Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]Br.[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[N:21]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[N:27]4)[N:20]=[C:19]([CH3:32])[CH:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)(=[O:6])[CH3:5].Cl[CH2:34]Cl.CO>C1COCC1>[OH:6][C:4]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]2[N:21]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[N:27]4)[N:20]=[C:19]([CH3:32])[CH:18]=2)(=[O:15])=[O:14])=[CH:11][CH:12]=1)([CH3:34])[CH3:5]
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2cc(C)nn2-c2cccc3ncccc23)cc1
Reactant: ClCCl
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)O)cc2)n(-c2cccc3ncccc23)n1
Temperature: -10 °C
Yield: 32 %

Procedure:
A solution of methyl magnesium bromide (1.4 M solution in 3:1 toluene/THF, 1.4 mL, 2.0 mmol) was added to a flask containing 4-acetyl-N-(3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-yl)benzenesulfonamide (0.059 g, 0.15 mmol) in THF (6 mL) at −45° C. with stirring. The reaction mixture was slowly warmed to −10° C. over 1 h and 4:1 dichloromethane/methanol was added (2 mL). The organic layer was washed with aqueous saturated ammonium chloride, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.020 g, 0.047 mmol, 32%). 1H NMR (400 MHz, CD3OD) δ 8.81 (d, J=4.4 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.51-7.47 (m, 3H), 7.36 (dd, J=4.4, 8.4 Hz, 1H), 5.73 (s, 1H), 2.15 (s, 3H), 1.56 (s, 6H); MS: (ES) m/z calculated for C22H23N4O3S [M+H]+ 433.2. found 433.0.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[OH:13][CH2:14][CH:15]1[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]1.N1C=CC=CC=1>O>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:13][CH2:14][CH:15]2[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]2)=[O:8])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)O1
Solvent: c1ccncc1
Solvent: O
Product: CN(C)c1ccc(C(=O)OCC2COC(C)(C)O2)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
4-Dimethylaminobenzoyl chloride (1.00 g, 5 mmol) is added in one portion to a mixture of 4-hydroxymethyl-2,2-dimethyl-1,3-dioxolane (1.19 g, 10 mmol) and abs. pyridine (20 ml), and the mixture is stirred at room temperature for 10 min. The mixture is subsequently stirred at 80-90° C. for 2 h. Water (50 ml) is added, the reaction mixture is extracted with dichloromethane (3×25 ml), and the combined organic extracts are dried over magnesium sulfate. The solvent is removed in vacuo, and the residue is purified by column chromatography.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:46]([C:49]1[S:53][CH:52]=[C:51]([C:54](O)=[O:55])[CH:50]=1)([CH3:48])[CH3:47].C(N(CC)CC)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:33]1[CH2:32][CH2:31][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:54]([C:51]3[CH:50]=[C:49]([CH:46]([CH3:48])[CH3:47])[S:53][CH:52]=3)=[O:55])[CH2:29]2)[CH2:35][CH2:34]1
Reactant: CC(C)c1cc(C(=O)O)cs1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.55 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)phenyl)ethanol (example 82, step a) (0.32 g), 5-isopropylthiophene-3-carboxylic acid (0.19 g) and triethylamine (0.61 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.4 g.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:21])([F:20])[O:7][C:8]1[CH:19]=[CH:18][C:11]([CH:12](O)[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][CH:9]=1>>[Cl:3][CH:12]([C:11]1[CH:18]=[CH:19][C:8]([O:7][C:6]([F:21])([F:20])[F:5])=[CH:9][CH:10]=1)[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Product: CC(C)(C)C(Cl)c1ccc(OC(F)(F)F)cc1
Reaction time: 8 h

Procedure:
To freshly distilled thionyl chloride (14.87 g, 0.125 mol) cooled in salt ice bath is added in portions the neopentyl alcohol of Example 24 (12.4 g, 0.05 mol) over 30 minutes. The ice bath is removed and the slurry is left to stand overnight. Evaporation of excess thionyl chloride gives a solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:7]([OH:9])=[O:8].[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[CH2:16].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:16][CH2:15][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:8]
Reactant: C=Cc1ccccn1
Reactant: O=C(O)C(c1cccs1)c1cccs1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: O=C(OCCc1ccccn1)C(c1cccs1)c1cccs1

