Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[S:13][CH:14]=[C:15]([Br:17])[N:16]=1>CN(C=O)C>[Br:17][C:15]1[N:16]=[C:12]([S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[S:13][CH:14]=1
Reactant: Fc1ccc(S)cc1
Reactant: Brc1csc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Sc2nc(Br)cs2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
4-Fluorothiophenol (0.48 mL, 4.5 mmol) was dissolved in DMF (10 mL) and then chilled to 0° C. in an ice bath. NaH (0.14 g, 5.8 mmol) was added slowly to the mixture and it was allowed to stir under inert atmosphere. After 1 hour, 2,4-dibromothiazole (1.0 g, 4.1 mmol) was added to the mixture and the ice bath was removed. The resulting mixture was allowed to stir 3 hours under an inert atmosphere. The mixture was quenched with 1N NaOH and diluted with DCM. The aqueous layer was extracted three times with 4:1 DCM/MeOH, and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (1-10% EtOAc/hexanes) to give 4-bromo-2-(4-fluorophenylthio)thiazole (1.0 g, 84% yield) as a white solid. MS (ESI pos. ion) m/z: 290 (MH+, 79Br), 292 (MH+, 81Br). Calculated exact mass for C9H5BrFNS2: 289 (79Br), 291 (81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[CH2:31][CH2:32][CH2:33][NH2:34]>>[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[CH2:31][CH2:32][CH2:33][NH:34][C:18]([C:12]1[CH:11]=[C:10]2[C:15]([C:16](=[O:17])[N:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:8](=[O:21])[NH:9]2)=[CH:14][CH:13]=1)=[O:19]
Reactant: O=C(O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Reactant: CC1CCCCN1CCCN
Product: CC1CCCCN1CCCNC(=O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1

Procedure:
65 mg (52%) of the target compound was obtained in the same manner of Example 1, using 3-(4-chloro-benzyl)-2,4-dioxoquinazoline-7-carboxylic acid (90 mg, 0.272 mol) obtained in Example 1 and 3-(2-methyl-piperidine-1-yl)-propylamine (103 mL, 0.598 mmol).
Reaction SMILES: [OH:1][CH:2]([CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]CC)[CH2:3][NH:4][C:5]([CH3:16])([CH3:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[ClH:27].OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1.[ClH:53].OC(COC1C=CC([Cl:78])=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:78].[OH:1][CH:2]([CH2:17][O:18][C:19]1[CH:20]=[C:21]([Cl:27])[CH:22]=[C:23]([Cl:53])[CH:24]=1)[CH2:3][NH:4][C:5]([CH3:15])([CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Reactant: CCCCCCCCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cc(Cl)cc(Cl)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 382 (M-15,1), 280 (11), 279 (9), 278 (65), 277 (16), 276 (100), 163 (8), 146 (5), 144 (5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:11][C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[C:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCC1
Reactant: O=[N+]([O-])c1cc(Cl)cc2c(-c3ccccc3)c[nH]c12
Product: Clc1cc(NC2CCCC2)c2[nH]cc(-c3ccccc3)c2c1

Procedure:
5-Chloro-7-nitro-3-phenyl-1H-indole prepared in Preparation 41 and cyclopentanone were reacted according to the same procedure as Example 1 to give the title compound.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC>[F:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1F
Temperature: 145 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
Potassium fluoride (69.6 g; 1.2 mole) and hexadecyltributylphosphonium bromide (25.2 g; 0.04 mole) were added to molten 2-chloronitrobenzene (157.5 g; 1 mole). After stirring at 145° C. for 24 hours and a similar work-up to Example 1, 2-fluoronitrobenzene was obtained in 91.2% yield together with 2.4% recovered 2-chloronitrobenzene.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:37])[C:11]2([CH2:16][CH2:15][N:14]([C:17]([CH:19]([NH:29][C:30](=[O:35])[C:31]([NH2:34])([CH3:33])[CH3:32])[CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:18])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:36].[BH4-].[Na+]>>[ClH:1].[CH3:2][C:3]1([CH3:37])[C:11]2([CH2:16][CH2:15][N:14]([C:17]([CH:19]([NH:29][C:30](=[O:35])[C:31]([NH2:34])([CH3:32])[CH3:33])[CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:18])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[OH:36]
Reactant: CC(C)(N)C(=O)NC(COCc1ccccc1)C(=O)N1CCC2(CC1)c1ccccc1C(=O)C2(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(N)C(=O)NC(COCc1ccccc1)C(=O)N1CCC2(CC1)c1ccccc1C(O)C2(C)C
Yield: 63.8 %

