Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].[O:16]1CCO[CH2:18][CH2:17]1>>[C:9]([O:8][CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:17](=[O:16])[CH3:18])[S:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: Nc1nc(CO)cs1
Reactant: CC(=O)OC(C)=O
Reactant: C1COCCO1
Product: CC(=O)Nc1nc(COC(C)=O)cs1
Yield: 30 %

Procedure:
2-Aminothiazol-4-yl-methanol (17 g, 131 mmol) and acetic anhydride (927 g, 261 mmol) were mixed in 100 mL dioxane in a 500 mL round bottom flask. The mixture was heated at reflux for 1 hour. After the solvent was evaporated, 300 mL saturated sodium bicarbonate was added to the flask. The mixture was extracted twice with 200 mL EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporating the solvent, the remaining residue was washed with hexane and ether three times each. This procedure provided 10 g of (2-acetamidothiazol-4-yl)methyl acetate (yield=30%). LCMS (API-ES) m/z (%) 215.2 (100%, M++H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([C:10]([O:12]C)=[O:11])[C@H:7]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[C@@H:6]1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:4].[OH-].[Li+].O.Cl>CO>[C:23]([O:22][C:20]([NH:19][C@H:6]1[C@@H:7]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:10]([OH:12])=[O:11])[CH2:9][C@@H:5]1[C:3]([OH:4])=[O:2])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)OC)[C@H](CNC(C)=O)[C@@H]1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)NC[C@@H]1[C@H](NC(=O)OC(C)(C)C)[C@@H](C(=O)O)C[C@H]1C(=O)O

Procedure:
(±)-(1S,2S,3R,4R)-2-(t-Butyloxycarbonylamino)-3-(acetamidomethyl)-cyclopentane-1,4-dicarboxylic acid dimethyl ester (255 mg, 0.68 mmole) and lithium hydroxide (2.2 equivalents) in 15 mL of 4:1 methanol:water were reacted at room temperature for 2 hours. The reaction was acidified with dilute HCl and extracted with ethyl acetate (3×60 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.CO.[CH3:16][NH2:17]>O>[CH2:12]([O:11][C:4]1[N:3]=[C:2]([NH:17][CH3:16])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[CH3:13]
Reactant: CCOc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CN
Solvent: O
Solvent: CO
Product: CCOc1ccc([N+](=O)[O-])c(NC)n1
Reaction time: 1.5 h

Procedure:
In a stirred mixture consisting of 202.6 g (1 mole) of 2-chlor-6-ethoxy-3-nitropyridine and 500 ml of methanol, 202 g (2.6 mole) of a 40% monomethylamine solution is added drop by drop while stirring in the course of 90 minutes and at 25°-30° C. sump temperature. Subsequently, the mixture is again stirred for yet another 5 hours, is reacted with 650 ml of water, and then the product is filtered off by suction, is washed again with ample water and dried. Melting point 106°-7° C., Yield: 183.2 g (92.9% of theory).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][C:17](=O)[C:16]([CH3:27])=[C:15]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:35]>O>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][C:17](=[S:35])[C:16]([CH3:27])=[C:15]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1c(-c2ccccc2)n(-c2ccccc2Cl)c(-c2ccccc2)cc1=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1c(-c2ccccc2)n(-c2ccccc2Cl)c(-c2ccccc2)cc1=S
Yield: 81 %

