Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][NH:19]2)=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1.N1C=CC=CC=1>[F:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][N:19]2[S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[CH:15][CH:14]=1
Reactant: Fc1ccc2c(c1)NCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2CCc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
4-Toluenesulfonyl chloride (460 mg, 2.4 mmol) was slowly added to a solution of 6-fluoro-2,3-dihydro-1H-indole (220 mg, 1.6 mmol) in THF (6 mL) and pyridine (260 μL). The reaction mixture was stirred at room temperature overnight. Upon the completion of the reaction, the mixture was cooled to 0° C., neutralized with aq. sat. NH4Cl (10 mL) and extracted with EtOAc (3×10 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3×10 mL), brine (10 mL) and dried (MgSO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc/hexanes=1/3) gave 283 mg (0.98 mmol) of the title product. Yield: 61%, colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.67 (d, J=8.2 Hz, 2H), 7.35 (dd, J=10.0, 2.3 Hz, 1H), 7.23 (d, J=8.2 Hz, 2H), 6.97 (m, 1H), 6.62 (m, 1H), 3.90 (t, J=8.4 Hz, 2H), 2.84 (t, J=8.4 Hz, 2H), 2.35 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 162.5 (d, J=241.4 Hz), 144.5, 143.3 (d, J=11.7 Hz), 133.6, 129.8, 127.2, 127.0 (d, J=2.6 Hz), 125.7 (d, J=9.8 Hz), 110.0 (d, J=22.6 Hz), 102.8 (d, J=28.4 Hz), 50.7, 27.1, 21.5 ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[C:5]=1[CH3:16])([O-:3])=[O:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[CH3:19][N:20]([CH:22]=[CH:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14])[CH3:21]
Reactant: COC(OC)N(C)C
Reactant: Cc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: CN(C)C=Cc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 90 %

Procedure:
A mixture of 2,4,6-trinitrotoluene (0.5 g, 2.2 mmol) and N,N-dimethylformamide dimethyl acetal (2.7 ml) was refluxed for 2 h under nitrogen atmosphere. A dark purple red product was separated. N,N-dimethylformamide dimethyl acetal was removed under reduced pressure to give the title compound (0.56 g, 90% yield). m.p.: 155-157° C.; IR (KBr): 1635, 1585, 1530 cm-1; 1H NMR (CDCl3): δ 3.05 (s, 6H, 2×CH3); 5.65 (d, J=13.17 Hz, 1H, α-CH); 6.87 (d, J=13.2 Hz, 1H, β-CH); 8.55 (s, 2H, Ar--H); UV: Imax: 474 nm (CH3CN).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH2:49]O)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:49][CH:46]2[CH2:47][CH2:48][N:43]([C:41]([O:40][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:42])[CH2:44][CH2:45]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1cccc(COc2ccccc2Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc(COc3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution of 272 mg (0.809 mmol) of 3-[(2-chlorophenoxy) methyl]phenol, as prepared in the preceding step, in methylene chloride (5 mL) containing 275 mg (1.05 mmol) of triphenylphosphine and 208 mg (0.97 mmol) of N-(tert-butoxycarbonyl)-4-piperidinemethanol, as prepared in step (b) of Example 1, was added slowly 165 μL (1.04 mmol) of diethyl azodicarboxylate. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was quenched with water, extracted into diethyl ether, dried (MgSO4), and flash chromatographed (hexane/ethyl acetate (1:4 to 1:2)) to give 221 mg (58% yield) of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.38 (dd, 1 H, J=1.5, 7.8 Hz), 7.28 (t, 1 H, J=8.1 Hz), 7.15-7.21 (m, 1 H), 8.82-7.03 (m, 5 H), 5.13 (s, 2 H), 3.82 (d, 2 H, J=6.4 Hz), 2.74 (t, 2 H), 1.91-2.00 (m, 1 H), 1.84 (d, 2 H), and 1.47 (s, 9 H). Mass spectrum (MALDI-TOF; α-cyano-4-hydroxycinnamic acid matrix) calcd. for C24H30ClNO4S: 454.2 (M+Na). Found: 454.4.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C([Li])CCC.COC[C:14]([O:16][CH3:17])=[O:15]>O1CCCC1>[CH3:1][S:2]([CH2:5][C:14]([O:16][CH3:17])=[O:15])(=[O:4])=[O:3]
Reactant: CS(C)(=O)=O
Reactant: COCC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a suspension of dimethyl sulfone (5.43 g) in tetrahydrofuran (10 mL) was addded 1.59 M n-butyl lithium (36.3 mL) in a dryice-acetone bath under a nitrogen atmosphere. After stirring for 0.5 hour, a solution of methyl methoxyacetate (2.00 g) in tetrahydrofuran (5 mL) was added. The resulting mixture was stirred for 2 hours in the bath and allowed to warm to room temperature over 2 hours. The mixture was partitioned between EtOAc and 4 N hydrochloric acid. The reaction was quenched by adding 4 N hydrochloric acid in EtOAc (15 mL). The mixture was partitioned between EtOAc (100 mL) and brine (100 mL). The aqueous layer was washed with EtOAc (100 mL, five times). The organic layer was combined, and the combined extracts were dried over MgSO4, and evaporated. Flash silicagel column chromatography (EtOAc-hexane=50-200 to 300-100) afforded 2-(methylsulfonyl)-1-methoxyethanone as a colorless oil (2.24 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[O:22]1[CH2:24][CH:23]1[CH2:25][O:26][CH2:27][C:28]1[O:29][CH:30]=[CH:31][CH:32]=1>>[O:29]1[CH:30]=[CH:31][CH:32]=[C:28]1[CH2:27][O:26][CH2:25][CH:23]([OH:22])[CH2:24][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: c1coc(COCC2CO2)c1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)COCc3ccco3)CC1)O2

