Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[CH:12][N:11]=2.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[CH:12][N:11]=2)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1-c1nc2cccnc2o1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1-c1nc2cccnc2o1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
An ice cold solution of 1 gram of 2-(2-aminophenyl)oxazolo[5,4-b]pyridine in 15 ml. of dry pyridine was treated with 1 gram of benzoyl chloride slowly. The reaction mixture was diluted with ice-water and stirred for 10 minutes and the resulting solid was collected on a filter and recrystallized from benzene to give 2-(2-benzoylaminophenyl)oxazolo[5,4-b]pyridine, m.p. 197°-198° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:18])[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCOCC1>[C:1]1([C:7]2[N:8]=[C:9]([NH:18][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([CH3:19])=[CH:21][CH:22]=3)[S:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2nc(-c3ccccc3)c(-c3ccccc3)s2)cc1

Procedure:
4,5-Diphenyl-thiazol-2-ylamine (50.5 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was subjected to microwave irradiation for 5 minutes at 200° C. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (18.6 mg, 0.0502 mmol, 25.1%). ESI-MS m/z calc. 370.1, found 371.2 (M+1)+ Retention time 4.13 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][N:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:34][C:31]3[CH:30]=[N:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=3)=[O:16])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: COc1ccc(N)cn1
Product: COc1ccc(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)cn1

Procedure:
50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-methoxy-5-aminopyridine via Procedure G. The product was purified on reverse phase HPLC to yield N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(6-methoxypyridin-3-yl)terephthalamide. MS (Q1) 459 (M)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.[C:24]([O-])(O)=O.[Na+]>C1COCC1>[CH3:24][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[N:9]=[C:8]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: Cc1cccc2nc(-c3ccccc3[N+](=O)[O-])[nH]c12
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cccc2c1nc(-c1ccccc1[N+](=O)[O-])n2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A solution 4-methyl-2-(2-nitrophenyl)-benzimidazole (5.06 g, 20 mmol) in THF (50 mL) was added to a stirring suspension of NaH (1.2 g, 60% dispersion in mineral oil, 30 mmol) in THF (50 mL) at 0° C. under N2. The mixture was stirred at 0° C. for 30 min. and was then allowed to warm to r.t. for 1 h to form a orange solution. MeI (8.52 g, 60 mmol) was transfered into the above mixture dropwisely by a cannular at r.t under N2. This mixture was stirred for 24 h under N2 to result in a pale yellow solution. Saturated NaHCO3 (100 mL) was added. The water layer was extracted with CHCl3, the combined extracts was washed with brine, dried over Na2SO4. After removing of solvent, the residue was purified by column chromatography on silica gel using a mixture of hexane/ethyl acetate (1:1) as the eluent to give N-methyl-4-methyl-2-(2-nitrophenyl)-benzimidazole (3.0 g, 58%) as a yellow needle crystal. Rf=0.21 (hexane/ethyl acetate 1:1); 1H NMR (300 MHz, CDCl3) δ 2.68 (s, 3H), 3.60 (s, 3H), 7.12 (m, 1H), 7.26 (m, 2H), 7.65-7.80 (m, 3H), 8.23 (d, J=7.9 Hz, 1H). HRMS: Calcd for C15H13N3O2 267.1007, found 267.1007.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:14][C:15]1[C:20]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:29][C:30]1[C:31](=O)[C:32](=[O:36])[C:33]=1[O:34]C>CO>[OH:14][C:15]1[C:20]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:29][C:30]1[C:33](=[O:34])[C:32](=[O:36])[C:31]=1[NH:13][CH:7]([C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:8]1([CH3:12])[CH2:9][O:10][CH2:11]1
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Reactant: COc1c(Nc2cccc(C(=O)N3CCOCC3)c2O)c(=O)c1=O
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc(C(=O)N4CCOCC4)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Reaction time: 72 h
Yield: 63.7 %

