Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:13][C:14]1[N:19]=[C:18]([N:8]2[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][O:10][C:9]2=[O:12])[CH:17]=[CH:16][N:15]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1OC[C@@H](c2ccccc2)N1c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
A solution of (R)-4-phenyloxazolidin-2-one (2.9484 g, 18.07 mmol) and 2,4-dichloropyrimidine (3.1872 g, 21.39 mmol, 1.184 equiv) in DMF (30 mL) was treated with NaH (95%, 0.4773 g, 18.89 mmol, 1.046 equiv), then the resulting mixture (yellow to red cloudy) was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (200 mL), washed with sat. NH4Cl (75 mL) and 4% aqueous NaCl (2×100 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided (R)-3-(2-chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one (2.7020 g, white sticky solid) in 46.9% yield. 1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=5.6 Hz, 1H), 8.18 (d, J=6.1 Hz, 1H), 7.38-7.30 (m, 5H), 5.81 (dd, J=8.6, 3.5 Hz, 1H), 4.88 (t, J=8.6 Hz, 1H), 4.37 (dd, J=8.6, 3.5 Hz, 1H); MS m/z 276.4 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:6][C:5]=1[CH3:18].[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].C(OCC)C>C1(C)C=CC=CC=1>[CH3:18][C:5]1[CH:6]=[C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1ccc(OCc2ccccn2)cc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc(OCc2ccccn2)ccc1CO
Temperature: -78 °C
Reaction time: 6 h
Yield: 93.1 %

Procedure:
To 1.0 g of 2-methyl-4-(2-pyridylmethoxy)benzoic acid methyl ester was added 8 mL of toluene under argon atmosphere. To the mixture cooled to −78° C., 8.7 mL of a solution of diisobutylaluminium hydride (1.0 mol/L) in toluene was added dropwise. The mixture was stirred at the same temperature for 6 hours and further stirred at −35° C. for 1 hour. To the reaction mixture, a saturated aqueous Rochelle salt solution was added, and the mixture was stirred at room temperature for 30 minutes. To this, 150 mL of diethyl ether was added, and the organic layer was separated. The obtained organic layer was dried over Na2SO4 and concentrated to give 0.83 g of the title compound (93% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([F:11])[CH:5]=1.CC(N=NC(C#N)(C)C)(C#N)C.[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:25])=[C:6]([F:11])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(F)c1
Yield: 41 %

Procedure:
3-Fluoro-4-methylbenzoic acid methyl ester from Example E3.1 (4.5 g, 26.6 mmol) was dissolved in carbon tetra-chloride (150 ml). AIBN (457 mg, 2.7 mmol) and N-bromosuccinimide (5.2 g, 29.3 mmol) were added and the mixture was heated at reflux for 18 h. The mixture was allowed to cool and further portions of AIBN (457 mg, 2.7 mmol) and N-bromosuccinimide (5.2 g, 29.3 mmol) were added. The mixture was heated at reflux for 56 h. The mixture was allowed to cool and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% EtOAc:90% pet ether) to yield the title compound (2.7 g, 41%).
Reaction SMILES: [C:1]([C:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]=1)([O:3][CH3:4])=[O:2].[Al]>O1CCCC1>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1=NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Agent: [Al]
Solvent: C1CCOC1
Product: COC(=O)C1NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Yield: 62.3 %

Procedure:
A solution of 75 g of benzyl α-(3-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-α-isopropylideneacetate in 900 ml of tetrahydrofuran containing 5% water is mixed with aluminium amalgam which has been prepared from 26.3 g of aluminium and 2.5% aqueous solution of mercuric chloride, and the mixture stirred under ice-cooling for 20 minutes. The reaction mixture is filtrated through Hyflo Super Cel, diluted with ethyl acetate, washed with an aqueous solution of sodium hydrogencarbonate and water, dried on sodium sulfate, concentrated and then mixed with ether. The resulting crystals are collected by filtration to yield 47.02 g of benzyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 62.4% yield.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.C1COCC1.[CH2:20]([NH2:22])[CH3:21].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:22]([CH2:20][CH3:21])[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Reactant: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCN1Cc2cc(Br)cc(Cl)c2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (0.684 g, 2.00 mmol), 2M THF solution of ethyl amine (1.3 mL, 2.6 mmol), and K2CO3 (0.552 g, 4.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-ethyl-2,3-dihydro-isoindol-1-one (0.203 g, 37%). GC-MS: m/z 275 (M)+, 258 (M−27)+. 1H NMR (300 MHz, CDCl3): δ (ppm) 1.24 (t, 3H), 3.64 (q, 2H) 4.34 (s, 2H), 7.50 (s, 1H), 7.58 (s, 1H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[OH-].[Na+].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[N:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH2:9][CH2:10]1)[CH3:24]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCCN1CCN(c2ncccn2)CC1
Temperature: 25 °C
Yield: 75 %