Procedure:
Compound 165 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(oxiran-2-ylmethoxy)methyl]furan and conditions outlined in procedure X. M.p.=143-145° C.; LCMS: 456 [M+H].
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29]>CN(C)C=O>[C:12]([O:11][C:1](=[O:10])[CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)o2)cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A mixture of di-tert-butyl malonate (4.3 g, 19.91 mmol, 1.99 equiv) and potassium carbonate (2.8 g, 20.29 mmol, 2.03 equiv) in N,N-dimethylformamide (30 mL) was stirred at 65° C. for 30 min. A solution of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (2.65 g, 10.00 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) was then added dropwise with stirring to the reaction mixture. The resulting solution was stirred at 65° C. overnight and then quenched with 60 mL of ice and water. The mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers was washed with 3×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 4.0 g (90%) of methyl 4-(4-(3-tert-butoxy-2-(tert-butoxycarbonyl)-3-oxopropyl)-5-methyloxazol-2-yl)benzoate as a light yellow solid. LC-MS: (ES, m/z): 446 [M+H]+, 390, 334, 272, 230, 115.
Reaction SMILES: [C:1]([C:4]1[C:8]([S:9]([CH3:11])=[O:10])=[C:7]([NH2:12])[N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:5]=1)(=O)[CH3:2].Cl.[CH3:26][NH:27][OH:28].N1C=CC=CC=1>CO>[CH3:26][N+:27]([O-:28])=[C:1]([C:4]1[C:8]([S:9]([CH3:11])=[O:10])=[C:7]([NH2:12])[N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:5]=1)[CH3:2]
Reactant: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reactant: CNO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O)=[N+](C)[O-]
Temperature: 20 °C
Reaction time: 68 h
Yield: 36.8 %

Procedure:
A mixture of 2.0 grams (0.005 mole) of 3-acetyl-5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole, 0.83 gram (0.01 mole) of N-methylhydroxylamine hydrochloride, 1.21 ml (0.015 mole) of pyridine and 150 ml of methanol was stirred 68 h at 20° C. The mixture was successively evaporated, washed with CH2Cl2 and water; filtered; washed in hot acetonitrile, acetone, hot methanol; and dried so as to give 0.79 gram of Compound No. 4 (m.p. about 228° C.).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH:12]([C:16](=[O:19])[CH2:17]Br)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].C12C[CH:33]([C:35](=[O:39])[CH2:36]OC)CC1CNC2>C(O)(C)C>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[CH:14]12[CH2:13][CH:12]([C:16](=[O:19])[CH2:17][O:39][CH:35]([CH3:36])[CH3:33])[CH2:11][CH:10]1[CH2:9][NH:8][CH2:15]2
Reactant: CC(C)(C)OC(=O)N1CC2CC(C(=O)CBr)CC2C1
Reactant: COCC(=O)C1CC2CNCC2C1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OCC(=O)C1CC2CNCC2C1