Procedure:
The crude product of newly synthesized dithiophenyl acetic acid (10 g, 59 mmol theoretically), freshly distilled 2-vinylpyridine (6.25 g, 59 mmol), and 1 mol % toluene sulfonic acid were dissolved in benzene and placed in a round bottom flask equipped with a vigreaux column and magnetic stirbar. The reaction was then heated to reflux and allowed to react for 16 hours. The viscous liquid that remained after the solvent was removed was then purified by column chromatography (silica 2/1 v/v hexane/ethyl acetate). Yield=3.9 g. 1H NMR (CDCl3) δ=3.042 (t, 2 H), δ=3.573 (t, 2 H), δ=4.233 (s, 2H ) δ=6.968-7.476 (m, 8H), δ=8.467, (d, 1H). 13C NMR (CDCl3) δ=35.627 (CH2), δ=36.180 (CH2), δ=58.323 (CH2), δ=121.932 (CH), δ=123.383 (CH2), δ=127.501 (CH), δ=128.818 (CH), δ=129.346 (CH), δ=137.272 (C), δ=149.668 (CH), δ=159.305 (C), δ=235.369 (C═S).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].CNN(CCC)NC>ClCCl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([NH:17][C:26](=[O:28])[CH3:27])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CCCN(C)C(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: CC(=O)Cl
Agent: CCCN(NC)NC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(NC(C)=O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 5-amino-N-methyl-N-propyl-isophthalamic acid methyl ester (1.64 g, 6.55 mmol) in dichloromethane (20 mL) and add triethylamine (0.993 g, 9.83 mmol), then acetyl chloride (772 mg, 9.83 mmol). Stir at room temperature for 1 h, add N,N-dimethylamino propylamine (0.5 mL), stir 10 min, dilute with dichloromethane, wash with 1 N HCl and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate to give the title compound as a solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([I:11])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[I:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([O:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH3:12])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccccc1Oc1cc(I)cc([N+](=O)[O-])c1
Temperature: 110 °C
Yield: 70.4 %

Procedure:
A mixture of 1-fluoro-3-iodo-5-nitrobenzene (5.0 g, 18.0 mmol), 2-methoxyphenol (2.3 g, 18.0 mmol) in dry DMSO (10.0 mL) and anhydrous K2CO3 (3.8 g, 27.5 mmol) was heated at 110° C. for 16 h. The mixture was poured into ice water and extracted with EtOAc (3×50 mL). The organic layer was sequentially washed with brine (2×75 mL), dried over anhydrous Na2SO4, concentrated by rotary evaporation, and purified by column chromatography to give 1-iodo-3-(2-methoxyphenoxy)-5-nitrobenzene (7) (4.7g, 70%). 1H NMR (400 MHz, CDCl3) δ 8.23-8.13 (m, 1H), 7.69-7.48 (m, 2H), 7.30-7.25 (m, 1H), 7.12-6.93 (m, 3H), 3.80 (d, J=1.9 Hz, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.BrCCCCO[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[C@@H:26]3[C@@H:21]([CH2:22][CH:23]=[CH:24][CH2:25]3)[C:20]2=[O:39])=CC=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:35][C:32]1[CH:31]=[CH:30][C:17]([CH2:16][N:19]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[C@@H:26]3[C@@H:21]([CH2:22][CH:23]=[CH:24][CH2:25]3)[C:20]2=[O:39])=[CH:18][CH:13]=1
Reactant: BrCCCCBr
Reactant: COc1ccc(C2=NN(c3ccc(OCCCCBr)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Product: COc1ccc(C2=NN(Cc3ccc(OCCCCBr)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from compound 7b and 1,4-dibromobutane as described for compound 6a. M. p. 42-46° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][NH2:11])=[O:4].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:39]=[N:40][C:41]([O:46][CH3:47])=[C:42]([O:44][CH3:45])[CH:43]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:45][O:44][C:42]1[CH:43]=[C:38]([CH:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:28][CH:27]=2)[C:23]2[NH:22][C:21](=[O:20])[N:10]([C:9]3[CH:8]=[CH:7][S:6][C:5]=3[C:3]([OH:2])=[O:4])[N:11]=2)[CH:39]=[N:40][C:41]=1[O:46][CH3:47]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cnc(OC)c(OC)c1
Reactant: COC(=O)c1sccc1NN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)cnc1OC
Temperature: 90 °C
Reaction time: 12 h

