Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:3]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:54]1[CH:59]=[C:58]([O:60][CH3:61])[N:57]=[C:56]([S:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[C:65]=2[F:71])[N:55]=1.[Cl-].[NH4+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CCOC(C)=O>[F:71][C:65]1[C:66]([F:70])=[CH:67][CH:68]=[CH:69][C:64]=1[CH2:63][S:62][C:56]1[N:55]=[C:54]([NH:12][S:9]([N:4]2[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]2)(=[O:10])=[O:11])[CH:59]=[C:58]([O:60][CH3:61])[N:57]=1
Reactant: C[C@@H]1CN(S(N)(=O)=O)C[C@H](C)N1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(NS(=O)(=O)N2C[C@@H](C)N[C@@H](C)C2)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of (3R,5S)-3,5-dimethylpiperazine-1-sulfonamide (the product of example 72, 0.26 g), tris(dibenzylideneacetone)-dipalladium (0) (61 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (32 mg), cesium carbonate (0.32 g) and 4-chloro-2[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of example 35 step i, 0.20 g) in anhydrous dioxane (8 ml) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 15 min. Saturated aqueous ammonium chloride (5 ml) and EtOAc (5 ml) were added, followed by H2O. The layers were separated and the organic layer extracted with H2O (×3). The organic layer was discarded and the combined aqueous extracts exhaustively extracted with further EtOAc. These extracts were combined, washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated. The resulting solid was washed with H2O to afford the title compound as a white solid. Yield: 0.111 g
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([S:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][OH:16])[N:13]=1)([CH3:7])[CH3:6])[CH3:2].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([S:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([Br:18])=[CH:20][CH:21]=2)[N:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)C(C)(C)Sc1nc(CCO)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Sc1nc(CCOCc2ccc(Br)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid ethyl ester (1.6 g) synthesized in Example 155-1 and 4-bromobenzylbromide (1.7 g) were dissolved in N,N-dimethylformamide (30 mL), potassium tert-butoxide (0.72 g) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 3:1) to give the title compound (1.3 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=1.O>CS(C)=O>[F:25][C:24]([F:27])([F:26])[C:22]1[CH:21]=[CH:20][N:19]=[C:18]([O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)[CH:23]=1
Reactant: OCCc1ccc(O)cc1
Reactant: Fc1cc(C(F)(F)F)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: OCCc1ccc(Oc2cc(C(F)(F)F)ccn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
2-(4-Hydroxyphenyl)ethanol (4.0 g, 29 mmol), K2CO3 (8.0 g, 58 mmol) and 2-fluoro-4-trifluoromethylpyridine (3.6 g, 22 mmol) were combined in DMSO (30 mL) and stirred at 25° C. for 20 h. The mixture was poured into H2O and extracted twice with Et2O. The combined Et2O extracts were washed with 1M NaOH, H2O, brine, and concentrated in vacuo to give 2-[4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethanol (4.7 g; 57%), mp 78-79° C.; EIMS m/z 283; 1H NMR (300 MHz, DMSO-d6) δ 8.38 (d, J=5.3 Hz, 1H), 7.0-7.5 (m, 8H), 4.67 (t, J=5.0 Hz, 2H), 2.74 (t, J=5.2 Hz, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S1C=CC=C1CC([NH:15][CH:16]1[C:42](=[O:43])[N:18]2[CH:19]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[C:20]([C:23](=[O:25])[CH3:24])=[CH:21][S:22][C@H:17]12)=O.N1C=CC=CC=1.C(Cl)Cl>CCCCCC.C(O)C(C)C>[NH2:15][CH:16]1[C:42](=[O:43])[N:18]2[CH:19]([C:26]([O:28][CH:29]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[C:20]([C:23](=[O:25])[CH3:24])=[CH:21][S:22][C@H:17]12
Reactant: CC(=O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(C)CO
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(=O)C1=CS[C@@H]2C(N)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64 %

