Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][N:9]=[CH:10][C:11](=[O:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH:25]=[O:26])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>C(O)(=O)C>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:9]=[C:10]([C:11](=[O:13])[CH3:12])[C:25]=2[OH:26])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(=O)C=NNCc1ccccc1
Reactant: CC(C)(C)c1ccc(C(=O)C=O)cc1
Solvent: CC(=O)O
Product: CC(=O)c1nn(Cc2ccccc2)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 100 °C
Reaction time: 6 h
Yield: 11 %

Procedure:
2-Oxopropanal benzylhydrazone (2.314 mmol, 408 mg) synthesized in the same manner as in Reference Synthetic Examples 1 and 2 and (4-tert-butylphenyl)(oxo)acetaldehyde (1.929 mmol, 366.9 mg) synthesized in Reference Synthetic Example 4 were dissolved in acetic acid (9 mL) and stirred at 100° C. for about 6 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/AcOEt=3/1, and 4/1) to give the desired product as a yellow solid (74.1 mg, yield 11%).
Reaction SMILES: [CH:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:6][C:5]([C:19]2[CH:20]=[C:21]([C:25]3([NH:29]S(C(C)(C)C)=O)[CH2:28][O:27][CH2:26]3)[CH:22]=[CH:23][CH:24]=2)=[N:4]1)=[CH2:2].Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>CO>[CH:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)=[CH:6][C:5]([C:19]2[CH:20]=[C:21]([C:25]3([NH2:29])[CH2:28][O:27][CH2:26]3)[CH:22]=[CH:23][CH:24]=2)=[N:4]1)=[CH2:2]
Reactant: C=Cn1nc(-c2cccc(C3(NS(=O)C(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: C=Cn1nc(-c2cccc(C3(N)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of N-{3-[3-(1-ethenyl-5-(4-trifluoromethylphenoxy)-1H-pyrazol-3-yl)phenyl]oxetan-3-yl}tert-butylsulfinamide (1.63 g, 3.22 mmol) in 40 mL of methanol was cooled in an ice bath. 4M HCl in dioxane (3.2 mL, 13 mmol) was added and the mixture was stirred for 45 min. Saturated aqueous NaHCO3 solution was added and mixture was warmed to ambient temperature and extracted with EtOAc. The EtOAc layer was washed with brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give 3-(3-{1-ethenyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)oxetan-3-amine as an oil. Calcd (M+1)+: 402.4. Found: 402.8
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(O[CH2:54][CH2:55][CH:56]1[CH2:60][O:59][C:58]([CH3:62])([CH3:61])[O:57]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:54][CH2:55][CH:56]4[CH2:60][O:59][C:58]([CH3:62])([CH3:61])[O:57]4)[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OCC(CCOS(C)(=O)=O)O1
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCC4COC(C)(C)O4)c4ccc(OC(F)F)cc34)nc12
Temperature: 65 °C

Procedure:
To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.156 mmol) in DMF (5 mL) was added 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl methanesulfonate (42 mg, 0.187 mmol) followed by K2CO3 (65 mg, 0.468 mmol). The mixture was heated at 65° C. for 2 hours. After cooling to room temperature, the mixture was poured into water, filtered, the filter cake washed with water and dried to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide. The crude product was used in the next step without purification. MS: (M+H)+=771.0.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:16][O:15]3)=[CH:10][N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19].Cl.O>CS(C)=O>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[CH:10][C:11]([CH:14]([OH:15])[CH2:16][NH:20][CH2:17][CH2:18][CH3:19])=[CH:12][CH:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1ccc(C2CO2)cn1
Reactant: CCCN
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CCCNCC(O)c1ccc(-n2c(C)ccc2C)nc1
Temperature: 40 °C
Yield: 100 %

