Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23](N)[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[Cl-:28].[Cs+]>Cl[Cu]>[Cl:28][C:23]1[S:24][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:15][C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=4)[N:14]=[CH:13][N:12]=3)[C:21]=2[N:22]=1
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Reactant: [Cl-]
Agent: Cl[Cu]
Agent: [Cs+]
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4sc(Cl)nc34)ncn2)cc1

Procedure:
The title compound was prepared in an analogous manner to the conditions of Example 91 by reacting 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine (Example 65) with CsCl and CuCl. MS (ESI, pos. ion.) m/z: 408 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[CH3:16]I>CN(C=O)C>[CH2:9]([C:8]([C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)([O:13][CH3:16])[CH2:11][CH3:12])[CH3:10]
Reactant: CCC(O)(CC)c1cccnc1C
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCC(CC)(OC)c1cccnc1C
Reaction time: 6 h
Yield: 36.7 %

Procedure:
A solution of 3-(2-methyl-pyridin-3-yl)-pentan-3-ol (0.444 g, 2.48 mmol) and NaOH (0.125 g, 5.2 mmol) in DMF (—mL) was stirred for 16 h. MeI (0.55 g, 3.9 mmol) was added. The mixture was stirred for 6 h, and the solvent was removed by evaporation under vacuum. Brine (25 mL) was added, and the aqueous mixture was extracted with CH2Cl2 (4×25 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (1:1 Et2O/CH2Cl2), affording 3-(1-ethyl-1-methoxy-propyl)-2-methyl-pyridine (0.176 g, 37%). 1H NMR (CDCl3) δ 0.73 (t, 6H, J=7.5 Hz), 1.87-2.04 (m, 4H), 2.77 (s, 3H), 3.01 (s, 3H), 7.09 (dd, 1H, J=8.1, 4.8 Hz), 7.56 (dd, 1H, J=8.1, 1.5 Hz), 8.40 (dd, 1H, J=4.8, 1.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1C1C=CC(C#N)=CC=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].FC1C=C(C2C(=O)N3C=CSC3=NC=2C)C=C(F)C=1>C1(C)C=CC=CC=1.O.C(O)C>[CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:25]1[CH:26]=[CH:27][C:22]([C:21]([F:32])([F:31])[F:20])=[CH:23][CH:24]=1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Yield: 159.8 %

Procedure:
The title compound was prepared by coupling reaction of Step 2 intermediate from Intermediate 4 (10.9 g, 37.312 mmol) with 4-(trifluoromethyl)phenyl boronic acid (9.9 g, 52.241 mmol) in the presence of Pd[(C6H5)3P]4 (1.72 g, 1.491 mmol) and sodium carbonate (23.7 g, 223.891 mol) in a mixture of toluene, ethanol and water according to the procedure described in Intermediate 3, step 3 yielded 18.5 g of the desired compound as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 7.53-7.59 (m, 4H), 7.58-7.80 (m, 1H), 8.01 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 311.28 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16]1([C:22]#[C:23][C:24]2[S:25][C:26]([C:29](O)=[O:30])=[CH:27][N:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOC(C)=O>[C:16]1([C:22]#[C:23][C:24]2[S:25][C:26]([C:29]([N:2]3[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]3)=[O:30])=[CH:27][N:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1cnc(C#Cc2ccccc2)s1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)c2cnc(C#Cc3ccccc3)s2)CC1
Reaction time: 1 h
Yield: 41 %

