Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[C:20]([C:22]([OH:24])=O)[O:19][N:18]=2)=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.Cl.[CH3:52][O:53][C:54](=[O:60])[C@H:55]([CH:57]([CH3:59])[CH3:58])[NH2:56]>CN(C=O)C.O>[CH3:52][O:53][C:54](=[O:60])[CH:55]([NH:56][C:22]([C:20]1[O:19][N:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[O:25])=[CH:16][CH:15]=2)[CH:21]=1)=[O:24])[CH:57]([CH3:59])[CH3:58]
Reactant: O=C(Nc1ccc(-c2cc(C(=O)O)on2)cc1)Nc1ccccc1F
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
3-(4-(3-(2-fluorophenyl)ureido)phenyl)isoxazole-5-carboxylic acid (1 g) was dissolved in DMF (20 ml). N,N′-Dicyclohexyl carbodiimide (906 mg) and 1-Hydroxy benzotriazole (396 mg) were added and the reaction mixture was stirred at RT for 15 minutes. L-Valine methyl ester hydrochloride (640 mg) was dissolved in DMF (5 ml), neutralized with TEA (0.53 ml) and added into the above reaction mixture, which was then stirred at RT for 16 h. DMF was removed under reduced pressure to get a pale brown solid which was taken in water and extracted with EtOAc. Organic layer was dried over Na2SO4 and concentrated to get a pale yellow solid which was purified by silica gel column chromatography in 2:8 EtOAc:CHCl3 to get off white solid which was crystallized from DCM/Pet ether to yield 1.1 gm (82%) white solid. 1HNMR (DMSO-d6, 300 MHz): δ 9.33 (s, 1H), 9.18 (d, 1H), 8.62 (s, 1H), 8.13 (m, 1H), 7.85 (d, 2H), 7.67 (s, 1H), 7.59 (d, 2H), 7.24 (m, 1H), 7.16 (m, 1H), 7.02 (m, 1H), 4.29 (m, 2H), 3.66 (s, 3H), 2.2 (m, 1H), 0.95 (d, 6H); MS (ES+): m/z 455 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13](C(=O)C)[CH2:12][CH2:11]1.[OH-].[K+]>CO>[NH:13]1[CH2:12][CH2:11][CH:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:15][CH2:14]1
Reactant: CC(=O)N1CCC(c2nc3ccccc3s2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: c1ccc2sc(C3CCNCC3)nc2c1
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution of 1.4 g of 1-(4-(benzothiazol-2-yl)piperidin-1-yl)ethanone in 10 mL of MeOH was added 7.5 mL of KOH (45 wt. % solution). After refluxing for 18 hours, the reaction was cooled to room temperature. The mixture was partitioned between EtOAc and water. The organic phase was washed with brine and dried over MgSO4. Concentration under reduced pressure gave 540 mg of the title compound as a solid.
Reaction SMILES: ClC1N=CC(C2N=CN(CCCC[N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])C=2)=CC=1C.ClC1C(C)=CC(C2N=CNC=2)=CN=1.C(=O)([O-])[O-].[K+].[K+].BrCCCCN1C(=O)C2=CC=CC=C2C1=O>CN(C=O)C>[C:18]1(=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25](=[O:26])[NH:17]1
Reactant: Cc1cc(-c2cn(CCCCN3C(=O)c4ccccc4C3=O)cn2)cnc1Cl
Agent: Cc1cc(-c2c[nH]cn2)cnc1Cl
Agent: O=C([O-])[O-]
Agent: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
2-{4-[4-(6-Chloro-5-methyl-pyridin-3-yl)-imidazol-1-yl]-butyl}-isoindole-1,3-dione. To a solution of 2-chloro-5-(1H-imidazol-4-yl)-3-methyl-pyridine (8.2 g, 42.3 mmoles) in DMF (80 ml) was added potassium carbonate (29 g, 212 mmoles) and N-(4-bromobutyl)phthalimide (30 g, 106 mmoles) at room temperature under dry conditions. The solution was left stirring at room temperature overnight. The reaction was filtered and the resulting clear solution was dumped onto ice (1 L). The precipitate was filtered and the solid was dissolved in DCM. The organic solution was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography using first a solvent gradient of 99% DCM, 1% MeOH, and 0.1% TEA, then 97% DCM, 3% MeOH, and 0.1% TEA to yield 2-14-[4-(6-chloro-5-methyl-pyridin-3-yl)-imidazol-1-yl]-butyl)-isoindole-1,3-dione (4.0 g, 27%). MH+(395)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[OH:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1>>[OH:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:27]1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Reactant: OC1CCCNC1