Procedure:
To 40 ml of pyridine were added 1.3 g (0.0035 mole) of 1-(2-chlorophenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone and 0.9 g (0.0042 mole) of phosphorus pentasulfide, followed by refluxing the resultant mixture for 3 hours. After cooling, the reaction mixture was poured into water and the resulting crystals were collected by filtration. The crystals were dissolved in 100 ml of chloroform, and washed first with 30 ml of 2N hydrochloric acid and then with 30 ml of a saturated aqueous solution of sodium hydrogencarbonate. After washing the chloroform solution further with water, it was dried over anhydrous sodium sulfate. After removal of sodium sulfate, the solvent was distilled off to obtain crystals. The crystals were recrystallized from a 1:1 mixture of acetone and hexane, thereby obtaining 1.1 g of 1-(2-chlorophenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinethione having a melting point of 271°-275° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[O:9].[OH-:10].[Na+]>>[CH2:8]([CH:2]([CH2:3][OH:10])[CH2:1][CH2:6][CH2:5][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[OH:9]
Reactant: C=O
Reactant: [OH-]
Reactant: Oc1ccccc1
Agent: [Na+]
Product: OCC(CO)CCCc1ccccc1O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
The mixture is cooled to 40° C, 470 g of phenol is added thereto, together with 665 g of (90%) paraformaldehyde, following by stirring for 1 hour at 40° C. Then over a period of 1 hour 300 g of (33%) caustic soda solution are added and the temperature is held at 40° C until the free formaldehyde content is below 1.5%. This lasts a further 3 to 4 hours, calculated from the paraformaldehyde addition.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.[C:9]([O:13][C:14]([N:16]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:17]1[C:18]2[C:25]([I:26])=[CH:24][N:23]([C@@H:27]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:29]([CH:39]=O)[CH2:28]3)[C:19]=2[N:20]=[CH:21][N:22]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[C:44]([O:43][C:41]([N:16]([C:14]([O:13][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:15])[C:17]1[C:18]2[C:25]([I:26])=[CH:24][N:23]([C@@H:27]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C@H:29]([CH2:39][N:2]([CH3:3])[CH3:1])[CH2:28]3)[C:19]=2[N:20]=[CH:21][N:22]=1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2c1c(I)cn2[C@H]1C[C@@H](C=O)N(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)C[C@@H]1C[C@H](n2cc(I)c3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncnc32)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1M dimethylamine THF solution (0.3 ml) and acetic acid (0.2 ml) were added to a solution of (2S,4S)-tert-butyl 4-(4-(bis(tert-butoxycarbonyl)amino)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-formylpyrrolidine-1-carboxylate (68 mg) obtained in Step 5 in methylene chloride (2 ml), and the resulting mixture was cooled to 0° C. Sodium triacetoxyborohydride (127 mg) was added to the reaction mixture, and stirred at 0° C. for 2 hours. The reaction mixture was neutralized using a sodium hydrogen carbonate aqueous solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a light-yellow, amorphous substance (31.9 mg). Physical properties: m/z [M+H]+ 687.2
Reaction SMILES: [N+](C1C=CC=CC=1O)([O-])=O.[C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][CH:12]=1.CC(C)N=C=NC(C)C.[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1.[ClH:47]>ClCC(Cl)C.CN(C=O)C.C(O)C>[ClH:47].[C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[CH:13][C:14]([CH2:17][C:18]([N:44]2[CH2:45][CH2:46][CH:41]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:42][CH2:43]2)=[O:20])=[CH:15][CH:16]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=[N+]([O-])c1ccccc1O
Solvent: CCO
Solvent: CC(Cl)CCl
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccccc2)cc1)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 29 %

Procedure:
To the polymeric nitrophenol (1.5 g, approx. 1 mmol) was added a filtered solution of 4-biphenylylacetic acid (1.10 g, 5.18 mmol) in a mixture of 1,2-dichloropropane (18 ml) and DMF (2 ml), followed by the addition of a solution of DIC (0.63 g, 4.99 mmol) in 1,2-dichloropropane (5 ml). The mixture was shaken at room temperature for 15 hours, filtered, and the polymer was extensively washed with DCM, DMF, and 1,2-dichloropropane. To the polymer was added 1,2-dichloropropane (5 ml) and a solution of 4-(1-pyrrolidinyl)piperidine (0.123 g, 0.80 mmol) in 1,2-dichloropropane (10 ml). The resulting mixture was shaken at room temperature for 21 hours and then at 60° C. for one hour, filtered, and the polymer was carefully washed with DCM and methanol. The combined filtrates were concentrated to yield the crude product, which was mixed with ethanol and 1 molar aqueous hydrochloric acid, concentrated, and the residual hydrochloride was recrystallized from ethanol. 90 mg (29%) of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])[CH2:6][CH2:7]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2ccccc2F)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2F)CC1)c1ccccc1
Yield: 56.7 %

