Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22])[CH3:13]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:12][CH3:13])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CCc1ccccc1N=C=O
Product: CCc1ccccc1NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 45.1 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-ethyl phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.44 g, 43%). EI-MS m/z 302(M+H)+
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].[F:30][C:31]([F:35])([F:34])[CH2:32]I>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[O:28][CH2:32][C:31]([F:35])([F:34])[F:30]
Reactant: FC(F)(F)CI
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OCC(F)(F)F)c2)n1

Procedure:
Using the compound obtained in Example 347 and 1,1,1-trifluoro-2-iodoethane, white powdery N-{2-[4-difluoromethoxy-3-(2,2,2-trifluoroethoxy)phenyl]-oxazol-4-ylmethyl}-2-ethoxy benzamide was obtained following the procedure of Example 348.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([O:37][C:38](=[O:44])[CH2:39][CH2:40][C:41](Cl)=[O:42])[CH3:36].C1COCC1>CCOC(C)=O>[CH2:35]([O:37][C:38](=[O:44])[CH2:39][CH2:40][C:41]([NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])=[NH:9])[S:11][C:12]=2[S:32][CH3:33])(=[O:17])=[O:16])[CH:19]=1)=[O:42])[CH3:36]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Reactant: CCOC(=O)CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Temperature: 50 °C

Procedure:
{[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (38.5 mg, 0.07 mmol, Example 25: step c) and 3-chlorocarbonyl-propionic acid ethyl ester (13 μL, 0.09 mmol) were dissolved into THF (1 mL) and heated to 50° C. for one hour. The reaction was dissolved into EtOAc and washed with brine. The combined organic layers were dried, (MgSO4) and the solvents were removed in vacuo. Purification by preparative TLC (30% EtOAc/hexanes) yielded the title compound. ESI-MS (m/z): Calcd. for C30H35N3O7S3: 646.2 (M+1); found: 645.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH2:11][O:10][C:9]2=[O:20])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31]>CS(C)=O>[C:30]([C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[O:19][C:15]1[CH:14]=[C:13]([C@H:12]2[CH2:11][O:10][C:9](=[O:20])[N:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:18]=[CH:17][CH:16]=1)#[N:31]
Reactant: O=C1OC[C@H](c2cccc(O)c2)N1c1ccc(Cl)cc1
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccccc1Oc1cccc([C@H]2COC(=O)N2c2ccc(Cl)cc2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To (S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)oxazolidin-2-one (0.07 mmol) is added K2CO3 (0.14 mmol) and 2-fluorobenzonitrile (0.08 mmol) in DMSO (1 mL). The mixture is degassed with N2 (2×) and stirred at 80° C. for 2-3 hours. The mixture is filtered through a Whatman 0.42 μM filter and purified by preparatory LC-MS (C-18, 10-90% ACN/water (0.05% TFA)). HPLC-MS calculated for C22H15ClN2O3 (M+H+): 391.1, found 391.0.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=2)=[CH:2]1.[CH2:15](O)[CH2:16][CH2:17][CH2:18][OH:19].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>C(OCC)(=O)C>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][N:8]=[N:9]1
Reactant: OCCCCO
Reactant: O=C(O)Cn1nnnc1-c1ccsc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(Cn1nnnc1-c1ccsc1)OCCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a suspension of 1 g (4.76 mM) of [5-(3-thienyl) tetrazol-1-yl]acetic acid and 514 mg (5.71 mM) of 1,4-butanediol in 20 ml of ethyl acetate was added 1.08 g (5.23 mM) of dicyclohexylcarbodiimide at room temperature. After the mixture was stirred at room temperature for 30 min, a small amount of acetic acid was added to the mixture and then was stirred for 30 min. The mixture was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent; chloroform/ethyl alcohol=30/1) for separation and purification, to give 520 mg (yield 38.7%) of [5-(3-thienyl)tetrazol-1-yl]acetic acid 4-hydroxybutyl ester.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:29][C:30]1[CH:43]=[CH:42][C:33]([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]Cl)=[CH:32][CH:31]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][O:35][CH2:34][C:33]3[CH:32]=[CH:31][C:30]([Cl:29])=[CH:43][CH:42]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: ClCCCCCOCc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOCc2ccc(Cl)cc2)CC1
Yield: 94.8 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.0 g) as starting compound, potassium carbonate (1.5 g) and 5-(4-chlorobenzyloxy)pentyl chloride (1.5 g) were reacted and treated in the same manner as in Example 168 to give 1.3 g of 4-amino-5-chloro-N-((1-(5-(4-chlorobenzyloxy)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[F:9][C:10]1[CH:11]=[C:12]([NH:17][CH:18]([C:20](O)=[O:21])[CH3:19])[CH:13]=[C:14]([F:16])[CH:15]=1>>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH:6][C:20](=[O:21])[CH:18]([CH3:19])[NH:17][C:12]1[CH:13]=[C:14]([F:16])[CH:15]=[C:10]([F:9])[CH:11]=1
Reactant: CC(Nc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)C(C)Nc1cc(F)cc(F)c1

