Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:32]([NH:34][C@H:35]([C:39]([NH:41][C@H:42]([C:48]([NH:50][C@H:51]([C:62]([NH:64][C@H:65]([C:70]([NH:72][C@H:73]([C:79]([NH:81][C@H:82]([C:87]([NH:89][C@H:90]([C:94]([OH:96])=[O:95])[C@@H:91]([CH3:93])[OH:92])=[O:88])[CH2:83][C:84](=[O:86])[NH2:85])=[O:80])[CH2:74][CH2:75][S:76]([CH3:78])=O)=[O:71])[CH2:66][CH:67]([CH3:69])[CH3:68])=[O:63])[CH2:52][C:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[NH:55][CH:54]=1)=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[NH2:46])=[O:40])[CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22])[CH2:17][C:18](=[O:20])[OH:19])=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[NH2:11])=[O:5])[CH3:3]>C(O)(=O)CS>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:32]([NH:34][C@H:35]([C:39]([NH:41][C@H:42]([C:48]([NH:50][C@H:51]([C:62]([NH:64][C@H:65]([C:70]([NH:72][C@H:73]([C:79]([NH:81][C@H:82]([C:87]([NH:89][C@H:90]([C:94]([OH:96])=[O:95])[C@@H:91]([CH3:93])[OH:92])=[O:88])[CH2:83][C:84](=[O:86])[NH2:85])=[O:80])[CH2:74][CH2:75][S:76][CH3:78])=[O:71])[CH2:66][CH:67]([CH3:69])[CH3:68])=[O:63])[CH2:52][C:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[NH:55][CH:54]=1)=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[NH2:46])=[O:40])[CH:36]([CH3:37])[CH3:38])=[O:33])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:22])[CH2:17][C:18](=[O:19])[OH:20])=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[NH2:11])=[O:5])[CH3:3]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)N)C(C)C)C(=O)N[C@@H](CCS(C)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Agent: O=C(O)CS
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)N)C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Reaction time: 24 h

Procedure:
In 3.0 ml of 5% thioglycolic acid-50% aqueous acetic acid was dissolved 30 mg of H-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met(O)-Asn-Thr-OH and reduction was carried out at 45° C. for 24 hours. The reaction mixture was run onto a column (3.4×57 cm) of Sephadex LH-20 and elution was carried out with 50% acetic acid. The fractions from 235 ml to 280 ml were pooled and lyophilized. Yield 23 mg; Rf3 0.72(Avicel®); amino acid analysis; Trp (0.76(1); Asp 2.15(2); Thr 0.93(1); Glu 2.15(2); Ala 0.97(1); Val 1.00(1); Met 0.92(1); Leu 1.02 (1); Phe 1.02(1) (peptide content 82%)
Reaction SMILES: C[O:2][C:3](=[O:18])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)\[CH2:8][CH3:9].[OH-].[Na+]>CO>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10](/[C:7](/[CH2:8][CH3:9])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:18])=[O:2])=[CH:15][CH:14]=1
Reactant: CC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reaction time: 2.5 h
Yield: 71.6 %

Procedure:
As described in Example 99, (E,E)-5-(4-methoxyphenyl)-2,4heptadienoic acid methyl ester (8 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 2.5 hours the reaction was worked up in the usual way and the acid crystallized from 2-propanol-hexane to give 5.4 g of (E,E)-5-(4-methoxyphenyl)-2,4-heptadienoic acid, mp 135.5°-137° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:16])[CH:15]=2)=[C:12]([O:17]C)[C:11]([O:19][CH3:20])=[C:10]([O:21]C)[CH:9]=3)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:16])[CH:15]=2)=[C:12]([OH:17])[C:11]([O:19][CH3:20])=[C:10]([OH:21])[CH:9]=3)=[CH:4][CH:3]=1
Reactant: COc1cc2oc(-c3ccc(N)cc3)cc(=O)c2c(OC)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1c(O)cc2oc(-c3ccc(N)cc3)cc(=O)c2c1O
Temperature: -20 °C
Reaction time: 5 h
Yield: 42.6 %