Procedure:
Example 75 was prepared via the process of Scheme 1, step 3, Method—B, supra, as follows: 2-Phenylethynyl-thiazole-5-carboxylic acid (0.100 g, 0.436 mmol) in tetrahydrofuran (1.7 mL) [Intermediate 1] was stirred, and N,N′-carbonyldiimidazole (0.079 g, 0.49 mmol) (Fluka Chemie AG) was added in one portion at room temperature. The mixture was stirred for 60 minutes and then 4-piperidone monohydrochloride (0.241 g, 1.78 mmol) (3B Pharmachem (Wuhan) International Co., LTD (Libertyville, Ill., USA)) was added, followed by the addition of triethylamine (192 uL, 1.38 mmol). The mixture was stirred for about 2 hours and was worked up by diluting with 25 mL of EtOAc and washing with 2×10 mL of 1.7% aq. HCl, 1×10 mL of water, 3×10 mL of 1.0 M K2CO3, and 1×10 mL of brine; dried (Na2SO4), and concentrated to give the title compound, 1-(2-phenylethynyl-thiazole-5-carbonyl)-piperidin-4-one (55 mg; 41%), as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.63-7.59 (m, 2H), 7.47-7.32 (m, 3H), 4.03 (t, J=6.3 Hz, 4H), 2.59 (t, J=6.3 Hz, 4H). LC/MS (Method 1), RT=1.05 min. Calculated [M+H]+=311; Observed [M+H]+=311.
Reaction SMILES: [C:1](OC1C=CC(C2C=CC=CC=2)=CC=1)(=[O:4])[C:2]#[CH:3].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C#C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C>[C:1](=[O:4])([S:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]#[CH:3]
Reactant: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Reactant: Sc1ccccc1
Agent: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: C#CC(=O)Sc1ccccc1
Yield: 84 %

Procedure:
The compound 19 was prepared according to the method described for compound 1 employing thiophenol (1 g, 9.07 mmol), propargylic acid (0.64 g, 9.07 mmol), DCC (1.87 g, 9.07 mmol) and DMAP (7.3 mg, 0.06 mmol) to give brownish liquid compound 19 (1.24 g, 84%). 1H NMR (300 MHz, CD2Cl2) δ 3.40 (s, 1H), 7.46 (s, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:10]=1[N:17]1[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:19](=[O:30])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=1.CCN(CC)CC.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=2)[CH:12]=[CH:11][C:10]=1[N:17]1[S:21](=[O:22])(=[O:23])[N:20]([CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[C:19](=[O:30])[CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(Br)n1
Reactant: C=Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cccc(/C=C/c2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(2-benzyloxy-4-vinylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (Example 81, step A) (75 mg, 0.17 mmol) in acetonitrile (2 mL), in a pressure vessel, is added 2-bromo-6-methoxypyridine (32 mg, 0.17 mmol), NEt3 (0.05 mL, 0.34 mmol), Pd(OAc)2 (8 mg, 0.034 mmol), and 2-(di-t-butylphosphino)biphenyl (20 mg, 0.068 mmol). The vessel is sealed and stirred at 100° C. for 18 h. The reaction is cooled to RT and filtered through Celite. The solvent is removed under reduced pressure and the crude material purified by column chromatography using a gradient of 0-35% EtOAc/hexanes as eluent to afford the title compound as a yellow oil: (M+H)+=552.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].[O:38]([C:45]1[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=1[C:47](O)=[O:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:47](=[O:48])[C:46]3[CH:50]=[CH:51][CH:52]=[CH:53][C:45]=3[O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Oc2ccccc2)cc1

Procedure:
The title compound was prepared from 5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Example 59, Step C) and 2-phenoxybenzoic acid (2.5 equivalents), CDI (2.5 equiv), and DBU (2.5 equiv) according to the procedure of Example 51. Flash chromatography of the crude product on silica gel (gradient elution with 0.5-1% MeOH in CH2Cl2) gave a 55% yield of the desired material as a stiff foam, homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 738 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:22].C(Cl)Cl.C([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=O)C>C(N(CC)CC)C>[C:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:22])=[C:2]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[N:11]=3)[C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cn(-c2ccccc2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1cn(-c2ccccc2)c2nc(N3CCNCC3)c(F)cc2c1=O