Procedure:
1-(3-Azabicyclo[3.3.0]oct-7-yl)-2-isopropoxy-1-ethanone trifluoroacetate was prepared from 1-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-7-yl)-2-bromo-1-ethanone (0.087 g, 0.27 mmol) and isopropanol, according to the procedure described above for the preparation of 1-(3-azabicyclo[3.3.0]oct-7-yl)-2-methoxy-1-ethanone trifluoroacetate, to give a mixture of cis and trans isomers (1H NMR (CD3OD, 300 MHz): δ 4.21 and 4.20 (s, 2H), 3.64 (heptet, J=6.1 Hz) 1H), 3.54-3.42 (m, 1H), 3.24-3.15 (m, 2H), 2.98-2.90 (m, 4H), 2.37-2.22 and 2.06-1.99 (m, 2H), 1.82-1.75 and 1.65-1.54 (m, 2H), 1.18 (d, J=6.1 Hz, 6H); MS (m/z): 212 (M+1)). This material exhibited Ki values at rat and human α4β2 of 427 nM and 261 nM respectively and did not pass HTS for α7.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[N:19]2[CH:20]=[CH:21][N:22]=[C:23]([N:24]3[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]3)[C:18]2=[CH:17][CH:16]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([NH:29][C@H:26]3[CH2:27][CH2:28][N:24]([C:23]4[C:18]5[N:19]([N:15]=[CH:16][CH:17]=5)[CH:20]=[CH:21][N:22]=4)[CH2:25]3)=[O:14])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ncn(-c2ccccc2)n1
Reactant: N[C@H]1CCN(c2nccn3nccc23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(c2nccn3nccc23)C1)c1ncn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of 1-phenyl-1H-1,2,4-triazole-3-carboxylic acid (0.093 g, 0.49 mmol, 1.4 eq) and (S)-1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-amine (0.10 g, 0.36 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.20 mL, 1.4 mmol, 2.6 eq) and HATU (0.21 g, 0.55 mmol, 1.5 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by HPLC to afford (S)-1-phenyl-N-(1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)-1H-1,2,4-triazole-3-carboxamide (0.095 g, 0.25 mmol, 52%). 1H NMR (400 MHz, CD3OD) δ 9.13 (s, 1 H), 8.16 (d, J=2.4 Hz, 1 H), 8.09 (d, J=5.8 Hz, 1 H), 7.86 (d, J=7.8 Hz, 2 H), 7.60-7.46 (m, 4 H), 7.19 (d, J=5.5 Hz, 1 H), 4.95-4.80 (m, 1 H), 4.78-3.80 (br, 4 H), 2.62-2.40 (m, 2 H); MS: (ES) m/z calculated for C19H18N8O [M+H]+ 375.2, found 375.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:15]=[C:14]([NH:16][C@:17]([CH3:23])([CH2:21][CH3:22])[C:18](O)=[O:19])[CH:13]=[CH:12][N:11]=2)=[CH:2]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[F:42][C:43]([F:47])([F:46])[CH2:44][NH2:45].C([O-])([O-])=O.[Na+].[Na+]>CC1OCCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:15]=[C:14]([NH:16][C@:17]([CH3:23])([CH2:21][CH3:22])[C:18]([NH:45][CH2:44][C:43]([F:47])([F:46])[F:42])=[O:19])[CH:13]=[CH:12][N:11]=2)=[CH:2]1
Reactant: NCC(F)(F)F
Reactant: CC[C@@](C)(Nc1ccnc(-c2c[nH]c3ncccc23)n1)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: CC[C@@](C)(Nc1ccnc(-c2c[nH]c3ncccc23)n1)C(=O)NCC(F)(F)F
Temperature: 62.5 °C
Reaction time: 0.5 h

