Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C:29]1[CH:30]=[C:31]([CH:78]=[CH:79][CH:80]=1)[CH2:32][NH:33][C:34](=[O:77])[CH:35]([C:62]1[CH:76]=[CH:75][C:65]([CH2:66][N:67]([CH2:71][C:72](O)=[O:73])[C:68](=[O:70])[CH3:69])=[CH:64][CH:63]=1)[NH:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[C:43]([N:47]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[N:42][CH:41]=[CH:40]2>C(Cl)Cl.CN(C=O)C>[C:68]([N:67]1[CH2:66][C:65]2=[CH:64][CH:63]=[C:62]([CH:76]=[CH:75]2)[CH:35]([NH:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[C:43]([N:47]([C:48]([O:50][C:51]([CH3:53])([CH3:54])[CH3:52])=[O:49])[C:55]([O:57][C:58]([CH3:60])([CH3:59])[CH3:61])=[O:56])=[N:42][CH:41]=[CH:40]3)[C:34](=[O:77])[NH:33][CH2:32][C:31]2[CH:30]=[C:29]([CH:80]=[CH:79][CH:78]=2)[NH:28][C:72](=[O:73])[CH2:71]1)(=[O:70])[CH3:69]
Reactant: CC(=O)N(CC(=O)O)Cc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)NCc2cccc(N)c2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N1CC(=O)Nc2cccc(c2)CNC(=O)C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2ccc(cc2)C1
Yield: 53.9 %

Procedure:
To a solution of BOP (30 mg, 0.065), TEA (0.07 mL, 0.5 mmol) in 40 mL of CH2Cl2, was added a solution of 80F (40 mg, 0.055 mmol) in DMF (8 mL) via a syringe pump over 6 h. The mixture was stirred r.t over night, then was quenched with sat. NH4Cl and extracted with EtOAc (3×20 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated. Purification via flash chromatography (0-10% MeOH/CH2Cl2) afforded 80G (21 mg, 54%). MS (ESI) m/z 709.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)OC(C)(C)C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)acetate (124.5 g, 321.3 mmol) was dissolved in THF (1,150 ml) and MeOH (1,900 ml), and an aqueous 6 M NaOH solution (1,300 ml) was added. The reaction mixture was stirred at room temperature for 1 hour and the organic solvents were then distilled off. The residue was taken up in aqueous 6 M HCl (2,000 ml) at 0° C. and the mixture was extracted with methylene chloride (2×1,000 ml). The combined organic phases were dried, filtered and concentrated to dryness in vacuo. The yield was 103.5 g (97%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([N:15]([CH3:25])[C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:9]1)C1C=CC=CC=1.Cl>C(O)C>[CH3:25][N:15]([CH:10]1[CH:11]([CH3:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[C:16]1[C:17]2[CH:24]=[CH:23][NH:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: CC1CCN(Cc2ccccc2)CC1N(C)c1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCO
Product: CC1CCNCC1N(C)c1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.3 %

Procedure:
To the product from Method B (0.7 grams, 2.19 mmol) dissolved in 15 mL of ethanol was added 1.5 mL of 2 N hydrochloric acid and the reaction mixture degassed by nitrogen purge. To the reaction mixture was then added 0.5 grams of 20% palladium hydroxide on carbon (50% water) (Aldrich) and the resulting mixture shaken (Parr-Shaker) under a 50 psi atmosphere of hydrogen at room temperature for 2 days. The Celite filtered reaction mixture was concentrated to dryness in vacuo and the residue purified by flash chromatography (silica; 5% methanol in dichoromethane) affording 0.48 grams (90%) of the title compound. LRMS: 246.1 (M+1).
Reaction SMILES: [CH2:1]([C@@H:4]1[C@H:10]2[C@H:8]([O:9]2)[CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[CH2:5]1)[CH:2]=[CH2:3].[N-:15]=[N+:16]=[N-:17].[Na+].[NH4+].[Cl-]>CO.O>[CH2:1]([C@H:4]1[CH2:5][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C@H:8]([N:15]=[N+:16]=[N-:17])[C@H:10]1[OH:9])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1CC(C(=O)OC)=C[C@H]2O[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CC[C@H]1CC(C(=O)OC)=C[C@H](N=[N+]=[N-])[C@H]1O

Procedure:
A solution of Example 1I, sodium azide (2.8 g, 43.1 mmol) and NH4Cl (1.0 g, 18.8 mL) in methanol (30 mL) and H2O (10 mL) was refluxed for 5 hours, diluted with H2O and extracted with ethyl acetate. The combined ethyl acetate layers were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (1/1) to afford 1.4 g (67% over steps I and J) of the desired product as a colorless oil.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH3:10][C:11]([CH3:13])=[O:12]>>[C:11]([C:13]1[CH:8]=[CH:9][C:4]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:5][C:6]=1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:12])[CH3:10]
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc(-c2ccccc2)cc1-c1ccccc1

