Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[CH:7][C:6]=2[CH:11]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](B(O)O)=[CH:14][N:13]=1.Cl.[CH2:26](OCC)C>C(OCC)(=O)C>[CH3:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([CH:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:12][N:13]([CH3:26])[CH2:14]3)=[CH:11][C:6]=2[CH:7]=1
Reactant: Cc1cc2cc(Br)ccc2s1
Reactant: OB(O)c1cncc2ccccc12
Reactant: CCOCC
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc2cc(C3CN(C)Cc4ccccc43)ccc2s1

Procedure:
4-(2-methylbenzo[b]thiophen-5-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline was prepared from 5-bromo-2-methylbenzothiophene and isoquinolin-4-ylboronic acid as described in Example 40 (Steps C to E). The free base was dissolved in ethyl acetate and treated with 2 M hydrogen chloride in diethyl ether (2 equiv) to give the corresponding hydrochloride salt (0.41 g, 98.8% AUC HPLC): 1H NMR (300 MHz, DMSO-d6) δ 11.09 (br s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.09-7.27 (m, 5H), 6.76 (d, J=7.5 Hz, 1H), 4.69 (dd, J=10.8, 6.3 Hz, 1H), 4.55 (br s, 2H), 3.54-3.83 (m, 2H), 2.94 (s, 1H), 2.57 (s, 3H); EI MS m/z=293 [C19H19NS]+. Anal. Calcd. for C19H20ClNS: C, 68.61; H, 6.10; N, 4.21 with 0.73% H2O. Found: C, 68.35; H, 6.55; N, 4.00.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[C:23]([NH:26][C:27](=[O:32])C(Cl)(Cl)Cl)[CH:22]=[CH:21][CH:20]=2>>[NH2:15][C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[C:23]([NH:26][C:27]([NH:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:8][CH:9]=1)=[O:32])[CH:22]=[CH:21][CH:20]=2
Reactant: Nc1cc2c(NC(=O)C(Cl)(Cl)Cl)cccc2cn1
Reactant: NCc1ccc(N2CCCCC2)cc1
Product: Nc1cc2c(NC(=O)NCc3ccc(N4CCCCC4)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 1B using 4-(1-piperidinyl)benzylamine and the product from Example 150A instead of 2-(3-fluorophenyl)ethylamine and the product from Example 1A. 1H NMR (300 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.22 (s, 1H), 7.87 (d, 1H, J=8 Hz), 7.46 (d, 1H, J=8 Hz), 7.16 (d, 2H, J=8.4 Hz), 7.07 (t, 1H, J=8 Hz), 6.91 (d, 2H, J=8.4 Hz), 6.82 (t, 1H, J=6 Hz), 6.70 (s, 1H), 5.91 (s, 2H), 4.22 (d, 2H, J=6 Hz), 3.10 (m, 4H), 1.70-1.45 (m, 6H). MS (ESI) 376 (M+H)+. Anal. Calcd for C22H25N5O.0.1H2O: C, 70.04; H, 6.73; N, 18.56. Found: C, 69.66; H, 6.50; N, 18.55.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:18][C:19](Br)=[CH:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[CH:36])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27].C(NC(C)C)(C)C>CN(C)C=O.O1CCCC1.[Cu]I>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:18][C:19]([C:36]#[C:35][C:32]4[CH:33]=[CH:34][C:29]([O:28][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:30][CH:31]=4)=[CH:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: C#Cc1ccc(OCCCC)cc1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Br)o3)cc2)C1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCOc1ccc(C#Cc2ccc(C(=O)Nc3ccc(N4CCC(N(C)C)C4)cc3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (75 mg) was dissolved together with 1-butoxy-4-ethynylbenzene (35 mg) in N,N-dimethylformamide (1 ml) and, under argon, added dropwise to a suspension of Pd(tBu3P)2Cl2 (4 mg), copper (I) iodide (75 mg) and N,N-diisopropylamine (20 mg) in anhydrous tetrahydrofuran (3 ml). The mixture was stirred at room temperature for 8 hours. The reaction was worked up by filtration through a syringe filter and concentrated, and the crude product was purified by preparative HPLC. This resulted in the product with the molecular weight of 471.6 (C29H33N3O3); MS (ESI): 472 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=1[S:11][CH2:12][CH:13]([CH3:15])[CH3:14].OO.C(O)(=[O:20])C>CCCCCC>[OH:10][C:4]1[CH2:5][C:6]([CH3:8])([CH3:9])[CH2:7][C:2](=[O:1])[C:3]=1[S:11]([CH2:12][CH:13]([CH3:15])[CH3:14])=[O:20]