Procedure:
To a solution of the flavone 10a (130 mg, 0.4 mmol) in CH2Cl2 (10 mL) was added a 1M solution of boron tribromide (1.5 mL, 1.5 mmol) in CH2Cl2 at −78° C. The solution was stirred for an additional 2 h and at −20° C. for 5 h, then quenched with water (10 mL). The precipitate was collected by filtration to give crude product 10b (51 mg, 43%). 1H NMR (400 MHz, DMSO) δ 3.89 (s, 3H), 6.68 (s, 1H), 6.74 (d, J=8.8 Hz, 2H), 6.87 (s, 1H), 7.82 (d, J=8.8 Hz, 2H).
Reaction SMILES: CC1(C)CNS(=O)(=O)N1.[H-].[Na+].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.C(OC([N:34]1[C:38]([CH3:40])([CH3:39])[CH2:37][N:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[S:35]1(=[O:49])=[O:48])=O)(C)(C)C>CN(C)C=O.O>[C:44]([O:43][C:41]([N:36]1[CH2:37][C:38]([CH3:40])([CH3:39])[NH:34][S:35]1(=[O:48])=[O:49])=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)N(C(=O)OC(C)(C)C)S1(=O)=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC1(C)CNS(=O)(=O)N1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CN(C(=O)OC(C)(C)C)S(=O)(=O)N1
Temperature: 40 °C
Reaction time: 0.83 h

Procedure:
To a stirred solution of 3,3-dimethyl-1,2,5-thiadiazolidine-1,1-dioxide (2.5 g, 16.6 mmol) in anhydrous dimethylformamide (50 ml) was added sodium hydride (60% dispersion in oil; 666 mg) in two portions. After being stirred at 40° C. for 50 minutes under nitrogen, the mixture was allowed to cool to room temperature, diluted with anhydrous dimethylformamide (20 ml) and treated with di-tert-butyldicarbonate (3.99 g, 18.26 mmol). After 1 hour 45 minutes of stirring at room temperature, the mixture was diluted with water (200 ml) and extracted with diethyl ether (3×100 ml). The organic phases were washed with brine (2×50 ml), dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel, dichloromethane to dichloromethane-diethyl ether 50:50) gave a mixture of the required product and 2,5-di-tert-butyloxycarbonyl-3,3-dimethyl-1,2,5-thiadiazolidine-1,1-dioxide. Trituration of this mixture with hot hexane afforded 1.26 g (30%) of the required title compound as a white solid; δH (250 MHz, CDCl3) 4.39 (1H, br s, --NH--), 3.70 (2H, s, --CH2 --), 1.54 (9H, s, t-Bu), 1.47 (6H, s, --CMe2); m/z (CI) 249 (M+ -1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].Br[CH2:17][CH2:18][CH2:19][P:20]([O:25][CH2:26][CH3:27])(=[O:24])[O:21][CH2:22][CH3:23]>>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[N:4]([CH2:17][CH2:18][CH2:19][P:20](=[O:24])([O:25][CH2:26][CH3:27])[O:21][CH2:22][CH3:23])[C:3]1=[O:15]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: CCCn1cnc2c1c(=O)n(CCCP(=O)(OCC)OCC)c(=O)n2C

Procedure:
The title substance was prepared from 0.048 mol of 3-methyl-7-propyl-xanthine and 0.058 mol of diethyl 3-bromopropanephosphonate analogously to Example 23.
Reaction SMILES: C1(=O)OC(=O)CC1.C(O)(=O)CCC(N)=O.C([NH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][C:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[C:24]([OH:36])[C:23]2=[O:37])(=O)C.Cl.N>C(O)C>[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][C:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[C:24]([OH:36])[C:23]2=[O:37]
Reactant: CC(=O)Nc1ccc2oc(-c3ccccc3)c(O)c(=O)c2c1
Agent: Cl
Agent: N
Agent: NC(=O)CCC(=O)O
Solvent: CCO
Product: Nc1ccc2oc(-c3ccccc3)c(O)c(=O)c2c1

Procedure:
With substantial amounts of 4 in hand, the next steps were to form the 6-acetamidoflavonol. Thus, the acetophenone 4 was treated with benzaldehyde and base to effect a Claisen-Schmidt condensation affording the chalcone 5 in 71% yield. The chalcone 5 was treated with alkaline hydrogen peroxide to enable an Algar-Flynn-Oyamada reaction, giving 6-acetamidoflavonol 6 in 50% yield. The next step was to unveil the 6-amino group of 6 to allow coupling with succinic anhydride for installation of the succinamic acid side chain. The 6-acetamidoflavonol 6 was treated with 5 M HCl in ethanol at reflux, followed by neutralization with aqueous ammonia to give 6-aminoflavonol.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@@H:8]2[C:20]([O:22]C)=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1.CO>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C@@H:8]([C:20]([OH:22])=[O:21])[CH2:9]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.6 %