Procedure:
Alternately, the title compound is prepared as follows: To a solution of 1.6 g. of compound (III) (R1 =C2H5, R=phenyl, X=Cl) (product of 1(c) in 50 ml. of methylene chloride is added 1 ml. of triethylamine and 710 mg. of N-acetylpiperazine. After heating for 2 hours, the solvent is washed with 50 ml. of 1N HCl solution and then with water. The methylene chloride solution is dried and evaporated to dryness, yielding 2.1 g. of compound (I) ##STR14##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=2[CH3:31])[CH2:15][CH2:14]1)[CH:9]1[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:40][N:41]1[C:50]2[NH:49][C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[NH:46][CH2:45][C:44]=2[CH:43]=[N:42]1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH:9]1[CH2:11][CH2:10]1)[CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19](=[O:32])[CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:46]3[CH2:45][C:44]4[CH:43]=[N:42][N:41]([CH3:40])[C:50]=4[NH:49][C:48]4[CH:51]=[CH:52][CH:53]=[CH:54][C:47]3=4)=[O:27])=[CH:24][C:23]=2[CH3:31])[CH2:17][CH2:18]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: Cc1cc(C(=O)O)ccc1CCC(=O)N1CCC(CN(C(=O)OC(C)(C)C)C2CC2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(CN(C(=O)OC(C)(C)C)C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
WSCD (1.08 g, 5.6 mmol) and DMAP (343 mg, 2.8 mmol) were added to a solution of 4-(3-{4-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidin-1-yl}-3-oxo-propyl)-3-methyl-benzoic acid from Example E86.2 (1.25 g, 2.8 mmol) in dichloromethane (100 ml) and triethylamine (0.783 ml, 5.6 mmol). The mixture was stirred for 1 h at room temperature then 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (676 mg, 3.4 mmol) was added. The mixture was heated at reflux for 2 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 2% methanol:98% EtOAc to 5% methanol:95% EtOAc) to yield the title compound (1.1 g, 62%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[OH:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23](Br)[CH:24]=[CH2:25].[CH3:27][C:28]([CH3:30])=O>>[CH2:23]([O:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH2:30][CH:28]=[CH2:27])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])[CH:24]=[CH2:25]
Reactant: C=CCBr
Reactant: CC(C)=O
Reactant: O=C(c1ccccc1)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C=CCOc1ccc(C(=O)c2ccccc2)cc1OCC=C
Temperature: 60 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
To a suspension of 3,4-dihydroxybenzophenone (2.140 g, 10 mmol) and cesium carbonate (7.010 g, 21.6 mmol) in dry acetone (50 mL) was added allylbromide (5.3 mL, 60 mmol). The mixture was stirred at 60° C. for 6 h and additional allybromide (3.0 mL, 34.7 mmol) and cesium carbonate (3.000 g, 9.2 mmol) were added. The mixture was stirred for 3 h, cooled to room temperature, filtered and washed with EtOAc. The filtrate and washing were combined and evaporated under reduced pressure. The crude product was partitioned between EtOAc (50 mL) and H2O (15 mL). The EtOAc phase was separated and evaporated to give a light yellow oil (2.922 g, 99%): 1H NMR (CDCl3, 300 MHz) δ 7.77 (m, 1H), 7.74 (m, 1H), 7.57 (m, 1H), 7.50-7.44 (m, 3H), 7.38 (ddd, J=0.9, 2.4, 8.7 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.08 (m, 2H), 5.47 (m, 1H), 5.41 (m, 1H), 5.32 (m, 2H), 4.68 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH2:18][C:19]([O:21]CC)=[O:20])[CH:15]=[C:14]([F:24])[C:12]=3[N:13]=2)[CH:7]=1.[OH-].[Na+]>C1COCC1.CO.Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[C:14]([F:24])[C:12]=3[N:13]=2)[CH:7]=1
Reactant: CCOC(=O)Cc1cc(F)c2nc(Nc3cc(F)ccc3C)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(F)cc1Nc1nc2c(F)cc(CC(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Ethyl (2-(5-fluoro-2-methylphenylamino)-4-fluoro-6-benzoxazolyl)acetate (215 mg, 0.62 mmol) was dissolved in THF/methanol (1/1, 20 ml). To the resulting solution was added 0.25N NaOH (12.4 ml, 3.10 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured in 1N HCl to acidify the mixture, followed by extraction with chloroform/methanol (10/1). The extract was dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to give (2-(5-fluoro-2-methylphenylamino)-4-fluoro-6-benzoxazolyl)acetic acid (165 mg, 83%) as a pale brown solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[N:4]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:3]=1.C[NH:40]CCNC.C(=O)(OC(C)(C)C)N.O>O1CCOCC1.[Cu]I.C(OCC)(=O)C>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:4]2[C:5]3=[N:6][CH:7]=[C:8]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:9]([N:11]4[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]4)=[C:10]3[C:2]([NH2:40])=[N:3]2)=[CH:36][CH:35]=1
Reactant: CNCCNC
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Agent: [Cu]I
Agent: CC(C)(C)OC(N)=O
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(N)c3c(N4CCNCC4)c(-c4ccccc4)cnc32)cc1
Temperature: 75 °C
Reaction time: 6 h
Yield: 97.4 %