Procedure:
To the epoxide from example 40 (900 mg, 4.2 mmol) in DMSO (5 ml) was added propylamine (4 ml, 4.8 mmol) and the reaction mixture was heated to 40° C. for 4 days. The reaction mixture was then cooled and 3M HCl (aq) (10 ml) and water (10 ml) were added before washing with diethyl ether (2×10 ml). This organic layer was discarded. The aqueous layer was basified with NH4OH (5 ml) and extracted with ethyl acetate (3×10 ml). The organic extracts were combined and dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as an oil (1.15 g, 4.2 mmol, 100%). 1H NMR (CDCl3, 400 MHz) δ: 0.93 (t, 3H), 1.62 (m, 2H), 2.11 (s, 6H), 2.69-2.82 (m, 3H), 3.06 (dd, 1H), 3.60 (bs, 2H), 4.92 (dd, 1H), 5.84 (s, 2H), 7.20 (d, 1H), 7.88 (d, 1H), 8.61 (s, 1H). LRMS: m/z 274 (M-H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[CH3:22][OH:23].C[O-].[Na+]>CO>[CH3:22][O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(SCCCCCCBr)CC1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COCCCCCCSC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 4-(6-bromohexylthio)-N-t-butyloxycarbonylpiperidine (4.95 g) in methanol (20 ml) was added 28% sodium methoxide methanol solution (26.6 ml), and the mixture was stirred under reflux for 4 hours. After cooling, the reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (400 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the object compound were collected and evaporated under reduced pressure to give 4-(6-methoxyhexylthio)-N-t-butyloxycarbonylpiperidine (3.32 g).
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[OH:14][CH2:15][CH2:16][C:17]1[O:18][CH:19]=[CH:20][CH:21]=1.CCOCC>CN(C=O)C>[CH3:6][C:7]([Si:10]([CH3:12])([CH3:11])[O:14][CH2:15][CH2:16][C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)([CH3:9])[CH3:8]
Reactant: OCCc1ccco1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCc1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
Imidazole (3.65 g, 53.6 mmol) and TBSCl (6.47 g, 42.9 mmol) were added to the solution of compound 255A (4.00 g, 35.7 mmol) in 50 mL of DMF. The mixture was stirred at rt for 2 h and then the reaction mixture was poured into ether. The ether solution was washed with water (1×), 1 N HCl (1×), water (1×) and brine (1×). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with 30% CH2Cl2/70% hexane gave 7.4 g (32.7 mmol, 91.7%) of 255B as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7](=[NH:10])[O:8][CH3:9].[CH2:15](O)[CH2:16][CH2:17]C>>[OH:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7](=[NH:10])[O:8][CH2:9][CH2:15][CH2:16][CH3:17]
Reactant: COC(=N)c1sc2ccccc2c1O
Reactant: CCCCO
Product: CCCCOC(=N)c1sc2ccccc2c1O

Procedure:
A solution of 12 g of methyl 3-hydroxy-benzo[b]thiophene-2-carboximidate (Example 1) in 300 m. of anhydrous n-butanol is heated under reflux for 4 hours and then concentrated to yield upon crystallization from ethyl acetate solution yellow crystals having an m.p. of 185° C.
Reaction SMILES: [I:1][C:2]1[C:3]2[S:9][CH:8]=[CH:7][C:4]=2[NH:5][N:6]=1.[CH3:10]C([O-])(C)C.[K+].IC>C1COCC1>[I:1][C:2]1[C:3]2[S:9][CH:8]=[CH:7][C:4]=2[N:5]([CH3:10])[N:6]=1
Reactant: CC(C)(C)[O-]
Reactant: Ic1n[nH]c2ccsc12
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2sccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of 3-iodo-1H-thieno[3,2-c]pyrazole (500 mg, 2.0 mmol) in THF (7 ml) at 0° C. was added KOt-Bu (314 mg, 2.8 mmol). The reaction mixture was stirred at 0° C. for 30 min then added iodomethane (0.17 ml, 2.8 mmol). Stirred at 0° C. for 30 min then warmed to room temperature and stirred for 1.5 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane to afford 292 mg (55%) of 3-iodo-1-methyl-1H-thieno[3,2-c]pyrazole as a light brown viscous oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.41 (d, J=5.3 Hz, 1H), 6.97 (d, J=5.3 Hz, 1H), 4.05 (s, 3H). Also isolated 141 mg (27%) of 3-iodo-2-methyl-2H-thieno[3,2-c]pyrazole as an off-white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.36 (d, J=5.3 Hz, 1H), 7.16 (d, J=5.3 Hz, 1H), 4.13 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C[Sn](C)(C)[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.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>[Cl:8][C:7]1[C:2]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ncccc2Cl)cc1
Yield: 82 %