Procedure:
205 mg (1.13 mmol) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in solution in 3 ml of methanol were added to a suspension of 249 mg (0.75 mmol) of 3-[2-hydroxy-3-(morpholine-4-carbonyl)phenylamino]-4-methoxycyclobut-3-ene-1,2-dione in 22 ml of methanol. The reaction medium was then heated at 50° C. for two hours and stirred at ambient temperature for 3 days. The reaction medium was concentrated. The residue was taken up with ethyl acetate and was washed twice with a 1 M aqueous sodium dihydrogen phosphate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (25 g prepacked column: eluent heptane/ethyl acetate from 80% to 100% of ethyl acetate). 0.23 g of product were obtained in the form of a yellow solid. Yield=64%, HPLC purity=98.01%
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([NH:9][C:10]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]([S:20]([O-:23])(=O)=[O:21])=[CH:12][CH:11]=1)(=[O:8])[CH3:7].[NH+]1C=CC=CC=1>CN1CCCC1=O>[C:6]([NH:9][C:10]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]([S:20]([Cl:3])(=[O:23])=[O:21])=[CH:12][CH:11]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)[O-])c2cccnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: c1cc[nH+]cc1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Cl)c2cccnc12
Temperature: 0 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
In a 1 liter 3-neck round bottomed flask, fitted with a mechanical stirrer and a calcium chloride drying tube, phosphorus oxychloride (360 ml) was chilled to less than 10° C. N-methylpyrrolidone (20 ml) was added (slight exotherm). When the temperature returned to <5° C., finely ground pyridinium 8-acetamido-5-quinolinesulfonate (36.0 g, 0.104 mole) was added. The reaction mixture was thoroughly packed in ice and stirred for 20 hrs. The resulting brown slurry was slowly added to ca. 2500 ml ice/water (cooled by an external ice-salt bath) with vigorous stirring. After stirring for one hour the product was collected by filtration and yielded 27.9 g (94 percent) of a tan powder, m.p. 203°-204° C. (decomp.).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]([OH:25])([CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[CH:12]([CH3:18])[CH2:13][S:14]C(=O)C>CO>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C@@:11]([OH:25])([CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[C@@H:12]([CH3:18])[CH2:13][SH:14]
Reactant: CC(=O)SCC(C)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](CS)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Under nitrogen atmosphere at room temperature a solution of potassium hydroxide (0.266 g; 4,74 mmoles) in methanol (40 ml) was dropped into a solution of thioacetic acid S-[3-(2,4-dichlorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl] ester, prepared as described in Example 6 (1.72 g; 4.6 mmoles) in methanol (40 ml).
Reaction SMILES: [CH2:1]=[C:2]([CH2:7][C:8]([O:10]C)=O)[C:3]([O:5][CH3:6])=[O:4].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1>CO>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:8](=[O:10])[CH2:7][CH:2]([C:3]([O:5][CH3:6])=[O:4])[CH2:1]2)=[CH:16][CH:15]=1
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: COc1ccc(CN)cc1
Solvent: CO
Product: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
A mixture of dimethyl 2-methylidenebutanedioate (47.5 g, 300 mmol) and 1-(4-methoxyphenyl)methanamine (41.2 g, 300 mmol) in 400 mL of MeOH was stirred at room temperature overnight. The resulting reaction mixture was concentrated in vacuo to remove methanol. The residual brown oil was stirred with 40 mL of EtOAc and 40 mL of PE vigorously. The precipitate was collected by filtration and washed with PE (40 mL×2) to afford methyl 1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carboxylate (68.0 g, yield: 86.1%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][N:50]1[C:58]2[C:53](=[CH:54][C:55]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)=[CH:56][CH:57]=2)[CH:52]=[CH:51]1>CN(C=O)C>[CH3:49][N:50]1[C:58]2[C:53](=[CH:54][C:55]([C:59]3[CH:60]=[C:61]([NH:65][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:62]=[CH:63][CH:64]=3)=[CH:56][CH:57]=2)[CH:52]=[CH:51]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Cn1ccc2cc(-c3cccc(N)c3)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ccc2cc(-c3cccc(NC(=O)c4cc5cccc(O)c5oc4=O)c3)ccc21
Temperature: 25 °C
Yield: 45 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-methyl-1H-indol-5-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.012 g of product in 48% yield: LCMS (ESI) m/z 411 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[CH2:15]([NH2:17])[CH3:16]>>[N:17]12[CH2:8][CH2:9][CH2:10][C:11]1([CH2:6][CH2:5][NH:12][C:2]1[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1)[CH2:2][CH2:16][CH2:15]2
Reactant: CCN
Reactant: O=[N+]([O-])c1ccc(Cl)c2ccccc12
Product: O=[N+]([O-])c1ccc(NCCC23CCCN2CCC3)c2ccccc12
Yield: 65.6 %