Procedure:
Phosphorous pentachloride (0.478 g.) was added to a stirred solution of 1.065 g. of benzhydryl 7-(2-thienylacetamido)-3-acetyl-2-cephem-4-carboxylate and 0.199 ml. of pyridine in 9 ml. of methylene chloride. The reaction mixture was allowed to stir at room temperature for 2.5 hours. After cooling the mixture for 5 minutes in an ice bath, 0.985 ml. of isobutanol was added, and the reaction mixture was subsequently stirred at room temperature for one hour. The addition of n-hexane resulted in the formation of a brown solid from which the liquid was decanted. The residue was dissolved in an ethyl acetate-aqueous sodium bicarbonate slurry and transferred to a separatory funnel with the aid of ethyl acetate. The organic layer was separated and washed successively with aqueous sodium bicarbonate solution, water, and brine (2X), and dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness provided a product which was chromatographed on a silica gel column using a toluene-ethyl acetate gradient to give a 0.521 g. (64 percent) of the title product as a tan froth:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:33])=[C:9]([CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([CH2:26][CH2:27][OH:28])[N:20]=3)=[CH:15][C:14]=2[O:31][CH3:32])[N:10]=1.[CH2:34]([P:43](=[O:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:33])=[C:9]([CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:34]/[P:43](=[O:50])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[CH:22][N:21]([CH2:26][CH2:27][OH:28])[N:20]=3)=[CH:15][C:14]=2[O:31][CH3:32])[N:10]=1
Reactant: COc1cc(COc2nn(CCO)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(CCO)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 9.8 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(2-hydroxyethyl)-1H-pyrazole-4-carbaldehyde (0.50 g), tetraethyl methylenediphosphonate (0.30 g) and N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil, 0.060 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (100:1, v/v) to give diethyl (E)-2-[3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.06 g, yield 15%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.[Br:16][C:17]1[CH:18]=[C:19]([F:24])[C:20](F)=[N:21][CH:22]=1.Cl>CS(C)=O.O>[Br:16][C:17]1[CH:18]=[C:19]([F:24])[C:20]([O:3][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)=[N:21][CH:22]=1
Reactant: Fc1cc(Br)cnc1F
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(Oc1ccc(Oc2ncc(Br)cc2F)cc1)C(=O)O
Reaction time: 0.33 h

Procedure:
A solution of NaOH (0.54 g, 0.013 mol) in a few ml of water was added to -2-(4-hydroxyphenoxy)propionic acid (1.22 g, 0.0067 mol) in 20 ml DMSO and the mixture was stirred for 20 minutes under N2. 5-Bromo-2,3-difluoropyridine (1.3 g, 0.0067 mol) was added and the mixture was stirred for 51/2 hours at 80°-90° C. The reaction mixture was poured into water, acidified with concentrated HCl to pH 1 and extracted into CH2Cl2. The solution was dried over Na2SO4 and the solvent was removed by rotary evaporation to yield a gum which became an off-white solid (0.78 g, 33%, M.P.94°-97° C.) upon standing.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.F[C:12]1[CH:13]=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([NH2:18])[CH:17]=1>>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:12]3[CH:13]=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([NH2:18])[CH:17]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Product: Nc1cc(N2CCC3(CC2)OCCO3)ccc1[N+](=O)[O-]

Procedure:
The title compound was synthesized as described in Method 10, Step 2 from 1,4-dioxa-8-aza-spiro[4.5]decane and 5-fluoro-2-nitrophenylamine. LC/MS (m/z) 280.3 (MH+), Rt 2.41 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:11]=1[C:12]([NH:14][C:15](Cl)=[O:16])=[O:13]>>[Cl:9][C:10]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:11]=1[C:12]([NH:14][C:15]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:16])=[O:13]
Reactant: O=C(Cl)NC(=O)c1c(F)cccc1Cl
Reactant: Nc1ccc(Cl)cn1
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(Cl)cn1

Procedure:
A portion of 5-chloro-2-aminopyridine is reacted with 2-chloro-6-fluorobenzamidocarboxylic acid chloride in the presence of a hydrogen halide acceptor as described in Example 12. The product, named in the heading above, is isolated as described in Example 12 to obtain the desired compound, identical to the product of Example 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=O)[CH2:23][CH3:24])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1.Cl.[CH3:27][O:28][NH2:29].C([O-])(=O)C.[K+]>CO>[CH3:27][O:28][N:29]=[C:22]([C:18]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([O:11][C:5]2[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=2)[CH:21]=[CH:20][CH:19]=1)[CH2:23][CH3:24]
Reactant: CON
Reactant: CCC(=O)c1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CCC(=NOC)c1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OC
Yield: 89.3 %

