Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Li+].[OH:3][CH2:4][CH2:5][CH2:6][C:7]1([C:20](OCC2C=CC=CC=2)=[O:21])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[OH:21][CH2:20][C:7]1([CH2:6][CH2:5][CH2:4][OH:3])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)(C(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CO)(CCCO)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
Lithium borohydride (500 mg, 22.7 mmol) was added to a solution of 1-(1,1-dimethylethyl) 4-phenylmethyl 4-(3-hydroxypropyl)-1,4-piperidinedicarboxylate (Description 136, 1.05 g, 2.79 mmol) in tetrahydrofuran/toluene (50:50, 20 mL). and the mixture was stirred at 60° C. for 4 hours. The mixture was cooled and hydrochloric acid (2M, 10 mL) was added. The mixture was poured into aqueous sodium carbonate (10%, 100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/MeOH (100:0 increasing to 95:5) to give the title compound (563 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 3.67 (2H, t, J 7 Hz), 3.48 (2H, s), 3.47–3.40 (2H, m), 3.35–3.25 (2H, m), 1.7 (2H, br s), 1.6–1.3 (8H, m), and 1.44 (9H, s).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:3]=1.[C:19]1([C:25]2[S:26][CH:27]=[CH:28][C:29]=2B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]1([C:25]2[S:26][CH:27]=[CH:28][C:29]=2[C:2]2[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:3]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OB(O)c1ccsc1-c1ccccc1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccsc1-c1ccccc1
Temperature: 80 °C
Yield: 22.6 %

Procedure:
A mixture of 3-bromo-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (137 mg, 0.428 mmol), (2-phenylthiophen-3-yl)boronic acid (87.4 mg, 0.428 mmol), Na2CO3 (136 mg, 1.28 mmol) and Pd(PPh3)4 (24.7 mg, 0.021 mmol) in DME (1.6 mL) and water (0.49 mL) was heated to 80° C. for 18 h under Ar atmosphere. The mixture was diluted with water, extracted with AcOEt, washed with NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=80/20 to 0/100) and recrystallized with AcOEt/heptane to yield the title compound (38.6 mg, 23% yield) as a white solid: mp 167-168° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.62 (1H, d, J=8.0 Hz), 7.30-7.41 (5H, m), 7.47 (1H, brs), 7.51 (1H, d, J=5.2 Hz), 7.55-7.72 (4H, m), 8.91 (1H, d, J=8.0 Hz). Anal. Calcd for C21H13F3N2OS: C, 63.31; H, 3.29; N, 7.03. Found: C, 63.08; H, 3.37; N, 7.01.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34](O)=[O:35])[CH2:27][CH2:26][CH2:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:33]=2[O:24][CH2:25][CH2:26][CH2:27]3)=[O:35])=[O:10])[N:12]=1
Reactant: O=C(O)c1cccc2c1OCCC2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCCC3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Chroman-8-carboxylic acid.
Reaction SMILES: C1([C:11]2[CH:12]=[CH:13][N:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[C:16]([C:21]([OH:23])=[O:22])[C:15]3=[O:24])C2C(=CC=CC=2)C=CC=1.O1C(C2C=CN3C(C=2)=CC=C(C(O)=O)C3=O)=CC2C=CC=CC1=2.[Mg]>>[O:24]=[C:15]1[N:14]2[C:19]([CH:20]=[CH:11][CH:12]=[CH:13]2)=[CH:18][CH:17]=[C:16]1[C:21]([OH:23])=[O:22]
Reactant: O=C(O)c1ccc2cc(-c3cccc4ccccc34)ccn2c1=O
Agent: O=C(O)c1ccc2cc(-c3cc4ccccc4o3)ccn2c1=O
Agent: [Mg]
Product: O=C(O)c1ccc2ccccn2c1=O

Procedure:
Fluorophores [6,7]-benzo-4-oxo-4H-quinolizine-3-carboxylic acid (3a) (FIG. 16), 1-[N,N-di(carboxymethyl)]-4-oxo-4H-quinolizine-3-carboxylic acid (11a) (FIG. 17), 8-(naphth-1-yl)-4-oxo-4H-quinolizine-3-carboxylic acid (23a) and 8-(benzo[b]furyl)-4-oxo-4H-quinolizine-3-carboxylic acid (24a), show an increase of the fluorescence emission when binding to Mg2+, and are sensitive to changing Mg2+ levels. The triacid 1-[N,N-di(carboxymethyl)]-4-oxo-4H-quinolizine-3-carboxylic acid (11a) exhibits a fluorescence maximum at 552 nm, making this compound an attractive fluorescent magnesium indicator. The presence of the amino group at the 1-position gave a hypsochromic shift of 117 nm with respect to 4-oxo-4H-quinolizine-3-carboxylic acid (1a). The introduction of an aromatic moiety at the 8-position (e.g., 8-(4-methoxyphenyl)-4-oxo-4H-quinolizine-3-carboxylic acid [22a]; 8-(naphth-1-yl)-4-oxo-4H-quinolizine-3-carboxylic acid [23a]; and 8-(benzo[b]furyl)-4-oxo-4H-quinolizine-3-carboxylic acid [24a]), or extension of the 7-system as in [6,7]-benzo-4-oxo-4H-quinolizine-3-carboxylic acid (3a) are believed to result in a hypsochromic shift to longer wavelengths, although it is not necessary to understand the mechanism in order to practice the present invention and it is not intended that the present invention be so limited. However, the hypsochromic shifts of these compounds are smaller in comparison to the hypsochromic shift exhibited by 1-[N,N-di(carboxymethyl)]-4-oxo-4H-quinolizine-3-carboxylic acid (11a).