Procedure:
66.7 g (0.451 mol) of 2,3-dichloropyridine and 115 g (0.451 mol) of trimethyl(p-tolyl)tin were dissolved in 1 L of toluene, after which 52.1 g (0.045 mol) of Pd(PPh3)4 was added, and the mixture was heated to reflux for 6˜7 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and to the concentration residue was added 700 mL of distilled water, followed by stirring. The organic layer was separated, treated with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 3-chloro-2-para-tolylpyridine as represented below in a 82% yield.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8](Cl)[N:9]=2)[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:18]3[CH:19]=[CH:20][S:16][CH:17]=3)[N:9]=2)[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: OB(O)c1ccsc1
Reactant: COC(=O)c1sc2ncc(Cl)nc2c1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc2ncc(-c3ccsc3)nc2c1N
Temperature: 95 °C
Yield: 88 %

Procedure:
A solution of the methyl 7-amino-2-chlorothieno[2,3-bjpyrazine-6carboxylate prepared as described in Example 10C (0.190 g), thiophene-3-boronic acid (0.100 g), Pd(dppf)Cl2 (0.032 g) and triethylamine (0.22 mL) in degassed DMF was heated to 95° C. for 4 h, cooled, quenched in water and extracted with 1:1Et2O/EtOAc (3×). The organics were washed 3× with water, brine, dried (Na2SO4), filtered and solvent evaporated to give 0.200 g (88%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.95 (3H, s), 6.23 (2H, br s), 7.50 (1H, dd), 7.79 (1H, dd), 8.05 (1H, dd), 9.00 (1H, s).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][N:9]([CH3:31])[CH2:10][CH:11]([OH:30])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[ClH:32]>CC(C)=O.O1CCOCC1>[ClH:32].[C:4]([O:30][CH:11]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][N:9]([CH3:8])[CH3:31])(=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: CN(C)CC(O)COc1ccccc1CCCCc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CN(C)CC(COc1ccccc1CCCCc1ccccc1)OC(=O)CCC(=O)O
Yield: 93 %

Procedure:
0.57 g of succinic anhydride was added to a solution of 1.79 g of 3-dimethylamino-1-[2-(4-phenylbutyl)phenoxy]-2-propanol [prepared as described in Example 1(b)] in 50 ml of acetone, and the resulting mixture was heated under reflux for 2 hours. At the end of this time, the reaction mixture was cooled, and 1.5 ml of a 4N solution of hydrogen chloride in dioxane were added, and the mixture was allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 2.20 g (yield 93%) of the title compound as colorless crystals, melting at 123°-125° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]=[CH2:17])=[N:5][CH:4]=[C:3]1[C:18]([O:20]CC)=O.[NH3:23]>>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]=[CH2:17])=[N:5][CH:4]=[C:3]1[C:18]([NH2:23])=[O:20]
Reactant: N
Reactant: C=CCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Product: C=CCOc1ccccc1-c1ncc(C(N)=O)c(=O)[nH]1
Reaction time: 18 h