Procedure:
1-tert-Butyl 3-methyl (3R,4S)-4-phenylpiperidine-1,3-dicarboxylate (585 mg) was dissolved in tetrahydrofuran (5 ml) and methanol (5 ml), and thereto was added 1M aqueous sodium hydroxide solution (5.5 ml), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and thereto was added a 5% potassium hydrogen sulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (546 mg).
Reaction SMILES: CO.[C:3]([O:7][C:8]([N:10]([CH2:38][C:39]1[CH:48]=[CH:47][C:42]2[O:43][CH2:44][CH2:45][O:46][C:41]=2[CH:40]=1)[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]([O:31]CCCC)=[O:30])[CH:27]=3)[C:22]([CH3:36])=[CH:21][C:20]2=[O:37])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O.[OH-].[Li+]>O>[C:3]([O:7][C:8]([N:10]([CH2:38][C:39]1[CH:48]=[CH:47][C:42]2[O:43][CH2:44][CH2:45][O:46][C:41]=2[CH:40]=1)[CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]([OH:31])=[O:30])[CH:27]=3)[C:22]([CH3:36])=[CH:21][C:20]2=[O:37])[CH2:15][CH2:16]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCCCOC(=O)c1ccc2c(C)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(C(=O)O)ccc12
Reaction time: 0.5 h
Yield: 101.3 %

Procedure:
To 11 mL of a methanol solution containing 0.65 g of butyl 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methyl-2-oxo-1,2-dihydroquinoline-7-carboxylate, 55 mg of lithium hydroxide monohydrate was added and stirred for 30 min. Then, 55 mg of lithium hydroxide monohydrate and 1.1 mL of water were added and stirred for 2 hours. The methanol was removed under reduced pressure, water and chloroform were added, and adjusted to pH 5.0 with acetic acid. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.60 g of 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methyl-2-oxo-1,2-dihydroquinoline-7-carboxylic acid as a white foam.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH2:21]([O:20][C:12]([CH:13]([C@@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19])[CH3:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Product: CCOC(=O)C(C(=O)OCC)[C@H](C[N+](=O)[O-])c1ccccc1
Reaction time: 12 h
Yield: 83 %

Procedure:
To a mixture of trans-β-nitrostyrene (149 mg, 1.0 mmol) and diethyl malonate (0.304 ml, 2.0 mmol) was added, as an asymmetric catalyst, (R,R)-trans-1-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(N,N-dimethylamino)cyclohexyl]thiourea (20.7 mg, 0.05 mmol), obtained in Example 1A at room temperature under an argon atmosphere. After 12 hr, the reaction mixture was purified by preparative TLC (elution solvent: n-hexane/diethyl ether) to give the title compound as colorless needle crystals (257 mg, yield 83%, optical purity 88%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17].O.O.C[N+]([O-])(C)C.[Li+].[CH3:26][CH:27]([N-:29][CH:30](C)C)C>C1COCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.CCOCC.CCCCC>[CH3:30][N:29]1[CH2:27][CH2:26][C@@H:9]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[OH:17])[C@@H:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1]
Reactant: Oc1ccc(Cl)cc1/C=C/c1ccccc1I
Reactant: CC(C)[N-]C(C)C
Agent: C[N+](C)(C)[O-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CN1CC[C@@H](c2cc(Cl)ccc2O)[C@@H]1c1ccccc1I
Temperature: 0 °C
Yield: 72 %