Procedure:
A mixture of tert-butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (1.55 g, 2.4780 mmol, see Example 9), CuI (0.47 g, 2.48 mmol), N1,N2-dimethylethane-1,2-diamine (0.53 ml, 4.96 mmol) and tert-butyl carbamate (2.90 g, 24.78 mmol) in dioxane (50 mL) was stirred at 75° C. (oil bath) for 6 hours. Water (50 mL) and ethyl acetate (50 mL) were added, and the organic layer was separated, washed with saturated ammonium chloride, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane:ethyl acetate=1:1) to give 1-(4-methoxybenzyl)-5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (1.00 g, 97%) as a solid. This solid was dissolved in DCM (20 mL), and TFA (4.77 mL, 62.0 mmol) was added. The reaction was stirred at room temperature for 4 hours. The solvent was removed. The residue was partitioned between saturated NaHCO3 (30 mL) and DCM (40 mL). The organic layer was separated, dried (sodium sulfate) and concentrated in vacuo to give 1-(4-methoxybenzyl)-5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (1.00 g, 97%) as a solid. LCMS (APCI+) m/z 415(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]3[CH:9]=[C:8]2/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1>CCO.CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]3[CH:9]=[C:8]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:23][CH:24]=1
Reactant: COc1cnc2c(c1)cc(/C=C/C(=O)O)n2Cc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cnc2c(c1)cc(CCC(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
To a solution of (E)-3-[1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-acrylic acid (Example 1; 95 mg, 0.277 mmol) in a mixture of EtOH (2 mL) and EtOAc (2 mL) was added Pd/C (˜20 mg) and maintained under an atmosphere of H2 for 12 hrs. The resulting slurry was filtered through celite eluting with EtOAc, and the solvent evaporated to afford the title acid as a colorless solid. LCMS (ESI) M+H 345.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH:12]=[CH:11][CH2:10]2)=[CH:5][N:4]=1.N1C=CC=CC=1.S(Cl)([Cl:27])=O>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([C:9]1([C:6]2[CH:5]=[N:4][C:3]([CH2:2][Cl:27])=[N:8][CH:7]=2)[CH2:13][CH:12]=[CH:11][CH2:10]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1(c2cnc(CO)nc2)CC=CC1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(c2cnc(CCl)nc2)CC=CC1
Temperature: 25 °C

