Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]4)=[CH:14][CH:15]=3)[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)#[N:27]>CN(C=O)C>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:35]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[C:16]4[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH:20]5[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]5)=[CH:14][CH:15]=4)[N:10]=[CH:9][N:8]=3)[CH2:6][CH2:5]2)=[O:36])=[CH:32][CH:33]=1)#[N:27]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: c1nc(N2CCNCC2)c2ccc(OCCC3CCCCN3)cc2n1
Solvent: CN(C)C=O
Product: N#Cc1ccc(NC(=O)N2CCN(c3ncnc4cc(OCCC5CCCCN5)ccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To DMF solution (2 mL) of 4-piperazinyl-7-(2-piperidylethoxy)quinazoline (from Example 1, Step E, 0.287 g, 0.84 mmol) added DMF solution (2 mL) of 4-cyanophenylisocyanate (0.181 g, 1.26 mmol) and the reaction was stirred at room temperature overnight. The solvent was evaporated and residue purified by RP-EHLC to afford desired product N-(4-cyanophenyl){4-[7-(2-piperidylethoxy)quinazolin-4-yl]piperazinyl}carboxamide as a white solid (200 mg, 50%). MS (ES) 487(M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=[CH:25][C:26]2[CH:38]=[CH:37][C:29]4[N:30](S(C)(=O)=O)[CH:31]=[N:32][C:28]=4[CH:27]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[K+]>>[N:30]1[C:29]2[CH:37]=[CH:38][C:26]([CH:25]=[CH:24][CH2:23][NH:22][CH2:21][CH2:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]=3[C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:27][C:28]=2[NH:32][CH:31]=1
Reactant: COc1ccc(-c2[nH]c3ccccc3c2CCNCC=Cc2ccc3c(c2)ncn3S(C)(=O)=O)cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(-c2[nH]c3ccccc3c2CCNCC=Cc2ccc3nc[nH]c3c2)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.6 %

Procedure:
To a solution of {2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]-ethyl}-[3-(1-methanesulfonyl-1H-benzoimidazol-5-yl)-allyl]amine (24 mg in 1.5 mL methanol) at 0° C. was added 0.225 niL of a 2N solution of potassium hydroxide and the mixture allowed to warm to room temperature. After 1.5 hours, the reaction was quenched by the addition of 0.30 mL of 1N hydrochloric acid, concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol, 88:12) to give the title compound (12 mg). m/e =453 (M+H)
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)[CH3:8]>>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[CH3:8]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: Brc1cccs1
Product: CCOc1ccc(-c2cccs2)cc1

Procedure:
2-Bromothiophene and 4-ethoxyphenylboronic acid were treated in a manner similar to Reference Example 20-(1) to give 2-(4-ethoxyphenyl)thiophene as a colorless solid. APCI-Mass m/Z 205 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N:4]([C:7]1[CH:22]=[CH:21][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:19][N:18]=[CH:17][C:16]=3[CH:20]=2)=[C:9]([C:23]([F:26])([F:25])[F:24])[CH:8]=1)=[C:5]=[O:6]>C(#N)C>[CH3:1][N:2]([CH3:3])[C:5]([NH:4][C:7]1[CH:22]=[CH:21][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:19][N:18]=[CH:17][C:16]=3[CH:20]=2)=[C:9]([C:23]([F:26])([F:25])[F:24])[CH:8]=1)=[O:6]
Reactant: CNC
Reactant: O=C=Nc1ccc(Oc2ccc3sncc3c2)c(C(F)(F)F)c1
Solvent: CC#N
Product: CN(C)C(=O)Nc1ccc(Oc2ccc3sncc3c2)c(C(F)(F)F)c1
Reaction time: 12 h
Yield: 86 %

Procedure:
5 parts of gaseous dimethylamine were passed into a solution of 33.6 parts of 5-(4'-isocyanato-2'-trifluoromethylphenoxy)-benzisothiazole in 400 parts of acetonitrile at from 10° to 20° C. and the reaction was allowed to continue for 12 hours at from 20° to 30° C., after which the solvent was removed under reduced pressure and the residue was recrystallized from chloroform. 32.7 parts (86% of theory) of 5-(4'-dimethylaminocarbonylamino-2'-trifluoromethylphenoxy)-benzisothiazole of melting point 188° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=3[N:21]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.CC1C=CC(S(O[CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([CH:41]=[O:42])[CH2:37][CH2:36]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[NH2:20][C:16]1[C:15]2[N:21]=[C:12]([S:11][C:3]3[C:2]([Br:1])=[CH:10][C:6]4[O:7][CH2:8][O:9][C:5]=4[CH:4]=3)[N:13]([CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][N:38]([CH:41]=[O:42])[CH2:37][CH2:36]3)[C:14]=2[CH:19]=[CH:18][N:17]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C=O)CC2)cc1
Reactant: Nc1nccc2[nH]c(Sc3cc4c(cc3Br)OCO4)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nccc2c1nc(Sc1cc3c(cc1Br)OCO3)n2CCC1CCN(C=O)CC1
Temperature: 25 °C
Yield: 42.1 %