Procedure:
Following General Procedure E and using L-alanine methyl ester hydrochloride (Sigma) and N-(3,5-difluorophenyl)-D,L-alanine (from Example C above), the title compound was prepared as a solid (mp=93-95° C.). The reaction was monitored by tlc (Rf=0.4 in 3% methanol/methylene chloride) and purification of this compound was by flash chromatography with 3% methanol/methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([CH3:18])=[C:12]([CH2:14][CH2:15][CH2:16][OH:17])[N:13]=2)=[CH:5][CH:4]=1.O[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=[O:31])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]([CH3:18])=[C:12]([CH2:14][CH2:15][CH2:16][O:17][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([CH:30]=[O:31])=[CH:22][CH:21]=3)[N:13]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: COc1ccc(-c2nc(CCCO)c(C)o2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(CCCOc3ccc(C=O)c4ccccc34)c(C)o2)cc1
Reaction time: 3 h

Procedure:
g of the above prepared 3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propan-1ol (4.04 mmol) was dissolved in 21 ml of toluene and treated successively at 0° C. with 0.696 g of 4-hydroxy-naphthalene-1-carbaldehyde (4.04 mmol), 1.061 g of triphenylphosphine (4.04 mmol), and 0.818 g (4.04 mmol) of DIAD. The cooling bath was then removed and stirring continued for 3 h. Pouring onto crashed ice, twofold extraction with AcOEt, washing with 3N NaOH and water, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=7/3) left finally 1.084 g of the title compound as light yellow gum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([Cl:19])=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([Cl:19])=[CH:12][C:10]=1[NH:11][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1OCc1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
Synthesis of the compounds of general class III begins with the reaction of 2-amino4-chloro-5-nitrophenol at 0-50° C., preferably at room temperature, with benzyl bromide in the presence of potassium carbonate and tetra-N-butylammonium iodide in DMF to give 2-benzyloxy-5-chloro-4-nitroaniline in 56% yield. Subsequent reaction of 2-benzyloxy-5-chloro-4-nitroaniline (25-80° C.), preferably refluxing, with benzoyl chloride in the presence of triethylamine provided N-(2-benzyloxy-5-chloro-4-nitrophenyl)benzamide in 85% yield. Reaction of N-(2-benzyloxy-5-chloro4-nitrophenyl)benzamide with sodium dimethyl malonate anion, generated from reaction of dimethyl malonate with sodium hydride in DMSO, in a DMSO solution at 80-150° C., preferably at 110° C., overnight gave dimethyl 2-(5-benzamido-4-benzyloxy-2-nitro)phenylmalonate in 36% yield. When dimethyl 2-(5-bybenzamido-4-benzyloxy-2-nitro)phenylmalonate was treated with NaOH in ethanol at 25-100° C., preferably refluxing, followed by acidification with HCl and mild heating at 25-100° C., preferably refluxing, provided the desired compound 2-(5-amino-4-benzyloxy-2-nitro)phenylacetic acid in 93% yield. Treatment of 2-(5-amino-4-benzyloxy-2-nitro)phenylacetic acid at 0-50° C., preferably at 5° C. then gradual warming to room temperature, with borane in THF selectively reduced the carboxylic acid group to an alcohol, 2-(5-amino-4-benzyloxy-2-nitro)phenylethanol in 52% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][C:22]2[CH:23]=[N:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1cnc2ccccc2c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1cnc2ccccc2c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 3-aminoquinoline (73.7 mg, 0.51 mmol). The title compound was obtained as a yellow solid (40 mg, 20% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.97 (1H, br), 9.066 (1H, m), 9.02 (2H, m), 8.77 (1H, m), 8.65 (1H, m), 7.95 (2H, m), 7.69 (1H, m), 7.59 (1H, m). MS m/z: 475.23, 477.28 [M+H]+.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:14]1[C:10]2[C:11](=[O:13])[O:12][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1Nc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1Oc2ccccc2Nc2ccccc21
Yield: 52.6 %