Procedure:
0.62 g of methyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-propionylbenzoate, 0.45 g of methoxyamine hydrochloride and 0.53 g of potassium acetate were added to 80 ml of methanol, and were heat-refluxed for 6 hours. The precipitated product was filtered out, and the solvent was distilled off. Water was added to the product, and the product was extracted with ethyl acetate. The product was then washed with water, and was dried with magnesium sulfate anhydride. After distilling off the solvent, the mixture was purified by column chromatography, and the purified product was crystallized with isopropyl ether/ethyl acetate to obtain 0.60 g of the aimed compound (melting point=75° to 77° C.) at a yield of 89.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([OH:22])=[O:21])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1.[SH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][S:26][O:21][C:20](=[O:22])[CH2:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:8]([C:6](=[O:7])[C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[CH3:23]
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: SCc1ccccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)c(CC(=O)OSCc1ccccn1)c(C)n2C(=O)c1ccc(Cl)cc1

Procedure:
6.5 g. (0.018 mol.) of 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indol acetic acid are dissolves in 60 ml. of chloroform. After the addition of 2.9 g. (0.023 mol.) of 2-mercaptomethylpyridine and 4.9 g. (0.023 mol.) of N,N'-dicyclohexyl carbodiimide, the reaction mixture is stirred for 24 hours with the exclusion of moisture. The precipitated material is filtered off and the solvent of the resulting solution is distilled in a vacuum. The resulting residue is subjected to chromatography over a silicic acid gel column using a 1:1-mixture of chloroform and hexane as eluant.
Reaction SMILES: CO.C(O)(=O)C.[Br:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([N+:18]([O-])=O)[CH:9]=1.C(=O)([O-])O.[Na+]>[Fe].C(OCC)(=O)C>[NH2:18][C:10]1[CH:9]=[C:8]([Br:7])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Yield: 56.5 %

Procedure:
Iron powder 2.6 g was added to a mixed solution of methanol 20 mL and acetic acid 20 mL of methyl 4-bromo-2-nitrobenzoate 4.0 g, it was heated and refluxed for 3 hours. After the reaction mixture was cooled to room temperature, saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution, and solvent was removed under reduced pressure. Hexane was added to the obtained residue, solid matter was filtrated to give methyl 2-amino-4-bromobenzoate 2.0 g of white solid.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16]CC2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C(=Cc1ccccc1OCc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccccc1CCCc1ccccc1
Yield: 83 %

Procedure:
The whole of this benzyl 2-(3-phenyl-1-propenyl)phenyl ether was treated with hydrogen in the presence of 100 mg of 5% w/w palladium-on-carbon in 40 ml of ethanol at room temperature for 3 hours. At the end of this time, insoluble materials were removed by filtration, and the filtrate was concentrated by distillation under reduced pressure, to give 0.230 g (yield 83%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[C:5]([Cl:10])=[C:4](C)[N:3]=1.NC1C=C(C)C=C(C)N=1>>[CH3:9][C:6]1[C:5]([Cl:10])=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=1[Cl:8]
Reactant: Cc1nc(N)c(Cl)c(C)c1Cl
Agent: Cc1cc(C)nc(N)c1
Product: Cc1c(Cl)cnc(N)c1Cl

Procedure:
Preparation of 2-Amino-3,5-dichloro-4,6-dimethylpyridine can be as described for 2-Amino-3,5-dichloro-4,6-methylpyridine but with 2-amino-4,6-dimethylpyridine as a starting material.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH2:13][NH2:14])[N:9]=1)=[O:7])[CH3:4].C(N(C(C)C)C(C)C)C.[Cl:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>[CH2:3]([O:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH2:13][NH:14][C:30]([C:28]2[S:29][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:31])[N:9]=1)=[O:7])[CH3:4]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CCOC(=O)c1nc(CN)no1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Yield: 81.6 %

Procedure:
To a stirred solution of 3-aminomethyl-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester dihydrochloride (555 mg) at r.t. in DMF (10 ml) under an argon atmosphere were added N-ethyldiisopropylamine (1.82 ml), 5-chloro-2-thiophenecarboxylic acid (565 mg) and BOP (1.54 mg). The mixture was stirred over night, then diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane->cyclohexane/EtOAc 1:1) to give 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (586 mg) as off-white solid. MS 316.0 ([M+H]+)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1C(O)=O)([O-])=O.[N+](C1C=C(C=CC=1)C(O)=O)([O-])=O.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O-])=O.[OH-].[Na+].N(C1C=CC=CC=1)NC1C=CC=CC=1.S(=O)(=O)(O)O>[Zn]>[NH2:25][C:28]1[CH:33]=[CH:32][C:31]([C:10]2[CH:11]=[CH:12][C:4]([NH2:1])=[CH:5][CH:9]=2)=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1ccc(-c2ccc(N)cc2)cc1