Procedure:
1.2 equivalents of 1-(2-pyrimidinyl)piperazine hydrochloride was dissolved in water and the solution made strongly basic (pH 12-14) with 10% NaOH. The 2-phase mixture (the product is a yellow oil) was extracted three times with methyl isobutyl ketone (MIBK). The MIBK solution resulting was placed in a single neck round bottom flask fitted with magnetic stirrer, condenser and nitrogen atmosphere, and a Dean-Stark trap. To this solution was added 1 equivalent of ethyl 4-bromobutyrate, 1.1 equivalent of Na2CO3 and a catalytic quantity of KI. The resulting mixture was then refluxed for 4 hours and then cooled to room temperature. Inorganic solids were filtered off and the filtrate was condensed to give the title compound yellow oil. Yield 75%.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:12][CH:11]2[CH:7]([CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10]2)[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([OH:20])[CH2:5]1)#[N:2].Cl>O1CCOCC1>[C:1]([CH2:3][CH:4]1[CH2:12][CH:11]2[CH:7]([CH2:8][NH:9][CH2:10]2)[C:6]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([OH:20])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC2CC(CC#N)CC(O)(c3ccccc3)C2C1
Agent: Cl
Solvent: C1COCCO1
Product: N#CCC1CC2CNCC2C(O)(c2ccccc2)C1
Yield: 83.4 %

Procedure:
The procedure is as described for Example 13 below, starting from 1.05 g of (3aRS,4RS,6RS,7aSR)-6-cyanomethyl-4-phenyl-2-tert-butyloxycarbonylperhydroisoindol-4-ol and 5 cm3 of a 7N solution of hydrochloric acid in dioxane, and gives 0.63 g of (3aRS,4RS,6RS,7aSR)-6-cyanomethyl-4-phenylperhydroisoindol-4-ol in the form of a thick white foam.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=O)[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12](=[NH:17])(OCC)[CH3:13].C(N(CC)CC)C>C(O)C>[CH3:13][C:12]1[NH:2][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:9]([CH3:10])[N:17]=1
Reactant: CCOC(=O)C(N)C(C)=O
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1[nH]c(C)nc1C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
Ethyl 2-amino-3-oxobutanoate hydrochloride (5 g) was added portionwise to a solution of ethyl ethaneimidate (34.0 g) and triethylamine (42 ml) in ethanol (500 ml), and the resulting yellow solution was stirred overnight. Solvent was removed in vacuo and the residue partitioned between water (200 ml) and ether (200 ml). The organic layer was separated and the aqueous phase further extracted with ether (2×200 ml). The dried organic extracts were evaporated in vacuo and the residue washed with cold ether and filtered to give the title compound as a white solid (1.1 g). m.p. 165-166° C.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10]=[C:11]2[NH:15][C:14](=[O:16])[CH:13]=[C:12]2[OH:17])=[CH:8][CH:7]=1>C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[C:11]2[NH:15][C:14](=[O:16])[C:13](=[N:1][OH:3])[C:12]2=[O:17])=[CH:18][CH:19]=1
Reactant: O=C1C=C(O)C(=Cc2ccc(Cl)cc2)N1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=Cc2ccc(Cl)cc2)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-(4-chlorobenzylidene)-4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H.-D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(4-chlorobenzylidene)-pyrrolidine-2,3,4-trione 3-oxime was 50%, with a melting point of 190° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15](=O)[CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CCO>[C:17]1([S:23][C:15]2([S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:10]=3)[C:9]3[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=3[CH2:12][CH2:13][CH2:14]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCNC(=O)Nc1nc2c(s1)C(=O)CCC2
Reactant: Sc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCNC(=O)Nc1nc2c(s1)C(Sc1ccccc1)(Sc1ccccc1)CCC2
Temperature: 20 °C
Reaction time: 2 h
Yield: 200.4 %

Procedure:
A suspension of N-ethyl-N′-(7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)urea (1.0 g, 4.18 mmol) and thiophenol (0.59 mL, 4.74 mmol) in EtOH (20 mL) was saturated with HCl (g) at about 0° C. The reaction mixture was stirred at about 20° C. for about 2 hrs then a second portion of thiophenol (0.59 mL, 4.74 mmol) was added and the reaction mixture stirred for about another 2 hrs. The ethanol was removed in vacuo and H2O was added. The aqueous phase was neutralized by addition of 2M NaOH and the product was extracted into CH2Cl2 (4 times). The combined organic phases were dried over MgSO4. Evaporation of the solvent gave 1.85 g (quantitative yield) pure product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:35][CH2:36][CH2:37][CH2:38][C:39]#[N:40]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:19]=[C:20]([O:22][CH2:35][CH2:36][CH2:37][CH2:38][C:39]#[N:40])[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCCCCBr
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCCCCC#N)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 99.9 %