Procedure:
To a solution of 2-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-1H-imidazo[4,5-c]pyridin-4-amine (175 mg, 0.480 mmol), 2-(1-formylpiperidin-4-yl)ethyl 4-methylbenzenesulfonate (194 mg, 0.624 mmol), and Cs2CO3 (267 mg, 0.816 mmol) in DMF (3.0 mL) was heated at 85° C. for 10 h. After cooling to RT, the mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuum. The residue was triturated with EtOAc, filtered, and dried to give the title compound (102 mg, 42%): 1H NMR (DMSO-d6) δ 7.94 (s, 1H), 7.72 (d, J=6.0 Hz, 2H), 7.39 (s, 1H), 6.79 (d, J=6.0 Hz, 2H), 6.66 (s, 1H), 6.41 (s, 2H), 6.07 (s, 2H), 4.20 (t, J=6.8 Hz, 2H), 4.10 (brd, J=13.6 Hz, 1H), 3.62 (brd, J=13.2 Hz, 1H), 2.91 (td, J=12.0, 2.4 Hz, 1H), 2.54 (m, 1H), 1.70 (t, J=6.8 Hz, 2H), 1.57-1.42 (m, 3H), 1.03 (m, 1H), 0.94 (m, 1H); LC/MS [M+H]+ 504.07.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:7][C:8]=1[CH3:9].[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([O:1][CH2:2][CH2:3][C:4]2[N:5]=[C:6]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[S:7][C:8]=2[CH3:9])=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)sc2C)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 4-(2-hydroxy-ethyl)-5-methyl-2-(4-trifluoromethyl-phenyl)thiazole (Example 3, 288 mg, 1.0 mmol) in THF (3 mL) add 4-hydroxy-benzoic acid methyl ester (167 mg, 1.1 mmol) followed by triphenylphosphine (288 mg, 1.1 mmol). To this solution, add, dropwise, diethyl azodicarboxylate (174 μL, 1.1 mmol). On complete addition, stir the resulting red solution for 20 min. concentrate under reduced pressure and purify the residue by flash chromatography (elute with 15% ethyl acetate/15% dichloromethane in heptane) to give the title compound as a white solid. (410 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>>[CH3:24][O:25][CH2:26][CH2:27][NH:28][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: COCCN
Product: COCCNc1cc(C(F)(F)F)cc2nc(NC(=O)c3cccnc3)nn12
Temperature: 120 °C
Yield: 43.2 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq) and 2-methoxyethylamine (55.0 mg; 0.73 mmol; 5.0 eq), heated at 120° C., to give the title compound as a white solid (23 mg, 40%). HPLC, Rt: 2.70 min. (purity 98.1%). LC/MS, M+(ESI): 380.8, M−(ESI): 378.9.
Reaction SMILES: [N+](C1C=C(S(CC[O:15][C:16](=[O:78])[CH:17]([NH:37][C:38](=[O:77])[CH2:39][O:40][C:41]2[CH:46]=[C:45]([CH3:47])[C:44]([S:48]([N:51]3[C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=4[N:53]=[C:52]3[S:60]([CH2:62][C:63]3[C:68]([CH3:69])=[C:67]([O:70][CH2:71][C:72]([F:75])([F:74])[F:73])[CH:66]=[CH:65][N:64]=3)=[O:61])(=[O:50])=[O:49])=[C:43]([CH3:76])[CH:42]=2)[CH2:18][CH2:19][C:20]([O:22]CCS(C2C=CC=C([N+]([O-])=O)C=2)(=O)=O)=[O:21])(=O)=O)C=CC=1)([O-])=O.C([O-])(O)=O.[Na+:83]>C1COCC1.O>[Na+:83].[CH3:47][C:45]1[CH:46]=[C:41]([CH:42]=[C:43]([CH3:76])[C:44]=1[S:48]([N:51]1[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2[N:53]=[C:52]1[S:60]([CH2:62][C:63]1[C:68]([CH3:69])=[C:67]([O:70][CH2:71][C:72]([F:73])([F:74])[F:75])[CH:66]=[CH:65][N:64]=1)=[O:61])(=[O:50])=[O:49])[O:40][CH2:39][C:38]([NH:37][CH:17]([CH2:18][CH2:19][C:20]([O-:22])=[O:21])[C:16]([O-:78])=[O:15])=[O:77].[Na+:83]
Reactant: Cc1cc(OCC(=O)NC(CCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)C(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc(C)c1S(=O)(=O)n1c(S(=O)Cc2nccc(OCC(F)(F)F)c2C)nc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCC(=O)NC(CCC(=O)[O-])C(=O)[O-])cc(C)c1S(=O)(=O)n1c(S(=O)Cc2nccc(OCC(F)(F)F)c2C)nc2ccccc21
Yield: 73.9 %