Procedure:
A mixture of trans-2-iodo-5′-chloro-2′-hydroxystilbene (56.1 grams, 157.6 mmol) and trimethylamine N-oxide dihydrate (52.55 g, 472.8 mmol) was dissolved in THF (570 ml) at room temperature while stirring. Not all of the trimethylamine N-oxide dihydrate dissolved. The mixture was cooled with an ice bath to 0° C. Then, a cooled LDA solution of ca. 4° C. (577.5 ml, 1.8 M in heptane/THF/ethylbenzene; 1.04 moles) was added drop wise with a dropping funnel over 25 minutes. The internal temperature rose to ca. 20-26° C. After the addition was complete the temperature of the resulting orange/yellow solution dropped to ca. 8° C. within 10 minutes. A sample was taken, quenched with some water and analyzed by LC to show >90% cycloadduct The ice-bath was removed and the reaction mixture was stirred for an additional 4 hours while warming to room temperature. Water (140 ml) was added and the mixture was stirred overnight at room temperature. Then 2 N HCl (200 ml) was added followed by ethyl acetate (500 ml). The organic layer was separated. The aqueous layer, which was still slightly basic (pH indicator paper), was again extracted with ethyl acetate (100 ml). The combined organic extracts were dried with Na2SO4. Evaporation under vacuum gave an oil. Diethyl ether (100 ml) was added to give a solution. Upon addition of n-pentane (300 ml) to this ether solution while stirring gave a yellow precipitate. Filtration over a glass filter and washing with n-pentane (2×25 ml) gave after drying under vacuum the pure cycloadduct (46.5 g, 112.6 mmol; LC>95% pure) as a yellow solid in 72% yield. M.p.: 123.1° C. (onset), 126.9° C. (peak). The filtrates were combined and evaporated under vacuum to give 23 grams oil, which contained a lot of product according to NMR analysis. Purification by chromatography on silica gel, eluting with ethyl acetate gave a second crop (17 g; 41.1 mmol; 26%). The overall yield was ca. 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[N:17]=[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=12.O.[O:30]=[CH:31][C@@H:32]([C@H:34]([C@H:36]([C@@H:38]([C:40]([OH:42])=[O:41])[OH:39])[OH:37])[OH:35])[OH:33]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12.[O:30]=[CH:31][C@@H:32]([C@H:34]([C@H:36]([C@@H:38]([C:40]([O-:42])=[O:41])[OH:39])[OH:37])[OH:35])[OH:33]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(=O)O
Agent: COc1cc(NS(C)(=O)=O)ccc1Nc1c2ccccc2nc2ccccc12
Solvent: O
Solvent: CCO
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(=O)[O-]
Reaction time: 16 h
Yield: 66.6 %

Procedure:
A solution of 3.93 gm of m-AMSA and 2.12 gm of D-galacturonic acid monohydrate in 325 ml of specially denatured 3A anhydrous ethanol at 70°-80° C. is filtered with suction. The filtrate is stirred and chilled to 0°-5° C., then stored at -20° C. for about 16 hours. The product is collected, washed with cold (about -20° C.) specially denatured 3A anhydrous ethanol, then with anhydrous diethyl ether and dried under reduced pressure at 50°-55° C. to give 3.9 gm of m-AMSA D-galacturonate. The salt obtained by this process retains a small amount about 3% of ethanol.
Reaction SMILES: CSC1C=CC(C2N([C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)N=C(C(F)F)C=2)=CC=1.ClC1C=C(C=CC=1)C(OO)=O>C(Cl)Cl.O>[C:17]1([S:20]([NH2:23])(=[O:22])=[O:21])[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: CSc1ccc(-c2cc(C(F)F)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
4-[5-(4-[Methylthio]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (0.5 g, 1.27 mmol) was dissolved in methylene chloride (30 mL) and cooled to 0° C. To this solution was added m-chloroperoxybenzoic acid (MCPBA) (60%, 0.77 g, 2.7 mmol) and the solution was allowed to warm to room temperature while stirring for 18 hours. A solution of Na2S2O5 (2 g) in H2O (25 mL) was added to the reaction mixture and the solution stirred vigorously for 0.5 hour. The layers were separated and the organic layer was washed with saturated NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4 and concentrated to yield 4-[5-4-[methylsulfonyl]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide as a white solid, 0.22 g, 40%, mp=209°-210° C.
Reaction SMILES: C(OC(N1CCCCC1[N:14]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([NH2:35])=[C:23]([C:25]3[S:26][C:27]4[C:33](Br)=[CH:32][CH:31]=[CH:30][C:28]=4[N:29]=3)[CH:24]=2)[CH:16]=[N:15]1)=O)(C)(C)C.[NH:36]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37]1.C(=O)([O-])[O-].[K+].[K+].[ClH:50]>O1CCOCC1.O.C(Cl)Cl.CCOCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:50].[ClH:50].[NH:21]1[CH2:22][CH2:23][CH:24]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[C:23]([C:25]4[S:26][C:27]5[C:33]([C:39]6[CH:38]=[N:37][NH:36][CH:40]=6)=[CH:32][CH:31]=[CH:30][C:28]=5[N:29]=4)[C:22]([NH2:35])=[N:21][CH:20]=3)[CH:16]=[N:15]2)[CH2:19][CH2:20]1
Reactant: OB(O)c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1n1cc(-c2cnc(N)c(-c3nc4cccc(Br)c4s3)c2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cccc(-c3cn[nH]c3)c2s1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[6-amino-5-(7-bromobenzothiazol-2-yl)-pyridin-3-yl]-pyrazol-1-ylpiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.050 mmol), 4-pyrazoleboronic acid (12 mg, 0.11 mmol), potassium carbonate (20 mg, 0.20 mmol) and Pd(dppf)Cl2 (2 mg, 0.01 mmol) in 1,4-dioxane (1.2 mL) and H2O (0.4 mL) was left to stir at 100° C. for 30 min in the microwave reactor. Then, the mixture was passed through PL-Thiol MP SPE resin and the filtrate was concentrated in vacuo. The resulting oil was partitioned between DCM and H2O (3×). The combined organic extracts were treated with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The Boc-protected intermediate was isolated via prep TLC (5% MeOH in DCM), MS (ES+): m/z=543 [MH+]. The resulting solid was taken up in DCM (1.0 mL) and 1M HCl in ether (1.0 mL) was added. The mixture was left to stir at rt for 1 h. The resulting precipitate was collected by vacuum filtration and washed with DCM, which afforded the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.30-2.44 (m, 4H), 3.21-3.29 (m, 2H), 3.56-3.67 (m, 2H), 4.59-4.71 (m, 1H), 7.68 (t, J=7.8 Hz, 1H), 7.79 (d, J=6.8 Hz, 1H), 8.07-8.12 (m, 2H), 8.27 (s, 2H), 8.37 (d, J=2.0 Hz, 1H), 8.42 (s, 1H), 8.85 (d, J=1.8 Hz, 1H), MS (ES+): m/z=443.14 (100) [MH+]. HPLC: tR=1.77 min (ZQ3, nonpolar—5 min).
Reaction SMILES: [OH:1][C@H:2]([CH:19]=[CH2:20])[C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O([Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])S(C(F)(F)F)(=O)=O.[Cl-].[NH4+]>C(Cl)Cl>[Si:29]([O:1][C@H:2]([CH:19]=[CH2:20])[C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C=C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 0.03 h
Yield: 103.8 %