Procedure:
Using 0.85 g (1.88 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic acid tert-butyl ester and 5-bromo-pentanenitrile (0.304 g, 1.88 mmol) and following the procedure of Example 42(b) afforded 1.0 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (3H, m), 1.4 (9H, s), 18 (7H, m), 2.6 (3H, m), 3.2 (1H, m), 3.7 (1H, m), 4.2 (2H, m), 6.76 (1H, d), 6.92 (1H, s), 7.14 (3H, m), 7.34 (1H, s), 7.88 (2H, d), 8.28 (1H, d).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li+].CC([N-]C(C)C)C.C([Li])CCC.C(NC(C)C)(C)C.I[CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49]>C1COCC1.CCCCCC>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CI
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(S(=O)(=O)CC[Si](C)(C)C)cc1C(=O)O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a stirred −70° C. suspension of 0.26 g (1 mmol) 2-isopropoxy-5-methanesulfonyl-benzoic acid (CAS: 845616-02-6) and 0.75 ml (5 mmol) TMEDA in 2.6 ml THF was added dropwise a LDA solution (prepared from a 1.3 ml (2.1 mmol) 1.6M n-butyllithium solution in hexane and 0.3 ml (2.1 mmol) diisopropylamine in 2.5 ml THF at 0° C.). The light yellow suspension was stirred at −70° C. for 30 minutes. A solution of 0.19 ml (1.3 mmol) (iodomethyl)trimethylsilane in 0.5 ml THF was added dropwise over a period of 5 minutes. The yellow suspension was stirred at −70° C. for 15 minutes and then allowed to warm to room temperature. The light yellow solution was stirred at room temperature for 1 hour and then quenched with 5 ml brine. The mixture was diluted with 5 ml water. The mixture was concentrated in vacuo. The aqueous layer was carefully acidified with HCl 1N and extracted 3 times with dichloromethane. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 0.21 g (63%) of the title compound as a yellow oil. MS (m/e): 343.0 [M−H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=1[OH:5].[C:11](O)(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].B(F)(F)F.CCOCC.O.O.O.C([O-])(=O)C.[Na+]>ClC(Cl)C.O>[OH:10][C:8]1[CH:9]=[C:3]([O:2][CH3:1])[C:4]([OH:5])=[CH:6][C:7]=1[C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: COc1cc(O)ccc1O
Reactant: O=C(O)CCCCC(=O)O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: COc1cc(O)c(C(=O)CCCCC(=O)O)cc1O

Procedure:
Seven grams of 2-methoxyhydroquinone and 13.6 g of the monomethyl ester of adipic acid in 60 ml of dichloroethane are mixed under nitrogen in a three-necked flask. Thirteen milliliters of boron trifluoride etherate is run in at room temperature. After five hours of refluxing, the reaction medium is poured into a mixture of 40 g of sodium acetate trihydrate and 100 ml of water. The product is extracted with 500 ml of ethyl acetate, washed, dried, and concentrated under vacuum. The residue is treated with a mixture of 1.4 ml of concentrated sulfuric acid, 14 ml of water, and 40 ml of acetic acid at 80° C. for three hours, then the solution is poured into 100 ml of ice water. The precipitate is filtered, washed several times with 20 ml of water, and dried. The solid is recrystallized from a mixture of ethyl acetate and isopropyl ether, yielding yellow crystals with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O)=O>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:3]=1[C:4]1[NH:14][C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Nc1cc(Cl)ccc1[N+](=O)[O-])c1cc([N+](=O)[O-])ccc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c(-c2nc3cc(Cl)ccc3[nH]2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 15.8 %

Procedure:
2-Chloro-N-(5-chloro-2-nitro-phenyl)-5-nitro-benzamide (1.78 g; 5 mmol) was dissolved in glacial acetic acid (30 ml) and heated to 70° C. Zinc powder (3.3 g; 50 mmol) was added portionwise. After 2 hours, the reaction was filtered and the solid washed with acetonitrile. The solvents were evaporated and the residue loaded onto a silica gel chromatography column using dichloromethane/triethylamine. Elution with 20% ethyl acetate in heptane gave 4-chloro-3-(5-chloro-1H-benzoimidazol-2-yl)-phenylamine as an orange powder (0.22 g, 16%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[N:12][C:11]([CH2:14][OH:15])=[N:10]1.[H-].[Na+].CS([C:22]1[N:23]([CH3:33])[C:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[N:25][N:26]=1)(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[N:12][C:11]([CH2:14][O:15][C:22]2[N:23]([CH3:33])[C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[N:10]1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Reactant: Cc1ccc(F)c(-n2nnc(CO)n2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(F)c(-n2nnc(COc3nnc(-c4ccncc4)n3C)n2)c1