Procedure:
The title compound (16.1 mg, 0.030 mmol) was prepared from the intermediate obtained from Example 9, Step D (25 mg, 0.047 mmol) according to the procedure described for Example 5 (Step A) except that a large excess of sodium borohydride was used instead of a slight excess.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([CH3:13])=[N:10][C:9]=2[CH:14]([CH3:18])[CH2:15][O:16][CH3:17])[CH:5]=[CH:4][N:3]=1.[O:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=1)(=[O:28])=[O:27].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].Cl.CCOCC>O1CCOCC1.CO.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:17][O:16][CH2:15][CH:14]([C:9]1[N:10]=[C:11]([CH3:13])[NH:12][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:32]2[CH:33]=[CH:34][C:29]([S:26](=[O:27])(=[O:28])[NH:25][CH2:24][CH:20]3[CH2:21][CH2:22][CH2:23][O:19]3)=[CH:30][CH:31]=2)[N:7]=1)[CH3:18]
Reactant: O=S(=O)(NCC1CCCO1)c1ccc(I)cc1
Reactant: COCC(C)c1nc(C)[nH]c1-c1ccnc(N)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CO
Product: COCC(C)c1nc(C)[nH]c1-c1ccnc(Nc2ccc(S(=O)(=O)NCC3CCCO3)cc2)n1
Temperature: 80 °C
Yield: 31.5 %

Procedure:
To a stirred solution of 2-amino-4-(1-methoxyprop-2-yl-2-methylimidazol-5-yl)pyrimidine (Method 53; 118 mg, 0.75 mmol), N-(tetrahydrofur-2-ylmethyl)4-iodobenzenesulphonamide (Method 68; 413 mg, 1.13 mmol), tris(dibenzylideneacetone) dipalladium (0) (35 mg, 0.038 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (47 mg, 0.076 mmol) in dioxane (10 mL) was added sodium t-butoxide (258 mg, 2.69 mmol) and the mixture heated at 80° C. overnight. The reaction was cooled to room temperature and MeOH (5 ml) was added and the mixture poured onto an Isolute SCX-2 column, eluted first with MeOH (10×30 ml) and the product was then eluted with 10% methanolic ammonia (10×30 ml). The solvent was removed by evaporation and the residue purified by flash chromatography on silica gel eluting with DCM/MeOH (100:0 increasing in polarity to 97:3) to yield a foam which was dissolved in MeOH (2 ml) and treated with 1M HCl in ether (300 μL, 0.30 mmol) for 5 minutes. Solvent was evaporated in vacuo to yield a yellow solid (115 mg, 30%). NMR: 1.52 (d, 3H), 1.75 (m, 4H), 2.70 (m, 2H), 2.79 (s, 3H); 3.16 (s, 3H), 3.63 (m, 5H), 5.65 (m, 1H), 7.25 (d, 1H), 7.56 (t, 1H), 7.70 (d, 2H), 7.88 (d, 2H), 8.21 (s, 1H), 8.68 (d, 1H), 10.19 (brs, 1H); m/z 487.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>O1CCCC1>[CH2:15]([N:17]([CH2:18][CH3:19])[S:11]([C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10])(=[O:13])=[O:12])[CH3:16]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)S(=O)(=O)c1sc(NC(C)=O)nc1C
Reaction time: 4 h