Procedure:
A mixture of ethyl 1,6-dihydro-6-oxo-2-(2-allyloxyphenyl)-pyrimidine-5-carboxylate (5.0 g.) and liquid ammonia (50 ml.) in a steel bomb was kept at 25° for 18 hours and then heated on a steam bath for 2.5 hours. The ammonia was removed. The residue was dissolved in water and the solution acidified with acetic acid. The precipitated title compound (4.4 g., 97%), m.p. 202-204° with resolodification and remelting at 275°-280° , was recrystallized from ethanol to give analytical material, m.p. 205°-207° .
Reaction SMILES: C([NH:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:7]2[C:8]([O:10][C:11](=[O:12])[C:6]=12)=O)(=O)C.[F:19][C:20]1[CH:26]=[CH:25][C:23]([OH:24])=[CH:22][C:21]=1[OH:27].CS(O)(=O)=O>O>[NH2:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:7]2[C:6]=1[C:11](=[O:12])[O:10][C:8]12[C:25]2[CH:26]=[C:20]([F:19])[C:21]([OH:27])=[CH:22][C:23]=2[O:24][C:23]2[C:25]1=[CH:26][C:20]([F:19])=[C:21]([OH:27])[CH:22]=2
Reactant: Oc1ccc(F)c(O)c1
Reactant: CC(=O)Nc1c([N+](=O)[O-])ccc2c1C(=O)OC2=O
Agent: CS(=O)(=O)O
Solvent: O
Product: Nc1c([N+](=O)[O-])ccc2c1C(=O)OC21c2cc(F)c(O)cc2Oc2cc(O)c(F)cc21
Temperature: 80 °C
Reaction time: 60 h
Yield: 60.7 %

Procedure:
3-Acetamido-4-nitrophthalic anhydride (1.3 g, 5.0 mmol) and 4fluororesorcinol (1.3 g, 10 mmol) were added to methanesulfonic acid (10 ml), and the mixture was stirred at 80° C. under an argon atmosphere for 60 hours. The reaction mixture was added with water (120 ml) and refluxed for 2 hours. The reaction mixture was adjusted to pH 2, and precipitates were collected by filtration. The obtained product was dried and purified by silica gel chromatography (3% methanol/97% dichloromethane, v/v) to obtain the title compound (1.3 g, 61%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.C([Li])CCC.[Br:25]C(Cl)(Cl)C(Br)(Cl)Cl.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:25][C:10]1[N:5]2[N:4]=[C:3]([S:2][CH3:1])[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: CSc1nn2ccccc2c1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolving tert-butyl N-[2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (220 mg) in tetrahydrofuran (3 mL), a solution of n-butyllithium in hexane (1.6 M; 1.51 mL) was added dropwise at −78° C. under a nitrogen stream, and the mixture was stirred for 30 minutes. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (384 mg) in tetrahydrofuran (2 mL) was added to the reaction mixture, and stirring was continued for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, the temperature was raised to room temperature, extraction was performed with ethyl acetate and the extract was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and tert-butyl N-[7-bromo-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate was obtained from the n-hexane:ethyl acetate (10:1) fraction as yellow crystals. After dissolving this in 1,2-dimethoxyethane (6 mL) and water (1 mL), 2,4-dichlorophenylboric acid (191 mg), tetrakis(triphenylphosphine)palladium (0) complex (116 mg) and barium hydroxide octahydrate (315 mg) were added and the mixture was heated and stirred at 80° C. for 4 hours under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (160 mg) was obtained from the n-hexane:ethyl acetate (20:1) fraction as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C@H:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)=[O:21])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([C@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:23]2)=[O:21])=[CH:17][CH:18]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: O=C(Nc1ccc(F)cc1)[C@H]1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1
Reaction time: 2.5 h
Yield: 82 %