Procedure:
A solution of 2-[2-(3,5-dimethyl-4-{2-[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}-phenoxy)acetylamino]-pentanedioic acid bis-[2-(3-nitro-benzenesulfonyl)-ethyl]ester (Intermediate 34, 800 mg, 0.69 mmol) and NaHCO3 (120 mg, 1.41 mmol, 2.05 eq) in THF-H2O (6 mL-3 mL) was heated to 70° C. for 3 h. Thereafter volatile materials were removed by evaporation under reduced pressure, the residual semi-solid was treated with EtOAc, and the mixture was filtered to remove undissolved materials. The filtrate was concentrated to total volume of about 3 mL, and then diethyl ether was added to the mixture. A solid precipitate formed and was collected by filtration to give Compound 13 (400 mg, 73%) as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[N:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1B(O)O>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[N:3]=1
Reactant: CC1(c2ccccc2)CCN(c2nccc(Cl)n2)C(=O)O1
Reactant: OB(O)c1c(Cl)cccc1Cl
Product: CC1(c2ccccc2)CCN(c2nccc(-c3c(Cl)cccc3Cl)n2)C(=O)O1

Procedure:
The title compound was prepared following procedures analogous to those in Example 56 using 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 2,6-dichlorophenylboronic acid. LC-MS Method 3, tR=1.317 min, m/z=414. 1H NMR (CDCl3) 1.70 (s, 3H), 2.30-2.40 (m, 1H), 2.48-2.52 (m, 1H), 3.47-3.51 (m, 1H), 4.10-4.15 (m, 1H), 7.10-7.40 (m, 10H), 8.78-8.79 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[F:36].O>CN(C=O)C>[F:36][C:30]1[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][N:3]1[C:4]2[CH:10]=[C:9]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: Cc1cccc(CBr)c1F
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc(C)c1F
Temperature: 80 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
A mixture of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate prepared as described in Example 26, step d (500 mg, 1.82 mmol), K2CO3 (502 mg, 3.64 mmol) and 1-(bromomethyl)-2-fluoro-3-methylbenzene (389 mg, 1.91 mmol) in DMF (25 mL) was stirred at 80° C. for 18 h. The reaction mixture was cooled, poured into water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel chromatography eluted with EtOAc:MeOH=100:1 to give the desired product (350 mg, 48%) as a red solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.24 (d, 3H, J=1.8 Hz), 2.47 (s, 3H), 3.09 (t, 4H, J=4.8 Hz), 3.75 (t, 4H, J=4.8 Hz), 3.86 (s, 3H), 5.51 (s, 2H), 6.62 (t, 1H, J=7.5 Hz),7.00 (t, 1H, J=7.5 Hz), 7.22 (t, 1H, J=7.5 Hz), 7.32 (d, 1H, J=2.4 Hz), 7.36 (d, 1H, J=2.4 Hz); LC-MS: m/e=398 [M+1]+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][C:4]=1[F:13])#[N:2].S(C)C>C1COCC1>[F:13][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][OH:11])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccc(CC(=O)O)cc1F
Solvent: C1CCOC1
Solvent: CSC
Product: N#Cc1ccc(CCO)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-cyano-3-fluorophenyl)acetic acid (25.6 g, 143 mmol) in 150 mL of dry THF was cooled by ice/water, and then BH3/Me2S (10 M, 15.7 mL, 157 mmol) was added slowly. The reaction was warmed to ambient temperature and stirred overnight. The mixture was quenched with MeOH and concentrated to dryness. The residue was partitioned between water and EtOAc. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford 2-fluoro-4-(2-hydroxyethyl)benzonitrile.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:32](=[O:33])[C:18]2=[C:19]([CH3:31])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:21](=[O:23])[CH:22]=[C:17]2[NH:16]1.C([O-])(=O)C.[Na+]>>[C:1]([N:16]1[C:17]2[C:18](=[C:19]([CH3:31])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:21](=[O:23])[CH:22]=2)[C:32](=[O:33])[N:15]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[Cl:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c2c(=O)n(-c3ccccc3Cl)[nH]c2cc(=O)n1Cc1ccccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)n1c2cc(=O)n(Cc3ccccn3)c(C)c2c(=O)n1-c1ccccc1Cl
Temperature: 40 °C
Yield: 82 %