Procedure:
2-Acetamido-4-methylthiazole-5-sulfonyl chloride (5.2 g) in tetrahydrofuran (100 cm3) was stirred at ambient temperature and treated portionwise with diethylamine (4.5 cm3). The mixture was stirred for 4 hours, evaporated under reduced pressure and the residue extracted into ethyl acetate (200 cm3), washed with water (2×100 cm3), dried (MgSO4) and re-evaporated under reduced pressure to give N,N-diethyl 2-acetamido-4-methylthiazole-5-sulfonamide (4.9 g). 1H NMR: δ 1.20(6H,t); 2.28(3H,s); 2.57(3H,s); 3.32(4H,q); 9.7(1H,br s); (solid).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:16])[C:3]=1[N:17]1[C:21](=[O:22])[NH:20][C:19]([C:23]2[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=2)=[N:18]1.[C:30]([CH:32]1[CH2:34][CH2:33]1)#[CH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:16])[C:3]=1[N:17]1[C:21](=[O:22])[NH:20][C:19]([C:23]2[CH:28]=[CH:27][C:26]([C:31]#[C:30][CH:32]3[CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[N:18]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1F
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c1F
Yield: 41 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 by using N-(4-chloro-2-fluoro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide (Intermediate-68, 0.050 g, 0.094 mmol), ethynylcyclopropane (0.009 g, 0.142 mmol), TBAF (0.074 g, 0.283 mmol), bis(triphenylphosphine)palladium(II) chloride (0.003 g, 0.003 mmol) and DMSO (3.0 mL) to afford 0.018 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 0.75 (m, 2H), 0.77-0.91 (m, 2H), 1.36 (s, 9H), 1.53-1.59 (m, 2H), 7.38 (t, J=5.9 Hz, 1H), 7.46-7.52 (m, 3H), 8.79 (d, J=4.4 Hz, 2H), 8.19 (t, J=4.3 Hz, 1H); MS (m/z): 467.15 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C:5](=[O:7])[CH2:4][C@H:3]1[C:8]([O:10]C)=[O:9].[OH-].[Na+].Cl>CO>[CH3:1][C@@H:2]1[CH2:6][C:5](=[O:7])[CH2:4][C@H:3]1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)[C@@H]1CC(=O)C[C@H]1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CC(=O)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
Methyl trans-2-methyl-4-oxocyclopentanecarboxylate [K. Kojima et at., Chem. Pharm. Bull., 33, 2750 (1985)] (495 mg) was dissolved in methanol (3 ml), and a 1N aqueous solution of sodium hydroxide (3.5 ml) was added to the solution at 0° C. After the mixture was stirred at room temperature for 1 hour, it was acidified with dilute hydrochloric acid, followed by extraction with ether. The extract was concentrated to dryness and the residue was subjected to silica gel column chromatography with ethyl acetate-chloroform (1:1) as eluent, and the eluted fractions were combined and concentrated to dryness to afford the title compound (219 mg) as crystals.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH2:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=3[C:27]3[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[N:31][CH:32]=3)=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH2:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=3[C:27]3[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[N:31][CH:32]=3)=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(OC)cc2CNc2ccc(-c3ccc(Cl)c(Cl)c3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(=O)NCCC(=O)O)nc2)c(CNc2ccc(-c3ccc(Cl)c(Cl)c3)cc2)c1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.20 mL, 0.60 mmol) was added to a THF solution (3 mL) of ethyl 3-(5-(2-(((3′,4′-dichloro-[1,1′-biphenyl]-4-yl)amino)methyl)-4-methoxyphenyl)picolinamido)propanoate (116 mg, 0.20 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:23]=[CH:22][C:10]([O:11][Si](C(C)C)(C(C)C)C(C)C)=[CH:9][C:8]=2[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:6][CH2:5]1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4]1([C:7]2[CH:23]=[CH:22][C:10]([OH:11])=[CH:9][C:8]=2[C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1(c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC1(c2ccc(O)cc2C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.8 %

Procedure:
To a solution of [4-(1-ethoxycyclopropyl)-3-tert-butyl-phenoxy]-triisopropyl-silane (Intermediate 108, 600.0 mg, 1.54 mmol) in 3 mL THF at 0° C. was added tetrabutylammonium fluoride (802.8.0 mg, 3.07 mmols; 3.1 mL of a 1M solution in THF). The solution was stirred at 0° C. for 30 minutes and then quenched by the addition of H2O. The mixture was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound (400 mg, 88%) was isolated from the residue by column chromatography (4-10% EtOAc-hexanes) as a colorless solid.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)=[N:16][CH:17]=2)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][CH2:30][CH3:31]>C(OCC)(=O)C.O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([CH2:29][CH2:30][CH3:31])[N:2]=3)[CH2:8][CH2:7]2)[C:10]([C:12]2[CH:17]=[N:16][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)=[N:14][CH:13]=2)=[O:11])[CH2:25][CH2:24]1
Reactant: CCCC(=N)NO
Reactant: N#CN1CCC(N(C(=O)c2cnc(-n3ccnc3)nc2)C2CC2)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1noc(N2CCC(N(C(=O)c3cnc(-n4ccnc4)nc3)C3CC3)CC2)n1
Reaction time: 24 h