Procedure:
To (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a) (limiting reagent) charge 2-methylTHF (7.5 vol), then charge T3P® (2.0 eq, 50% w/w in 2-MeTHF). Heat the mixture to 60-65° C. and maintain this temperature for no less than 3 hrs and the solids are completely dissolved. Cool to 20-25° C. then charge 2,2,2-trifluoroethylamine (2.0 eq). Continue agitation for no less than 6 hrs at 20-25° C. and until HPLC analysis showed <1.0% of (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a). Slowly charge a Na2CO3 solution (15 vol, 1.165M) while maintaining a batch temperature<30° C. Stir the mixture for 30 min then separate the phases. Wash the organic phase with water (4 vol). Emulsions have been observed at this point and can be addressed through addition of NaCl solution. Charge methanol (7 vol) then distill to 4 vol. Repeat 3 times. Prior to crystallization, adjust the total volume to approximately 11 vol. Heat the mixture to 50-55° C. then add water (2.45 vol, final solvent composition 22% water in methanol) over 30 min. Seed the batch with (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (Ia) (1 wt % seed based on the compound of Formula (4a)). Stir for 4 hrs at 50-55° C. then add water over 24 h until the mixture is approximately 58 wt % water in methanol. Cool to 20-25° C., stir 1 h, then filter. Wash the cake with water (2 vol). Dry the solids at 60-65° C. to give (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (Ia).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[Br:6][C:7]1[CH:8]=[C:9]([O:17][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=2[Cl:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]([NH:13][C:14]([NH2:16])=[S:15])=[N:11][CH:12]=1.C(N(CC)CC)C>C(O)C>[Br:6][C:7]1[CH:8]=[C:9]([O:17][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=2[Cl:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]([NH:13][C:14]2[S:15][CH:2]=[C:3]([CH3:4])[N:16]=2)=[N:11][CH:12]=1
Reactant: CC(=O)CCl
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2cc(Br)cnc2NC(N)=S)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(Br)cnc2Nc2nc(C)cs2)c1
Yield: 88.1 %

Procedure:
1-chloropropan-2-one (0.469 g; 5.07 mmol), ethyl 3-(5-bromo-2-thioureidopyridin-3-yloxy)-4-chlorobenzoate (1.680 g, 3.39 mmol), triethylamine (0.671 g, 6.63 mmol), and ethanol (70 mL) were reacted according to the method of Example 10, Step E, to provide the title compound (1.40 g, 77% yield). 1H NMR (d6-DMSO) δ 8.26 (d, 1H), 7.78 (m, 2H), 7.50 (s, 1H), 7.46 (d, 1H), 6.59 (s, 1H), 4.29 (q, 2H), 2.23 (s, 3H), 1.28 (t, 3H); Mass spectrum (apci) m/z=470.1 (M+H).
Reaction SMILES: F[B-](F)(F)F.[C:6]1([CH2:12][CH2:13][C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[FH:17].F.F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[C:6]1([CH2:12][CH2:13][C:14]([F:17])=[O:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: F
Reactant: O=C(O)CCc1ccccc1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(F)CCc1ccccc1
Reaction time: 24 h
Yield: 69 %

Procedure:
To a suspension of diethylaminosulfinium tetrafluoroborate (750 mg, 3.3 mmol) in dichloromethane (10 mL) at room temperature was added 3-phenylpropanoic acid (245 mg, 1.6 mmol) and triethylamine trihydrofluoride (266 μl, 1.6 mmol). The reaction mixture was stirred for 24 hours, then an aqueous solution of sodium bicarbonate (5%) was added and stirring was continued for 30 minutes. The organic phase was isolated and dried with magnesium sulphate. The solution was diluted with pentane (10 mL) and the solution was passed through a pad of silica gel with pentane elution. Solvent were evaporated in vacuum to provide 3-phenylpropanoyl fluoride (168 mg, 68%) as a clear liquid. 1H NMR (CDCl3, 300 MHz) δ 7.30-7.17 (m, 5H), 2.96 (t, J=7.6 Hz, 2H), 2.79 (t, J=7.6 Hz, 2H); 19F NMR (CDCl3, 282 MHz) δ 44.8 (s, 1F); 13C NMR (CDCl3, 75 MHz) δ 163.0 (d, 1JC-F=180.2 Hz), 139.1, 128.9, 128.5, 127.0, 34.7 (d, =50.7 Hz), 30.2.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[N:5]=[CH:4]1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:19]([C:18]1[C:13]([N:8]2[CH2:9][CH2:10][C:11]3[NH:3][CH:4]=[N:5][C:6]=3[CH2:7]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([O-:21])=[O:20]
Reactant: c1nc2c([nH]1)CCNC2
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1N1CCc2[nH]cnc2C1
Temperature: 25 °C