Product: O=c1[nH]c2cc(CN3CCCC(O)C3)ccc2cc1-c1csc(-c2ccncc2)n1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and 3-hydroxypiperidine to give a yellow solid. MS m/z: 419.2 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][C:18]3=[O:23])[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1.Cl[CH2:27][C:28]1[NH:29][C:30](=[O:38])[C:31]2[CH2:37][O:36][CH2:35][CH2:34][C:32]=2[N:33]=1>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:27][C:28]4[NH:29][C:30](=[O:38])[C:31]5[CH2:37][O:36][CH2:35][CH2:34][C:32]=5[N:33]=4)[C:18]3=[O:23])[CH2:13][CH2:12]2)=[O:10])=[CH:24][CH:25]=1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Reactant: COc1ccc(C(=O)C2CCN(C3CCCNC3=O)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(C3CCCN(Cc4nc5c(c(=O)[nH]4)COCC5)C3=O)CC2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
To a stirred solution of NaH (23.8 mg, 0.942 mmol, 2.1 eq) in THF (10 mL) were added 4-(4-methoxy-benzoyl)-[1,3′]bipiperidinyl-2′-one (142 mg, 0.449 mmol, 1.0 eq) and 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (90 mg, 0.449 mmol, 1.0 eq). The reaction was let to stir at 70° C. for 3 h. The solid precipitate was filtered off and washed with CH2Cl2. The solvent of the mother liquor was evaporated and the residue purified by flash chromatography on silica gel (0-15% MeOH/CH2Cl2) to afford the title compound as an off-white powder (60 mg, 0.139 mmol, 31.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (br s, 1H) 7.94 (d, J=8.59 Hz, 2H) 7.03 (d, J=8.59 Hz, 2H) 4.14-4.54 (m, 5H) 4.06-4.10 (m, 1H) 3.45 (br s, 1H) 3.18 (d, J=5.05 Hz, 3H) 3.03 (br s, 1H) 2.85 (br s, 2H) 2.30-2.65 (m, 5H) 1.30-2.05 (m, 9H). HR-MS (m/z, MH+): 481.2461, 482.2471. HPLC retention time: 2.78 min (Agilent column 3.0×100 mm 3 um C18 column; flow rate of 1.0 mL/min with gradient from 5% to 95% acetonitrile in 10 min, 0.1% FA)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14]([CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:26]1C=C(C2NN=C(NC(C3CC4C(=CC=CC=4)C3)=O)C=2)C=C[CH:31]=1>>[CH2:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH:16]1[C:14]([NH:13][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][CH:2]=[C:3]([CH:26]=[CH2:31])[CH:4]=2)[NH:12][N:11]=1)=[O:15]
Reactant: O=C(Nc1cc(-c2ccc(Br)cc2)[nH]n1)C1Cc2ccccc2C1
Reactant: O=C(Nc1cc(-c2cccc(Br)c2)[nH]n1)C1Cc2ccccc2C1
Product: C=Cc1cccc(-c2cc(NC(=O)C3Cc4ccccc4C3)n[nH]2)c1

Procedure:
The title compound was prepared in the same manner as that described in Example 33 except that 5-(4-bromophenyl)-3-(2-indanyl)carbonylaminopyrazole used in Example 33 was replaced with 5-(3-bromophenyl)-3-(2-indanyl)carbonylaminopyrazole.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[H-].[Na+].[S:20]([O:30][CH2:31][CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>CN(C=O)C>[C:26]1([CH3:27])[CH:25]=[CH:24][C:23]([S:20]([O:30][CH2:31][CH2:32][O:1][CH:2]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]2)(=[O:22])=[O:21])=[CH:29][CH:28]=1
Reactant: COC(=O)C1CC(O)CN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(OCCOS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 27.1 %

Procedure:
A solution of 2.45 g (10.0 mmol) of 1-tert-butyl 2-methyl 4-[hydroxy]pyrrolidine-1,2-dicarboxylate (24) in DMF (10 ml) was added to a suspension of 0.65 g (15 mmol) of sodium hydride in DMF (20 ml). After 15 min, a solution of 5.56 g (15.0 mmol) of 1,2-ethanediol bistosylate in DMF (10 ml) was added. The batch was subsequently reacted in 3 portions at 100° C. in a microwave for 45 minutes. The batch was concentrated and treated with water and ethyl acetate. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate). 1.2 g (27%) of 1-tert-butyl 2-methyl 4-[2-(toluene-4-sulfonyloxy)ethoxy]pyrrolidine-1,2-dicarboxylate were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.[CH3:29][N:30]=[C:31]=[O:32]>C(Cl)Cl>[C:14]([C:12]1[N:13]=[C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:10][C:11]=1[C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][N:26]([C:31]([NH:30][CH3:29])=[O:32])[CH2:27][CH2:28]2)=[CH:21][CH:22]=1)(=[O:15])[NH2:16]