Reaction SMILES: Br[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[S:29][CH:28]=[N:27][CH:26]=1)CCC>>[S:29]1[C:25]([C:2]2[O:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)=[CH:26][N:27]=[CH:28]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)o1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2cncs2)o1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from (R)-3′-(5-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 5-(tri-n-butylstannyl)thiazole. The title compound (40 mg) was obtained as a pale solid, m/z 332 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].N1C=CC=CC=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH:6][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCCc1ccccc1Br
Solvent: c1ccncc1
Solvent: O
Product: O=C(NCCc1ccccc1Br)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottomed flask was added 2-bromophenethylamine (1800 mg, 9 mmol, Aldrich), pyridine (5 mL), 4-(trifluoromethyl)benzoyl chloride (2 mL, 9 mmol, Fluka). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with water (30 mL), saturated NaCl (30 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give N-(2-bromophenethyl)-4-(trifluoromethyl)benzamide. MS (ESI pos. ion) m/z: 372 (M+1).
Reaction SMILES: [F:1][C:2]([F:5])(O)[CH3:3].C(P(CCCC)CCCC)CCC.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:59]=[CH:60][C:61]=1[O:62][CH3:63])[CH2:38][N:39]1[C:48](=[O:49])[C:47]2[C:42](=[CH:43][C:44]([F:51])=[C:45]([OH:50])[CH:46]=2)[N:41]([CH:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)[C:40]1=[O:58]>C1COCC1>[F:1][CH:2]([F:5])[CH2:3][O:50][C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][C:44]=1[F:51])[N:41]([CH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)[C:40](=[O:58])[N:39]([CH2:38][C:37]1[CH:59]=[CH:60][C:61]([O:62][CH3:63])=[C:35]([O:34][CH3:33])[CH:36]=1)[C:48]2=[O:49]
Reactant: COc1ccc(Cn2c(=O)c3cc(O)c(F)cc3n(C3CCOCC3)c2=O)cc1OC
Reactant: CC(O)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3cc(OCC(F)F)c(F)cc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
0.125 g of difluoroethanol, 0.47 g of tributylphosphine and 0.38 g of DIAD are successively added to a solution of 0.4 g of the compound obtained in Step 4.7 in 15 ml of THF. This mixture is stirred overnight at room temperature. The reaction medium is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a PE/EtOAc mixture from (100/0, v/v) to (30/70) to give 0.38 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][OH:28])[CH2:23][CH2:22]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][OH:28])[CH2:23][CH2:22]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: OCC1CCNCC1
Product: O=C(c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1)N1CCC(CO)CC1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and piperidin-4-ylmethanol (59 mg, 0.51 mmol). The title compound was obtained as a solid (70 mg, 36% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 7.89 (1H, s), 4.50 (1H, m), 4.25 (2H, m), 3.24 (2H, m), 1.68 (3H, m), 1.09 (2H, m). MS m/z: 448.34, 450.34 [M+H]+.
Reaction SMILES: CO.C[O-].[Na+].C(O)(=O)C.[CH:10]([NH2:12])=[NH:11].[F:13][CH:14]([CH2:23][CH2:24][CH2:25][CH3:26])[C:15](=O)[CH2:16][C:17](OCC)=[O:18]>CO>[F:13][CH:14]([C:15]1[N:12]=[CH:10][NH:11][C:17](=[O:18])[CH:16]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC(F)C(=O)CC(=O)OCC
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCC(F)c1cc(=O)[nH]cn1
Temperature: 60 °C
Reaction time: 5 h
Yield: 67.1 %

Procedure:
To a solution in which 3.80 g of ethyl 4-fluoro-3-oxooctanoate had been dissolved in 10 ml of methanol were added 8.97 g of a 28% sodium methoxide methanol solution and 3.72 g of formamidine acetate, and the mixture was stirred at 60° C. for 5 hours. Then, the reaction mixture was concentrated under reduced pressure. To the concentrated solution were added 30 ml of water and 5.0 g of conc. hydrochloric acid, followed by cooling the mixture to 10 C, and the precipitated crystals were separated by filtration. These crystals were recrystallized from 20 ml of 2-propanol to obtain 2.30 g of 6-(1-fluoropentyl)-4-pyrimidone (isolated yield: 67.1%).