Procedure:
A mixture of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine dihydrochloride (2.0 g, 12.5 mmol; prepared essentially as described by Habermehl, E., Heterocycles 5:127,133 (1976)), 2-chloro-3-nitropyridine (1.7 g, 11.25 mmol) and K2CO3 (5.2 g, 37.5 mmol) in 25 mL of DMF is heated at 50° C. for 4 hours and then allowed to cool to room temperature. The mixture is then partitioned between ethyl acetate and water and the layers are separated. The aqueous layer is then further extracted with ethyl acetate and the combined organic extracts are dried over Na2SO4, filtered and the solvents removed under reduced pressure. Column chromatography of the residue on silica gel (5% MeOH in CH2Cl2 as eluent) gives 5-(3-nitro-pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine as a yellow solid (1.5 g). 1H NMR δ (CDCl3): 8.34 (d, 1H), 8.16 (dd, 1H), 7.53(s, 1H), 6.74 (q, 1H), 4.31 (s, 2H), 3.94(t, 2H) and 2.91(t, 2H). MS: 246.3 (m+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[CH3:18][NH:19][CH3:20].O1CCCC1>CN1C(=O)CCC1>[CH3:18][N:19]([CH3:20])[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Reactant: CNC
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CN(C)c1ccc([N+](=O)[O-])c(Nc2ccccc2)c1
Yield: 100 %

Procedure:
A solution of 5-bromo-2-nitro-N-phenylbenzenamine (0.2 g, 0.68 mmol) and 2.0 M dimethylamine in tetrahydrofuran (1.3 ml, 2.7 mmol) in 10 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. The mixture was extracted with ethyl acetate (3×30 ml) and dried over anhydrous sodium sulfate. N1,N1-dimethyl-4-nitro-N3-phenylbenzene-1,3-diamine (0.17 g, 100%) was obtained by flash column chromatograph (30% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.02 (s, 6H), 6.21 (d, J=2.6 Hz, 1H), 6.23 (s, 1H), 7.22-7.45 (m, 5H), 8.17 (d, J=2.6 Hz, 1H), 9.96 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 40.5, 93.6, 104.8, 124.9, 125.4, 129.5, 130.0, 139.8, 145.9, 155.5.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[C:7]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23].O.[CH3:26]N(C)C=O>>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:26])[C:8]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[C:7]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: O=C(O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)O)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 5.98 g) was added in portions to a stirred, cooled (0° C.) solution of 5-chloro-2-(4-chlorophenyl)-1H-indole-3-propanoic acid (Description 11, 10 g, 30 mmol) in dimethylformamide (100 mL) and the mixture was stirred at 0° C. for 30 min. lodomethane (9 mL) was added and the mixture was stirred at room temperature for 30 min. Water (1.5 L) was added and the mixture was extracted with ether (3×400 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (240 mL) and aqueous sodium hydroxide (4M, 60 mL) was added. The mixture was heated under reflux for 1 h., cooled and the pH was adjusted to 1.0 with hydrochloric acid (2M). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane and the solid was collected and dried in vacuo to give the the title compound (7.5 g, 72%). 1H NMR (360 MHz, CDCl3) δ2.54-2.59 (2H, m), 2.96-3.00 (2H, m), 3.53 (3H, s), 7.18-7.30 (4H, m), 7.44-7.48 (2H, m), and 7.58 (1H, d, J 1.8 Hz).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[N:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1>[OH-].[K+].O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:26][C:23]2[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1C(=Cc2ccncc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 21.7 %

Procedure:
6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.50 g, 1.95 mmol) was reacted with 4-pyridinecarboxaldehyde (0.248 g, 2.3 mmol) in 2.5 mL of 4% KOH for 8 hours at room temperature. The reaction was diluted with water, the resulting mixture was filtered, and the filtrate was extracted into EtOAc. The combined extracts were evaporated to dryness, and the resulting yellow solid was purified twice by flash chromatography (silica gel, 120 g, 9% MeOH in DCM) to afford 0.146 g of a yellow oil which crystallized on standing. Recrystallization from minimal iPrOH afforded the title compound as a light yellow powder (0.041 g, 6%), mp 128.5-129° C.; CI-MS mi/e 345 (M+), 346 (M+ +1);
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3cc(F)cc(F)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3,5-difluoro-phenylboronic acid to give [1-(3,5-difluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 353(MH+).