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(N2CCNCC2)cc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1CCN(c2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a suspension of 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide (0.029 g, 0.075 mmol) in DCM (3 mL) was added methyl isocyanate (8 uL, 0.136 mmol). The resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo to afford 4-(4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)phenyl)-N-methylpiperazine-1-carboxamide (0.026 g, 0.059 mmol, 79%) as a yellow solid. 1H NMR (DMSO) 2.85 (3H, d), 3.34 (4H, m), 3.56 (4H, m), 4.46 (1H, br. q), 5.49 (1H, br. s), 6.95 (2H, d), 7.07 (2H, t), 7.20 (1H, br. s), 7.46 (1H, m), 8.32 (2H, d). LCMS (2) Rt: 2.43 min; m/z (ES+) 442.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:21][C@H:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=2)[CH3:23])=[N:4][C:5]([NH:11][C:12]2[CH:16]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[NH:14][N:13]=2)=[C:6]([N+:8]([O-])=O)[CH:7]=1.[CH2:31](O)C.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]=[CH:31][N:11]([C:12]3[CH:16]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[NH:14][N:13]=3)[C:5]2=[N:4][C:3]=1[NH:21][C@H:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=1)[CH3:23]
Reactant: CCO
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)c(Cl)cc2[N+](=O)[O-])n[nH]1
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(-n2cnc3cc(Cl)c(N[C@@H](C)c4ccc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
3-Chloro-N2-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-N6-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyridine-2,6-diamine (Intermediate 39, 0.5 g) was dissolved into ethanol (20 mL) with Pd—C (150 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formylamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.12 g desired product. MS (electrospray): 416 (M+1) for C19H19ClFN7O. 1H NMR (300 MHz, CD3OD) δ ppm 8.40 (s, 1H) 8.30 (s, 1H) 7.90 (d, 1H) 7.50 (m 2H) 6.70 (d, 1H) 6.00 (s, 1H) 5.40 (m, 1H) 4.60 (m, 1H) 1.60 (d, 3H) 1.40 (d, 6H).
Reaction SMILES: C[O-].[Na+].FC(F)(F)[C:6]([OH:8])=O.[CH2:11]([N:13]1[C:17](S(C)(=O)=O)=[N:16][N:15]=[C:14]1[C@H:22]([NH2:24])[CH3:23])[CH3:12]>CCOCC>[CH2:11]([N:13]1[C:17]([O:8][CH3:6])=[N:16][N:15]=[C:14]1[C@H:22]([NH2:24])[CH3:23])[CH3:12]
Reactant: CCn1c([C@@H](C)N)nnc1S(C)(=O)=O
Reactant: O=C(O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCn1c(OC)nnc1[C@@H](C)N
Temperature: 25 °C

Procedure:
NaOMe (18 ml, 2.0N, MeOH solution) was added to the (R)-1-(4-ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)ethylamine trifluoroacetate (3.0 g) obtained in Example 8-(6), and the mixture was heated for 1 hour under reflux. The reaction mixture was cooled to room temperature, and Et2O (100 ml) was added. After the mixture was cooled to 0° C., precipitated crystals were filtered. The filtrate was concentrated, and the resulting crude product was purified by NH silica gel chromatography using a solvent mixture of Et2O and MeOH to obtain the captioned compound (Compound 519) as a colorless oily substance (1.55 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[CH:9]=[N:8][C:7](N)=[N:6][C:5]=2[C:4]([CH3:13])([CH3:12])[O:3]1.N([O-])=O.[Na+].[Cl:19]CCl>Cl.[Cl-].[Zn+2].[Cl-]>[Cl:19][C:7]1[N:8]=[CH:9][C:10]2[C:2]([CH3:14])([CH3:1])[O:3][C:4]([CH3:13])([CH3:12])[C:5]=2[N:6]=1
Reactant: CC1(C)OC(C)(C)c2nc(N)ncc21
Reactant: ClCCl
Agent: Cl
Agent: O=N[O-]
Agent: [Cl-]
Product: CC1(C)OC(C)(C)c2nc(Cl)ncc21
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 5,5,7,7-tetramethyl-5,7-dihydro-furo[3,4-d]pyrimidin-2-ylamine (38.6 g, 200.0 mmol, 1.0 equiv) in dichloromethane (80 mL) and 37% HCl (70 mL) at 0° C. was added zinc(II) chloride (46.3 g, 340.0 mmol, 1.7 equiv) in portions within 30 min. After the addition was completed, sodium nitrite (23.5 g, 340.0 mmol, 1.7 equiv) was added slowly within 3 h keeping the reaction temperature below 5° C. After stirring for an additional time period of 1 h, the reaction mixture was poured on ice and then extracted with dichloromethane (3×200 mL), the combined organic phases washed with a sat. solution of sodium carbonate (2×100 mL), dried over MgSO4 and concentrated by evaporation under reduced pressure. The reaction product was dissolved in diethyl ether (200 mL), filtered and the organic solvent removed by evaporation under reduced pressure yielding 33.2 g (78%) of the title compound. MS (EI): 213 [M]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[CH:28][C:23]=2[O:22][CH2:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29]([C:27]1[CH:26]=[CH:25][C:24]2[O:20][CH2:21][O:22][C:23]=2[CH:28]=1)=[O:30]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)OCO2