Procedure:
After adding 38 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 0.030 ml of triethylamine to a solution of 100 mg of {2-(5,6-dimethoxypyridin-3-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 1 ml of DMF, the mixture was stirred at 90° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 1.5 ml of methanol and 0.1 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 3 hours. Next, 1.0 ml of a 5N aqueous sodium hydroxide solution was added and the mixture was stirred at room temperature for 2 hours. After then adding 0.3 ml of acetic acid, the reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product of 3-(3-{(5,6-dimethoxypyridin-3-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic acid.
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[C:11]1[C:12]2[N:13]([CH:25]=[N:26][N:27]=2)[C:14](SC)=[N:15][C:16]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[C:28]1([CH2:34][C@H:35]([NH2:38])[CH2:36][NH2:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C=O)C>[NH2:38][C@@H:35]([CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:36][NH:37][C:14]1[N:13]2[CH:25]=[N:26][N:27]=[C:12]2[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[C:16]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:15]=1
Reactant: NC[C@@H](N)Cc1ccccc1
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c2nncn12
Solvent: CN(C)C=O
Solvent: O
Product: N[C@H](CNc1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c2nncn12)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
8-(2-naphthyl)-5-methylthio-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidine (350 mg, 1 mmol), K3CO3 (100 mg) and (2S)-3-phenylpropane-1,2-diamine (150 mg, 1 mmol) were combined in dry DMF (ca. 5 mL) and the mixture was stirred at room temperature for 48 h. To the reaction solution was added water (ca. 10 mL) at RT and a precipitate formed. The suspension was stirred at RT for 1 h. The solid was filtered off and washed with water (3×10 ml) and dried under vacuum at 50° C. overnight; MS (m/z) 472.3 (M+H)+; C29H25N7 requir. 471.56.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]([N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([CH3:40])[CH:38]=2)[C:33]([C:41]([OH:43])=O)=[CH:32]1)([CH3:30])[CH3:29].[NH2:44][C:45]1[S:46][CH:47]=[CH:48][N:49]=1>C(Cl)Cl>[S:46]1[CH:47]=[CH:48][N:49]=[C:45]1[NH:44][C:41]([C:33]1[C:34]2[C:39](=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:31]([CH:28]([CH3:29])[CH3:30])[CH:32]=1)=[O:43]
Reactant: Cc1ccc2c(C(=O)O)cn(C(C)C)c2c1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc2c(C(=O)Nc3nccs3)cn(C(C)C)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 41.6 %

Procedure:
A solution of triphenylphosphine (628 mg, 2.39 mmol) in methylene chloride (5 mL) cooled to 0° C. was treated with N-bromosuccinimide (425 mg, 2.39 mmol). The reaction was stirred at 0° C. for 15 min and then was treated with 1-isopropyl-6-methyl-1H-indole-3-carboxylic acid (400 mg, 1.84 mmol). The reaction was stirred at 0° C. for 15 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 2-aminothiazole (424 mg, 4.23 mmol) and stirred at 25° C. for 16 h. At this time, the mixture was partitioned between water (75 mL) and ethyl acetate (75 mL) and treated with a 1N aqueous hydrochloric acid solution (40 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×40 mL) and a saturated aqueous sodium chloride solution (1×40 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) afforded 1-isopropyl-6-methyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (229 mg, 41.5%) as a tan solid: mp 215-217° C.; EI-HRMS m/e calcd for C16H17N3OS (M+) 363.0041, found 363.0034.
Reaction SMILES: C([O:4][CH:5]1[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]([O:9]C(=O)C)[C@H:6]1[NH2:7])(=O)C.[C:25]1([S:39](Cl)(=[O:41])=[O:40])[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[C:27]([S:35](Cl)(=[O:37])=[O:36])[CH:26]=1>C(#N)C.N1C=CC=CC=1>[C:25]1([S:39]([C:5]2([O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]([OH:9])[C@H:6]2[NH2:7])[OH:4])(=[O:41])=[O:40])[CH:30]=[C:29]([S:31]([C:5]2([O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]([OH:9])[C@H:6]2[NH2:7])[OH:4])(=[O:33])=[O:32])[CH:28]=[C:27]([S:35]([C:5]2([O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]([OH:9])[C@H:6]2[NH2:7])[OH:4])(=[O:37])=[O:36])[CH:26]=1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=S(=O)(Cl)c1cc(S(=O)(=O)Cl)cc(S(=O)(=O)Cl)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1(O)S(=O)(=O)c1cc(S(=O)(=O)C2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)cc(S(=O)(=O)C2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)c1

