sonicated and triturated, then filtered. Solids were triturated with more diethyl ether (10 mL). The product was suction dried to give title compound of Step B as a light pink solid (0.938 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (br. s., 2H), 7.07 (d, J=7.2 Hz, 1H), 3.33 (s, 2H), 3.01-3.14 (m, 1H), 2.78-3.01 (m, 2H), 1.80-2.02 (m, 4H), 1.17-1.47 (m, 4H).
Reaction SMILES: OO.[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([OH:12])[C:6]([CH3:14])([CH3:13])[CH2:5]1.N=O.[C:17]([OH:21])([CH3:20])([CH3:19])[CH3:18]>>[OH:3][CH:4]1[CH2:9][C:8]([CH3:10])([CH3:11])[N:7]([O:12][CH2:18][C:17]([OH:21])([CH3:20])[CH3:19])[C:6]([CH3:14])([CH3:13])[CH2:5]1
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: N=O
Agent: OO
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 50 °C

Procedure:
A solution of 50.7 g (0.75 mol) of 50% aqueous hydrogen peroxide mixed with 25 mL of tert-butyl alcohol is added over two hours to a mixture of 25.8 g (0.15 mol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 8.95 g (0.045 mol) of ferrous chloride tetrahydrate and 110 mL of tert-butyl alcohol at 50° C. The reaction mixture is then maintained at 50° C. for six hours and monitored by gas chromatography. Another 17.7 g (0.26 mol) of 50% hydrogen peroxide is added and the reaction mixture is heated at 50° C. for two more hours to bring about complete reaction of the starting nitroxyl compound. The reaction mixture is filtered to remove solids, and the filtrate is diluted with water. The tert-butyl alcohol-water solution is extracted three times with methylene chloride and the aqueous layer is thoroughly extracted with ethyl acetate to afford 7.4 g of the title compound. The combined organic layers are washed once with saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give 21.7 g of an orange oil. The orange oil is purified by flash chromatography on silica gel with 3:2 heptane:ethyl acetate to afford another 12.4 g of the title compound and 4.2 g of a compound which has the same retention time by gas chromatography as an authenic sample of 1-(2-hydroxy-2-methylpropoxy)-2,2,6,6-tetramethylpiperidin-4-one.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]1([C:15]2[NH:19][N:18]=[C:17]([NH2:20])[CH:16]=2)[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:20][C:17]2[CH:16]=[C:15]([CH:12]3[CH2:14][CH2:13]3)[NH:19][N:18]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
A mixture of 2,4-dichloro-5-nitropyrimidine (2 g) and 5-cyclopropyl-1H-pyrazol-3-amine (2 g) in acetonitrile (20 mL) with diisopropylethylamine (2 mL) was stirred at room temperature for 24 hours, The resulting mixture was concentrated, and the resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to afford 2.1 g desired product. MS (electrospray): 281 (M+1) for C10H9ClN6O2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:23])[NH:17][C@@H:18]([CH2:21][CH3:22])[CH2:19][OH:20])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[O:20]=[CH:19][C@@H:18]([NH:17][C:16](=[O:23])[O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:21][CH3:22]
Reactant: CC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
Under an atmosphere of argon, oxalyl chloride (7.01 g, 4.75 ml, 55.3 mmol, Eq: 1.00) was combined with CH2Cl2 (100 ml) to give a colorless solution. The reaction was cooled to −60° C. Then dimethyl sulfoxide (10.8 g, 9.8 ml, 138 mmol, Eq: 2.5) diluted in CH2Cl2 (20 ml) was added dropwise at −60° C. The reaction was stirred for 10 min at −60° C. Then (S)-tert-butyl-1-hydroxybutan-2-ylcarbamate (11.62 g, 55.3 mmol, Eq: 1.00) dissolved in 20 ml CH2Cl2 was added dropwise at −70° C. The reaction was allowed to warm to −40° C. for 10 min and then cooled to −70° C. again. A solution of triethylamine (15.7 g, 21.6 ml, 155 mmol, Eq: 2.8) in 20 ml CH2Cl2 was added dropwise. The reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was poured into 100 ml satd. sodium dihydrogenphosphate solution and extracted with ethyl acetate (2×150 mL). The organic layer was back-extracted with brine (1×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as a light yellow oil (11.12 g, quant., MS (m/e)=188.2 [M+H+]).
Reaction SMILES: OO.C([C@@H]1COC(=O)N1[C:16](=[O:34])[C@@H:17]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])C1C=CC=CC=1.C[O:36]C1C=C(OC)C=CC=1C=O.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:22]([O:21][C:20]([NH:19][CH2:18][C@H:17]([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:16]([OH:34])=[O:36])=[O:26])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)cc1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 93.8 %

