Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:21])[CH2:17][CH2:18][CH2:19]Cl)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>CN(C)C=O>[C:6]([C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:21])[CH2:17][CH2:18][CH2:19][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:14][CH:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C(=O)CCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a 0° C. slurry of 8.24 g of imidazole in 15 ml. dry dimethylformamide was added 5.79 g of p-t-butyl-gamma-chlorobutyrophenone and the mixture was stirred overnight at room temperature, then for one day at 60° C. The above solution was poured into 400 ml. of water and extracted three times with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent evaporated to afford 5.25 g of 1-[4-(4-t-butylphenyl)butan-4-onyl]imidazole as a golden oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:17]([OH:19])=O)=[CH:11][N:12]([CH3:16])[C:13](=[O:15])[CH:14]=2)=[C:4]([F:20])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:42]([O:44][CH2:45][CH2:46][O:47][NH2:48])=[CH2:43].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH:42]([O:44][CH2:45][CH2:46][O:47][NH:48][C:17]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:20])=[CH:14][C:13](=[O:15])[N:12]([CH3:16])[CH:11]=1)=[O:19])=[CH2:43]
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=COCCONC(=O)c1cn(C)c(=O)cc1Nc1ccc(Br)cc1F
Reaction time: 3 h
Yield: 52 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.120 g, 0.352 mmol), EDCI (0.10 g, 0.53 mmol), and HOBt (0.071 g, 0.53 mmol) in DMF (5 mL) was stirred for 3 hours. O-(2-Vinyloxy-ethyl)-hydroxylamine (0.071 mL, 0.70 mmol) was added followed by Et3N (0.098 mL, 0.70 mmol). After 2 hours, the reaction mixture was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (3% MeOH in methylene chloride) gave 0.078 g (52%) clean desired product.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH2:36][C:37](O)=[O:38])[C:30]=2[CH3:40])=[CH:25][CH:24]=1.P(Cl)(Cl)(Cl)=O>O1CCCC1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH2:36][C:37]([NH:2][C:3]3([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]3)=[O:38])[C:30]=2[CH3:40])=[CH:27][CH:28]=1
Reactant: COC(=O)C1(N)CCC(F)(F)CC1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)c(C)c1CC(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)Cc2c(C)ccc(-c3ccc(Cl)cc3)c2C)CCC(F)(F)CC1
Reaction time: 0.08 h

Procedure:
2.53 g (11 mmol) of the compound from Example 4A were initially charged in 50 ml of absolute tetrahydrofuran (THF). At 20° C., 3.07 ml of triethylamine were added dropwise, the mixture was stirred for 5 min and 2.75 g (10 mmol) of (4′-chloro-2,4-dimethylbiphenyl-3-yl)acetic acid were added. After 15 min, a further 2.3 ml of triethylamine were added, followed immediately by the dropwise addition of 0.58 ml (6.2 mmol) of phosphorus oxychloride, and the mixture was stirred under reflux for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by means of flash chromatography on silica gel using the mobile phase n-hexane/ethyl acetate 1:1. This gave 2.59 g (53% of theory) of the title compound of melting point 179-183° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:8]=[C:7]3[C:20]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:21]=4[O:22][C:5]=1[C:6]=23)([O-])=O>CN(C=O)C.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:8]=[C:7]3[C:20]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:21]=4[O:22][C:5]=1[C:6]=23
Reactant: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)Oc1cc(O)ccc1-2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCN(CC)CCn1nc2c3c(c(N)ccc31)Oc1cc(O)ccc1-2

Procedure:
A solution of 5.0 g of 5-nitro-2-[2-(diethylamino)-ethyl]-2H-[1]benzopyrano[4,3,2-cd]indazol-8-ol in 200 ml of DMF with 0.2 g of 20% palladium hydroxide on carbon was stirred under a hydrogen atmosphere for 24 hours. The mixture was filtered and the filtrate was evaporated in vacuo to leave the product 5-amino-2-[2-(diethylamino)-ethyl]-2H-[1]benzopyrano[4,3,2-cd]indazol-8-ol as an oily solid.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:10][CH2:9][CH:8]([C:11](Cl)=O)[CH2:7][CH2:6]1)=O.[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[N:29]=C(N4CCNCC4)[N:27]=[C:26]([O:36]CC)[C:22]=3[NH:23][C:24]=2[CH:25]=1.O>C(Cl)Cl.N1C=CC=CC=1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[N:29]=[C:11]([CH:8]4[CH2:7][CH2:6][NH:5][CH2:10][CH2:9]4)[N:27]=[C:26]([OH:36])[C:22]=3[NH:23][C:24]=2[CH:25]=1
Reactant: CCOc1nc(N2CCNCC2)nc2c1[nH]c1cc(Br)ccc12
Reactant: O=C(Cl)C1CCN(C(=O)C(F)(F)F)CC1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Oc1nc(C2CCNCC2)nc2c1[nH]c1cc(Br)ccc12
Reaction time: 0.67 h
Yield: 89.4 %

Procedure:
767 mg (3.15 mmol) 1-(2,2,2-trifluoroacetyl)piperidine-4-carboxylic acid chloride dissolved in CH2Cl2 was slowly added drop-wise to 526 mg (2.10 mmol) 3-amino-6-bromo-1H-indole-2-carboxylic acid amide (Example 4) in pyridine at 0° C. Then, stirring was carried out at room temperature for 40 min. After the addition of water, the solvent was removed in vacuo and the residue was taken up in methanol. After the addition of 2 M NaOH (excess), the reaction was kept at reflux for 45 min. Thereafter, the methanol was removed in vacuo, the precipitate was sucked off and washed with water. 652 mg (89%) 7-bromo-2-(4-piperidyl)-5H-pyrimido[5,4-b]indol-4-ol was obtained. ESI-MS [m/z]: 347, 349 [M+H]+
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:15][C:16]1[C:17]([F:31])=[C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[C:19]([O:22][CH3:23])=[CH:20][CH:21]=1>C1COCC1>[Cl:30][C:26]1[CH:25]=[C:24]([C:18]2[C:19]([O:22][CH3:23])=[CH:20][CH:21]=[C:16]([CH2:15][N:1]3[CH:5]=[C:4]([C:6]4[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=4)[N:3]=[CH:2]3)[C:17]=2[F:31])[CH:29]=[CH:28][CH:27]=1
Reactant: c1cncc(-c2c[nH]cn2)c1
Reactant: COc1ccc(CBr)c(F)c1-c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc(-c3cccnc3)c2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Yield: 39.2 %

Procedure:
A flask was charged with 3-(1H-Imidazol-4-yl)-pyridine (165 mg, 0.75 mmol) and THF (5 mL). Then NaH (60% dispersion in mineral oil, 60 mg, 1.5 mmol) was added slowly (gas evolution). After 2 min. of stirring at room temperature 3-Bromomethyl-3′-chloro-2-fluoro-6-methoxy-biphenyl (165 mg, 0.5 mmol) was added. The reaction mixture was stirred at rt. After overnight stirring the reaction mixture was quenched with water (20 mL). The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated in-vacuo. The crude was purified by silica gel column chromatography, eluted with dichloromethane/MeOH (200:5) to produce 77.1 mg (39% yield) of the product (P-479) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d) δ 3.75 (s, 3H), 5.26 (s, 2H), 7.02 (d, J=, 8.59 Hz, 1H), 7.28-7.50 (m, 6H), 7.78-7.88 (m, 2H), 8.04-8.11 (m, 1H), 8.38 (dd, J=4.7, 1.2 Hz, 1H), 8.96 (d, J=1.5 Hz, 1H) ppm.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH:46]1([CH2:49][C:50]([N:52]2[CH2:57][CH2:56][N:55]([C:58]3[CH:63]=[CH:62][C:61]([C:64]4[CH:65]=[C:66]5[C:72]([C:73]6[CH:74]=[N:75][N:76]([CH2:78][C:79]7[CH:84]=[CH:83][CH:82]=[C:81]([F:85])[CH:80]=7)[CH:77]=6)=[CH:71][N:70](S(C6C=CC(C)=CC=6)(=O)=O)[C:67]5=[N:68][CH:69]=4)=[CH:60][N:59]=3)[CH2:54][CH2:53]2)=[O:51])[CH2:48][CH2:47]1.[OH-].[Li+]>C1COCC1.CO.O>[CH:46]1([CH2:49][C:50]([N:52]2[CH2:57][CH2:56][N:55]([C:58]3[CH:63]=[CH:62][C:61]([C:64]4[CH:65]=[C:66]5[C:72]([C:73]6[CH:74]=[N:75][N:76]([CH2:78][C:79]7[CH:84]=[CH:83][CH:82]=[C:81]([F:85])[CH:80]=7)[CH:77]=6)=[CH:71][NH:70][C:67]5=[N:68][CH:69]=4)=[CH:60][N:59]=3)[CH2:54][CH2:53]2)=[O:51])[CH2:47][CH2:48]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)CC6CC6)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC1CC1)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Yield: 6.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 2-cyclopropyl-1-(4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl) ethanone (80 mg, 0.116 mmol) was hydrolyzed with lithium hydroxide (25 mg, 0.58 mmol) in THF/methanol/water (3/2/1 mL) to yield 4 mg (6.4% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.52-8.45 (m, 3H), 8.33-8.32 (d, 1H), 8.225-8.222 (d, 1H), 7.993-7.990 (d, 1H), 7.73 (s, 1H), 7.50-7.46 (d, 1H), 7.38-7.33 (m, 1H), 7.12-7.09 (d, 1H), 7.04-6.89 (m, 3H), 6.50-6.43 (dt, 1H), 5.44 (s, 2H), 3.93-3.85 (m, 8H), 2.35-2.25 (m, 2H), 1.13-1.08 (t, 3H). MS: m/z=536.4 (M+1), HPLC: 97.55% in method B.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([N:14]3[CH2:15][CH2:16][N:17]([CH2:22][C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=4)[CH2:18][CH2:19]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Fc1ccc([C@H]2CC[C@H](N3CCNCC3)CC2)cc1
Agent: Cl
Product: Fc1ccc([C@H]2CC[C@H](N3CCN(Cc4ccc5ccccc5n4)CC3)CC2)cc1

Procedure:
This compound was prepared from trans 1-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine (2.4 mmole) and 2-chloromethylquinoline hydrochloride (2.4 mmole) by the method described in Example 45 to give the product (82%, mp 160-162° C.). Calc'd for C26H30FN3.0.2H2O: C, 76.70%; H, 7.53%; N, 10.32% Found: C, 76.68%; H, 7.49%; N, 10.32%.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH2:4][NH:3]1.Cl.[F:15][C:16]([F:36])([F:35])[C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([C:25]2[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=2)[NH2:24])=[CH:19][CH:18]=1>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:24][C@@H:23]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([F:36])([F:15])[F:35])=[CH:18][CH:19]=3)[C:25]3[C:30]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:28]=[CH:27][N:26]=3)=[O:13])=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Reactant: O=C(O)c1ccc2c(c1)CNC2=O
Agent: Cl
Product: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F)c1ccc2c(c1)CNC2=O

Procedure:
1-Oxoisoindoline-5-carboxylic acid was then coupled with Intermediate 1 using the general methods described above for the amide coupling reaction (Table 2) to provide the title compound, (S)-1-oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide, as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.92 (d, J=4.7 Hz, 1H), 8.36 (d, J=7.4 Hz, 1H), 8.09-7.99 (m, 2H), 7.97-7.88 (m, 2H), 7.65-7.53 (m, 5H), 7.51 (dd, J=4.9, 7.8 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 4.54 (s, 2H). MS (ESI pos. ion) m/z: 480.2 (M+H).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:8][CH:7]=2)[CH:5]=1.Cl>CCOC(C)=O>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][NH2:14])=[CH:10][CH:11]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-n2cnnc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCc1ccc(-n2cnnc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A suspension of tert-butyl 2-[4(4H-1,2,4-triazol-4-yl)phenyl]ethylcarbamate (250 mg, 0.87 mmol) in EtOAc (4 mL) at 0° C. was saturated with HCl(g). After stirring at 0° C. for two hours, the reaction was concentrated to give 2-[4-(4H-1,2,4-triazol-4-yl)phenyl]ethanamine, which was used without further purification. LCMS (ES) 189.3 m/z (M+H)+.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][N:7]([C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH3:10])[C:6](=[O:19])[CH2:5]1)(=[O:3])[CH3:2].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(O)CCC>[C:1]([C@H:4]1[CH2:8][N:7]([C@H:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH3:10])[C:6](=[O:19])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc([C@H](C)N2CC(C(C)=O)CC2=O)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCCCO
Product: COc1ccc([C@H](C)N2C[C@H](C(C)=O)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
103 g of a mixture of diastereoisomers (R/S)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one is dissolved in 155 mL 1-butanol at 25° C. 18 mL benzyltrimethylammonium hydroxide (40% solution in methanol) is added. The solution is stirred for 30 minutes at 25° C. The solution is cooled to 0° C. Precipitation starts. The suspension is stirred for 15 minutes at 0° C. 100 mL n-heptane is added slowly and the suspension is stirred for 30 minutes at 0° C. The addition of 100 mL portions of n-heptane is repeated 4 times with subsequent stirring of the suspension at 0° C. for 30 minutes. The precipitate is isolated, washed with n-heptane and dried at 50° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:33])([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[CH:17][C:16]=1[Cl:32])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)Br.[P:39]([O:44]C)([O:42][CH3:43])[O:40][CH3:41].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:33])([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=2)=[CH:17][C:16]=1[Cl:32])[CH2:10][O:11][P:39]([O:42][CH3:43])([O:40][CH3:41])=[O:44])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)CCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1Cl
Reactant: COP(OC)OC
Agent: BrC(Br)(Br)Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: COP(=O)(OC)OC[C@@](C)(CCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1Cl)NC(=O)OC(C)(C)C

Procedure:
To a solution of the compound of Example 16 (456 mg) in pyridine (5 mL) was added under ice cooling carbon tetrabromide (620 mg) and trimethyl phosphite (219 μL), and the resultant solution was then stirred at 0° C. for 1 hour. To the reaction solution was added 10% aqueous citric acid, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to obtain the target product (533 mg) as a colorless oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([CH3:25])[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>>[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([CH3:25])[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N+:16]([O-:9])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(Cl)ccnc2c1C
Product: COc1ccc2c(Cl)cc[n+]([O-])c2c1C
Yield: 18.3 %

Procedure:
Metachloroperbenzoic acid (90.2 g, 366.0 mmol) was added portion wise over 3 h to a solution of 4-chloro-7-methoxy-8-methylquinoline (60, 15.2 g, 73.2 mmol) in CHCl2 (1 L). Then, the solution was partitioned between ice-cooled NaOH 1N and CH2Cl2 (8 successive extractions). The organic layers were combined, dried (Na2SO4) and evaporated. The residue was purified by column chromatography (gradient of AcOEt/CH2Cl2, 1:2 to 1:0) to give 3.0 g (18.3%) of the title product 61 as a pale yellow powder: m/z=224 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:15]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[N:21][C:22](SC)=[N:23][CH:24]=2)[N:19]1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH2:40][CH2:39][N:38]([CH3:41])[C:37]2=[O:42])[N:31]=1)[CH:16]=[CH2:17]>>[CH2:15]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[N:21][C:22]([NH:12][C:11]3[CH:13]=[CH:14][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:9][CH:10]=3)=[N:23][CH:24]=2)[N:19]1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH2:40][CH2:39][N:38]([CH3:41])[C:37]2=[O:42])[N:31]=1)[CH:16]=[CH2:17]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(N2CCN(C)C2=O)n1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n1-c1cccc(N2CCN(C)C2=O)n1

Procedure:
In the same manner as in Example 29-2, but using 4-(4-methylpiperazin-1-yl)aniline in place of [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2 and using 2-allyl-1-[6-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one in place of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one, 115.6 mg of the entitled compound was obtained as a yellow solid.
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][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[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][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccncc2)cc1
Yield: 77.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(pyridin-4-yl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), pyridin-4-ylboronic acid (0.025 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.051 g (77%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(pyridin-4-yl)benzamide as a white solid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1>>[CH3:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1Cc2ccccc2N1
Agent: [Na+]
Product: CC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 59 %

Procedure:
2-[2-(2-Methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one is prepared by following the procedure described in example 1e (step 4e) using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 510 mg of 2-methyl-2,3-dihydro-1H-indole. 400 mg of 2-[2-(2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][O:7]C(Cl)Cl.[CH2:11]([CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:12].Cl>ClCCl>[CH2:11]([CH:13]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[C:24]([CH:6]=[O:7])[CH:25]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:12]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)cc1
Reactant: COC(Cl)Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(C=O)c1
Temperature: -20 °C
Yield: 97.5 %

Procedure:
Under an argon atmosphere, stirring and cooling at −20° C., titanium chloride (IV) (35.0 mL, 318 mmol) and dichloromethyl methyl ether (13.4 mL, 148 mmol) were added dropwise in sequence to a solution of ethyl 2-ethyl-3-(4-methoxyphenyl)propanoate (10.0 g, 42.3 mmol) in dichloromethane (500 mL). The mixture was stirred for 6 hours at −20° C. to −5° C. The reaction mixture was poured into a mixture of ice (600 g) with 3 mol/L hydrochloric acid (400 mL) and the dichloromethane layer was separated, which was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent n-hexane:ethyl acetate=4:1 v/v) to afford 10.9 g (97%) of the title compound as a light brown oily product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[Br:21][C:22]1[C:23]([CH3:39])=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:25]([NH2:28])=[N:26][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Br:21][C:22]1[C:23]([CH3:39])=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=2)[C:25]([NH:28][C:12](=[O:14])[CH2:11][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)=[N:26][CH:27]=1
Reactant: Cc1c(Br)cnc(N)c1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Br)cnc(NC(=O)Cc2ccc(S(C)(=O)=O)cc2)c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
To a suspension of 4-(methylsulfonyl)phenylacetic acid (388 mg, 1.8 mmol) in dry DCM (5 mL) was added oxalyl chloride (320 μL, 3.6 mmol) followed by DMF (2 drops). The reaction mixture was stirred at RT for 3 hrs then the solvent was removed in vacuo. The resultant residue was taken up in DCM (2 mL) and added dropwise to a stirring solution of 5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine (Int. 1, 500 mg, 1.51 mmol) and triethylamine (420 μL, 36.02 mmol) in DCM (2 mL) at 0-5° C. The reaction mixture was stirred at 0-5° C. for 3 hrs then gradually warmed to RT over 5 hrs. The reaction mixture was partitioned between saturated sodium hydrogen carbonate solution and DCM. The organic phase was concentrated in vacuo and purified by flash chromatography eluting with a gradient of 0-100% EtOAc in cyclohexane to give the title compound as an orange glass (308 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH2:14]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23](Cl)[N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:8][CH:9]=2)[N:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: Nc1ccc(-c2ccncc2)cc1
Product: Cc1cc(Cc2ccccc2)nc(Nc2ccc(-c3ccncc3)cc2)n1

Procedure:
Prepared in analogy to example 62 from 4-(pyridin-4-yl) aniline and 4-benzyl-2-chloro-6-methyl-pyrimidine (example 43a). The title compound was obtained as a brownish oil (Yield=31%). MS ISP (m/e): 353.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.80 (s, 1H), 8.57 (d, 2H), 7.95 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.40-7.15 (m, 5H), 6.68 (s, 1H), 3.95 (s, 2H), 2.34 (s, 3H).