Procedure:
A solution of 2-(2-Hydroxy-phenylamino)-benzoic acid (2.0 g, 9 mmol) and p-toluenesulfonic acid (0.5 g) in toluene (200 ml) was heated under N2 with the H2O formed being collected in a Dean-Stark receiver. Upon completion, the organic layer was washed with saturated NaHCO3, dried over anhydrous MgSO4, filtered, and evaporated by a rotatory evaporator to obtain the product (1.0 g, 53%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[C:16]([C:21]([NH2:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[C:16]([C:21]([NH2:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:8])[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: NC(=O)c1ncccc1N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccccc1C(=O)Nc1cccnc1C(N)=O

Procedure:
In a similar manner to Example 1 a) reaction of 2-propoxybenzoyl chloride (0.99 g), 3-aminopicolinamide (0.69 g) and triethylamine (0.51 g) in acetonitrile (15 ml) afforded a crude product which was recrystallised from methanol to afford 3-(2-propoxybenzamido)picolinamide, 0.91 g, m.p. 116°-118° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O)([O-:10])=[O:9].[CH:19]([C:22]1[N:23]=[C:24]([CH3:27])[S:25][CH:26]=1)([CH3:21])[CH3:20]>>[CH:19]([C:22]1[N:23]=[C:24](/[CH:27]=[CH:14]/[C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=2)[S:25][CH:26]=1)([CH3:21])[CH3:20]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: Cc1nc(C(C)C)cs1
Solvent: CC(=O)OC(C)=O
Product: CC(C)c1csc(/C=C/c2cccc([N+](=O)[O-])c2)n1
Yield: 31.9 %

