Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])([OH:10])=[O:9].[C:12]([O:15][C@@H:16]1[C@@H:20]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:19][C@@H:18]([N:26]2[CH:36]=[CH:35][C:30]([NH:31][C:32](=[O:34])[CH3:33])=[N:29][C:27]2=[O:28])[C@H:17]1O)(=[O:14])[CH3:13]>>[N+:8]([O:11][C@H:17]1[C@H:16]([O:15][C:12](=[O:14])[CH3:13])[C@@H:20]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:19][C@H:18]1[N:26]1[CH:36]=[CH:35][C:30]([NH:31][C:32](=[O:34])[CH3:33])=[N:29][C:27]1=[O:28])([O-:10])=[O:9]
Reactant: CC(=O)Nc1ccn([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2O)c(=O)n1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccn([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2O[N+](=O)[O-])c(=O)n1
Temperature: -30 °C
Yield: 86.3 %

Procedure:
Acetic anhydride (20 ml., 212 mmol) was added gradually to fuming nitric acid (20 ml., 477 mmol) with efficient stirring, while the temperature was kept between -30° to -35° C. by external cooling. While the mixture was being stirred vigorously, 1-(3,5-di-O-acetyl-β-D-arabinofuranosyl)-N4 -acetylcytosine (10 g., 27 mmol) was added in batches to the homogeneous mixture while maintaining the temperature at about -30° C. The clear reaction mixture was allowed to warm gradually to 0° C. After being stirred for 30 minutes at this temperature, the solution was poured into a mixture of ice and saturated aqueous (NH4)2SO4 solution (250 ml.) that was stirred until all the ice had melted. The aqueous phase was then extracted with ethyl acetate (3×250 ml). The combined extracts were washed with saturated aqueous sodium bicarbonate (2×200 ml.) and water (3×200 ml.), and was then dried (Na2SO4) Crude 1 -(2-O-nitro-3,5-di-O-acetyl-β-D-arabinofuranosyl)-N4 -acetylcytosine (10.66 g., 95%) was obtained by removing the ethyl acetate under reduced pressure. The solid residue was crystallized from ethyl acetate to obtain pure 1-(2-O-nitro-3,5-di-O-acetyl-β-D-arabinofuranosyl)-N4 -acetylcytosine (9.65 g., 86% yield): m.p. 159.7°-160.6° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:27]([O:29][C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32]([NH:34][NH2:35])=O)[CH3:28]>C(Cl)Cl.C(Cl)Cl.CN(C=O)C>[CH2:27]([O:29][C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32]1[O:12][C:10]([C:8]2[S:9][C:5]([C:3](=[O:4])[C:2]([F:1])([F:14])[F:13])=[CH:6][CH:7]=2)=[N:35][N:34]=1)[CH3:28]
Reactant: CCOc1ccccc1C(=O)NN
Reactant: O=C(O)c1ccc(C(=O)C(F)(F)F)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccccc1-c1nnc(-c2ccc(C(=O)C(F)(F)F)s2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the carboxylic acid (A1) in DCM was added to PS-CDI (1.7 eq., loading 1.30 mmol/g), and the suspension stirred at RT for 30 min. 2-Ethoxybenzohydrazide (1.3 eq.) dissolved in DCM/DMF was added, and the resulting suspension was stirred at RT overnight. The suspension was filtered and the filtrate evaporated. The crude N′-(2-ethoxybenzoyl)-5-(trifluoroacetyl)thiophene-2-carbohydrazide (MS (ES) C16H13F3N2O4S requires: 386, found: 427 (M+H20+Na)+ and 385 (M−H+e)−) was used as such, without any purification. It was dissolved in excess thionyl chloride and the solution was heated in a microwave oven (sealed tube, 100° C., 5 min) and the thionyl chloride was evaporated. The desired product was isolated by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents (column: C18). The pooled product fractions were evaporated to afford the title compound. 1H NMR (300 MHz, CD3CN): 8.1-8.08 (1H, m), 8.06-8.01 (1H, m), 7.95-7.90 (1H, m), 7.63-7.56 (1H, m), 7.23-7.17 (1H, m), 7.16-7.09 (1H, m), 4.23 (2H, q, J=7 Hz), 1.48 (3H, t, J=7 Hz). 19F NMR (282 MHz, CD3CN); δ −74.25 (keto form), −86.14 (hydrate form). MS (ES) C16H11F3N2O3S requires: 368, found: 369 (M+H)+ and 387 (M+H2O+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.Cl.[SH:18][C:19]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:20]=1[NH2:21]>CO.O>[CH:12]1([O:11][C:4]2[CH:5]=[C:6]([C:7]3[S:18][C:19]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:20]=4[N:21]=3)[CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1cc(F)ccc1S