Procedure:
1-Chloro-4-nitronaphthalene and 2-(1-azabicyclo-3.3.0]octan-5-yl)ethylamine were reacted in the same manner as in Example 1 to obtain the titled compound in a yield of 65.6%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:27]([F:32])([F:31])C([O-])=O.[Na+]>C(#N)C.O>[Cl:1][C:2]1[C:3]([O:19][CH:27]([F:32])[F:31])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(O)cc21
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(OC(F)F)cc21
Temperature: 80 °C
Yield: 10.6 %

Procedure:
To the stirred solution of 8-chloro-9-hydroxy-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.5 g, 1.456 mmol), prepared as described in Example 89, Part B in acetonitrile (5 mL) was added K2CO3 (0.604 g, 4.37 mmol) followed by sodium 2-chloro-2,2-difluoroacetate (0.444 g, 2.91 mmol). The mixture was heated to 80° C. for 18 h. After cooling, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×80 mL). The organic layer was washed with brine solution, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 8-chloro-9-(difluoromethoxy)-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (50 mg, 0.154 mmol, 11% crude yield) as a semi solid. The material was carried on without further purification. LC/MS (ESI) m/e 325.0 [(M+H)+, calcd for C15H12ClF2N2O2 325.04]; LC/MS retention time (method C): tR=2.39 min.
Reaction SMILES: Br[C:2]1[C:3]([CH3:26])=[C:4]([C:15]([NH:18]C(OC(C)(C)C)=O)=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[NH2:18][C:15]1[C:4]([C:5]([O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:6])=[C:3]([CH3:26])[C:2]([C:27]#[N:28])=[CH:17][CH:16]=1
Reactant: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)OCc1ccccc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1c(C#N)ccc(N)c1C(=O)OCc1ccccc1

Procedure:
A mixture of Example 108A (2 g, 4.8 mmol), zinc cyanide (335 mg, 2.9 mmol), and DMF (48 mL) was degassed with argon for 30 minutes, treated with Pd(PPh3)4 (330 mg, 0.28 mmol), heated to reflux for 1.5 hours, cooled, and filtered. The filtrate was concentrated and purified using a Biotage 40 gram silica gel cartridge to provide the desired product. MS (ESI(−)) m/e 265 (M−H)−; (DCI) m/e 267 (M+H)+, 284 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 7.45 (m, 6H), 6.66 (d, 1H), 6.57 (s, 2H), 5.34 (s, 2H), 3.27 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[N:23]1([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[NH:37])=[CH:31][CH:30]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:38]=[C:36]([NH:35][C:32]4[CH:31]=[CH:30][C:29]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:34][CH:33]=4)[N:37]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Cc1nc2c(s1)-c1nc(Nc3ccc(N4CCOCC4)cc3)ncc1CC2
Yield: 2.1 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (200 mg, 7.6 mmol), N-(4-morpholin-4-yl-phenyl)-guanidine nitrate (215 mg, 7.6 mmol), NaOH (30 mg, 7.6 mmol), and 2-methoxyethanol (2 mL) was heated under reflux for 20 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (5% MeOH:CH2Cl2), followed by crystallisation from EtOAc gave the pure title product as dark orange crystals (60 mg, 21%): mp 236-237° C. Anal. RP-HPLC: tR 13.4 min (0-60% MeCN, purity 100%). 1H-NMR (DMSO-d6): δ 9.26 (s, 1H, NH), 8.20 (s, 1H, Py-H), 7.58 (d, 2H, J 9.2, Ph-H), 6.84 (d, 2H, J 9.2, Ph-H), 3.70 (t, 4H, J 4.8, 2×CH2), 2.99 (t, 4H, J 4.8, 2×CH2), 2.90 (m, 4H, CH2—CH2), 2.66 (s, 3H, CH3).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[Br:15][C:16]1[CH:31]=[CH:30][C:19]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([NH2:29])[CH:25]=[C:26]([Cl:28])[CH:27]=2)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:31]=[CH:30][C:19]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([NH:29][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:25]=[C:26]([Cl:28])[CH:27]=2)=[CH:18][CH:17]=1
Reactant: Nc1cc(Cl)cc(OCc2ccc(Br)cc2)c1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(Cl)cc(OCc4ccc(Br)cc4)c3)ccnc2n1