Procedure:
10.0 ml of acetic anhydride was added to a mixture of 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione (Compound of Formula (Ia) (0.250 g, 0.682 mmol, 1 equiv.) and sodium acetate (0.056 g, 0.682 mmol, 1 equiv). The resulting mixture was heated at 40° C. for 1 h and then concentrated in vacuo. The resulting residue was dissolved in EtOAc and washed with water. The organic phase was dried over Na2SO4 and concentrated in vacuo until dryness to afford 0.228 g of the desired compound 1-acetyl-2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione as a white solid (82% yield). Rf (EtOAc) 0.34; 1H NMR (500 MHz, CDCl3) 2.08 (s, 3H), 2.95 (s, 3H), 5.47 (s, 2H), 7.04 (s, 1H), 7.21 (m, 1H), 7.37-7.32 (m, 4H), 7.56 (m, 1H), 7.67 (td, J 7.6, 1.9 Hz, 1H), 8.51 (m, 1H); MS (ESI+): 409.2; MS (ESI−): 407.7.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:20]=[C:19]([F:29])[CH:18]=2)=[CH:7][CH:6]=1.[O:31]1[C:35]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1>>[O:31]1[C:35]2([CH2:40][CH2:39][N:38]([CH2:2][CH2:3][O:4][C:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]([NH:15][C:16](=[O:30])[C:17]4[CH:22]=[C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[CH:20]=[C:19]([F:29])[CH:18]=4)=[CH:7][CH:6]=3)[CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1
Reactant: O=C(Nc1ccc(OCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Reactant: C1CC2(CCN1)OCCO2
Product: O=C(Nc1ccc(OCCN2CCC3(CC2)OCCO3)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from N-[4-(2-chloroethoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and 1,4-dioxa-8-aza-spiro[4.5]decane according to conditions described in general procedure N. 1H NMR 300 MHz (CDCl3) 8.32 (dd, 1H, J=1.8 and 8.7 Hz), 7.9 (s, 1H), 7.83 (d, 1H, J=7.8 Hz), 7.73 (d, 1H, J=8.4 Hz), 7.53 (m, 2H), 7.31 (s, 1H), 6.99 (d, 1H, J=8.4 Hz), 6.84 (d, 1H, J=8.4 Hz), 6.76 (d, 1H, J=11.7 Hz), 4.31 (t, 2H, J=5.7 Hz), 3.97 (s, 4H), 3.28 (m, 4H), 3.02 (t, 2H, J=6.9 Hz), 2.76 (m, 4H), 1.8 (t, 4H, J=5.7 Hz), 1.62-1.67 (m, 6H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH:16]([C:26]([OH:28])=[O:27])[N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[C:7]=1[C:31]([O:33]C(C)(C)C)=[O:32])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH:16]([C:26]([OH:28])=[O:27])[N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[C:7]=1[C:31]([OH:33])=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(C(=O)O)n3ccc4ccccc43)C2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)O)n3ccc4ccccc43)C2SC1
Reaction time: 0.17 h