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nc3cc(F)ccc3s2)cc1OC1CCCC1
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of (440 mg, 2 mmoles) 4-methoxy-3-cyclopentyloxy benzaldehyde and (400 mg, 2.1 mmoles) 2-mercapto-5-fluoroaniline hydrochloride was heated on a steam bath for 15 minutes. The resulting thick orange oil was cooled and dissolved in 5 ml of 10% FeCl3 in methanol and allowed to stir overnight. The reaction was diluted with water and extracted with CH2Cl2. The CH2Cl2 layer was dried and evaporated to give 760 mg of crude product which was purified on silica gel with CH2 Cl2 to give 500 mg of product. Recrystallization from isopropanol gave 140 mg of product. M.P.: 96°-97° C. Elemental Analysis Calc'd for C19H18O2NSF : Calc'd: C, 66.45; H, 5.28; N, 4.08. Found: C, 66.44; H. 5.13; N. 4.06.
Reaction SMILES: [CH3:1][P:2](Cl)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH3:11][O:12][C:13](=[O:27])[C@@H:14]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.CN1CCOCC1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:11][O:12][C:13](=[O:27])[C@@H:14]([CH2:23][CH:24]([CH3:25])[CH3:26])[N:15]([P:2]([CH3:1])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3])[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](CC(C)C)NCc1cccnc1
Reactant: CP(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](CC(C)C)N(Cc1cccnc1)P(C)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Methylphenylphosphinic chloride (12.23 g, 70 mmol) is taken up in dichloromethane (100 mL) and cooled to 0° C. To this is added a solution of N-(3-picolyl) D-leucine methyl ester (15.5 g, 65.6 mmol) and N-methyl morpholine (19.24 mL, 175 mmol) in dichloromethane (100 mL). A catalytic amount of 4-dimethylaminopyridine is added and the reaction stirs for 16 hours at room temperature. More methylphenylphosphinic chloride is added (2 g, 11.46 mmol). The reaction continues to stir for 24 hours until complete. By TLC, the diastereomers do not separate. The product is purified by silica gel flash chromatography (5:95 ethanol:ethyl acetate) to give N-((R/S)-methylphenyl-phosphinyl)-N-(3-picolyl) D-leucine methyl ester as an oil. To this ester is added a solution of NH2OK (250 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478. The reaction is stirred for 16 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The product is purified by silica gel flash chromatography (10:90 ethanol:ethyl acetate) to give 8.6 g of N-hydroxy-2(R)-[[(R/S)-methylphenylphosphinyl]3-picolylamino]-4-methylpentanamide as a 60 (R)/40 (S) mixture of diastereomers: MS-IS m/z 376 [M+H]+, 398[M+Na]+. (R1 =3-pyridyl methyl, R2 =isobutyl, R3 =methyl, R4 =phenyl).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][C:11]([CH3:18])([CH2:16]O)[C:12]([O:14][CH3:15])=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>C1COCC1>[CH3:15][O:14][C:12](=[O:13])[C:11]([CH3:18])([CH3:16])[CH2:10][O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:9])[CH:6]=1
Reactant: Nc1ncc(Br)cc1O
Reactant: COC(=O)C(C)(C)CO
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)COc1cc(Br)cnc1N
Temperature: 0 °C
Yield: 38.7 %

Procedure:
To a suspension of 2-amino-5-bromopyridin-3-ol (1.42 g, 7.51 mmol) in THF (40 mL) was added methyl 2,2-dimethyl-3-hydroxypropionate (1.2 mL, 9.0 mmol) and triphenyl phosphine (2.36 g, 9.00 mmol). The mixture was cooled to 0° C., then treated with diethyl diazodicarboxylate (1.70 g, 9.75 mmol). The mixture was heated in microwave at 120° C. for 20 min. The solvent was concentrated, and the residue was purified by chromatography (silica gel, hexanes/EtOAc, 75:25 to 60:40) to give the title compound (0.88 g, 39%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=2.1 Hz, 1H), 7.02 (d, J=2.1 Hz, 1H), 4.65 (br s, 2H), 3.96 (s, 2H), 3.71 (s, 3H), 1.34 (s, 6H); ESI MS m/e 303 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.Cl>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][O:19][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(OCCc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 40 °C

Procedure:
To a suspension of sodium hydride (60%, 2.2 g, 55 mmol) in dry tetrahydrofuran (250 ml) was added a solution of 1-benzyloxy-4-(2-hydroxyethyl)benzene (11.4 g, 50 mmol) in tetrahydrofuran (50 ml). The reaction was heated to 40° C. for 1 hour. 4-Fluorobenzonitrile (6.7 g, 55 mmol) was added and the mixture was heated to reflux for 5 hours, cooled and neutralized with concentrated HCl. The precipitate was filtered, the filtrate was concentrated to dryness and the resulting solid was recrystallized from ethanol (12 g).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:6][CH:5]=1.O.NN.O>C(O)COCCO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:8][CH:9]=1
Reactant: O=C(O)CCCCCC(=O)CCc1ccc(Cl)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: O=C(O)CCCCCCCCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
To a solution of 3.4 gms KOH in 23 ml diethylene glycol was added 5.4 gms 9(4-chlorophenyl)-7-ketononanoic acid and 3 ml hydrazine hydrate. The resulting mixture was heated at 145° for 1 hour. The mixture was cooled, attached to a water aspirator, and the excess water and hydrazine distilled off. The mixture was then re-heated to 145° for 3 hours and cooled. The oily reaction mixture was diluted with water, acidified with conc. HCl, and the precipitated solid filtered off. Since the NMR showed starting material still present, the solid was dissolved in 25 ml diethylene glycol and 4.1 ml hydrazine hydrate was added. This solution was refluxed for 3 hr, then the water and hydrazine were distilled off under vacuum as before. 5.2 gms KOH was added and the resulting mixture was heated at 160° for 3.5 hours, then cooled to room temperature overnight. It was dissolved in water and acidified with conc. HCl. The precipitated solid was dissolved in 10% KOH solution, washed three times with ether, filtered, acidified with conc. HCl, and placed in the cold overnight. The solid was filtered off, dried and recrystallized from hexanes to give 3.1 gm white solid of m.p. 73°-5° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH3:18][O:17][C:15](=[O:16])[CH2:14][N:13]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)[CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCNC1

Procedure:
3-[(4-Chloro-benzyl)-methoxycarbonylmethyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (3.5 g, 9.1 mmol) was dissolved in 4N HCl in dioxane (60 mL). The resultant solution was stirred for 2 h at rt then concentrated to provide the desired product as a white solid. LCMS (retention time=1.26, ES+283).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C@H:7]([N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][CH2:9]I)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]1[C:41]([CH3:43])([CH3:42])[C:40](=[O:44])[NH:39][C:38]1=[O:45].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[C:1]([O:5][C:6](=[O:35])[C@H:7]([N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][CH2:9][N:39]1[C:40](=[O:44])[C:41]([CH3:43])([CH3:42])[N:37]([CH3:36])[C:38]1=[O:45])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1C(=O)NC(=O)C1(C)C
Reactant: CC(C)(C)OC(=O)[C@@H](CCI)N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(CC[C@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)S(=O)(=O)c2ccc(-c3ccc(Cl)cc3)cc2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of the title F compound, (2R)-[t-butyloxycarbonyl(4′-chlorobiphenyl-4-sulfonyl)amino]-4-iodobutyric acid t-butyl ester (0.6 g, 0.94 mmol) in 10 mL DMF is added 3,4,4-trimethyl-2,5-dioxoimidazolidine and potassium carbonate (0.65 g, 4.72 mmol) followed by 2 mg of 18-crown-6. The reaction mixture is stirred at room RT for 3 h, then partitioned between water and EtOAc. The organic solution is washed with brine, dried over anhydrous Na2SO4 and concentrated. Chomatography on silica gel (eluant; 1/19—EtOAc/hexane) affords the title compound as a white foam (0.25 g, 41%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:12]1[C:13]([CH3:24])=[CH:14][C:15]2[CH:20]=[C:19]3[O:21][CH2:22][O:23][C:18]3=[CH:17][C:16]=2[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[N:11]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Product: CC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C=C1C)OCO3