Procedure:
Nitrobenzene is stripped with steam and the solid residue is dissolved into acetone. After filtration and the acetone evaporation, 400 g of crude product is obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][CH:37]4[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c12) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow foam.
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:10][CH:11]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[C:12]1([C:9]2[N:8]3[C:3](=[S:2])[NH:4][N:5]=[CH:6][C:7]3=[CH:11][N:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CSC(=S)NN=Cc1c[nH]c(-c2ccccc2)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: S=c1[nH]ncc2cnc(-c3ccccc3)n12

Procedure:
A suspension of 7.05 gm. of 3-(2-phenyl-4-imidazolylmethylene)dithiocarbazic acid methyl ester in 100 ml. of diphenyl ether is reacted as described in Example 58 giving the desired product, m.p. 210° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([C:26](OCC)=[O:27])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=3)(=[O:13])=[O:14])[CH:10]=[C:9]([CH2:26][OH:27])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)n1cc(CO)cc1-c1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
A solution (30 mL) of ethyl 5-phenyl-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}-1H-pyrrole-3-carboxylate (1.33 g) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L solution (8.0 mL) of diisobutylaluminum hydride in toluene was added dropwise, and the mixture was further stirred at −78° C. for 3 hr. 1 mol/L hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was diluted with ethyl acetate. Insoluble material was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2) to give the title compound as an oil (yield 0.71 g, 59%).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:24][CH2:25][C:26]([CH3:33])([CH3:32])[C:27]([O:29]CC)=[O:28])=[O:23])[N:4]=1)#[N:2].O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:24][CH2:25][C:26]([CH3:33])([CH3:32])[C:27]([OH:29])=[O:28])=[O:23])[N:4]=1)#[N:2]
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cccc(F)c3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3cccc(F)c3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl 3-(1-cyano-7-(3-fluorophenoxy)-4-hydroxyisoquinoline-3-carboxamido)-2,2-dimethylpropanoate (22 mg, 0.05 mmol) was dissolved in MeOH (4 mL) and 2 N NaOH (4 mL). After stirring for 5 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 15 mg. MS: (−) m/z 421.91 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:5].[CH2:32]([N:36]=[C:37]=[O:38])[CH2:33][CH2:34][CH3:35]>>[CH2:32]([NH:36][C:37](=[O:38])[NH:1][C:2]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:13]1)=[O:5])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCN=C=O
Reactant: Nc1cc(Cl)ccc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: CCCCNC(=O)Nc1cc(Cl)ccc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
{2-amino-4-chloro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide and n-butylisocyanate}: mp 195°-197° C.; 1H NMR (CDCl3)ppm: 0.93 (3H, t), 1.30-1.90 (11H, m), 2.91 (2H, m), 3.24 (2H, td), 3.31 (2H, dd), 4.25 (1H, s), 4.67 (1H, bs), 6.36 (1H, bs), 6.87 (1H, dd), 7.14-7.41 (11H, m), 8.51 (1H, d), 10.38 (1H, s).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].Cl>O1CCOCC1>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:7]2[C:8](=[O:10])[CH2:9][C@@H:5]([C:3]([OH:4])=[O:2])[CH2:6]2)=[CH:16][CH:15]=1
Reactant: COC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 2f), the hydrolysis of (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester with hydrochloric acid (37%) in dioxane yields the (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid as a white solid. MS: m/e=330 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])O.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li]CCCC.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]=[CH:2][CH3:4].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC
Temperature: -78 °C
Reaction time: 0.02 h