Procedure:
The title compound is prepared from [2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol), sodium hydride (1.5 mmol) and 4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[O:7])=[CH:4][CH:3]=1.[OH:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].C(N(CC)CC)C.[OH-].[Na+].Cl>C(#N)C>[OH:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])=[CH:4][CH:3]=1)=[O:24]
Reactant: COC(=O)CCCCCNC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)CCCCCNC(=O)c1ccc(NC(=O)c2ccccc2O)cc1

Procedure:
To a solution of 2.81 g (10.64 mmol) of methyl 6-(4-aminobenzoylamino)hexanoate dissolved in 50 ml of acetonitrile, very slowly add 1.42 g (9.10 mmol) of 2-hydroxybenzoyl chloride dissolved in 5 ml of acetonitrile. Then add 0.92 g (9.10 mmol) of triethylamine and keep the reaction mixture at room temperature for 24 hours. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the solid has completely disappeared. Immediately acidify with concentrated hydrochloric acid, filter the resulting solid and wash several times with water. Purify the reaction product by recrystallization (EtOH/H2O). This yields 1.11 g (33%) of 6-[4-(2-hydroxybenzoylamino)benzoylamino]hexanoic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[CH2:13]([O:15][C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH3:14]>C1(C)C=CC=CC=1>[C:7]1([C:5]2[CH:6]=[C:2]([NH:1][C:19]([NH:18][C:16](=[O:17])[O:15][CH2:13][CH3:14])=[S:20])[NH:3][N:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Reactant: CCOC(=O)N=C=S
Solvent: Cc1ccccc1
Product: CCOC(=O)NC(=S)Nc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.3 %

Procedure:
To a cold (0° C.) solution of 3-amino-5-phenylpyrazole (10.0 g, 62.8 mmol) in toluene (100 mL) was added ethoxycarbonyl isothiocyanate (8.3 mL, 70 mmol) dropwise via a pressure equalizing funnel. Upon complete addition, the cold bath was removed and the resulting solution was stirred at room temperature for 15hours, at which time a heavy white precipitate had formed. The precipitate was collected by filtration and dried to give ethyl [(3-phenyl-1H-pyrazol-5-yl)amino]carbothioylcarbamate (11 g, 60%) as a white solid. 1H-NMR (DMSO-d6): δ 13.25 (s, 1H), 12.06 (s, 1H), 11.40 (s, 1H), 7.75 (d, 2H), 7.5–7.3 (m, 4H), 4.25 (q, 2H), 1.29 (t, 3H); MS m/z 291 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1.[CH3:30][S:31]([CH2:34][CH2:35][NH2:36])(=[O:33])=[O:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:36][CH2:35][CH2:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:25])=[CH:27][CH:28]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1
Reactant: CS(=O)(=O)CCN
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)cc2)c2ccc(Cl)cc2F)ccc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)NCCS(C)(=O)=O)cc2)c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-[1-(4-chloro-2-fluoro-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-benzoic acid (example 311, step 4) was coupled with 2-methanesulfonyl-ethylamine using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a colourless foam, MS (ESI+): m/z=519.2 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=O)=[CH:26][C:21]=2[O:20][CH2:19]1>>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]3[N:2]([CH3:1])[C:3](=[O:4])[C:5]4[C:6]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=5[Cl:17])=[N:7][O:8][C:9]=4[CH:10]=3)=[CH:26][C:21]=2[O:20][CH2:19]1
Reactant: CNC(=O)c1c(-c2ccccc2Cl)noc1C
Reactant: O=Cc1ccc2c(c1)OCO2
Product: Cn1c(-c2ccc3c(c2)OCO3)cc2onc(-c3ccccc3Cl)c2c1=O

Procedure:
This compound is obtained using 3-(2-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid methylamide and benzo[1,3]dioxole-5-carbaldehyde in 35% as a beige solid. Mass spectrum: m/z (M+H)+: 380.9, 382.9
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:15]([CH2:18][CH3:19])([O-:17])=[O:16]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:18]([N+:15]([O-:17])=[O:16])[CH3:19])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1ccc(Cl)cc1)[N+](=O)[O-]
Temperature: 105 °C
Yield: 40 %

Procedure:
2.00 g (14.2 mmol) 4-chlorobenzaldehyde (Aldrich, Milwaukee, Wis.), 5.48 g (71.1 mmol) ammonium acetate (Fluka), and 50 g (666 Mmol) nitroethane, 98% (Aldrich) were combined in a 100 ml round bottom flask equipped with magnetic stirrer and nitrogen inlet. The reaction mixture was heated to 105° C. for 90 minutes and the solvent was removed under vacuum to give a dark yellow liquid which was recrystallized from cold methyl alcohol three times to give yellow needles in 40% yield. 1H NMR spectra is shown in FIG. 2.