Procedure:
To a 250 mL round bottom flask containing tert-butyl (2S,3R)-3-hydroxy-1-phenylpent-4-en-2-ylcarbamate (3.080 g, 11 mmol) was added DCM (50 mL) and the mixture was allowed to stir at 23° C. for 2 min. At this time, TEA (4.7 ml, 33 mmol) was added via syringe before dropwise addition of tert-butyldimethylsilyl triflate (2.8 ml, 12 mmol). The reaction was allowed to stir for 4 h and then poured into saturated ammonium chloride. The aqueous layer was extracted with DCM (3×75 mL) and the combined organics were washed with brine and dried with sodium sulfate. The solution was filtered and concentrated to provide 4.47 g of a yellow solid. The material was taken on to the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)[NH:9][CH:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:9][CH:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH3:11])[C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: CC(NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1cccs1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(NC(c1ccc(F)cc1)c1cccc(N)c1)c1cccs1

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (59b), 2.41 of N-[(4-fluorophenyl)-(3-nitrophenyl)methyl]-N-[1-(thiophen-2-yl)ethyl]amine [prepared as described in step (a) above], 3.22 g of nickel chloride hexahydrate and 1.03 g of sodium borohydride were reacted, to obtain 687 mg of isomer A and 552 mg of isomer B of the title compound as pale yellow oils, respectively.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:19](Cl)(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26]>C1COCC1>[C:19]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: C=CCCCCCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-(-)-4-benzyl-2-oxazolidinone (12.4 g, 69.79 mmol) in THF (200 mL) at −78° C. was added dropwise n-BuLi (30.7 mL, 2.5M solution in hexane, 76.77 mmol). After stirring for 30 min at the same temperature, the reaction mixture was then treated with 7-octenoyl chloride (11.21 g, 69.79 mmol). The reaction mixture was stirred and allowed to warm to 10° C. over 5 h, and then quenched with saturated aqueous NH4Cl solution (200 mL). The aqueous layer was extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine, and dried over MgSO4. Removal of the solvent under reduced pressure yielded the title compound. MH+302.