Procedure:
To 2-imidazol-1-yl-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide (50 mg, Intermediate 33) and N-hydroxy-butyramidine (30 mg) in ethyl acetate (12 mL) and tetrahydrofuran is added zinc chloride (0.64 mL, 0.7 M in tetrahydrofuran) and the mixture is stirred for two weeks. Again zinc chloride solution and N-hydroxy-butyramidine are added and stirring is continued at room temperature for 24 h. The solvents are removed in vacuo, ethanol (15 mL) and concentrated HCl solution (0.5 mL) are added and the mixture is stirred for 3 h under reflux. After removal of the solvent the residue is purified by HPLC (MeOH, H2O, ammonia) to yield the desired product. LC (method 3): tR=1.51 min; Mass spectrum (ESI+): m/z=423 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([CH3:15])=[N:12][C:11]=2[CH:16]=1.O1C2C=CC=CC=2N=C1.[N+:26]([O-])([OH:28])=[O:27]>>[F:6][C:7]1[C:8]([N+:26]([O-:28])=[O:27])=[CH:9][C:10]2[O:14][C:13]([CH3:15])=[N:12][C:11]=2[CH:16]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc2cc(F)ccc2o1
Agent: O=S(=O)(O)O
Agent: c1ccc2ocnc2c1
Product: Cc1nc2cc(F)c([N+](=O)[O-])cc2o1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Concentrated sulfuric acid (60 mL) was stirred mechanically and cooled in an ice/water bath. To this was gradually added 5-fluoro-2-methylbenzoxazole (9), (20 g, 0.132 Moles), at such a rate that the temperature stayed at 15–20° C., over a 15–20 minute period. A solution of concentrated sulfuric acid (11 mL), and concentrated nitric acid (10 mL), was prepared and added drop by drop to the benzoxazole solution at such a rate that the temperature was maintained at approximately 10° C. When this acid solution had been added the cooling bath was removed and the mixture allowed to stir at room temperature for 1 hour. At the end of this period the solution was carefully poured onto ice with good stirring. Sufficient water was then added to get good mixing. The solid was filtered off, washed well with water and air-dried. Yield 16.0 g.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[O:5][C:6]([C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:8]=1.[CH3:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1>CN(C)C=O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:8]=[C:4]([N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH3:23])[O:5][C:6]=2[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:11]=1
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)C(=O)c1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
Sodium hydride(oil, 60%, 710 mg) was gradually added to a mixture of ethyl 2-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]-2-oxoacetate(4.63 g), 2-methylimidazole(1.45 g) and N,N-dimethylformamide(50 ml) at 0° C. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice water to give ethyl 2-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]-2-oxoacetate(3.12 g, 59%). This was recrystallized from ethyl acetate-hexane to give colorless prisms. mp 126-127° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[C:4]([CH3:25])[CH:3]=1.[H-].[Na+].[CH:28]([OH:31])([CH3:30])[CH3:29]>C1COCC1>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:8][N:7]3[C:2]([O:31][CH:28]([CH3:30])[CH3:29])=[CH:3][C:4]([CH3:25])=[N:5][C:6]=23)=[CH:16][CH:15]=1
Reactant: CC(C)O
Reactant: Cc1cc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OC(C)C)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reaction time: 1 h

Procedure:
To a solution of 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (I-3A-4b; 59 mg, 0.15 mmol) in THF (0.5 ml) and isopropanol (0.5 ml) was added NaH (60% dispersion in oil, 30 mg, 0.76 mmol). After stirring for 1 hour, the reaction was extracted from saturated aqueous NaHCO3 with ethyl acetate, the combined organic layers were dried (MgSO4), concentrated and purified on a Biotage™ Flash 12M column using 0–35% ethyl acetate in hexanes as eluant to afford 8A-1 (59 mg, 95%) as a colorless solid: +ESI MS (M+1) 412.4; 1H NMR (400 MHz, CD2Cl2) δ 7.50–7.36 (m, 6H), 7.23 (d, J=8.7 Hz, 2H), 6.19 (s, 1H), 4.99 (septuplet, J=6.1 Hz, 1H), 2.62 (s, 3H), 1.57 (d, J=5.8 Hz, 6H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]([CH3:20])(/[C:15](/[CH2:18][CH3:19])=[CH:16]/[CH3:17])[CH2:13][OH:14].C(N(CC)CC)C>ClCCl.O>[CH3:11][C:12]([CH3:20])(/[C:15](/[CH2:18][CH3:19])=[CH:16]/[CH3:17])[CH:13]=[O:14]
Reactant: C/C=C(\CC)C(C)(C)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: C/C=C(\CC)C(C)(C)C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 62.9 %