Procedure:
0.2 g (0.000956 mol) of 1-(2-fluoro-benzyl)-piperidin-4-ol and 0.16 ml (0.00147 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.122 ml (0.00105 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.17 g (57%) of 1-(2-fluoro-benzyl)-piperidin-4-yl benzoate was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26])=[CH:19][CH:18]=1.C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23](=[O:28])[C:24](=[CH:13][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:25](=[O:27])[CH3:26])=[CH:21][CH:22]=1
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: COc1ccc(C(=O)CC(C)=O)cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COc1ccc(C(=O)C(=Cc2cccc3c(=O)cc(C)oc23)C(C)=O)cc1

Procedure:
250 mg (1.32 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 281 mg (1.46 mmol) of 1-(4-methoxyphenyl)butane-1,3-dione, 100 mg (1.66 mmol) of acetic acid and 11 mg (0.13 mmol) of piperidine in 5 ml of dichloromethane and, after addition of molecular sieves, heated under reflux under argon for 4 h. The solvent is removed after filtration in vacuo. 480 mg (99% of theory) of the title compound are obtained and are employed without further purification in the next stage.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:41]1[CH2:46][CH2:45][O:44][C:43]2[CH:47]=[C:48]([C@@H:51]([O:55][C:56]3[CH:57]=[C:58]4[C:62](=[CH:63][CH:64]=3)[N:61]([C:65]3[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=3)[N:60]=[CH:59]4)[C@@H:52]([NH2:54])[CH3:53])[CH:49]=[CH:50][C:42]1=2>CN1C(=O)CCC1.O>[O:41]1[CH2:46][CH2:45][O:44][C:43]2[CH:47]=[C:48]([C@@H:51]([O:55][C:56]3[CH:57]=[C:58]4[C:62](=[CH:63][CH:64]=3)[N:61]([C:65]3[CH:66]=[CH:67][C:68]([F:71])=[CH:69][CH:70]=3)[N:60]=[CH:59]4)[C@@H:52]([NH:54][C:5]([C:2]3([CH3:1])[CH2:4][CH2:3]3)=[O:7])[CH3:53])[CH:49]=[CH:50][C:42]1=2
Reactant: CC1(C(=O)O)CC1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@H](NC(=O)C1(C)CC1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-methylcyclopropanecarboxylic acid (39 mg, 0.39 mmol), HATU (150 mg, 0.39 mmol) and DIPEA (170 μl, 0.97 mmol) in NMP (2 mL) was stirred at r.t. for 5 min until a solution had formed. To this solution was added (1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine (19a) (102 mg, 0.24 mmol) dissolved in NMP (1 mL). The reaction mixture was stirred for 2 h at r.t. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL), the organic phases was then washed with brine, dried over Na2SO4, filtered and evaporated. The remaining oily residue was purified by HPLC. Fractions containing product was freezedried. Yield 68 mg (55%10).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].C([O-])(O)=O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:19]([O:18][C:16]([NH:1][CH:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:7]([OH:9])=[O:8])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 817.3 %