Procedure:
To a solution of ethyl 1-(2-hydroxymethylpyrimidin-5-yl)cyclopent-3-ene carboxylate (5.0 g, 20.1 mmol), in chloroform (50 ml) was added pyridine (5.1 ml), followed by thionyl chloride (4.4 ml, 60.3 mmol). The reaction mixture was refluxed for 30 minutes, cooled to room temperature and quenched with water (50 ml). The chloroform layer was collected, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic extract was dried over MgSO4 and then evaporated to an oily residue, which was purified by flashe chromatography with hexanes/ethyl acetate (3:1) as eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[CH:13]1[NH:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14]1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1>>[F:30][C:29]([F:31])([F:32])[O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:18]2[CH:13]([C:4]3[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[CH:6][C:5]=3[O:11][CH3:12])[CH2:14][CH2:15][CH2:16][C:17]2=[O:19])=[CH:23][CH:24]=1
Reactant: COc1cc(OC)c(C2CCCC(=O)N2)c(OC)c1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: COc1cc(OC)c(C2CCCC(=O)N2Cc2ccc(OC(F)(F)F)cc2)c(OC)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,4,6-trimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.10 min.; [M+H]+: 439.78 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[SH:12].[CH3:13][C:14]1([CH3:29])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18]([C:26](Cl)=[O:27])[CH:17]=[CH:16][C:15]1=2>C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[S:12][C:26]([C:18]1[CH:17]=[CH:16][C:15]2[C:14]([CH3:29])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]=2[CH:19]=1)=[O:27]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Reactant: COC(=O)c1ccc(C)c(S)c1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(SC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Yield: 88.3 %

Procedure:
In a manner analogous to Example 1(a), starting with 1.83 g (10 mmol) of methyl 3-mercapto-4-methyl benzoate, 1.5 ml of triethylamine and 2.76 g (11 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtoyl chloride, methyl 4-methyl-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtoylthio)-benzoate (3.50 g; 88%) is produced.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[C:19](#[N:21])[CH3:20].[H-].[Na+]>C1(C)C=CC=CC=1.Cl>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][O:6][CH2:5][C:4]([CH3:16])([CH3:17])[C:3](=[O:18])[CH2:20][C:19]#[N:21])=[CH:13][CH:12]=1
Reactant: COC(=O)C(C)(C)COCc1ccc(OC)cc1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(COCC(C)(C)C(=O)CC#N)cc1
Temperature: 25 °C
Yield: 104.2 %

Procedure:
A solution of 3.66 g (14.5 mmol) of 2,2-dimethyl-3-(4-methoxybenzyl-oxy)-propionic acid methyl ester and 1.07 mL (20.5 mmol) of acetonitrile in anhydrous toluene (10 mL) is added dropwise to a refluxing suspension of 0.83 g (20.5 mmol) of sodium hydride (60% dispersion in mineral oil) in toluene (20 mL). After the addition is complete, the mixture is stirred at reflux for 3 h, then allowed to cool to room temperature. The reaction mixture is then diluted with 1M aqueous HCl solution to neutral pH, and extracted with ethyl acetate (3×40 mL). The combined organic extracts are washed with water and brine, then dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to afford 3.95 g of 5-(4-methoxy-benzyloxy)-4,4-dimethyl-3-oxo-pentanenitrile, which is used in the next step without further purification. Yield: assumed quantitative, no spectroscopic analysis performed.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18]2=[O:24])(=O)=O)=CC=1.[CH:26]([CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(C)(C)C>[CH:26]([CH:39]1[CH2:44][CH2:43][N:42]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:18](=[O:24])[CH2:19][O:20][CH2:21][C:22]2=[O:23])[CH2:41][CH2:40]1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCN2C(=O)COCC2=O)cc1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Solvent: CC(C)(C)O
Product: O=C1COCC(=O)N1CCCCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Yield: 149.6 %

Procedure:
To a solution of 9.75 grams (26.39 millimoles) of 6-(3,5-dioxomorpholino)hexyl p-toluenesulfonate (prepared as described in Example IX) in 160 milliliters of warm tertiary butyl alcohol was added portionwise at temperatures in the range of 30°-32° C. over a period of about 23 minutes, 63 grams (26.38 millimoles) of 4-benzhydrylpiperidine in 160 milliliters of tertiary-butyl alcohol. The reaction mixture was heated at reflux temperature for about 22 hours and thereafter the solvent removed by vaporization to obtain 17.7 grams of a 4-[6-(4-benzhydrylpiperidino)hexyl]-3,5-dioxomorpholine product as a yellow oil. Crystallization (twice) from ethyl acetate produced 4.19 grams of white crystals, m.p., 121°-124.5° C. and having NMR, UV and IR spectral characteristics appropriate for the product.