Yield: 70 %

Procedure:
A suspension of 1.0 g (3.1 mmol) of 5-(4-nitrophenyl)-8-methyl-9H-7H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine is heated in 10 ml of acetic anhydride for 7 hours to 130°-140° C. The solution is poured on ice, and the precipitate is suctioned off. 0.99 g (87% of theory) of a yellow powder is obtained. After combining the corresponding fractions and concentration by evaporation, flash chromatography of this crude product on silica gel 60 with benzene/ethyl acetate (4:1) as a mobile solvent yields 0.78 g (70% of theory) of 7-acetyl-5-(4-nitrophenyl)-8-methyl-7H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine as a solid with a melting point of 200°-202° C. A sample is recrystallized from ethanol and then has a melting point of 205°-207° C. (minor decomposition).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>>[OH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:23][CH:22]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Oc1ccc(S)cc1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(O)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-hydroxy-thiophenol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1(O)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[NH:12][C:11]1=[O:21])[CH3:2].N1C=CC=CC=1.O=S(Cl)[Cl:31]>C(Cl)Cl>[Cl:31][C:10]1([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[NH:12][C:11]1=[O:21]
Reactant: CCOc1ccccc1C1(O)C(=O)Nc2ccc(OC)cc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccccc1C1(Cl)C(=O)Nc2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
5 g (16.7 mmol) of the intermediate from step A and 2.6 g (33.4 mmol) pyridine were dissolved in 50 mL CH2Cl2 and at 0° C. 3 g (25.1 mmol) SOCl2 were added slowly. Then the reaction mixture was stirred for 30 min. at 0° C. The reaction mixture was poured into an ice/water mixture and the organic phase was separated, washed with H2O, dried over magnesium sulfate and finally the solvent was removed in vacuo. The resulting residue was suspended in ether. The solid residue was separated and dried to give 3.2 g of the intermediate, which was used without further purification.
Reaction SMILES: [CH3:1]/[C:2](/[C:5]([CH3:7])=[O:6])=[N:3]\[OH:4].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH:18]=O.Cl>C(O)(=O)C>[CH3:1][C:2]1[N+:3]([O-:4])=[C:18]([C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[O:6][C:5]=1[CH3:7]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(=O)/C(C)=N/O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc3ccccc3c2)[n+]([O-])c1C

Procedure:
18.4 g of diacetyl monoxime and 31.2 g of 2-naphthaldehyde are added to 50 ml of glacial acetic acid, and HCl gas is introduced with ice-cooling for 30 minutes. The product is precipitated as the hydrochloride by addition of methyl tert-butyl ether and filtered off with suction, and the precipitate is washed with methyl tert-butyl ether. The precipitate is suspended in a mixture of dichloromethane and water, and a basic pH is established using ammonia. The mixture is extracted three times with in each case 500 ml of dichloromethane and ethyl acetate, the combined organic phases are dried over MgSO4 and the solvent is then removed under reduced pressure. This gives 40.3 g of 4,5-dimethyl-2-naphthalen-2-yloxazole 3-oxide as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:12]2)=[CH:3][C:2]=1[Br:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc([N+](=O)[O-])c(Br)c2)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(N)c(Br)c2)C1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A solution of (S)-tert-butyl 1-(3-bromo-4-nitrophenyl)pyrrolidin-3-ylcarbamate (2.5 g, 6.5 mmol), ammonium chloride (380 mg, 7.1 mmol), and iron (1.8 g, 32 mmol) in ethanol (20 mL) and water (10 mL) was heated to reflux for 1 h. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated to afford the desired product (2.3 g, >99%) as a blue solid: ESI MS m/z 357 [C15H22BrN3O2+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH3:22]>>[C:10]([C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([CH2:14][CH2:13][C:12](=[O:15])[NH2:11])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])[NH2:22]
Reactant: N
Reactant: O=C(O)CCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1=O
Product: NC(=O)CCC(CCC(=O)O)(C(N)=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.30 g of racemic 3-(3,4-dichlorophenyl)-2,6-dioxopiperidine-3-propionic acid are placed in 20 ml of an aqueous solution of aqueous ammonia at 30% and stirred at room temperature. After 2 hours, the solution is degassed under vacuum to remove the excess aqueous ammonia and then diluted to 50 ml with water. The medium is slowly acidified to pH 2-3 with 1 N HCl. The precipitate formed is filtered, drained and then dried over KOH to give 3.13 g of the expected compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[O:5][N:4]=1.C[O:16][C:17](=[O:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][C:21]=1[CH3:27]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][S:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:17]([OH:28])=[O:16])=[C:21]([CH3:27])[CH:22]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: ClCc1cc(-c2ccc(Cl)cc2)on1
Reactant: COC(=O)COc1ccc(S)cc1C
Product: Cc1cc(SCc2cc(-c3ccc(Cl)cc3)on2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole and 2C. mp 79-80° C.; MS m/z 404 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[NH2:26].Cl.[N:28]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:6]=1[NH:26][N:28]=[C:12]2[S:13]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cc(F)cc1OCCCl
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cc(F)cc12
Temperature: 3 °C

Procedure:
A mixture of 2-(2-chloro-ethoxy)-4-fluoro-6-(naphthalene-1-sulfonyl-methyl)-phenylamine (0.91 g, 2.31 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.16 g, 2.4 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.9 g, 2.2 mmoles).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][N:12]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)=[CH:13][N:12]=1
Reactant: Brc1ccc(Nc2cc3ccccc3o2)nc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc(Nc3cc4ccccc4o3)nc2)cn1
Temperature: 100 °C

Procedure:
A suspension of 3-benzofuran-2-yl-5-bromopyridin-2-ylamine (65.2 mg, 0.226 mmol, 1 eq), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (56.7 mg, 0.272 mmol, 1.2 eq), Pd(PPh3)4 (18.6 mg, 0.0161 mmol, 7 mol %), and potassium carbonate (101.1 mg, 0.732 mmol, 3.2 eq) in a 4:1 mixture of DME:H2O (2.5 mL) was evacuated and charged with nitrogen several times, after which the sample was heated in the microwave reactor to 100° C. for 45 min. EtOAc was added to dilute the reaction, which was then washed with water (2×) and brine (1×), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to dryness. The crude material was purified by column chromatography on silica gel [0.5″×10″ glass column, eluting with CH2Cl2:EtOAc 1:0→4:1→1:1→2:3→3:7→1:9→0:1]. Fractions containing product were combined and concentrated in vacuo. DCM and heptane were added to the residue and the solvent was concentrated in vacuo until all CH2Cl2 had been removed; a solid precipitated at this point. The solid was triturated in hot heptane and filtered off, giving the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=3.86 (s, 3H), 6.28 (br s, 2H), 7.24-7.37 (m, 2H), 7.39 (d, J=0.8 Hz, 1H), 7.64-7.70 (m, 2H), 7.86 (d, J=0.8 Hz, 1H), 8.11 (d, J=2.3 Hz, 1H), 8.13 (s, 1H), 8.31 (d, J=2.3 Hz, 1H). MS (ES+): m/z=291.09 (100) [MH+]. HPLC: tR=2.65 min (ZQ3, polar—5 min).