Procedure:
To 11.3 ml of acetic anhydride were added 29.0 g of 3-nitrobenzaldehyde and 27.1 g of 4-isopropyl-2-methylthiazole and the reaction was carried out under nitrogen gas stream at 170° C. for 23 hours. After completion of the reaction, low boiling materials were evaporated under reduced pressure and the residue was recrystallized from ethyl ether-n-hexane to give 16.8 g (yield 32%) of the title compound as yellowish white crystals.
Reaction SMILES: N1([C:6]([C:8]2[CH:9]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[NH:10][C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[O:7])C=CN=C1.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][CH2:41][OH:42]>>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[C:8]([C:6]([O:42][CH2:41][CH2:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)=[O:7])=[C:13]([CH3:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=3)[C:11](=[O:25])[NH:10]2)=[CH:33][CH:32]=1)#[N:31]
Reactant: OCCc1ccccn1
Reactant: CC1=C(C(=O)n2ccnc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Product: CC1=C(C(=O)OCCc2ccccn2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml 2-(2-pyridinyl)ethanol. The reaction mixture is stirred at approx. 100° C. for 1 hour. After cooling the reaction mixture is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% conc. ammonia; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 500 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[CH:9]1([C:15]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)C2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To commercially available nitromethane (5 ml) were added commercially available anisole (0.5 ml), commercially available cyclohexanecarbonyl chloride (0.63 ml) and commercially available ytterbium(III) trifluoromethanesulfonate (288 mg), and the admixture was stirred at 60° C. for 3 hours. The reaction mixture was partitioned between water and chloroform, and the chloroform layer was washed with saturated aqueous sodium hydrogen carbonate and brine and then dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with chloroform to obtain 517 mg of the title compound (yield: 51%).
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][C:34]([O:36]CC)=[O:35])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11].[OH-].[Na+]>>[ClH:1].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][C:34]([OH:36])=[O:35])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccn3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride and sodium hydroxide solution.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:12]([I:13])=[N:11][NH:10][C:7]2=[N:8][CH:9]=1.[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:12]([I:13])=[N:11][N:10]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:7]2=[N:8][CH:9]=1
Reactant: Brc1cnc2[nH]nc(I)c2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
NaH (1.31 g, 32.7 mmol, 60% suspension in mineral oil) was added portionwise to a cold (0° C.) solution of 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (5.3 g, 16.4 mmol) in dry DMF (40 mL) The reaction mixture was stirred at 0° C. for 10 minutes before 2-(trimethylsilyl)ethoxymethyl chloride (4.91 mL, 27.8 mmol) was added dropwise via a syringe. The cold bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was placed in an ice bath, diluted with ethyl acetate (400 mL) and carefully quenched with water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (20:1) to give 5-bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (6.59 g, 89%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-])=O)=[CH:15][C:14]=3[Cl:23])[N:9]=2)=[CH:4][CH:3]=1>C1COCC1.C(O)C.[Pt](=O)=O>[Cl:23][C:14]1[CH:15]=[C:16]([CH:17]=[C:18]([Cl:19])[C:13]=1[N:10]1[CH:11]=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[NH2:20]
Reactant: O=[N+]([O-])c1cc(Cl)c(-n2ccc(-c3ccc(Cl)cc3)n2)c(Cl)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(Cl)c(-n2ccc(-c3ccc(Cl)cc3)n2)c(Cl)c1
Reaction time: 2 h

Procedure:
A solution of 3-(4-chlorophenyl)-1-(2,6-dichloro-4-nitrophenyl)-pyrazole (0.69 g, 1.87 mmol), prepared following the procedure of Example 9, in THF/ethanol (1:4; 35 ml) is treated with platinum dioxide (43 mg) and stirred under H2 at atmospheric pressure for 2 hours. The reaction mixture is filtered and concentrated to give 3,5-dichloro-4-[3-(4-chlorophenyl)-1-pyrazolyl]aniline.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[CH:18]=[CH:19][C:20]([CH:25]=C)=[CH:21][C:22]=5[O:23][CH2:24][C:13]=34)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+].O>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[CH:18]=[CH:19][C:20]([CH:25]=[O:35])=[CH:21][C:22]=5[O:23][CH2:24][C:13]=34)[C:8]=2[C:27]([F:28])([F:30])[F:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)OCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc2c(c1)OCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.5 %

Procedure:
To a mixture of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4H-chromeno[4,3-c]isoxazole (Preparation 62G, 0.060 g, 0.146 mmol) and a 50% aqueous solution of NMO (0.030 mL, 0.146 mmol) at room temperature was added a 4% aqueous solution of osmium tetroxide (0.046 mL, 5.85 μmol). The reaction mixture was stirred at room temperature for 5 h. The intermediate diol had an HPLC ret. time=3.09 min and an LCMS M+1=445.0. Sodium periodate (0.047 g, 0.219 mmol) was added to the homogeneous mixture followed by water (0.10 mL), and the reaction was stirred for 60 min. at room temperature. Concentration under reduced pressure afforded a tan solid residue that was then diluted with ethyl acetate (40 mL), washed with the water (10 mL), and washed with brine (10 mL). The organic layer was collected, and the aqueous layer was washed with ethyl acetate (40 mL). The combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4H-chromeno[4,3-c]isoxazole-7-carbaldehyde (0.057 g, 0.138 mmol, 95% yield) as a pale yellow solid. The product had an HPLC ret. time=3.49 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA.