Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:8](=[O:20])[CH2:7][CH2:6]1)=O.[NH3:21]>CO>[O:20]=[C:8]1[N:9]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]([C:3]([NH2:21])=[O:2])[CH2:6][CH2:7]1
Reactant: COC(=O)C1CCC(=O)N1CC#CCN1CCCCC1
Reactant: N
Solvent: CO
Product: NC(=O)C1CCC(=O)N1CC#CCN1CCCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
An ice water chilled solution of 5-methoxycarbonyl-1-[4-(1-piperidinyl)-2-butynyl]-2-pyrrolidinone (5.44 g) in sieve dried methanol (175 ml) was treated with anhydrous ammonia for fifteen minutes and was allowed to stand at ambient temperature overnight. The solution was concentrated to a brown solid (5.00 g). The solid was recrystallized from toluene (125 mL) to give 3.85 g of slightly brown crystals, mp 143°-145° C.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:21]=[C:22]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31][CH:32](P(=O)(OCC)OCC)[C:33]3=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(O)C>O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31]/[C:32](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:33]3=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3cccc(F)c3)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4cccc(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 77.7 %

Procedure:
Lithium hydroxide (0.217 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.49 g) and diethyl [(3S,8aR)-3-(3-fluorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (1.9 g) in tetrahydrofuran (4 mL)-ethanol (16 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.76 g of the title compound as a colorless solid. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:23]S(C)=O.[OH-].[Na+].CI>O>[CH2:1]([C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CS(C)=O
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a two necked round bottomed flask with a reflux condenser is added 3-pentadecyl phenol, DMSO, sodium hydroxide followed by dropwise addition of alkylating agent such as methyl iodide with constant stirring at room temperature. The stirring is continued for about 6-8 hrs. The reaction mixture is then poured into deionized water and the organic matter is extracted in diethyl ether, separated the organic layer, washed with water and dried, purified to obtain 3-pentadecyl anisole.
Reaction SMILES: C(OC(=O)C[C:6]1[C:15]([C:16]([OH:18])=[O:17])=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)C.O=P(Cl)(Cl)[Cl:22].CN(C=O)C>ClCCl>[Cl:22][C:6]1[C:15]([C:16]([OH:18])=[O:17])=[N:14][C:13]2[C:8]([N:7]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1nc2ccccc2nc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)c1nc2ccccc2nc1Cl
Temperature: 75 °C
Reaction time: 1 h

Procedure:
From crude 16d, with a changed ratio of 1 g 16d: 0.8 mL POCl3: 1.6 mL DMF. The reaction mixture was heated, with moisture exclusion, at 75° C. for 16 h, then cooled, diluted with cold dichloromethane, and kept at −18° C. for 1 h. The brick red solid was filtered and washed exhaustively, with thorough stirring, with cold dichloromethane to give the dione (22% from 3-chloroquinoxaline-2-carboxylic acid), mp 133-139° C. 1H NMR (d6-DMSO): δ 3.27 (s, 3H, NCH3), 3.57 (s, 3H, NCH3), 7.66 (ddd, J=8.3, 6.6, 1.6 Hz, 1H), 7.81-7.92 (m, 2-H), 8.04 (d, J=7.8 Hz, 1H), 8.66 (s, 1H, ═HCNMe2). 13C NMR (d6-DMSO): δ 45.0 (CH3), 48.3 (CH3), 87.0 (C), 127.2 (CH), 128.3 (CH), 130.3 (CH), 133.3 (C), 133.7 (CH), 139.4 (C), 143.2 (C), 150.3 (C), 157.6 (C), 159.7 (C), 161.1 (CH).
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4]C1C=CC(Cl)=C2C=1C=C([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)N=C2.[F:34][C:35]1[CH:44]=[CH:43][C:42]([F:45])=[C:41]2[C:36]=1[CH:37]=[C:38](OS(C(F)(F)F)(=O)=O)[N:39]=[CH:40]2>>[ClH:4].[ClH:1].[ClH:4].[F:34][C:35]1[CH:44]=[CH:43][C:42]([F:45])=[C:41]2[C:36]=1[CH:37]=[C:38]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[CH:26]=3)[CH:21]=1)[N:39]=[CH:40]2
Reactant: O=S(=O)(Oc1cc2c(F)ccc(F)c2cn1)C(F)(F)F
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Agent: Cl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(F)ccc(F)c2cn1

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 5,8-difluoroisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester, affording the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.09-2.30 (m, 4H), 3.04-3.17 (m, 2H), 3.41 (d, J=12.1 Hz, 2H), 4.48-4.59 (m, 1H), 7.57-7.68 (m, 1H), 7.79 (td, J=8.8, 3.6 Hz, 1H), 8.15 (s, 1H), 8.47 (s, 1H), 8.68 (s, 1H), 8.83 (br. s., 1H), 9.01 (br. s., 1H), 9.65 (s, 1H). MS (ES+): m/z=407.16 [MH+]. HPLC: tR=1.76 min (ZQ2, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:9]2)=[N:4][CH:3]=1.[NH2:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:22]=2[N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[N:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([C:25]2[CH:26]=[CH:27][C:21]4[O:20][C:19]([NH2:18])=[N:23][C:22]=4[CH:24]=2)=[CH:11]3)[CH2:13][CH2:14]1
Reactant: Brc1cnc2ccc(N3CCOCC3)nc2c1
Reactant: Nc1nc2cc(B(O)O)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc2cc(-c3cnc4ccc(N5CCOCC5)nc4c3)ccc2o1
Yield: 67.2 %

Procedure:
A mixture of 7-bromo-2-morpholino-1,5-naphthyridine (F-32) (180 mg, 0.6 mmol, 1.0 eq), 2-aminobenzo[d]oxazol-5-ylboronic acid (131 mg, 0.73 mmol, 1.2 eq), Pd(PPh3)4 (71 mg, 0.06 mmol, 0.1 eq), and Na2CO3 (195 mg, 1.8 mmol, 3.0 eq) were dissolved in a mixture of 1,4-dioxane (10 mL) and water (10 mL). The resulting mixture was degassed and back-filled with argon three times and heated at reflux under an argon atmosphere for 2 h. The reaction was complete based on TLC analysis. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (3-5% MeOH-DCM) to afford 5-(6-morpholino-1,5-naphthyridin-3-yl)benzo[d]oxazol-2-amine (73) (140 mg, 67.2% yield). 1H NMR (400 MHz, DMSO-d6) δ: 8.93 (s, 1H), 8.10 (m, 2H), 7.66 (s, 1H), 7.53 (s, 2H), 7.45 (m, 3H), 3.74 (m, 8H); ESI-MS m/z: 348.11 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17](I)([CH3:19])[CH3:18]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:17]([CH3:19])[CH3:18])[CH:7]=1
Reactant: CC(C)I
Reactant: COc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Br)cc1OC(C)C
Temperature: 20 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 5-bromo-2-methoxyphenol (0.200 g, 1 mmol) in DMF (4 mL) was added potassium carbonate (0.209 g, 1.5 mmol) and isopropyliodide (120 μL, 1.2 mmol), the reaction mixture was stirred at room temperature (20° C.) for 3 h. After this time the crude reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2×100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil (200 mg, 0.81 mmol, 82%). No further purification was required.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.S(O)(O)(=O)=O.[NH2:60][C:61]1[NH:62][CH:63]=[CH:64][N:65]=1>CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:60][C:61]2[NH:62][CH:63]=[CH:64][N:65]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ncc[nH]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncc[nH]1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 33 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 200 mg, 0.70 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (310 mg, 0.70 mmol), N,N-diisopropylethylamine (244 μL, 1.40 mmol), and 2-aminoimidazole sulfate (140 mg, 1.05 mmol) in dry N,N-dimethylformamide (5 mL) was stirred at 25° C. under nitrogen for 15 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed sequentially with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(1H-imidazol-2-yl)-propionamide (81.4 mg, 33%) as a white solid: mp 58–60° C.; EI-HRMS m/e calcd for C17H19Cl2N3O (M+) 351.0905, found 351.0901.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[CH:24]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:27]([NH2:29])[CH3:28]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][C:15]=2[CH2:24][NH:29][CH2:27][CH3:28])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2cc(C(F)(F)F)ccc2C=O)c1
Product: CCNCc1ccc(C(F)(F)F)cc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: (2′-formyl-6-methoxy-5′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: FC1C([O:8][C:9](=O)[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)=C(F)C(F)=C(F)C=1F.CCN(C(C)C)C(C)C.[NH2:46][CH2:47][C:48]([NH:50][C@H:51]([C:59]([NH:61][C@H:62]([C:67]([OH:69])=[O:68])[CH2:63][CH:64]([CH3:66])[CH3:65])=[O:60])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:49]>CN(C=O)C>[NH:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:46][CH2:47][C:48]([NH:50][C@H:51]([C:59]([NH:61][C@H:62]([C:67]([OH:69])=[O:68])[CH2:63][CH:64]([CH3:65])[CH3:66])=[O:60])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:49])=[O:8]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CN)C(=O)O
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H]1CCCN1)C(=O)O
Reaction time: 3 h

Procedure:
Fmoc-L-proline pentafluorophenyl ester (50 mg, 0.1 mmol) is dissolved in anhydrous DMF (1 mL) containing DIEA (17 μL, 0.1 mmol). About 0.5-1.0 mL of this solution is added to Gly-L-Phe-L-Leu ELAMS™ in a test tube and the tube vortexed for about 3 hours. The ELAMS™ are pelleted and washed with DMF (4×) and methylene chloride (2×). Deprotection can be effected by treatment with a solution of 20% piperidine in DMF for 30 min. The ELAMS™ are then washed with DMF (2×), ethanol (2×) and methylene chloride (2×) and dried at 60° C. for 4 hours. The identifier tag for each ELAMS™ is detected and recorded.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:32])[CH2:31][CH2:30][NH:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[C:33](O)(=[O:35])[CH3:34].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:32])[CH2:31][CH2:30][N:29]([C:33](=[O:35])[CH3:34])[CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCNC5)s4)c(Cl)cnc32)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(O)(c2ncc(-c3c(Cl)cnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ambient solution of 3-(5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)pyrrolidin-3-ol (Example 117D) (180 mg, 0.300 mmol) in N,N-dimethylformamide (10 mL) was added acetic acid (36 mg, 0.599 mmol), triethylamine (0.125 mL, 0.899 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (137 mg, 0.359 mmol). The reaction was stirred at room temperature for 3 hours and was quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purifed by flash column chromatography on silica gel, eluting with a gradient of 0 to 5% methanol in dichloromethane, to give the title compound. MS ESI(+) m/z 643.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)#[N:19]>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([O:26][C:23]3[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: N#Cc1ccc(O)cc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: N#Cc1ccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-cyano-phenol to give 4-[3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-benzonitrile. LC-MS m/e 328(MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH:10](OCC)=[O:11]>>[CH:10]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)=[O:11]
Reactant: NCCN1CCOCC1
Reactant: CCOC=O
Product: O=CNCCN1CCOCC1
Yield: 100 %

Procedure:
The procedure of B. V. Cheney et al. [J. Med. Chem., 28, 1853-1864 (1985)] was used. A solution of 4-(2-aminoethyl)morpholine (1.00 g, 76.8 mmol) and ethyl formate (213 mL, 2640 mmol) was refluxed overnight under an atmosphere of nitrogen. Vacuum distillation gave 11.46 g (100% yield) of a clear, colorless liquid (bp0.3 118°-120° C.). The 1H NMR spectral data were consistent with the structure of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[C:35]([CH3:54])=[C:36]([C:40]2[C:49](=[O:50])[C:48]3[C:43](=[CH:44][C:45]([N:51]([CH3:53])[CH3:52])=[CH:46][CH:47]=3)[NH:42][CH:41]=2)[CH:37]=[CH:38][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:53][N:51]([CH3:52])[C:45]1[CH:44]=[C:43]2[C:48]([C:49](=[O:50])[C:40]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([C:6]4[CH:5]=[C:4]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([C:24]([N:26]6[CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)=[O:25])=[CH:20][N:19]=5)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=4)[C:35]=3[CH3:54])=[CH:41][NH:42]2)=[CH:47][CH:46]=1
Reactant: Cc1c(Br)cccc1-c1c[nH]c2cc(N(C)C)ccc2c1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)c2)cccc1-c1c[nH]c2cc(N(C)C)ccc2c1=O
Temperature: 100 °C
Yield: 38.7 %

Procedure:
To Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (27 mg, 0.062 mmol), 3-(3-Bromo-2-methyl-phenyl)-7-dimethylamino-1H-quinolin-4-one (22 mg, 0.062 mmol), potassium phosphate (26 mg, 0.12 mmol), 2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (1.7 mg, 0.0036 mmol), and bis(dibenzylidineacetone)palladium(0) (1.0 mg, 0.0018 mmol) was added 4 mL of degassed 1:3 water/n-butanol. The headspace of the vessel was evacuated and backfilled with argon 4 times. This was heated at 100° C. for 1 hour. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by preparative TLC (5% methanol/dichloromethane) to yield 7-Dimethylamino-3-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1H-quinolin-4-one (14 mg, 0.024 mmol). MS (ESI) 591.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[CH2:12][CH3:13].[H][H]>C(O)(=O)C.[Pd]>[CH2:12]([C:4]1[CH:5]=[CH:6][C:7]([NH2:9])=[CH:8][C:3]=1[CH3:2])[CH3:13]
Reactant: CCc1ccc([N+](=O)[O-])cc1CCl
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCc1ccc(N)cc1C

Procedure:
α-Chloro-2-ethyl-5-nitrotoluene (40.0 g.) was dissolved in glacial acetic acid and shaken with 5% Pd/C in a hydrogen atmosphere (6.7 g.) in a Parr hydrogenator. When reduction was complete, the crude product was isolated, taken up in ether, washed with water, dilute base and water. After stirring the ether solution over solid K2CO3, the product was isolated as a liquid, 96% pure by glc.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][C:13]3[NH:14][CH:15]=[C:16]([CH2:20][C:21]4[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[CH3:37]CN(C(C)C)C(C)C.CI>ClC(Cl)C>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][C:13]3[N:14]([CH3:37])[CH:15]=[C:16]([CH2:20][C:21]4[CH:26]=[N:25][C:24]([O:27][CH3:28])=[N:23][CH:22]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:33]([F:34])([F:35])[F:36]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ncc(Cc2c[nH]c(CCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Solvent: CC(Cl)Cl
Solvent: CI
Product: COc1ncc(Cc2cn(C)c(CCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.8 %

Procedure:
To the solution of 2-(4-(4-chloro-3-(trifluoromethyl)phenoxy)phenethyl)-5-((2-methoxypyrimidin-5-yl)methyl)pyrimidin-4(1H)-one (308 mg, 0.596 mmol) in dichloroethane (8 mL) was added DIPEA (0.208 mL, 1.192 mmol) and MeI (0.045 mL, 0.715 mmol). The reaction mixture was stirred at room temp overnight. Concentration and purification via MDAP then provided the title compound (50 mg, 15.81% yield). LCMS: rt=3.09 min, [M+H+]=531
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[CH2:14][CH2:15][Cl:16].[N:17]1([C:23]2[C:28]3[CH:29]=[CH:30][S:31][C:27]=3[CH:26]=[CH:25][N:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[ClH:16].[NH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[CH2:14][CH2:15][N:20]1[CH2:21][CH2:22][N:17]([C:23]2[C:28]3[CH:29]=[CH:30][S:31][C:27]=3[CH:26]=[CH:25][N:24]=2)[CH2:18][CH2:19]1
Reactant: c1cc2sccc2c(N2CCNCC2)n1
Reactant: Nc1ccc2[nH]c(=O)cc(CCCl)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2[nH]c(=O)cc(CCN3CCN(c4nccc5sccc45)CC3)c2c1
Temperature: 60 °C

Procedure:
A mixture of 0.35 g (1.35 mmol) of 6-amino-4-(2-chloroethyl)-2(1H)-quinolone hydrochloride, 0.33 g (1.5 mmol) of 4-(1-piperazinyl)thieno[3,2-c]pyridine and 0.17 g (2 mmol) of sodium bicarbonate in 10 ml of dimethylformamide is heated to 60° C. for 24 hours. After cooling to room temperature, the reaction medium is diluted in 50 ml of water and the crude product is extracted with chloroform. The organic phase is dried over sodium sulpbate and concentrated. The crude product is purified by flash chromatography on silica, eluting first with a methanol/ethyl acetate (6.5:93.5) mixture containing traces of triethylamine and then with a methanol/dichloromethane (6.5:93.5) mixture comprising traces of aqueous ammonia.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[S:24][CH:23]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][C:28]([Cl:35])=[N:29][C:30]=3Cl)[CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:36]>>[Si:1]([O:18][CH2:19][C@H:20]1[S:24][CH:23]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][C:28]([Cl:35])=[N:29][C:30]=3[NH2:36])[CH2:22][CH2:21]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N
Reactant: CC(C)(C)[Si](OC[C@@H]1CCC(n2cnc3c(Cl)nc(Cl)nc32)S1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)[Si](OC[C@@H]1CCC(n2cnc3c(N)nc(Cl)nc32)S1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 86 %

Procedure:
A mixture of 12 (150 mg) and saturated ethanolic ammonia (50 mL) was heated at 50° C. in a glass-lined stainless steel pressure vessel for 48 hours. The reaction mixture was evaporated to dryness to afford a syrup which was purified on two silica gel thick plates (Analtech, GF, 1000 μm) that were developed in 99:1CHCl3 -MeOH. The product was eluted with CHCl3 and evaporated. The residue was crystallized from EtOAc-cyclohexane to give pure 15 (125 mg, 86%); mp. 123°-125° C.; FAB MS 524 (M+H)+ ; 1H NMR (CDCl3) δ 8.14 (s, 1, H-8), 7.72 (m, 4, ArH), 7.42 (m, 6, ArH), 6.02 (brs, 2, NH2), 6.16 (m, i'-H), 3.93 (m, 1, 5'-H), 3.84 (m, 1, 5'-H), 3.73 (m, 1, 4'-H), 2.36 (m, 2, 2'-H), 2.18 (m, 1, 3'-H), 1.90 (m, 1, 3'-H), 1.1 (s, 9, t-butyl).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[CH:14]([C:20](=O)[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)(O)[O-].[Na+]>CC(O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:21])[N:12]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Nc1ncc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1c(C)nc2c(Cl)cc(C(F)(F)F)cn12
Temperature: 150 °C
Yield: 17.3 %

Procedure:
A mixture of 3-chloro-5-(trifluoromethyl)pyridin-2-amine (2 g), ethyl 2-chloro-3-oxobutanoate (1.18 g) and 2-propanol (12 mL) was stirred with heating with microwave irradiation at 150° C. for 7 hr. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (380 mg).