Procedure:
To a solution of O-protected pyridine dimethylcarbinol (3.0 g, 10.6 mmol) in THF (50 mL) at −78° C. was added n-BuLi 2.5 N in hexanes (4.7 ml, 11.7 mmol) followed, 1 min later, by phenylthionochloroformate (2.76 g, 16.0 mmol). The reaction was stirred at −78° C. for 40 min, then allowed to warm to RT and stirred 4 h. The final mixture was treated with saturated NaHCO3, extracted with DCM and AcOEt and combined organic layers were dried over Na2SO4 and concentrated. Purification of the residue by flash chromatography over silica gel (eluting hexane to DCM) afforded 1.5 g of O-protected pyridine propene as well as 1.8 g of starting O-protected pyridine dimethylcarbinol.
Reaction SMILES: O.[OH:2][C:3]([C:6]1[N:7]=[C:8]([CH2:54][CH2:55][CH3:56])[N:9]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48](=[O:53])[C:49]([O:51][CH3:52])=[O:50])=[CH:38][CH:37]=2)[C:10]=1[C:11]1[N:12]=[N:13][N:14](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:15]=1)([CH3:5])[CH3:4]>C(O)(=O)C>[OH:2][C:3]([C:6]1[N:7]=[C:8]([CH2:54][CH2:55][CH3:56])[N:9]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48](=[O:53])[C:49]([O:51][CH3:52])=[O:50])=[CH:40][CH:41]=2)[C:10]=1[C:11]1[NH:15][N:14]=[N:13][N:12]=1)([CH3:5])[CH3:4]
Reactant: CCCc1nc(C(C)(C)O)c(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCc1nc(C(C)(C)O)c(-c2nnn[nH]2)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
1.5 ml of water were added to a solution of 527 mg of methyl {4'-[4-(1-hydroxy-1-methylethyl)-2-propyl-5-(2-trityltetrazol-5-yl)imidazol-1-ylmethyl]biphenyl-2-yl}glyoxylate [prepared as described in step (a) above] dissolved in 3.5 ml of acetic acid, and the resulting mixture was stirred at 70° C. for 1.5 hours. At the end of this time, 2 ml of water were added to the mixture. The resulting mixture was ice-cooled, and then the precipitate was removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and the residual acetic acid was removed by azeotropic distillation with toluene, to give 206 mg of the title compound, as crystals melting at 131°-132° C. (after crystallization from a mixture of diethyl ether and ethyl acetate).
Reaction SMILES: CN(C=O)C.C[O-].[K+].[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[CH3:19])([O-:11])=[O:10].[N:20](OCCCC)=[O:21]>C(O)(=O)C.O>[CH3:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N+:9]([O-:11])=[O:10])[C:13]=1[CH:19]=[N:20][OH:21]
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: CCCCON=O
Agent: C[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cccc([N+](=O)[O-])c1C=NO
Temperature: -40 °C

Procedure:
1200 ml of anhydrous DMF are initially charged in a 4 l reaction flask and cooled to −40° C. At this temperature, 336.5 g (4.56 mol) of potassium methoxide (95%) are added with stirring and suspended. A mixture of 300 g (1.92 mol) of 3-nitro-o-xylene (97%) and 274 g (2.52 mol) of n-butyl nitrite (95%) is subsequently added dropwise at −40° C. over a period of 7 hours (if the mixture is cooled appropriately, the duration of this addition can be reduced at will). By HPLC, it is checked that the starting material has been converted completely. The reaction discharge is subsequently added with stirring to a mixture of 300 ml of water and 300 ml of glacial acetic acid, at from −5 to 0° C. The reaction mixture is then poured into 6 kg of ice-water and the solid is separated off by filtration and washed twice with 500 ml of water each time.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14](=[N:20][OH:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1>[NH2:13][C:14](=[N:20][O:21][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(N)=NOC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of 4-nitrobenzoyl chloride (10 g) in tetrahydrofuran (150 ml) was added a suspension of ethyl 2-amino-2-hydroxyiminoacetate (7.1 g) in tetrahydrofuran (30 ml). After stirring for 2 hours, the precipitates were collected by filtration and washed with diethyl ether to afford ethyl 2-amino-2-(4-nitrobenzoyloxyimino)acetate (12.19 g).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:19]3[C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[S:22][C:18]=3[C:17]([CH3:27])=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)=[CH:5][C:4]=1[CH3:28].Cl.[NH+]1C=CC=CC=1>>[CH3:9][C:8]1[CH:7]=[C:6]([C:10]2[C:19]3[C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[S:22][C:18]=3[C:17]([CH3:27])=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:5]=[C:4]([CH3:28])[C:3]=1[OH:2]
Reactant: COc1c(C)cc(-c2c3ccccc3c(C)c3sc4ccccc4c23)cc1C
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Cc1cc(-c2c3ccccc3c(C)c3sc4ccccc4c23)cc(C)c1O
Temperature: 240 °C
Yield: 64.1 %