Procedure:
4-Fluorobenzoyl chloride (53 mL, 0.45 mmol) was added at 0° C. to a solution of (S)-piperidine-3-carboxylic acid (4-fluoro-phenyl)-amide hydrochloride (0.116 g, 0.45 mmol) and triethylamine (131 mL, 0.94 mmol) in dichloromethane (3 mL), under nitrogen atmosphere. The reaction mixture was kept under stiffing at R.T. for 2.5 h, the solvent was evaporated and the residue was diluted with water and ethyl acetate. The phases were separated and the organic layer was washed with HCl 1N (10 mL), with Na2CO3 2M (aq.) (10 mL) and with brine (10 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to give 0.127 g of (S)-1-(4-fluoro-benzoyl)-piperidine-3-carboxylic acid (4-fluoro-phenyl)-amide as a white solid. Yield: 82%; mp=163-164° C.; [α]D20=+54.7° (c=0.995, CHCl3); LCMS (Tr): 6.68 min (Method A); MS (ES+) gave m/z: 345.0.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([NH:16]C(=O)OC(C)(C)C)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)([O-:3])=[O:2].[ClH:24]>O1CCOCC1>[ClH:24].[N+:1]([CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=1)[NH2:16])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NC(C[N+](=O)[O-])c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: NC(C[N+](=O)[O-])c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
Of the compound from Example 12A, 340 mg (1.02 mmol) were admixed at RT with 6.8 ml of a 4N solution of hydrogen chloride in dioxane, and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and dried in an HV. This gave 274 mg (99% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:22]/[C:23](/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:24]\[O:25][CH3:26]>>[CH3:26][O:25]/[N:24]=[C:23](/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)\[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(O)cc2)cc1
Reactant: CO/N=C(\CBr)c1ccccc1
Product: CO/N=C(\COc1ccc(-c2ccc(CCC(=O)O)cc2)cc1)c1ccccc1

Procedure:
Compound 115 was synthesized from ethyl 3-(4′-hydroxybiphenyl-4-yl)propanoate (0.27 g, 1 mmol) and (1Z)-2-bromo-N-methoxy-1-phenylethanimine (0.23 g, 1 mmol) by following the procedure described in scheme 39. (0.2 g, 49.8%) purity: 99.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].[H-].[Na+].[CH2:13]([O:15][C:16](=[O:27])[C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])[CH3:14]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[O:10][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:22]=1)[C:16]([O:15][CH2:13][CH3:14])=[O:27]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CCOC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(Oc2cc(Cl)c(Cl)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 38.8 %

Procedure:
2,4,5-Trichlorophenol (20 g) in dry dimethylacetamide (40 ml) was treated with sodium hydride (5.28 g of 50% dispersion in oil) in portions and the resulting mixture heated to 120° C. Ethyl-5-chloro-2-nitrobenzoate (16.5 g) was added in solution in dry dimethylacetamide (60 ml) and the mixture heated at 160° C. for ten hours. The solvent was removed and the residue washed with water and extracted with ether. The ether solution was extracted with ether. The ether solution was evaporated. The remaining oil solidified and was recrystallised from ethanol to give ethyl 5(2,4,5-trichlorophenoxy)-2-nitrobenzoate (10.9 g) with a melting point of 99°-102° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11].CO[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17].C[O-].[Na+]>C(O)C>[NH2:19][C:18]1[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH3:2])[N:11]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: COC=C(C#N)C#N
Reactant: COc1ccccc1NN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1-n1ncc(C#N)c1N
Yield: 53 %

Procedure:
To a solution of 1-(2-methoxyphenyl)hydrazine hydrogen chloride (3 g, 0.017 mol) in ethanol (50 mL) was added 2-(methoxymethylene)malononitrile (1.89 g, 0.9 eq.) and sodium methoxide (1.92 g, 2.1 eq). The reaction mixture was heated at reflux for 18 h and concentrated. The reaction mixture was partitioned between brine and ethyl acetate. The organic layer was separated, dried with magnesium sulfate, filtered and concentrated. MPLC Biotage chromatography eluting with 20-60% ethyl acetate/hexanes afforded the title compound in 53% yield (1.9 g). 400 MHz 1H NMR (CDCl3) δ 7.64 (m, 1 H), 7.40 (m, 2H), 7.08 (m,2H), 4.51 (bs, 2H), 3.87 (s, 3 H); MS: (M+H m/z=215.2).