Procedure:
The novel intermediate benzene 1,3,5-trisulfonyl trisglucosamine compound is prepared by reacting tetra-O-acetyl glucosamine (II) with 1,3,5-benzenetrisulfonyl chloride in a weakly basic polar medium such as acetonitrile-pyridine for 24 hours. The solvent is concentrated and the tetraacetyl trisulfonyl derivative (III) is precipitated from ice water and extracted into methylene dichloride. The solvent is evaporated and the material is dissolved in cold methanol saturated with ammonia. Standing in the cold for 24 hours, followed by the addition of nitrogen gas to remove ammonia, produces a thick oil (IV) on evaporation. The oil is purified from water with activated charcoal, filtration and drying to give the intermediate glucopyranose.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].C(N(CC)CC)C.[IH:14].[O:15]=[C:16]1[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][C:18]2=[C:25]([C:28](SC)=[NH:29])[N:26]=[CH:27][N:17]12>CC#N>[IH:14].[CH3:1][O:2][C:3](=[O:6])[CH2:4][NH:5][C:28]([C:25]1[N:26]=[CH:27][N:17]2[C:16](=[O:15])[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][C:18]=12)=[NH:29]
Reactant: COC(=O)CN
Reactant: C#CCn1nnc2c(C(=N)SC)ncn2c1=O
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#CCn1nnc2c(C(=N)NCC(=O)OC)ncn2c1=O
Reaction time: 0.17 h

Procedure:
Glycine methyl ester (0.14 mmol) was suspended in dry MeCN (1 mL). Triethylamine (0.14 mmol) was added and the solution stirred for 10 minutes. Methyl 4-oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbimidothioate hydroiodide (0.13 mmol) was then added and the reaction stirred at room temperature for 2 hours. The resulting precipitate was then filtered and washed with MeCN and ether. δH (DMSO-d6) 9.70 (2H, bs), 9.22 (1H, s), 5.76 (1H, s), 5.24 (2H, d, J=2.4), 4.45 (2H, s), 3.74 (3H, s), 3.60 (1H, t, J=2.4).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(N1C2C=CC=CC=2N=N1)(=O)=O.CCN(C(C)C)C(C)C>C1COCC1>[NH2:1][C:2]1[C:7]([C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: Nc1ccccc1
Agent: CS(=O)(=O)n1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)cc1C(=O)Nc1ccccc1
Temperature: 160 °C
Yield: 63.7 %