Procedure:
The product from Example 2g (100 mg, 0.39 mmol) was reacted with the product from Example 196b (120 mg, 0.39 mmol) for 22 h following the procedure from Example 1g giving the crude title compound which was purified by trituration with EtOAc providing the title compound (1990 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.96 (t, J=7.4 Hz, 3H), 1.83 (sextet, J=7.4 Hz, 2H), 2.97 (t, J=7.4 Hz, 2H), 5.18 (s, 2H), 6.91 (d, J=6.7 Hz, 1H), 7.05-7.17 (m, 3H), 7.43 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.5 Hz, 1H), 8.51 (d, J=6.7 Hz, 1H), 9.05 (d, J=8.5 Hz, 1H); MS (ESI+) m/z 482, 484, 486 (M+H)+, (ESI−) m/z 480, 482, 484 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.[CH2:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([Sn](C)(C)C)=[CH:27][N:26]=1)[CH2:22][CH3:23].[Cl-].[Li+]>O1CCOCC1.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:21][CH2:22][CH3:23])=[N:26][CH:27]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: CCCOc1ccc([Sn](C)(C)C)cn1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CCCOc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-bromophenyl)oxazoline (VP4) (2.0 g, 2.9 mmol) was mixed with 2-n-propyloxy-5-trimethylstannylpyridine (4.6 g, 50%, 7.7 mmol), Pd(PPh3)4 (0.35 g, 0.3 mmol) and lithium chloride (50 mg) in dioxane and refluxed under nitrogen (7 hours). After chromatography and recrystallization in heptane/ethyl acetate 95:5, 2-(2,6-difluorophenyl)-4-[4-(2-n-propyloxypyridin-5-yl)phenyl]oxazoline was obtained, 1.21 g, colorless crystals;
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=2[CH3:11])[CH:18]=1)[CH3:13]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: Cc1cc(Br)ccc1C(=O)O
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)cc2C)c1

Procedure:
4-Bromo-2-methylbenzoic acid (120 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:5]=1)([O-])=O.O.C(Cl)Cl.[C:21](O)(=[O:23])[CH3:22]>[Fe]>[CH3:15][CH:14]([S:11]([CH2:10][C:6]1[CH:5]=[C:4]([NH:1][C:21](=[O:23])[CH3:22])[CH:9]=[CH:8][CH:7]=1)(=[O:13])=[O:12])[CH3:16]
Reactant: CC(C)S(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: [Fe]
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cccc(CS(=O)(=O)C(C)C)c1
Temperature: 110 °C

Procedure:
A suspension of crude 1-nitro-3-[(propan-2-ylsulfonyl)methyl]benzene (5.0 g) in acetic acid (58 mL) was treated with iron powder (4.7 g), heated for 22 hours at 110° C. bath temperature and cooled to room temperature. Then water (250 mL) and DCM (250 mL) were added, stirred, filtered, dried with sodium sulfate and condensed. An analytical sample (200 mg) of the crude title compound (5.6 g) was recrystallized from diethyl ether/ethanol (121 mg). Lit.:[Grohmann and Hathaway, Molbank 2006, M502].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[CH2:27](I)[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([N:11]1[C:12]([C:13]([F:16])([F:14])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)=[N:10]1)[CH3:28]
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F

Procedure:
4-(4-Fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole from step 3 (1.81 g, 4.3 mmol) and ethyl iodide (0.86 g, 5.5 mmol) were stirred vigorously in 20 mL dry dimethylformamide (DMF) with finely powdered potassium carbonate (0.58 g, 4.2 mmol) under nitrogen at 25° C. for 18 hours. The mixture was diluted with ethyl acetate and filtered to remove solids. The organic filtrate was washed with two portions of water followed by brine, dried over MgSO4 and concentrated in vacuo. The desired 1-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole was isolated by chromatography on silica gel using ethyl acetate/toluene (10/90) as the eluant, giving 0.65 g (69%) of a white solid: mp 133-135.5° C.