Procedure:
A mixture of 11-(4-methoxy-3,5-dimethyl-phenyl)-6-methyl-benzo[b]naphtho[2,3-d]thiophene (0.55 g, 1.44 mmol) and pyridinium hydrochloride (1.0 g, 8.64 mmol) was heated in a 240° C. oil bath for 1.25 hour. During this time an additional amount of pyridinium hydrochloride was added (1.0 g, 8.64 mmol). The reaction mixture was cooled to room temperature and partitioned between dilute HCl and ether. Silica gel was added to the ether phase and the solvent was removed. The adsorbate was flash chromatographed (9:1 petroleum ether:ethyl acetate) to provide a light yellow solid (340 mg). This solid was recrystallized from acetic acid to provide the title compound as a light yellow solid (0.215 g, 41%): mp 147-149° C.: NMR (CDCl3); δ 8.15 (ddd, J=8, 1, 1 Hz, 1H), 7.80 (ddd, J=8, 1, 1 Hz, 1H), 7.71 (ddd, J=8, 1, 1 Hz, 1H), 7.56 (ddd, J=8, 7, 1 Hz, 1H), 7.39 (ddd, J=8, 7, 1 Hz, 1H), 7.35 (ddd, J=8, 8, 1 Hz, 1H), 7.09 (ddd, J=8, 7, 1 Hz, 1H), 7.01 (s, 2H), 6.79 (ddd, J=8, 1, 1 Hz, 1H), 2.96 (s, 3H), 2.36 (s, 6H); MS (EI): 368 (100%, MI); Anal. Calc. for C25H20OS: C, 81.49, H, 5.47, N, 0.00. Found: C, 81.62, H, 5.32, N, -0.03.
Reaction SMILES: C([NH:4][C:5]1[CH:17]=[CH:16][N:8]([C@@H:9]2[O:15][C@H:12]([CH2:13][OH:14])[CH2:11][CH2:10]2)[C:7](=[O:18])[N:6]=1)(=O)C.N>CO>[C@@H:9]1([N:8]2[CH:16]=[CH:17][C:5]([NH2:4])=[N:6][C:7]2=[O:18])[O:15][C@H:12]([CH2:13][OH:14])[CH2:11][CH2:10]1
Reactant: CC(=O)Nc1ccn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Agent: N
Solvent: CO
Product: Nc1ccn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Yield: 78.9 %

Procedure:
A solution of 34 (0 6 g, 2.4 mmol ) in methanol saturated with ammonia (20 ml ) was stirred at 50° C. for 12 hours in a pressure vessel. The reaction mixture was concentrated and the residue was triturated with isopropanol, filtered, and dried to yield 0.4 g (80%) of 4: mp 207°-209° C. (benzene-ethanol); 1H NMR (DMSO-d6) δ 1.50-2.50 (4H, m, 2' and 3'-H), 3.63 (2H, m, 5'-H), 4.00 (1H, m, 4'-H), 4.96 (1H, t, J=4.9 Hz, OH), 5.69 (1H, d, J=7.25 Hz, 5-H), 5.95 (1H, m, 1'-H), 7.05 (2H, s, NH2), 7.89 (1 H, d, J=7.3 Hz, 6-H).
Reaction SMILES: CCN=C=NCCCN(C)C.[NH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:13]([C:18]([OH:20])=O)[CH2:14][CH:15]([CH3:17])[CH3:16].O.Cl.[NH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C1C=CC2N(O)N=NC=2C=1>ClCCl>[NH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:13]([C:18]([NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:20])[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 42 h
Yield: 56.6 %

Procedure:
9.10 Milliliters of WSC was gradually added to 100 ml of a solution of 12.47 g of Boc-Leu-OH.H2O, 6.98 g of HCl.H-Gly-OEt and 6.76 g of HOBT dissolved in dichloromethane, with ice-cooling. The mixture was stirred for 42 hours at room temperature. The reaction mixture was mixed with 100 ml of 1N hydrochloric acid, and the resulting precipitate was removed by filtration. The filtrate was washed with 100 ml of 1N hydrochloric acid, two 100-ml portions of a saturated aqueous sodium bicarbonate solution and 100 ml of a saturated aqueous sodium chloride solution in this order, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added petroleum ether to crystallize the residue. The resulting crystal was recrystallized from ethyl acetate-petroleum ether to obtain 8.68 g (yield: 56.6%) of the above objective compound. Melting point: 79.5°-82.5° C.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[C:8]1([S:14]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5998.8 %

Procedure:
To a well-agitated suspension of sodium hydroxide (4.46 g, 111 mmol) in methylene chloride (26 mL) at 0° C. is added pyrrole (2.5 g, 0.37 mmol), and the reaction mixture is stirred for 10 min, following which a solution of benzenesulfonyl chloride (7.86 g, 0.44 mmol) in methylene chloride (5.15 mL) is slowly added, allowed to warm to room temperature and stirred overnight. The reaction is quenched by pouring into water (100 mL). The organic layer is separated, and the aqueous layer is extracted with methylene chloride three times. The combined organic extracts are water, dried with sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (10% ethyl acetate-hexane) provides 4.6 g (60%) of the title compound as a white solid. 1H NMR (CDCl3): δ 7.80 (m, 2H), 7.50 (m, 3H), 7.25 (m, 2H), 6.30 (m, 2H).