Procedure:
A mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (203 mg, 0.9354 mmol), aniline (87.11 mg, 85.23 μL, 0.9354 mmol), 1-methylsulfonylbenzotriazole (276.7 mg, 1.403 mmol) and DIPEA (241.8 mg, 325.9 μL, 1.871 mmol) in THF (2.0 mL) was heated in the microwave at 160° C. for 10 mins. The reaction mixture was concentrated and the residue partitioned between EtOAc and 2M NaOH. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo to give the product as a yellow solid (174 mg, 64% Yield). 1H NMR (400.0 MHz, DMSO) δ 7.77 (br s, 2H), 8.18 (d, 1H) and 8.32 (d, 1H); ppm; MS (ES+) 293.94.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:11](=[O:18])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4](=[C:5]23)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:29]Br)[CH3:27].CN(C)C=O>O>[CH2:26]([CH:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:29][O:1][C:2]1[CH:19]=[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:11](=[O:18])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4](=[C:5]23)[CH:3]=1)[CH3:27]
Reactant: CCCCC(CC)CBr
Reactant: O=C1c2ccccc2-c2cc(O)cc3cccc1c23
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1cc2c3c(cccc3c1)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A 500 ml three neck flask was equipped with a mechanical stirrer, heating mantle and condenser. To the flask was added 25 g 2-hydroxy-7H-benzo[de]anthracene-7-one, 18 g powdered potassium carbonate, 25 g 2-ethylhexyl bromide and 250 g dimethylformamide (DMF). The mixture was heated to reflux. After seven hours, 4.5 g 2-ethylhexyl bromide was added and the mixture heated at reflux for an additional three hours. The mixture was then cooled to room temperature and 500 g deionized water was added. The solution was extracted twice with 200 g chloroform. The organic layers were combined and washed twice with 250 g water. The solvent was removed on a rotary evaporator, then the crude product was passed through a flash silica gel column using methylene chloride as the elutant. The product fractions were collected and the solvent removed using a rotary evaporator. The yield of 2-[(2-ethylhexyl)oxy]-7H-benzo[de]anthracene-7-one was 28.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:31])[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C@H:15]([NH:19][C:20]([CH:22]3[CH2:26][CH2:25][C:24](=[CH2:27])[CH2:23]3)=[O:21])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:30])[CH3:29])=[CH:4][CH:3]=1.C(=O)(O)[O-:33].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([OH:31])[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C@H:15]([NH:19][C:20]([CH:22]3[CH2:26][CH2:25][C:24]4([O:33][CH2:27]4)[CH2:23]3)=[O:21])[CH:16]([CH3:17])[CH3:18])[CH2:10][C:9]2([CH3:29])[CH3:30])=[CH:6][CH:7]=1
Reactant: C=C1CCC(C(=O)N[C@@H](C(=O)N2CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C2)C(C)C)C1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@@H](NC(=O)C1CCC2(CO2)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A mixture of N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-methylenecyclopentanecarboxamide (535 mg, 1.197 mmol) and sodium bicarbonate (141 mg, 1.676 mmol) in methylene chloride (4 mL) and water (2 mL) was cooled to 5° C. and treated with m-CPBA (318 mg, 1.436 mmol). The mixture was stirred at 5° C. for 1 hour, then allowed to warm to room temperature and stirred for 18 hours. The mixture was cooled to 5° C., treated with saturated sodium sulfite, and stirred at room temperature for 30 minutes. The layers were separated, and the aqueous phase was extracted 3× with methylene chloride. The organic phases were combined and concentrated in vacuo, and the residue was taken up in ethyl acetate. The solution was washed 3× with saturated sodium carbonate, once with water, and once with brine, then dried over sodium sulfate, and concentrated in vacuo to yield the title compound (535 mg, 1.155 mmol, 97% yield) as a glass and a mixture of diastereomers. 1H NMR (400 MHz, CD3OD) (NMR shows several rotomers) δ ppm 7.54-7.40 (m, 2 H), 7.37-7.26 (m, 2 H), 4.90-4.82 (m, 1 H+H2O), 4.63-4.48 (m, 0.6 H), 4.12-3.96 (m, 1 H+residual ethyl acetate), 3.68-3.46 (m, 1.6 H), 3.23-3.02 (m, 1.6 H), 2.98-2.90 (m, 0.4 H), 2.90-2.77 (m, 2 H), 2.76-2.53 (m, 1 H), 2.31-1.79 (m, 6 H+residual ethyl acetate), 1.79-1.64 (m, 1.6 H), 1.60 (bd, 0.4 H, J=14.1 Hz), 1.57-1.48 (m, 0.6 H), 1.04 (dd, 1.4 H, J=6.6, 3.1 Hz), 1.00 (t, 1.6 H, J=6.4 Hz), 0.96-0.90 (m, 3.2 H), 0.87-0.79 (dd, 3 H, J=5.5, 3.0 Hz), 0.79-0.71 (m, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH2:18][CH2:19]Cl)[CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[N:3]=1.[I-].[Na+].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(#N)C.O>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH2:18][CH2:19][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[N:3]=1
Reactant: C1CCNCC1
Reactant: Nc1nc(-c2ccccc2O)cc(-c2cccc(NC(=O)CCCl)c2)c1CO
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Nc1nc(-c2ccccc2O)cc(-c2cccc(NC(=O)CCN3CCCCC3)c2)c1CO
Temperature: 75 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of N-{3-[2-amino-3-(hydroxymethyl)-6-(2-hydroxyphenyl)-4-pyridinyl]phenyl}-3-chloropropanamide (0.065 g, 0.16 mmol) and sodium iodide (0.007 g, 0.05 mmol) in acetonitrile (5 mL) was added piperidine (0.16 mL, 1.63 mmol), and the mixture was stirred at 75° C. overnight. After cooled to room temperature, the resulting mixture was diluted with water and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (chloroform:methanol, 85:15) to give N-{3-[2-amino-3-(hydroxymethyl)-6-(2-hydroxyphenyl)-4-pyridinyl]phenyl}-3-(1-piperidinyl)propanamide as a white foam (0.055 g, yield 75%).