Procedure:
35% H2O2 (0.240 mL, 2.91 mmol) was added to a solution of LiO—H2O (0.0978 g, 2.33 mmol) in 2:1 THF:H2O (33 mL). The reaction mixture was stirred at room temperature for 35 minutes and then cooled to 0° C. A solution containing a mixture of tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropylcarbamate (0.535 g, 1.17 mmol) and 2,4-dimethoxybenzaldehyde (0.194 g, 1.17 mmol) in THF (7 mL) was added dropwise by addition funnel. The reaction mixture was placed in an ice bath to slowly warm the reaction mixture and it was stirred overnight. The reaction mixture was then cooled to 0° C., and 1M Na2SO3 (7 mL) was added to the mixture. The mixture was stirred for 5 minutes and then warmed to room temperature while being stirred for 20 minutes. The reaction mixture was then transferred to a separatory funnel and washed with ether (3×). The aqueous layer was acidified with KHSO4(s), and the mixture was extracted with DCM (2×). The combined extracts were dried (Na2SO4), filtered, and concentrated to give (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (0.329 g, 94.2% yield) as a white residue. LC/MS (APCI+) m/z 200 [M−BOC+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH:30]=[CH2:31].CCN(CC)CC>CN(C=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].CCOCC>[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH:30]=[CH:31][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: Clc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C=Cc1ccccc1
Temperature: 40 °C
Yield: 38.6 %

Procedure:
Chlorobenzene (2825 mg, 25 mmoles), NiBr2 (1095 mg, 5 mmoles), NaI(4125 mg, 27.5 mmoles) and PPh3 (2620 mg, 10 mmoles) were mixed in DMF (20 ml) and heated in 40° C. oil bath for 5 h. The mixture was cooled and treated with ethyl acrylate (2750 mg, 27.5 mmoles), Et3N (2778 mg, 27.5 mmoles), palladium diacetate (56 mg, 0.25 mmoles), and PPh3 (262 mg, 1 mmole). The mixture was heated in a 140° C. oil bath for 18 h. The crude reaction mixture was mixed with Et2O, filtered and washed three times with 50 ml of water. The organic fraction was dried over MgSO4, the solvent was removed on the rotary evaporator and the residue purified by radial chromatography (5:1 volume mixture of hexane and Et2O, two purifications) to give 1700 mg (39% isolated yield) of ethyl cinnamate as a light yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17].[NH:32]1[CH2:36][CH2:35][C@H:34]([CH2:37][OH:38])[CH2:33]1>CC(O)C.CCOC(C)=O>[Br:10][C:11]1[C:12]([N:32]2[CH2:36][CH2:35][C@H:34]([CH2:37][OH:38])[CH2:33]2)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17]
Reactant: OC[C@H]1CCNC1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Temperature: 140 °C

Procedure:
DIPEA (4.89 mL, 28.0 mmol) was added to a solution of 5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 11.2, 2.88 g, 7.0 mmol) and (S)-1-pyrrolidin-3-yl-methanol (1.156, 8.40 mmol) in iPrOH (7.0 mL) in a vial, which was sealed and then heated at 140° C. for 1 h. After cooling at RT, the RM was dissolved in EtOAc, washed with aq. 0.5 M HCl and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was triturated with iPr2O, filtered and dried to give the title compound as a beige crystalline powder. HPLC (Condition 4) tR=6.17 min, UPLC-MS (Condition 3) tR=1.20 min, m/z=476.2/478.2 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[N:10][CH:9]=1>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Cl:3])=[N:10][CH:9]=1
Reactant: COC(=O)c1ccc(CO)nc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CCl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Thionyl chloride (5.0 ml, 2.0 eq) was added dropwise to a solution of alcohol (III, 5.7 g) in anhydrous chloroform (50 mL) cooling with a water bath. The resulting solution was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate solution followed by CH2Cl2 extractions. The combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and then passed through a silica gel pad (eluent 5% MeOH in CH2Cl2) to afford the desired product (7.0 g, 90%) as a off-white solid. MS-ESI m/z 186.09 (M+H)+; 1H NMR (CDCl3) δ 9.18 (d, J=2 Hz, 1H), 8.35 (dd, J=2 and 8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 4.74 (s, 2H), 3.98 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)C(C)C>[CH3:10][C@@H:7]1[N:6]2[C:5]3[C:14]([C:13]([C:12]([C:17]([OH:19])=[O:18])=[CH:11]2)=[O:16])=[CH:15][C:2]([F:1])=[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[C:4]=3[O:9][CH2:8]1
Reactant: CN1CCNCC1
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CC(C)CO
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 0 °C
Reaction time: 60 h
Yield: 73.4 %

Procedure:
3 g (10.67 mmole) of (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4]benzoxazine-6-carboxylic acid was put in suspension in 21 mL of isobutanol and 4.75 mL (43 mmole) of N-methyl piperazine. The reaction mixture was heated to reflux for 6 hours, then slurried at ambient temperature for 60 hours and heated again to reflux for 7 hours until completion of the reaction. During that time, the reaction mixture became soluble at reflux temperature. The mixture was then cooled to 0° C., filtered under vacuum, washed with 7 mL isobutanol and 10 mL n-heptane, and dried overnight to obtain 2.83 g (77.3%) of levofloxacin.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)=[C:9]2[C:26]([O:28]CC)=[O:27])=[CH:4][CH:3]=1.C1OC2C=CC(C3C4C(=CC=CC=4)C(=O)C=3C(OCC)=O)=CC=2O1.FC1C=CC([Mg]Br)=CC=1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(F)cc1
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: O=C(O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 0.75 h
Yield: 35 %

Procedure:
Ethyl (1RS)-1-(4-Fluorophenyl)-1-hydroxy-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.31 mmol) in THF (5 ml) under an argon atmosphere at 0° C. was added a solution of freshly prepared 4-fluorophenyl magnesium bromide (0.62 mmol). After stirring for 45 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound (45 mg, 35%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].N1C=CC=CC=1SSC1C=CC=CN=1.[S:29](Cl)(=[O:32])(=[O:31])[OH:30].[OH-].[Na+]>ClCCCl.CCOC(C)=O.CCCCCC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH:11]([S:29]([OH:32])(=[O:31])=[O:30])[C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCCSSc1ccccn1
Reactant: O=S(=O)(O)Cl
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(O)C(CCSSc1ccccn1)S(=O)(=O)O
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 30.2 %

Procedure:
To a solution of 4-(pyridin-2-yldisulfanyl)butanoic acid (725 mg, 3.16 mmol) and 1,2-di(pyridin-2-yl)disulfane (700 mg, 3.18 mmol) in 15 ml of DCE (1,2-dichloroethane) at 75° C. was added chlorosulfuric acid (300 μL, 4.51 mmol). After stirring for 20 min at 75° C., another portion of chlorosulfuric acid (300 μL, 4.51 mmol) was added. The mixture was allowed to stir at 75° C. for 20 min, then another portion of chlorosulfuric acid (200 μL, 3.0 mmol) was added. Again 25 min later, the final portion of chlorosulfuric acid (200 μL, 3.0 mmol) was added and the mixture was stirred for further 25 min. The mixture was immediately cooled on ice bath, neutralized with 1M NaOH to pH ˜7, diluted with EtOAc/Hexane (1:1), separated, and the organic layer was washed with pure water (3×25 ml) while the generated each of aqueous layer was washed with EtOAc/Hexane (1:1, 35 ml). The aqueous layers were combined, acidified with HCl/HOAc to pH 3˜4, concentrated to ˜10 ml, diluted with MeCN (100 ml), sonicated (or quickly stirred) for 1 h, filtered, and the resulting pellet washed with water/MeCN (1:10). The solution was then concentrated and purified on a SiO2 cartridge (40 g) eluting with water/MeCN/HOAc (1:10:0.01). To the pooled fractions containing the product, DMF (˜5 ml) was added and evaporated to dryness to afford 4-(pyridin-2-yldisulfanyl)-2-sulfobutanoic acid (295 mg, 0.954 mmol, 30.2% yield).
Reaction SMILES: [CH3:1][P:2]([CH3:13])([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1)=[O:3].CCO.[ClH:17]>[Pd]>[ClH:17].[CH3:1][P:2]([CH3:13])([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3]
Reactant: CP(C)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CP(C)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1-(Dimethyl-phosphinoyl)-4-nitro-benzene (2.04 g, 10.2 mmol) and 10% palladium on carbon (0.411 g) in 103 mL of absolute EtOH containing 1.15 mL (11.4 mmol) of conc. HCl was flushed with H2 and stirred at ambient temperature (H2 balloon) for 2 h. The reaction mixture was filtered through Celite, the Celite washed with EtOH, and the combined filtrates concentrated to provide the crude product. Recrystallization from boiling iPrOH (10 mL) provided, after several crops, 1.17 g of an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.61 (dd, J=11.1, 8.4 Hz, 2H), 7.04 (dd, J=8.4, 2.0 Hz, 2H), 1.64 (s, 3H), 1.60 (s, 3H). 31P NMR (121 MHz, DMSO-d6) δ 39.299.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+]>C(O)C>[N+:13]([CH:16]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)([O-:15])=[O:14]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Using an analogous reaction procedure and workup as described in Example 1, step 1, naphthalene-2-carbaldehyde (3 g, 19.20 mmol) in ethanol (35 mL) was reacted with nitro methane (1.17 g, 19.49 mmol) and 10N NaOH (0.807 g, 20.17 mmol). The resulting mixture was stirred at 0° C. for 1 hour to afford 3.2 g of the product (84.21% yield).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13]([O:27]C)(=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]>C(CC(C)(C)C)(C)C>[C:22]([O:24][CH:25]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)(=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:27]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: COC(=O)CCCCCCCCC(=O)OC
Solvent: CC(C)CC(C)(C)C
Product: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O

Procedure:
Following the procedure of Example 2, 36.2 g (0.21 mol, a 5 mol % excess) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol, 23.0 g (0.1 mol) of dimethyl sebacate and 110 ml of isooctane are reacted to give orange crystals melting at 101°-103° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@H:10]1[CH2:15][O:14][C:13]2[CH:16]=[CH:17][C:18]([N+:24]([O-])=O)=[C:19]([CH2:20][C:21](O)=[O:22])[C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34]([OH:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>[Pt].CO>[CH3:38][C:28]1[CH:29]=[CH:30][C:31]([S:34]([OH:37])(=[O:36])=[O:35])=[CH:32][CH:33]=1.[CH2:1]([NH:8][CH2:9][C@@H:10]1[O:11][C:12]2=[C:19]3[C:18](=[CH:17][CH:16]=[C:13]2[O:14][CH2:15]1)[NH:24][C:21](=[O:22])[CH2:20]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1c([N+](=O)[O-])ccc2c1O[C@@H](CNCc1ccccc1)CO2
Agent: [Pt]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=C1Cc2c(ccc3c2O[C@@H](CNCc2ccccc2)CO3)N1
Temperature: 50 °C
Reaction time: 18 h
Yield: 61.1 %

Procedure:
A 50 mL two necked flask equipped with a magnetic stir bar, gas inlet adapter and gas outlet adapter is charged with {(3S)-3-[(benzylamino)methyl]-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl}acetic acid [from above (1.36 g, 3.80 mmol)], methanol (20 mL), and p-toluenesulfonic acid monohydrate (1.80 g, 9.5 mmol) and platinum (5% on carbon, 62% w/w water, 0.27 g). The flask head space is flushed with hydrogen gas (100 mL), the gas outlet adapter is closed and the slurry is stirred under a hydrogen atmosphere for 18 h under hydrogen, at which point the reaction is complete by LCMS. The catalyst is removed by vacuum filtration, and the resulting solution is heated to 50° C. (external) in an oil bath for 48 h. The solids are collected by vacuum filtration, the filter cake is washed with cold MeOH (10 mL) and dried under nitrogen giving (2S)-2-[(benzylamino)methyl]-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]indol-8-one 4-methylbenzenesulfonate (1.12 g, 61%) as an off-white powder.