Reactant: CC(=O)O
Reactant: CC(C)CSC1=C(O)CC(C)(C)CC1=O
Agent: OO
Solvent: CCCCCC
Product: CC(C)CS(=O)C1=C(O)CC(C)(C)CC1=O
Temperature: 0 °C
Reaction time: 19 h

Procedure:
A mixture of 3-hydroxy-2-isobutylthio-5,5-dimethyl-2-cyclohexen-1-one (10 g., 0.044 mole), 30 percent hydrogen peroxide (5.0 g., 0.044 mole), and 100 ml. of glacial acetic acid was allowed to stand at room temperature for 19 hours. The solution was poured into ice-water and the solid filtered to give 4.7 g. of crude product. After two from hexane the pure product was obtained as pink crystals 3.3 g., m.p. b 48.5°-50°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:15][C:14]3[C:13](=[O:16])[NH:12][C:11]4([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[NH:10][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[OH:22]N1C2C=CC=CC=2N=N1.Cl.[CH2:33]([N:35]=C=NCCCN(C)C)[CH3:34]>C(OC(NCC(O)=O)=O)(C)(C)C.CN(C=O)C>[NH2:35][CH2:33][C:34]([N:19]1[CH2:20][CH2:21][C:11]2([NH:10][C:9]3[CH:8]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[S:15][C:14]=3[C:13](=[O:16])[NH:12]2)[CH2:17][CH2:18]1)=[O:22]
Reactant: O=C1NC2(CCNCC2)Nc2cc(-c3ccncc3)sc21
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: NCC(=O)N1CCC2(CC1)NC(=O)c1sc(-c3ccncc3)cc1N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 2.8 %

Procedure:
A mixture of 6′-(pyridin-4-yl)-1′H-spiro[piperidine-4,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one in DMF (0.16 M, 0.50 mL, 0.080 mmol), N-(tert-butoxycarbonyl)glycine in DMF (0.192 M, 0.50 mL, 0.096 mmol) and a solution of 1-hydroxybenzotriazole and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in DMF (0.192 M, 0.50 mL, 0.096 mmol for each) was stirred for 16 h at room temperature. The reaction mixture was extracted with EtOAc (3.5 mL) and 2% aqueous sodium hydrogen carbonate (1 mL). After evaporating the organic solvent, 1 M methanesulfonic acid in MeCN (0.5 mL) was added to the residue. The mixture was stirred for 16 h at room temperature. After neutralizing the reaction mixture with 1 M N-ethyl-N-(1-methylethyl)propan-2-amine (0.5 mL), the crude product was chromatographed on preparative HPLC (YMC CombiPrep. Hydrosphere C18, 10 mM NH4HCO3 in water/MeCN) to afford the title compound (0.8 mg, 2.8%):
Reaction SMILES: [CH3:1][O:2][C:3]1[C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:37][C:38]2[CH:42]=[C:41]([C:43](=[O:61])[NH:44][C:45]3[CH:50]=[CH:49][C:48]([C:51]4[CH:55]=[C:54]([C:56]([O:58][CH3:59])=[O:57])[N:53]([CH3:60])[CH:52]=4)=[CH:47][CH:46]=3)[N:40]([CH3:62])[CH:39]=2)=[O:36])=[CH:29][C:6]2[N:7](C(OCC=C)=O)[C@@H:8](OC3CCCCO3)[C@@H:9]3[CH2:15][CH2:14][CH2:13][N:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1.N1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:37][C:38]2[CH:42]=[C:41]([C:43]([NH:44][C:45]3[CH:50]=[CH:49][C:48]([C:51]4[CH:55]=[C:54]([C:56]([O:58][CH3:59])=[O:57])[N:53]([CH3:60])[CH:52]=4)=[CH:47][CH:46]=3)=[O:61])[N:40]([CH3:62])[CH:39]=2)=[O:36])=[CH:29][C:6]2[N:7]=[CH:8][C@@H:9]3[CH2:15][CH2:14][CH2:13][N:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: C=CCOC(=O)N1c2cc(OCCCC(=O)Nc3cc(C(=O)Nc4ccc(-c5cc(C(=O)OC)n(C)c5)cc4)n(C)c3)c(OC)cc2C(=O)N2CCC[C@H]2[C@@H]1OC1CCCCO1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(NC(=O)c3cc(NC(=O)CCCOc4cc5c(cc4OC)C(=O)N4CCC[C@H]4C=N5)cn3C)cc2)cn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