Procedure:
A solution of 3-[(acetyloxy)methyl]-7-[[2-carboxy-2-(1H-indol-1-yl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid, tert-butyl ester (0.05 mole) in 10 ml of trifluoroacetic acid maintained at 0° C. is stirred for 10 minutes. The trifluoroacetic acid is removed under vacuum. The residue is treated with ethyl ether to give a solid material. Filtration gives the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=2)[CH:15]=1)=[O:13].[C:25]([O:29][C:30]([N:32]1[C@H:37]([C:38]([OH:40])=[O:39])[CH2:36][C@@H:35]2[C@H:33]1[CH2:34]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[C@@H:33]12[CH2:34][C@@H:35]1[CH2:36][C@@H:37]([C:38]([O:40][CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=3)[CH:15]=1)=[O:13])=[O:39])[N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: O=C(CBr)c1ccc2cc(Br)ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
DIPEA (3.47 mL, 19.88 mmol) was added to a stirred slurry of crude 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (4.35 g, 13.3 mmol) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (3.01 g, 13.25 mmol) in acetonitrile (80 mL) and the reaction was stirred at rt overnight. The reaction was concentrated to dryness and purified by BIOTAGE® Horizon (160 g SiO2, 10-20% EtOAc/hexanes). The fractions containing the desired product were allowed to stand for 3 d. Some fractions had crashed large crystals (collected 240 mg, pure desired product by 1H NMR). All fractions containing the desired product were collected and concentrated to a yellow solidified foam which was slurried with Et2O (˜40 mL). The white solid that formed was collected by filtration and rinsed with Et2O to yield (1R,3S,5R)-3-(2-(6-bromonaphthalen-2-yl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (3.24 g). LC-MS retention time 2.760 min; m/z 472, 474.02 (1:1) (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 mHz, MeOD) d ppm 8.61 (br s, 1H), 8.17 (s, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.71 (dd, J=8.6, 1.8 Hz, 1H), 5.75-5.66 (m, 1H), 5.61-5.46 (m, 1H), 4.34-4.26 (m, 1H), 3.46 (br s, 1H), 2.69-2.59 (m, 1H), 2.55-2.44 (m, 1H), 1.73 (br s, 1H), 1.54-1.43 (m, 9H), 0.88 (br s, 1H), 0.59-0.53 (m, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Br:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[N:15][N:16]2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[C:12]([NH:29][C:30]([C:32]2[N:33]=[C:34]([CH2:37]Cl)[S:35][CH:36]=2)=[O:31])[CH:11]=1>C(#N)C>[Br:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[N:15][N:16]2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[C:12]([NH:29][C:30]([C:32]2[N:33]=[C:34]([CH2:37][N:4]3[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]3)[S:35][CH:36]=2)=[O:31])[CH:11]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(NC(=O)c4csc(CCl)n4)cc(Br)cc32)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ncc3c(NC(=O)c4csc(CN5C[C@@H](C)O[C@@H](C)C5)n4)cc(Br)cc32)cc1
Reaction time: 8 h

Procedure:
Acetonitrile (15 mL) and (2R,6S)-2,6-dimethylmorpholine (1.4 ml) were added to N-{6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-yl}-2-(chloromethyl)-1,3-thiazole-4-carboxamide (2 g) and the reaction mixture was refluxed for 3 h. On cooling a solid precipitated. The mixture was diluted with acetonitrile (15 ml) and the solid was collected by filtration, washing with acetonitrile. The solid was dried on the vacuum pump overnight to give title compound (1.86 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)([CH2:22][CH2:23]O)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:33][C@@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)([CH2:22][CH2:23][N:36]4[CH2:37][CH2:38][C@@H:34]([F:33])[CH2:35]4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: F[C@@H]1CCNC1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCN2CC[C@@H](F)C2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 178 using (R)-3-fluoropyrrolidine in Step 2. LC-MS Method 2 tR=1.2 min, m/z=509.1; 1H NMR (CDCl3) 0.67-0.86 (m, 1H), 1.47 (d, 6H), 1.87-2.34 (m, 7H), 2.70-2.91 (m, 3H), 5.00-5.23 (d, 2H), 5.63 (m, 1H), 6.92-7.06 (m, 6H), 7.25 (m, 4H), 7.39 (m, 2H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[N:11][NH:12][C:13]=2[NH:14]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([O:20][CH:21]=[CH2:22])[CH3:19]>C(Cl)Cl.O1CCOCC1>[CH2:18]([O:20][CH:21]([N:12]1[C:13]([NH2:14])=[C:9]([C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:10]=[N:11]1)[CH3:22])[CH3:19]
Reactant: CC(=O)Nc1[nH]ncc1C#Cc1ccccc1
Reactant: C=COCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(C)n1ncc(C#Cc2ccccc2)c1N
Temperature: 75 °C
Yield: 80.3 %

Procedure:
A solution of N-(4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide (17.6 g, 78 mmol), ethoxyethene (11.2 mL, 117 mmol) and HO in 1,4-dioxane (1 mL, 4 mmol) in CH2Cl2 (520 mL) was stirred at room temperature for 1 h and concentrated in vacuo. The residue was dissolved in ethanol (260 mL) and 25% aq. NaOH solution (260 mL) and the reaction mixture was heated to 75° C. for 4 h and cooled to room temperature. The ethanol was partly concentrated in vacuo and the resulting solid collected by filtration, washed with water and minimum cold ethanol and dried in vacuo to provide the title compound as a solid (16 g).