Procedure:
A 2-nitrobenzoic acid derivative (e.g. sodium 2-nitrobenzoate) or a 3-nitrobenzoic acid derivative (e.g. sodium 3-nitrobenzoate) and nitrobenzene are treated with zinc dust in the presence of an alkali (e.g. sodium hydroxide) and the resulting hydrazobenzene derivative is treated with sulfuric acid, to give the corresponding 4,4′-diaminobiphenyl derivative. This is diazotized using sodium nitrite under acidic conditions in the presence of hydrochloric acid, followed by reaction with sodium azide, to give the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[CH2:12][CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH:16]=3)=[CH:10][C:3]=12.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O.C(O)C>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][C:9]([C:11]4[CH2:12][CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH:16]=4)=[CH:10][C:3]=23)[CH:23]=1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(Br)ccnc3[nH]2)CC1
Reactant: CC1(C)OB(c2cc(F)ccc2N)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CS(=O)(=O)N1CC=C(c2cc3c(-c4cc(F)ccc4N)ccnc3[nH]2)CC1
Temperature: 25 °C

Procedure:
To a mixture of Example 5F (500 mg, 1.404 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (399 mg, 1.684 mmol) and dichlorobis(triphenylphosphine)palladium (II) (99 mg, 0.14 mmol) in 7:3:2 1,2-dimethoxyethane/water/ethanol (14 mL) was added 2.45 mL 2M aqueous sodium carbonate. The suspension was stirred at room temperature for a few seconds and then stirred in a microwave reactor (Biotage Initiator) at 150° C. for 30 minutes. The mixture was partitioned between ethyl acetate and brine and the organic phase was concentrated. The residue was stirred in 2% methanol in methylene chloride and the solid was collected by filtration to provide the title compound. The mother liquor was purified by flash chromatography on silica gel (Teledyne CombiFlash Rf, 0-15% methanol in dichloromethane) to provide additional title compound. MS (ESI+) m/z 387 (M+H)+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH:11]([N:16]2[CH2:21][CH2:20][C:19]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[CH2:18][CH2:17]2)[CH2:10]1)=O)(C)(C)C>CCOC(C)=O>[ClH:1].[ClH:1].[OH:15][CH:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH:11]1[N:16]1[CH2:21][CH2:20][C:19]2([C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(N2CCC3(CCCc4ccccc43)CC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC1CCNCC1N1CCC2(CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
HCl gas was bubbled for 30 min through a soln of 20c (800 mg, 2.1 mmol) in EtOAc (10 mL) while the flask was maintained in an ice bath. The resulting solution was subsequently stirred at room temperature for 30 min, and the volatiles were removed under reduced pressure. The white solid thus obtained was recrystallized from 50% isopropyl alcohol-hexanes to provide the hydrochlorides of 21c as a white powder (80%). Elemental analysis: Calc: C=61.12, H=8.1, N=7.5; Fnd: C=59.96, H=Elemental analysis: Gale: C=61.12, H=8.1, N=7.5; Fnd: C=59.96, H=7.95, N=6.86.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:36]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:36])=[O:17])=[N:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cc1cc(C(=O)O)ncc1C(Sc1ccc(F)cc1)c1c(F)ccc(F)c1F
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(N)=O)ncc1C(Sc1ccc(F)cc1)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of 5-[[(4-fluorophenyl)thio](2,3,6-trifluorophenyl)methyl]-4-m ethylpyridine-2-carboxylic acid (407 mg, 1.00 mmol) obtained in Example 34 in N,N-dimethylformamide (10 ml), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (781 mg, 1.50 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol), ammonium chloride (107 mg, 2.00 mmol), and N-ethyldiisopropylamine (0.697 ml, 4.00 mmol) were added in an argon atmosphere at room temperature. After stirring for 16 hours at room temperature, ethyl acetate was added to the reaction mixture, and the resulting mixture was washed with 0.5 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=2:1 was concentrated under reduced pressure to obtain the title compound (392 mg, 0.96 mmol, 96%) as a white solid.