Palladium tetrakis[triphenylphosphine](12.17 mg, 10.5 μM, 0.05 equiv) was added to a solution of Alloc-THP-PBD conjugate 15e (179 mg, 0.21 mmol), pyrrolidine (17.91 mg, 0.25 mmol, 1.2 eq) and triphenylphosphine (13.81 mg, 0.25 equiv) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 h at which point TLC showed completion of reaction. Excess DCM was removed by rotary evaporation under reduced pressure and the resulting residue dried in vacuo to remove pyrrolidone. The product was purified by high performance liquid chromatography (eluted with acetone:water gradient with 1% TFA) to give the product as a light yellowish solid, 16e (48 mg, 34% after HPLC purification).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[NH2:21])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[NH:14][CH2:13][CH:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[O:29])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1cnccc1NCC1CCN(c2ccncc2)CC1
Product: COc1ccc(C(=O)Nc2cnccc2NCC2CCN(c3ccncc3)CC2)cc1
Yield: 6.2 %

Procedure:
Using a similar procedure to that described in Example 2, Part D, N4-[1-(4-pyridyl)piperidin-4-ylmethyl]-3,4-pyridinediamine (110 mg, 0.388 mmol) and 4-methoxybenzoyl chloride (0.66 mL, 0.388 mmol) yielded 10 mg (6%) of the title compound as a hydrochloride salt.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([OH:8])[CH2:6][CH2:5][O:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:1][CH2:2][C@@H:3]2[C@@H:7]([OH:8])[CH2:6][CH2:5][O:4]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1OCC[C@@H]1O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2OCC[C@@H]2O)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
(2R,3S)-2-(hydroxymethyl)tetrahydrofuran-3-ol (1.59 g, 13.46 mmol) (prepared as described in Chenault, K. H.; Mandes, R. F. Tetrahedron, 1997, 53(32), 11033-11038) is dissolved in dry pyridine (15 mL) and the solution cooled to −40° C. in a dry ice/acetone bath for 30 min. p-Toluenesulfonyl chloride (2.58 g, 13.51 mmol) is added slowly over 5 min and the solution allowed to warm up to room temperature over 4 h. The solution is concentrated to provide 3.59 g (86%) of the title compound which is used without further purification. LC-ES/MS m/z 295.0 [M+Na]+, TR=1.76 min. (Symyx Draw 3.1 (IUPAC Name) provides the name for the compound of Preparation 12.)
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([CH2:10][NH2:11])=[C:4]2[CH:3]=[CH:2]1.C(N(CC)CC)C.[C:19]([N:26]1[CH:30]=[CH:29]N=C1)(N1C=CN=C1)=[O:20].N[CH2:32][C:33]1[CH:34]=[C:35]([NH:39][C:40](=[O:48])[C:41]#[C:42][CH:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)[CH:36]=CC=1>O1CCCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:19](=[O:20])[NH:26][CH2:30][C:29]3[CH:36]=[C:35]([NH:39][C:40](=[O:48])[C:41]#[C:42][CH:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)[CH:34]=[CH:33][CH:32]=3)=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1cccc(NC(=O)C#CC2CCCC2)c1
Reactant: NCc1ccnc2[nH]ccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C#CC1CCCC1)Nc1cccc(CNC(=O)NCc2ccnc3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
To a solution of (1H-pyrrolo[2,3-b]pyridin-4-yl)methanamine (198 mg, 1.345 mmol) in tetrahydrofuran (6 mL) were added triethylamine (0.563 mL, 4.04 mmol) and carbonyldiimidazole (327 mg, 2.018 mmol), and the mixture was stirred at room temperature for 18 h. N-(3-(aminomethyl)phenyl)-3-cyclopentylpropiolamide (326 mg, 1.345 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using reverse-phase HPLC. The fractions containing the product were combined and concentrated. The residue was washed with 10% NaHCO3 and dried under vacuum to give 185 mg of product (N24229-78-A1)) as a white solid. MS: (M+H)+=416.3 1H NMR (400 MHz, DMSO-d6) δ ppm 2.75-2.86 (m, 6H), 3.16-3.27 (m, 2H), 3.57 (t, J=6.44 Hz, 2H), 5.41 (s, 2H), 6.56 (dd, J=8.08, 1.77 Hz, 1H), 7.10 (d, J=1.77 Hz, 1H), 7.20-7.29 (m, 1H), 8.56 (s, 1H), 8.77 (s, 1H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.CO[C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:24][CH2:25][C:26](Cl)=O.