Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:54])[C@@H:5]([O:51][CH2:52][CH3:53])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[C:16](/[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27](/[C:30](/[CH3:50])=[CH:31]/[CH2:32][O:33][C:34]4[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([O:47][CH2:48][CH3:49])[C:42]([O:44]CC)=[O:43])=[CH:36][CH:35]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)\[CH3:17])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C.O.C(OCC)(=O)C>[C:42]([C@@H:41]([O:47][CH2:48][CH3:49])[CH2:40][C:37]1[CH:36]=[CH:35][C:34]([O:33][CH2:32]/[CH:31]=[C:30](/[C:27]2[CH:28]=[CH:29][C:24]([C:21]3[CH:22]=[CH:23][C:18](/[C:16](/[CH3:17])=[CH:15]/[CH2:14][O:13][C:10]4[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:51][CH2:52][CH3:53])[C:4]([OH:54])=[O:3])=[CH:12][CH:11]=4)=[CH:19][CH:20]=3)=[CH:25][CH:26]=2)\[CH3:50])=[CH:39][CH:38]=1)([OH:44])=[O:43]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(/C(C)=C/COc4ccc(C[C@H](OCC)C(=O)OCC)cc4)cc3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(/C(C)=C/COc4ccc(C[C@H](OCC)C(=O)O)cc4)cc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
To a solution of (E)(E)(S)(S) 2-ethoxy-3-{4-[3-(4′-{3-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-1-methyl-propenyl}-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionic acid ethyl ester (example 11) (367 mg 0.5 mmol) in ethanol (10 mL) was added 1N sodium hydroxide (2 mL). The reaction mixture was stirred at room temperature for 18 h, and at 60° C. 1 h. The resulting mixture was diluted with water and ethyl acetate, the aqueous layer collected and further extracted with ethyl acetate (3×). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to give 180 mg (53%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](S(O)(=O)=O)=[CH:6][CH:7]=1.[C:12]1(=[O:18])CC[CH2:15][CH2:14][CH2:13]1.CC(CCO)=C>C1(C)C=CC=CC=1>[CH3:15][C:14]1[CH2:1][C:2]2([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[O:18][CH2:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1CCCCC1
Agent: C=C(C)CCO
Solvent: Cc1ccccc1
Product: CC1=CCOC2(CCCCC2)C1
Temperature: 115 °C
Yield: 80 %

Procedure:
A mixture of p-TSA (20 g, 0.105 mol) and toluene (2 L) was heated to 115° C. To this mixture were added cyclohexanone (980 g, 10 mols) and isoprenol (946 g, 11 mols) and heated further for 3-6 h. Water was removed from the reaction azeotropically. The reaction mixture was then cooled to room temperature. The organic phase was washed with a 5% Na2CO3 solution, washed with water dried and concentrated and distilled further to provideto 4-methyl-1-oxaspiro [5.5] undec-3-ene (1.32 kg) having a purity of 98% (sum of the isomers) for a total yield of 80%.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C@@H:20]1(N)[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[NH2:26].[CH:28]1(NCC)CCC[CH2:29]1>O1CCOCC1.[Cu]I>[CH:22]1([CH2:21][N:26]([CH2:28][CH3:29])[C:2]2[C:11]([C:12]#[N:13])=[CH:10][C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=2)[CH2:23][CH2:24][CH2:25][CH2:20]1
Reactant: N#Cc1cc2c(nc1Cl)CCCC2
Reactant: CCNC1CCCC1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCN(CC1CCCC1)c1nc2c(cc1C#N)CCCC2
Yield: 135.8 %

Procedure:
Dry dioxane (15 mL) was added to a mixture of 2-chloro-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (3.0 g, 15.62 mmol), potassium carbonate (8.6 g, 62.5 mmol), CuI (5 mol %, 0.064 g), and trans-1,2-cyclohexanediamine (5 mol %, 0.089 g) under an argon atmosphere. A solution of N-cyclopentyl-ethylamine (2.3 g, 18.75 mmol) in dioxane was them added to the stirred reaction mixture, which was then refluxed for 24 h. After this time, the solvent was evaporated under vacuum, and the residue was purified by column chromatography over silica gel (100-200 mesh), eluted with 2% ethyl acetate and petroleum ether, to afford 2-(cyclopentylmethyl-ethyl-amino)-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (0.3 g), yield: 10%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1.N1C=CC=CC=1.[C:51]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[S:59](Cl)(=[O:61])=[O:60])#[N:52]>ClCCCl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[O:26])[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][S:59]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=3[C:51]#[N:52])(=[O:61])=[O:60])[CH2:9][CH2:10]2)=[O:44])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N)CC1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NS(=O)(=O)c2ccccc2C#N)CC1
Yield: 85.4 %

Procedure:
To a 50 mL round-bottomed flask equipped with stirring was added tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Example 20) (154 mg, 0.25 mmol), 1,2-dichloroethane (10 mL) and pyridine (0.03 mL, 0.3/5 mmol). The reaction mixture was stirred for 5 min at RT, treated with 2-cyanobenzenesulfonyl chloride (Lancaster Synthesis) (50 mg, 0.25 mmol) and stirred at RT for 16 h. The reaction was quenched with satd NH4Cl (10 mL), the organic layer separated, and the aqueous layer extracted with CH2Cl2 (2×10 mL). The organic fractions were combined, washed with satd NaCl (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (167 mg). MS (ESI, pos. ion) m/z: 782 (M+1); MS (ESI, neg. ion) m/z: 780 (M−1). Calc'd for C42H44ClN5O6S: 781.27.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7].[CH:23]([S:26](Cl)(=[O:28])=[O:27])([CH3:25])[CH3:24]>>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][S:26]([CH:23]([CH3:25])[CH3:24])(=[O:28])=[O:27])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CN
Product: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CNS(=O)(=O)C(C)C

Procedure:
From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid (3-methyl-butyl)amide (precursor 5c) and isopropylsulfonyl chloride, according to the general working procedure followed by purification by flash chromatography 16 mg of 2′-(isopropylsulfonylaminomethyl)biphenyl-2-carboxylic acid (3-methylbutyl)amide were obtained as an oil. MS (ES+): m/e 403 (M+1).
Reaction SMILES: [SH:1][CH:2]([CH3:10])[C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].Br[CH2:12][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(#N)C>[CH2:17]([O:16][C:14](=[O:15])[C:13]([OH:19])=[CH:12][S:1][CH:2]([C:3](=[O:4])[NH:5][CH2:6][C:7]([OH:9])=[O:8])[CH3:10])[CH3:18]
Reactant: CC(S)C(=O)NCC(=O)O
Reactant: CCOC(=O)C(=O)CBr
Solvent: CC#N
Product: CCOC(=O)C(O)=CSC(C)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A solution of N-(2-mercaptopropionyl)glycine (1.17 g, 7.17 mmol) and ethyl bromopyruvate (1 mL, 7.17 mmol, 90% purity) in acetonitrile (30 mL) was stirred at room temperature for 3 h. After removal of the solvent, the residue was dissolved in a mixed solvent of ethanol (15 mL) and water (15 mL). After the pH was adjusted to 7-8 with satd. NaHCO3 solution, the mixture was stirred at room temperature overnight. The mixture was acidified to pH 1-2 with concentrated hydrochloric acid and then rotary evaporated to dryness. The residue was purified by column chromatography eluted with EtOAc giving 3-[1-(carboxymethylcarbamoyl)ethylsulfanyl]-2-hydroxyacrylic acid ethyl ester as yellow solid (1.06 g, yield 53.3%). 1H NMR (CDCl3, 300.16 MHz) δ (ppm): 9.10 (broad s, 1H), 7.22 (d, J=0.9 Hz, 1H), 4.62 (d, J=17.7 Hz, 1H), 4.53 (d, J=17.7 Hz, 1H), 4.28 (q, J=7.1 Hz, 1H), 3.47 (qd, J=6.2 & 0.9 Hz, 1H), 1.48 (d, J=6.2 Hz, 3H) and 1.30 (t, J=7.1 Hz, 3H). 13C NMR (CDCl3, 75.48 MHz) δ (ppm): 174.02, 165.84, 160.57, 130.27, 120.20, 62.04, 46.76, 37.11, 14.45 and 14.09. MS (ESI) m/z: 260 (M+—OH, 100).
Reaction SMILES: [C:1]1(=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[ClH:41]>ClC(Cl)C.C(OCC)C>[ClH:41].[CH2:33]([NH:40][CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C1CCCc2c1[nH]c1ccccc21
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: c1ccc(CNC2CCCc3c2[nH]c2ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a solution of 2,3,4,9-tetrahydro-1H-carbazol-1-one (0.1 g, 0.52 mmol) in dichloroethane (5 mL) was added sodium triacetoxyborohydride (0.17 g, 0.80 mmol), acetic acid (0.046 mL, 0.80 mmol) and benzyl amine (0.087 mL, 0.80 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was quenched by adding saturated NaHCO3 (5 mL) and EtOAc (5 mL) and stirred for 30 minutes. The layers were separated, the aqueous layer extracted with EtOAc (2×5 mL), the organic layers combined, dried over Na2SO4, filtered and evaporated. Purification was accomplished by silica gel chromatography with hexanes/ethyl acetate as the eluant to afford yellowish oil. The compound was dissolved in diethyl ether and a solution of HCl in diethyl ethyl ether was added to yield a white precipitate was upon evaporation. Recrystallization from methanol/diethyl ether afforded a white solid (42 mg, 35%). 1H-NMR (DMSO-ds): δ 11.2 (s, 1H), 9.70 (s, 1H), 9.58 (s, 1H), 7.64 (d, 2H), 7.43 (m, 5H), 7.14 (t, 1H), 7.02 (t, 1H), 4.67 (s, 1H), 4.29 (s, 2H), 2.71 (m, 2H), 2.22 (m, 2H), 2.08 (m, 1H), 1.82(m, 1H); 13C-NMR (CDCl3): δ 140.7, 136.2, 135.7, 128.5, 128.1, 127.5, 127.1, 121.5, 119.0, 118.3, 111.2, 110.8, 51.9, 50.4, 30.5, 21.8, 21.0; MS m/z 277 (M).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[O:5][N:4]=1.[Li+].[Br-:16].CC(=O)OCC>C1COCC1>[Br:16][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[O:5][N:4]=1
Reactant: [Br-]
Reactant: ClCc1noc(-c2cccc(Cl)c2)n1
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1cccc(-c2nc(CBr)no2)c1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
3-(chloromethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (1.38 g, 6.0 mmol) and LiBr (0.90 g, 10.3 mmol) in THF (50 ml) was heated to reflux under a nitrogen atmosphere o.n. After cooling to r.t. EA was added and the organic phase was washed with H2O and brine, dried and evaporated to give the title compound (1.40 g, 85%). MS (M++1) 275
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:13][OH:14].N1C=CC=CC=1.[Cl:21][C:22]([C:32]([F:35])([F:34])[F:33])=[CH:23][C@@H:24]1[C@H:26]([C:27](Cl)=[O:28])[C:25]1([CH3:31])[CH3:30].CCCCCCC>C1(C)C=CC=CC=1>[Cl:21][C:22]([C:32]([F:33])([F:34])[F:35])=[CH:23][C@@H:24]1[C@H:26]([C:27]([O:14][CH2:13][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N:8]3[CH:12]=[CH:11][CH:10]=[CH:9]3)[C:2]=2[CH3:1])=[O:28])[C:25]1([CH3:31])[CH3:30]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: Cc1c(CO)cccc1-n1cccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCCCCCC
Product: Cc1c(COC(=O)[C@H]2[C@@H](C=C(Cl)C(F)(F)F)C2(C)C)cccc1-n1cccc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of 2.0 grams (0.011 mole) of 2-methyl-3-(pyrrol-1-yl)phenylmethanol (prepared in Example 2), and 0.9 gram (0.011 mole) of pyridine in 30 ml of toluene was warmed to 50° C. Under a dry-nitrogen atmosphere 2.8 grams (0.011 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride in 2 ml of toluene was added in one portion. The addition caused an exothermic reaction which raised the reaction mixture temperature from 50° C. to 55° C. Upon complete addition the reaction mixture was heated to 60° C. where it was stirred for 2.5 hours. The reaction mixture was cooled and poured into a separatory funnel with 300 ml of heptane. The resultant organic layer was washed with 100 ml of an aqueous solution of 2 N hydrochloric acid then with 200 ml of an aqueous solution of 2 N sodium hydroxide. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was purified by distillation using a Kugelrohr distilling system to give 3.8 grams of [2-methyl-3-(pyrrol-1-yl)phenyl]methyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate, bp 135° C./0.04 mm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)[CH3:2].[Cl:11][S:12](O)(=[O:14])=[O:13]>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[S:12]([Cl:11])(=[O:14])=[O:13])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCOc1ccc(C)cc1
Solvent: ClCCl
Product: CCOc1ccc(C)cc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
A solution of 6.8 g (50 mmol) of 4-ethoxytoluene in 20 mL of dichloromethane was added to a solution of 10 mL (150 mmol) of chlorosulfonic acid in 10 mL of dichloromethane at 0° C. with cooling and stirring. The mixture was stirred 1 hour at 0° C. and was then warmed to ambient temperature and stirred another hour. The resulting tan solution was poured into 200 mL of ice water and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The residual 7.9 g (68 percent of theory) of light tan solid melting at 59-61° C. was the title compound.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[NH:6][C:7]2[C:8](=[CH:10][CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:9]=1.IC.[C:24](=O)(O)[O-].[Na+]>CO.O1CCCC1.Cl>[CH3:24][N:9]1[C:8]2=[CH:10][CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:7]2[N:6]=[C:5]1[CH3:4]
Reactant: COC(=O)c1ccc2nc(C)[nH]c2c1C(=O)OC
Reactant: O=C([O-])O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CI
Product: COC(=O)c1ccc2c(nc(C)n2C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium methoxide (1.98 g, 36.6 mmol) is added to a solution of dimethyl 2-methyl-4,5-benzimidazoledicarboxylate (7.44 g, 33.3 mmol) in methanol and tetrahydrofuran. After 5 minutes, iodomethane (2.18 mL, 35.0 mmol) is added and the mixture is stirred for 24 hours at room temperature. Additional sodium methoxide (1.80 g, 33.3 mmol) and iodomethane (2.07 mL, 33.3 mmol) are added and stirring is continued for another 15 hours. The reaction mixture is concentrated in vacuo to give a residue which is dispersed in dilute hydrochloric acid, and treated with sodium bicarbonate to pH 8 and extracted with chloroform. The combined organic extracts are dried (MgSO4) and concentrated in vacuo to give a residue which is recrystallized from ethyl acetate to afford the title product as an orange solid, mp 205°-208° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22]([Cl:27])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C(OC([NH:36][C@H]1CCN(S(C2C3C(Cl)=CN=C(Cl)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22]([NH2:36])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Product: Cl
Product: Nc1ncc(Cl)c2c(S(=O)(=O)N3CC[C@@H](N)C3)cccc12

Procedure:
Intermediate 26b can be used in the method of Example 39-1 instead of Intermediate 26a to obtain the title compound as hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[NH2:27][C@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C@H:29]1[OH:37]>>[F:15][C:16]1[CH:17]=[C:18]([S:23]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:27][C@H:28]2[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][C@H:29]2[OH:37])=[N:9]3)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: O=S(=O)(Nc1cccc2nc(N[C@H]3c4ccccc4C[C@H]3O)ccc12)c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=468.5 (M+H+), was prepared in accordance with the general method of example 13 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonyl chloride and (1S,2R)-(−)-1-amino-2-indanol.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:12]=1.[CH3:25][C:26]([CH3:28])=[O:27]>C1(C)C=CC=CC=1>[CH:16]([Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:14][CH2:13][C:11]1[CH:12]=[C:7]([C:26]([OH:27])([CH3:28])[CH3:25])[CH:8]=[N:9][CH:10]=1)([CH3:18])[CH3:17]
Reactant: CC(C)[Si](OCc1cncc(Br)c1)(C(C)C)C(C)C
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)[Si](OCc1cncc(C(C)(C)O)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.38 h
Yield: 94.7 %

Procedure:
Toluene (30 mL) in a 3-necked flask was cooled down to −78° C. n-BuLi (1.6 M in hexane, 8.35 mL, 0.13.35 mmol) was slowly added to the toluene. After 10 minutes a solution of the 3-bromo-5-((triisopropylsilyloxy)methyl)pyridine (4.0 g, 11.62 mmol) in toluene (30 mL) was added dropwise. A yellow solid precipitated. The resulting slurry was aged for 15-30 min, then THF (20 mL) was added slowly, keeping the internal temperature at <−50° C. The mixture was aged for 15 min, then acetone (1.7 mL, 23.24 mmol) was added over 2 min. The solids dissolved and a brown homogeneous solution was obtained. The reaction solution was warmed to rt and quenched with saturated aqueous NH4Cl and diluted with EtOAc. The phases were separated and aqueous layer was extracted with EtOAc twice. The organic layers were combined and concentrated to dryness. Purification by flash chromatography (silica gel, hexanes/EtOAc) gave 2-(5-((triisopropylsilyloxy)methyl)pyridin-3-yl)propan-2-ol as a light yellow solid (3.56 g, 96%). 1H NMR (CDCl3): d: 1.250-1.055 (m, 21H), 1.606 (s, 6H), 4.865 (s, 2H), 7.830 (s, 1H), 8.458 (s, 1H), 8.621 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7](Cl)[C:3]=1[C:4]([OH:6])=[O:5].OO.C1CCCCCCC=1.[C:22]([O-])([OH:24])=[O:23].[Na+]>CC#N.CCOCC.O>[C:22]([OH:24])(=[O:23])[CH2:2][CH2:10][CH2:9][CH2:8][CH2:7][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: O=C([O-])O
Agent: C1=CCCCCCC1
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: O=C(O)CCCCCCC(=O)O
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To a mixture of [Mn2O3(Me3-TACN)4] (PF6)2.H2O (8.1 mg, 10 μmol, 0.1 mol %) and 2,6-dichlorobenzoic acid (57.3 mg, 0.30 mmol, 3.0 mol %) in CH3CN (7 ml) was added H2O2 (30 μl of a 50% aq. solution, 0.53 mmol) at room temperature and the resulting mixture was stirred for 20 min. Subsequently cyclooctene (1.16 g, 10 mmol) was added together with CH3CN (2 ml) and water (1 ml). H2O2 (2.83 ml of a 50% aq. solution, 50 mmol, 5.0 equiv.) was then added at room temperature using a syringe pump (0.07 ml/h). New batches of [Mn2O3(Me3-TACN)2] (PF6)2.H2O (8.1 mg, 10 μmol, 0.1 mol % per batch) were added to the reaction mixture 17, 25 and 40.5 hours after the addition of H2O2 had commenced. When the addition of H2O2 was completed, the mixture was stirred for additional 1 hour. Water (10 ml) and Et2O (10 ml) were added and the pH of the aqueous layer was set to pH >9 by adding some saturated NaHCO3 (aq.). The organic layer was separated and the aqueous layer was washed with Et2O (3×15 ml). The pH of the aqueous layer was subsequently set to pH <2 with some 10% HCl (aq.) and was extracted with Et2O (3×20 ml). The combined organic extracts were dried over anhydrous Na2SO4. The solvents were removed in vacuo yielding 868 mg of a solid with a purity of circa 95% (determined by 1H NMR), 47% yield of suberic acid. 1H NMR (400 MHz, acetone-d6) δ 1.34-1.39 (m, 4H), 1.56-1.63 (m, 4H), 2.28 (t, J=7.4, 4H). N.B. NMR showed other compounds as well, including 2,6-dichlorobenzoic acid.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([C:6]([O:8][CH2:9][O:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:22]([OH:25])[C:23]#[CH:24]>C(N(CC)CC)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>[OH:25][CH2:22][C:23]#[C:24][C:2]1[CH:21]=[CH:20][C:5]([C:6]([O:8][CH2:9][O:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([C:4]#[C:5][CH2:6][OH:7])=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(OCOC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCOC(=O)c1ccc(C#CCO)cc1)c1ccc(C#CCO)cc1
Reaction time: 240 h
Yield: 85 %

Procedure:
Bis (triphenylphosphine)palladium dichloride (17.0 mg, 0.02 mmol) and cuprous iodide (2.0 mg, 0.01 mmol) are added to a suspension of methylene bis (p-bromobenzoate) prepared as described in Example 4 (n) (0.500 g, 1.21 mmol) and propargyl alcohol (0.16 ml, 2.66 mmol) in triethylamine (10 ml) with good stirring, at 20° C., under a dry N2 atmosphere. After 10 days at 20° C., the triethylamine is removed under reduced pressure, water (20 ml) is added and the mixture is extracted with dichloromethane (3×15 ml). The dichloromethane phases are washed with hydrochloric acid (0.5M, 10 ml), dried (MgSO4) and the dichloromethane removed under reduced pressure to give 0.37 g (85%) of the crude product. 1H NMR (60 MHz, CDCl3): δ3.67 (2H, s, OH), 4.47 (4H, s, CH2 --O), 6.18 (2H, s, O--CH2 --O), 7.2-7.5 (4H, Ar), 7.8-8.0 (4H, Ar).