Procedure:
A solution of dimethyl sulfoxide (18.7 ml, 260 mmol) in 80 ml of dichloromethane is added dropwise within 5 min to a stirred solution of oxalyl chloride (11 ml, 130 mmol) in 400 ml of dichloromethane cooled to −78° C. The mixture is stirred for 10 min at −70° C. A solution of (E)-2,2-Dimethyl-3-ethyl-3-penten-1-ol 24 (15.57 g, 110 mmol) in 60 ml of dichloromethane is added dropwise within 5 min. The mixture is stirred for 1 h at −70° C. The reaction is quenched by dropwise addition of triethyl amine (76.3 ml, 550 mmol). The mixture is warmed to r.t. within 45 min. Water (400 ml) is added and the mixture is stirred for 10 min. The organic layer is separated off, and the aqueous layer is extracted with diethyl ether (3×200 ml). The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by vacuum distillation affords the title compound 25 (9.7 g, 63%) as a colourless liquid (b.p. 85-86° C./28 mbar). 13C-NMR (100 MHz, CDCl3): δ=203.5; 141.4; 122.6; 52.7; 24.2; 20.9; 14.1; 13.8
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(C=C(C(=O)O)c2ccc(O)cc2)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(C=C(C(=O)O)c2ccc(Oc3ccc(C=O)cc3)cc2)c1
Reaction time: 16 h
Yield: 79.8 %

Procedure:
To a solution of 44 (2.65 g, 10 mmol) in DMF (20 mL) was added sodium hydride (60% dispersion in mineral oil, 0.88 g, 22 mmol). After gas evolution ceased 4-fluorobenzaldehyde (1.60 g, 15 mmol) was added and the reaction was stirred for 16 h. The mixture was poured over 10% citric acid (100 mL), after which a bright yellow solid formed. The solid was washed with water and then the wet solid was azeotroped and recrystallized from toluene to yield 2.97 g (80%) of a yellow solid 45.
Reaction SMILES: C(O)(C)(C)C.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C@H:19]([CH3:20])[CH2:18][N:17]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26](C(O)=O)[CH:25]=3)=[O:22])[C@@H:16]([CH3:33])[CH2:15]2)=[CH:10][C:9]=1[C:34]([F:37])([F:36])[F:35])#[N:7].C1C=CC(P([N:52]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>C(N(CC)CC)C>[NH2:52][C:26]1[CH:25]=[C:24]([NH:23][C:21]([N:17]2[CH2:18][C@@H:19]([CH3:20])[N:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]#[N:7])=[C:9]([C:34]([F:35])([F:37])[F:36])[CH:10]=3)[CH2:15][C@@H:16]2[CH3:33])=[O:22])[CH:29]=[CH:28][N:27]=1
Reactant: C[C@@H]1CN(C(=O)Nc2ccnc(C(=O)O)c2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: C[C@@H]1CN(C(=O)Nc2ccnc(N)c2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 50 ml portion of t-butanol solution containing 1.38 g of (+/−)-trans-4-{[4-(4-cyano-3-trifluoromethylphenyl)-2,5-dimethylpiperazine-1-carbonyl]amino}pyridine-2-carboxylic acid synthesized in the same manner as described in Example 12-1, 1.5 ml of DPPA and 1.5 ml of triethylamine was heated under reflux for 8 hours, and then the solvent was evaporated under reduced pressure. This was mixed with 30 ml of trifluoroacetic acid and stirred at room temperature for 1 hour, the solvent was evaporated under reduced pressure, and then the resulting residue was alkalified with saturated sodium bicarbonate solution. Next, this was extracted with ethyl acetate, the organic layer was washed with purified water and then with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by a silica gel column chromatography to obtain 0.94 g of the title compound from chloroform-methanol (10:1, v/v) eluate. Thereafter, this was crystallized from ethyl acetate-hexane to obtain 0.72 g of the title compound as white crystals.