[O:29]=P(Cl)(Cl)Cl>>[O:29]1[C:20]2[CH:19]=[CH:18][C:17]([CH2:24][CH2:25][C:26]3[O:11][C:10]([C:8]4[CH:7]=[CH:6][C:5]5[NH:1][CH:2]=[N:3][C:4]=5[CH:9]=4)=[N:12][N:13]=3)=[CH:16][C:21]=2[O:22][CH2:23]1
Reactant: COc1cccc(CCC(=O)Cl)c1OC
Reactant: O=P(Cl)(Cl)Cl
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Product: c1nc2cc(-c3nnc(CCc4ccc5c(c4)OCO5)o3)ccc2[nH]1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol), TEA (0.153 ml; 1.1 mmol), 2,3-dimethoxyphenylpropionylchloride (228 mg, 1.1 mmol) and POCl3 (0.5 ml; 5.5 mmol) as described in method 1; yield: 0.016 mg (4.6%); MS m/z: 351.3 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.06-3.10 (m, 2H); 3.17-3.21 (m, 2H); 3.73 (s, 3H); 3.79 (s, 3H); 6.82-6.84 (m, 1H); 6.90-6.92 (m, 1H); 6.95-6.99 (m, 1H); 7.75-7.77 (m, 1H); 7.80-7.82 (m, 1H); 8.14 (br s, 1H); 8.41 (s, 1H); HPLC (METHOD [A]): rt 11.49 min (94.5%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:19])[C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](CO)N(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 50 °C

Procedure:
A solution of 2A (2 g, 7.2 mmol) in DMF (20 mL) was added with an. K2CO3 (1.5 mol eq, 1.49 g) and, after few minutes, iodomethane (1.2 mol eq, 0.8 ml) was added and the mixture heated at 50° C. for 12 h. The solvent was removed under reduced pressure, water was added to the residue (100 mL) and the aqueous phase extracted with EtOAc (3×40 mL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to obtain 3A as a pale yellow oil (2.3 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 2.82 (s, 3H), 3.50 (s, 3H), 3.69 (m, 3H), 4.60 (t, 1H, J=6), 5.12 (t, 1H, J=6.1), 7.44 (m, 2H), 7.83 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[CH:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=2)[C:19]2[C:18](=[O:30])[NH:17][C:16](=[O:31])[N:15]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:14]=2[N:13]1C.[CH3:37][O:38][CH2:39][CH2:40][NH2:41].[C:42](P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:41][CH2:40][CH2:39][O:38][CH3:37])=[O:29])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:16](=[O:31])[N:17]([CH3:42])[C:18]2=[O:30])=[N:13]1
Reactant: CC(C)Cn1c2c(c(=O)[nH]c1=O)C(c1cc(C(=O)O)cn1C)N(Cc1c[nH]c3ccc(Cl)cc13)N2C
Reactant: CCOP(=O)(C#N)OCC
Reactant: COCCN
Product: COCCNC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-1-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and 2-methoxyethylamine using diethyl cyanophosphonate as a coupling reagent. Mass: 566.10 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[OH:11])=[O:5])[CH3:2].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C1CCCC1OC1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
A solution of 2-hydroxy-cyclopentanecarboxylic acid ethyl ester (3.5 g, 22.12 mmol) in methylene chloride (147.5 mL) was treated with 3,4-dihydro-2H-pyran (3.03 mL, 33.1 mmol) and pyridinium p-toluenesulfonate (556 mg, 2.21 mmol). This solution was stirred at 25° C. for 5 h. The reaction was then washed with a half-saturated aqueous sodium chloride solution (2×75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(tetrahydro-pyran-2-yloxy)-cyclopentanecarboxylic acid ethyl ester (4.7 g, 87.7%) as a clear liquid: EI-HRMS m/e calcd for C13H22O4 (M+) 242.1518 found 242.1521.
Reaction SMILES: Cl[C:2]12[CH2:10][CH2:9][C:5]([CH3:11])([C:6]([Cl:8])=[N:7]1)[O:4][C:3]2=[O:12].[CH2:13]1CCN2C(=NCCC2)C[CH2:14]1.C(O)C>C(Cl)(Cl)Cl>[Cl:8][C:6]1[N:7]=[C:2]([C:3]([O:4][CH2:13][CH3:14])=[O:12])[CH:10]=[CH:9][C:5]=1[CH3:11]
Reactant: CC12CCC(Cl)(N=C1Cl)C(=O)O2
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(C)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4,6-Dichloro-1-methyl-2-oxa-5-azabicyclo[2.2.2]oct-5-en-3-one (26-3) (3.0 g, 14.4 mmol, 1 eq) was dissolved in chloroform (30 mL) and DBU (6.5 mL, 43 mmol, 3 eq) was added. After 5 minutes of stirring at ambient temperature, ethanol (0.84 mL, 16 mmol, 1.1 eq) was added and there was a slight exotherm. After 15 minutes of stirring at ambient temperature, the reaction mixture was concentrated and the crude residue was purified by flash chromatography (80 g SiO2, 0-100% EtOAc in hexanes) to afford ethyl 6-chloro-5-methylpyridine-2-carboxylate (26-4) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J=7.6 Hz, 1 H); 7.69 (d, J=7.6 Hz, 1 H); 4.47 (q, J=7.2 Hz, 2 H); 2.46 (s, 3 H); 1.43 (t, J=7.2 Hz, 3H). LRMS m/z (M+H) 200.0 found, 200.0 required.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[CH2:29][C:30]1[O:34][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH3:20][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][CH2:29][C:30]2[O:34][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:31]=2)[C:7]=1[C:8]#[C:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=1
Reactant: Cc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(CCl)o1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CNc2ncnc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1
Reaction time: 10 h

Procedure:
A mixture of 4-amino-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine (2 g), triethylamine (0.76 g), ethyl 5-chloromethyl-2-furancarboxylate (1.4 g) and toluene (60 ml) was heated to reflux while stirring for 10 hours. The mixture thus obtained was concentrated under reduced pressure. After the resultant residue was washed with water added thereto, an organic phase was dried over anhydrous sodium sulfate and evaporated. The resultant residue was purified by column chromatography to obtain a target substance (0.6 g). The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: C([Sn](CCCC)(CCCC)C1C=CN=CC=1)CCC.C([O:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30](Br)[CH:29]=1)C1C=CC=CC=1.[C:36]1([OH:42])[CH:41]=[CH:40][CH:39]=CC=1>>[F:34][C:32]1[CH:33]=[C:28]([OH:27])[CH:29]=[C:30]([C:40]2[CH:41]=[CH:36][O:42][CH:39]=2)[CH:31]=1
Reactant: Oc1ccccc1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Product: Oc1cc(F)cc(-c2ccoc2)c1

Procedure:
Following the procedures described in Phenol 1, Steps 2 and 3, but substituting 3-tributylstannylfuran for 4-tributylstannylpyridine, and O-(3,4-dimethoxy)benzyl-3-bromo-5-fluorophenol from Phenol 2, Step 1 for O-benzyl-3-bromo-5-fluorophenol, the title compound was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:31]=[CH:30][N:29]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])[N:28]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([NH:26][C:27]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]([OH:35])([CH3:34])[CH3:36])[N:28]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCOCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCOCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
2-(3,4-Dichloro-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (152 mg, 0.50 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylfomamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 270 μL, 0.53 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was concentrated in vacuo and the residue was then taken up in methylene chloride (5 mL). This solution was then added dropwise to a flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 78 mg, 0.50 mmol), 2,6-lutidine (130 μL, 1.00 mmol), and methylene chloride (5 mL) which was 0° C. The reaction was allowed to warm to 25° C. and stirred for a period of 2 h. After this time, the reaction was quenched with a small amount of methanol and then concentrated in vacuo. It was then dissolved in ethyl acetate (25 mL) and washed with a 1N hydrochloric acid solution (1×10 mL) and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was then dried over sodium sulfate and concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 100% ethyl acetate) to afford 2-(3,4-dichloro-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (149 mg, 81%) a 1:1 enantiomeric reaction as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH:22]=[CH:21][N:20]=1)=[O:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([O:25][C:23]3[CH:22]=[CH:21][N:20]=[C:19]([C:17](=[O:18])[NH:16][CH3:15])[CH:24]=3)=[CH:32][CH:31]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Reaction time: 22 h
Yield: 93.2 %

Procedure:
A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 mmol) in CH2Cl2 (35 mL) was added dropwise to a suspension of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH2Cl2 (35 mL) at 0° C. The resulting mixture was stirred at room temp. for 22 h. The resulting yellow solids were removed by filtration, then washed with CH2Cl2 (2×30 mL) and dried under reduced pressure (approximately 1 mmHg) to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as an off-white solid (28.5 g, 93%): mp 207-209° C.; 1H-NMR (DMSO-d6) δ2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 1H), 7.62 (m, 4H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 465 ((M+H)+).