Procedure:
To a solution of L-tert-leucine (1) (50.0 g, 38.0 mmol) and NaHCO3 (96.0 g, 114 mmol) in ice (500 g) and water (500 ml) was added benzyl chloroformate (65.0 ml, 74.0 mmol) and the reaction stirred at 0° C. for 3 hours then at room temperature for 18 hours. 0.1N Na2CO3 was added until the oily layer dissolved and the solution was washed with 10% EtOAc in hexanes (2×500 ml). The iced aqueous phase was acidified to pH 1 using 12N HCl then extracted using EtOAc (3×350 ml). The combined organic extracts were dried over Na2SO4, filtered and evaporated to give the title compound as a colorless oil (82.4 g, 81.5% yield): 1H-NMR (500 MHz, CDCl3) δ1.02 (s, 9H), 4.22 (d, 1H), 5.10–5.14 (m, 2H), 5.31 (d, 1H), 7.26–7.37 (m, 5H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[F:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:44](=[O:45])[C:43]2[CH:47]=[CH:48][C:40]([CH2:39][N:20]3[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]4([CH2:31][O:30][C:29]5[CH:32]=[C:33]6[C:37](=[CH:38][C:28]4=5)[CH2:36][CH2:35][O:34]6)[C:19]3=[O:18])=[CH:41][CH:42]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1F
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1c(F)cccc1NC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 3-fluoro-2-methylaniline to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(3-fluoro-2-methylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (35%) as a colorless solid: mp 143-144° C.; 1H NMR (300 MHz, CDCl3) δ 7.91-7.84 (m, 2H), 7.74-7.64 (m, 2H), 7.52-7.45 (m, 2H), 7.29-7.17 (m, 3H), 7.10-7.02 (m, 1H), 6.96-6.87 (m, 1H), 6.80-6.74 (m, 1H), 6.49 (s, 1H), 6.44 (s, 1H), 5.04 (ABq, 2H), 4.85 (ABq, 2H), 4.60-4.51 (m, 2H), 3.10-2.91 (m, 2H), 2.23 (d, J=1.51 Hz, 3H); MS (ES+) m/z 521.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[C:25]([N+:27]([O-])=O)[CH:26]=2)[O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:23])([CH3:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.CO>C(OCC)(=O)C>[NH2:27][C:25]1[CH:24]=[C:9]([CH:8]=[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:31][CH:30]=2)[CH:26]=1)[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:22])([CH3:23])[C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=1
Reactant: COC(=O)C(C)(C)c1ccc(Oc2cc(Oc3ccc(F)cc3)cc([N+](=O)[O-])c2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(C)(C)c1ccc(Oc2cc(N)cc(Oc3ccc(F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
Under an argon atmosphere, to a 500-mL pear-shaped evaporating flask was added the compound prepared in Example 5 (53.6 g) to which a mixed solution of methanol (50 mL) and ethyl acetate (175 mL) was added. The mixture was heated until dissolution, and the flask was purged with argon prior to addition of 5% palladium carbon (10.8 g). The flask was degassed and charged with hydrogen gas. The flask was vigorously stirred at room temperature for 3 hours. The reaction system was purged with argon, filtered with celite and washed with ethyl acetate. The obtained filtrate was subjected to distillation under reduced pressure to give the titled compound (43.9 g) having the following physical properties.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>CN(C)C=O.O>[Cl:32][C:29]1[CH:28]=[N:27][C:26]([O:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[N:31][CH:30]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccccc1S
Reactant: Clc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2ccccc2Oc2ncc(Cl)cn2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0°, 4.0 grams (0.025 moles) of 2-chloro-5-nitropyridine is added to a mixture of 3.0 grams (0.0023 mole) 2-mercaptophenol and 7.0 grams of potassium carbonate stirring in 50 ml of dimethylformamide. After stirring overnight at room temperature, 4.0 grams of 2,5-dichloropyrimidine is added and the mixture is heated at 80° for 5 hours. The mixture is then poured into excess H2O and the aqueous mixture is extracted with ethyl ether (200 ml), washed with saturated sodium bicarbonate, brine, dried (MgSO4), and the solvent is evaporated to yield the crude product.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([CH2:15][N+:16]([O-:18])=[O:17])(=[O:14])=[O:13])=[C:7]([CH3:19])[CH:6]=1)(=O)C.Cl.O>C(O)C>[NH2:4][C:5]1[CH:6]=[C:7]([CH3:19])[C:8]([S:12]([CH2:15][N+:16]([O-:18])=[O:17])(=[O:14])=[O:13])=[C:9]([CH3:11])[CH:10]=1
Reactant: CC(=O)Nc1cc(C)c(S(=O)(=O)C[N+](=O)[O-])c(C)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 73 %

Procedure:
(4-Acetamido-2,6-dimethylphenylsulfonyl)nitromethane (11.5 g, 40 mM) is added in one portion to a boiling mixture of concentrated hydrochloric acid (22 mL), water (110 mL) and ethanol (45 mL). The mixture is stirred at reflux until a clear solution is formed (about 20 minutes) and then for a further 10 mins. The hot reaction mixture is then poured into an excess of ice-cold saturated sodium bicarbonate solution. The aqueous mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (MgSO4) and the solvent removed by evaporation to give (4-amino-2,6-dimethylphenylsulfonyl)nitromethane, as a solid, m.p. 132°-133° C. [after recrystallisation from ethanol] in 73% yield; NMR(d6 -DMSO, 200 MHz): 2.39(6H, s), 6.19(4H, s), 6.35(2H, s); microanalysis, found: C,44.5; H,4.9; N,11.6%; C9H12N2O4S requires: C,44.3; H,4.9; N,11.5%.
Reaction SMILES: C(O[C:4](=O)[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12](C)[CH:11]=[C:10]([CH3:15])[CH:9]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH2:23].C(Cl)Cl.[CH3:27]O>O1CCCC1>[CH3:27][CH2:4][CH2:5][CH:6]([NH:7][C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=1)[OH:23]
Reactant: CO
Reactant: CCOC(=O)CCNc1cc(C)cc(C)c1
Reactant: O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCC(O)Nc1cccc(C)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
3-(3,5-dimethyl-phenylamino)-propionic acid ethyl ester (0.00226 mol) in tetrahydrofuran (5 ml) was added drop wise to a slurry of LiAlH4 (0.0034 mol) in tetrahydrofuran (10 ml) at 5° C. under N2 flow. The mixture was stirred at 5° C. for 1 hour. A minimum of water and CH2Cl2/CH3OH (95/5) were added. The solution was dried (over MgSO4), filtered and the solvent was evaporated until dryness, yielding 0.35 g of 3-(3,5-dimethyl-phenylamino-propan-1-ol (86%). 5-(3,5-dimethyl-phenylamino)-pentan-1-ol was prepared analogously.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31]([OH:34])(=[O:33])=O)[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][NH:39][CH3:40]>>[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][N:39]([CH3:40])[S:31]([C:5]1[C:6](=[CH:27][C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1)(=[O:34])=[O:33]
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Reactant: CNCCN(C)C
Product: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)N(C)CCN(C)C)n2C)n(CCC)c1=O
Yield: 49.5 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using 500 mg (0.98 mmol) of Compound 1 obtained in Example 1 and 0.62 mi (4.9 mmol) of N,N,N'-trimethyl-ethylenediamine. The resulting crude crystals were recrystallized from cyclohexane/toluene to give 280 mg (yield 48%) of Compound 6 as yellow needles.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([N+:12]([O-])=O)[C:6]=1[CH3:15])(=[O:3])[CH3:2].[H][H]>CO.C(O)C.C(O)(=O)C.[C].[Pd]>[C:1]([NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C)ccc([N+](=O)[O-])c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)Nc1c(C)ccc(N)c1C

Procedure:
N-Acetyl-2,6-dimethyl-3-nitroaniline (30.6 g; 0.15 mole) was dissolved in a mixture of methanol (100 ml), ethanol (50 ml) and acetic acid (100 ml). To the resulting solution was added 2.0 g of 10% palladium carbon and the mixture was stirred in a stream of hydrogen at room temperature for 26 hours. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol-ether to give 22.0 g (84%) of the title object compound as crystals, m.p. 195°-197° C.