Reaction SMILES: [CH:1]1([C:4]2[NH:9][C:8](=[O:10])[C:7]([N+:11]([O-])=O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1>[Pd].C(OCC)(=O)C>[NH2:11][C:7]1[C:8](=[O:10])[NH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(C2CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1ccc(N)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-cyclopropyl-3-nitro-2-pyridinone (2 g, 13.3 mmol) and 10% palladium on carbon (600 mg) in ethyl acetate (100 ml) was stirred at room temperature under an atmosphere of hydrogen overnight. The catalyst was removed by filtration through a bed of Celite and the filtrate concentrated to yield product as a white microcrystalline solid. 1H NMR (CDCl3) d 0.94 (t, J=7.3 Hz, 3 H), 1.67 (m, 2 H), 2.49 (t, J=7.5 Hz, 2 H), 4.00 (br s), 5.88 (d, J=7.1 Hz, 1 H), 6.59 (d, J=7.1 Hz, 1 H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13](=[O:15])[N:12]([CH3:16])[N:11]=2)=[CH:6][CH:5]=1.Cl[CH:18]([F:20])[F:19]>O.O1CCOCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:14]=[C:13]([O:15][CH:18]([F:20])[F:19])[N:12]([CH3:16])[N:11]=2)=[CH:8][CH:9]=1
Reactant: FC(F)Cl
Reactant: CN1N=C(c2ccc(Cl)cc2)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2ccc(Cl)cc2)cc1OC(F)F

Procedure:
A solution of 162 g (4.0 mol) of sodium hydroxide in l 1 of water was addedto a solution of 169.1 g (0,811 mol) of 3-(4-chlorophenyl)-1-methyl-2-pyrazolin-5-one in 2.5 1 of dioxane. Chlorodifluoromethane (about 175 g) was passed in over the course of 5 hours at 60°-65° C., after which the reaction solution was stirred into 1.5 1 of water. Extraction three times with methyl tertbutyl ether, followed by drying of the organic phase and removal of the solvent in vacuo, gave the crude product, which was purified further by chromatography on silica gel (hexane/ethyl acetate 7:3). Yield: 142.9 g; 1H-NMR (400 MHz, in CDCl3): δ [ppm]=7.60 (d,2H), 7.28 (d,2H), 6.54 (t,1H), 6.08 (s,1H), 3.69 (s,3H).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:6]2[N:5]=1)=O.[N:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH2:32])=[CH:31][C:26]=2[NH:25][CH:24]=1>>[N:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=5)[N:6]4[N:5]=3)=[CH:31][C:26]=2[NH:25][CH:24]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Product: CS(=O)(=O)c1ccc(-c2ccc3cnc(Nc4ccc5nc[nH]c5c4)nn23)cc1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 2-methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.22 mmol) was coupled with 3H-benzimidazol-5-ylamine (51 mg, 0.38 mmol) at 105° C. in a for 86 h to afford the title compound. Yield of TFA salt: 46 mg (40%) of brown powder; LC/MS: 405 (M+H); HPLC: 90% pure, RT=2.14 min; 1H NMR: (DMSO, δ) 9.96 (s, 1H), 9.48 (s, 1H), 9.13 (s, 1H), 8.51 (d, J=8.6, 2H), 8.18 (s, 1H), 8.07 (d, J=8.6, 2H), 7.86 (m, 2H), 7.42 (d, J=4.8, 1H), 7.07 (d, J=4.8, 1H), 3.28 (s, 3H)-benzimidazole NH presumably underwent rapid exchange with residual water.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[CH2:32])([O-:24])=[O:23].C(=O)([O-])O.[K+].ClN1C(=O)CCC1=O>C(OCC)(=O)C.O>[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]1[O:1][N:2]=[C:3]([C:4]2[N:5]=[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[S:7][CH:8]=2)[CH2:32]1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Reactant: C=Cc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4[N+](=O)[O-])C3)cs2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-(4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl)piperidine-1-carboxylate (2.80 g) and 1-nitro-2-vinylbenzene (1.60 g) in ethyl acetate (50 ml) were added, at room temperature, potassium hydrogencarbonate (4.50 g) and N-chlorosuccinimide (1.44 g) and then one drop of water. After stirring at 60° C. overnight, the reaction mixture was admixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl 4-{4-[5-(2-nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (2.10 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])OC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.CN(CCCCCCCCCCCC)C>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NCc1cccnc1
Reactant: COC(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: CCCCCCCCCCCCN(C)C
Solvent: Cc1ccccc1C
Product: O=C(NCc1cccnc1)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 4 h
Yield: 80.3 %

Procedure:
196.13 g (1 mole) of methyl N-(4-nitrophenyl)-carbamate, 108.14 g (1 mole) of 3-aminomethyl-pyridine and 106.7 g (0.5 mole) of N,N-dimethyl-n-dodecylamine are dissolved in 3 liters of xylene. The reaction mixture is refluxed, and the spures of water present are removed from the mixture together with the alcohol formed in a Dean-Stark trap. The end-product starts to separate from the mixture within 15-20 minutes from the beginning of boiling. The mixture is boiled for 4 hours, thereafter the suspension is filtered at about 100° to 110° C. The filter cake is washed twice with 100 ml of hot xylene, each, and with a small amount of acetone, and then dried in vacuo. 218.6 g (80.3%) of N-(4-nitrophenyl)-N'-(3-pyridylmethyl)-urea are obtained; m.p.: 221°-223° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31]>CN(C=O)C.C(OCC)C>[CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH3:31])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(CO)cc2)cccc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCc1ccc(CN(Cc2ccccc2)c2cccc([N+](=O)[O-])c2C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The product from Example 38A (0.1 g, 0.276 mmoles) in DMF (0.7 mL) was treated with sodium hydride (0.012 g, 0.3 mmoles, 60% dispersion). After 10 minutes, the reaction mixture was treated with iodomethane (0.02 mL, 0.36 mmoles) and then stirred overnight at room temperature. The mixture was diluted with diethyl ether (100 mL), washed with saturated ammonium chloride (50 mL) and water (50 mL) twice, washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: O=[C:2]([CH2:16][CH2:17][C:18]([O-:20])=[O:19])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:34]([O:41][C:42]([NH:44][C@H:45]1[CH2:49][O:48][NH:47][C:46]1=[O:50])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[CH2:34]([O:41][C:42]([NH:44][C@H:45]1[CH2:49][O:48][N:47]([C:2]2([C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=3)=[O:4])[CH2:16][CH2:17][C:18](=[O:19])[O:20]2)[C:46]1=[O:50])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Reactant: O=C([O-])CCC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@H](NC(=O)OCc3ccccc3)C2=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
In 10 ml of dichloromethane was dissolved 282 mg of Compound (1), and the solution was cooled on a sodium chloride-ice bath, to which were added 140 μ1 of triethylamine and 96 μ1 of ethyl chlorocarbonate. To the mixture was added 119 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone. The mixture was stirred for one hour under ice-cooling and for one hour at room temperature. The solvent was evaporated off under reduced pressure. The residue was subjected to extraction with ethyl acetate, and the organic layer was washed with an aqueous solution of sodium hydrogen carbonate, then with a saturated saline solution, followed by drying (MgSO4). Then, the solvent was evaporated off, and the residue was subjected to a silica gel chromatography, followed by elution with 1,2-dichloroethane-ethyl acetate (9:1), then with hexane-ethyl acetate (1:1) to give 73 mg of the subject Compound (9).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Cl:8][C:9]1[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:14]([C:12]1[S:13][C:9]([Cl:8])=[CH:10][CH:11]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: OCCNCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Cl)s1)N(CCO)CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a stirred solution of diethanolamine (1.45 g, 13.8 mmol) in THF (20 mL) was added at 0° C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (1.15 g, 88%) as a white solid. MS (ISN) 284.3 [(M−H)−], mp 69° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=O)=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S@@:20]([NH2:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[N:22][S@@:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: Cc1ccc([S@@](N)=O)cc1
Reactant: CC(C)(C=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: Cc1ccc([S@@](=O)N=CC(C)(C)c2ccc(Cl)cc2)cc1

Procedure:
The 2-(4-chlorophenyl)-2-methylpropionaldehyde (5.60 g, 30.7 mmol) and (S)-4-methyl-benzenesulfinic acid amide (5.00 g, 32.2 mmol) were dissolved in 300 mL of DCM and treated with Ti(OEt)4 (32.1 mL, 153 mmol). The mixture was heated to reflux under nitrogen for four hours. The solution was cooled in an ice bath and quenched with the dropwise-addition of 200 mL of water. The resulting precipitate (Ti salts) were removed by filtration through a plug of celite and washed with DCM. The resulting filtrate was separated, and the aqueous was extracted with more DCM. The combined organic was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by filtration through a plug of silica gel (hexanes:ethyl acetate, 1:1) to afford the (R)-4-methylbenzenesulfinic acid [2-(4-chlorophenyl)-2-methylpropyliden]-amide as a colorless oil, which solidified upon standing to give a white solid (9.28 g, 95%). 1H NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.8 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H), 7.14 (m, 2H), 2.42 (s, 3H), 1.52 (s, 3H), 1.47 (s, 3H).