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with benzo[1,3]-dioxole-5-carboxylic acid. MS: 408.4 (M+H).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=2[N+:34]([O-])=O)[C:18](=O)[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=1)#[N:3]>[Fe].CO>[CH2:19]([C:18]1[N:17]([CH2:16][C:13]2[CH:14]=[CH:15][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:2]#[N:3])=[CH:11][CH:12]=2)[C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=2[N:34]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CCCCc1nc2cc(C(=O)OC)ccc2n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 54.1 %

Procedure:
To a mixture of conc. HCl (4.0 ml) and methanol (10 ml) was added methyl 4-[N-(2'-cyanobiphenyl-4-yl)methyl-N-valerylamino]-3-nitrobenzoate (3.5 g). To the resultant mixture was added, with stirring, iron powder (1.3 g) in portions and the mixture was stirred for one hour at 70°--80° C., followed by filtering off an insoluble material. The filtrate was concentrated, which was dissolved in ethyl acetate, washed with water, dried and concentrated to dryness. The resultant syrup was purified by column chromatography on silica gel to afford a yellow syrup (1.7 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][C:3]=1[CH2:13][C:14]([F:17])([F:16])[F:15].[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CCO>[Cl:1][C:2]1[C:3]([CH2:13][C:14]([F:16])([F:17])[F:15])=[CH:4][C:5]([NH2:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)c(CC(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Cl)c(CC(F)(F)F)cc1N
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A mixture of 1-chloro-5-methoxy-4-nitro-2-(2,2,2-trifluoroethyl)benzene (1.2 g, 4.51 mmol), tin(II) chloride dehydrate (5.0 g, 22.5 mmol) in EtOH (20 mL) was stirred at reflux for 2 h. After cooled to RT, the reaction mixture was added saturated NaHCO3 solution to adjusted pH to 7-8 and then extracted with ethyl acetate. The organic layer washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the desired product (900 mg, 85% yield). 1H NMR (400 MHz, DMSO-d6) δ: 7.29 (s, 1H), 7.11 (s, 1H), 5.41 (s, 2H), 4.21 (s, 3H), 3.99 (dd, J=1.7, 11.2 Hz, 2H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:15][C:16]1[N:21]=[C:20]([CH2:22]O)[CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]1(=[O:53])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45](=[O:52])[NH:44]1>C1COCC1>[CH3:15][C:16]1[N:21]=[C:20]([CH2:22][N:44]2[C:45](=[O:52])[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:43]2=[O:53])[CH:19]=[CH:18][CH:17]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cccc(CO)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Reaction time: 2 h

Procedure:
2.5 mL of Diisopropylazodicarboxylate in 1.5 mL of THF was added dropwise to a solution of 250 mg of (6-methylpyridin-2-yl)methanol, 2.8 g of Triphenylphosphine and 1.6 g of isoindoline-1,3-dione in anhydrous THF at room temperature. The reaction was stirred for 2 hours and monitored by TLC. Upon complection, the solvent was concentrated, the crude material was extracted in water and Chloroform 3 times and dried over Magnesium Sulfate. The crude was purified via ISCO Combi-Flash to yield 2-((6-methylpyridin-2-yl)methyl)isoindoline-1,3-dione. 350 mg of 2-((6-methylpyridin-2-yl)methyl)isoindoline-1,3-dione was treated with 440 μL of Hydrazine Monohydrate in EtOH and refluxed for several hours to yield (6-methylpyridin-2-yl)methanamine. The crude (6-methylpyridin-2-yl)methanamine was evaporated and directly coupled to 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-((6-methylpyridin-2-yl)methyl)terephthalamide. MS (Q1) 491.1 (M)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12]([C:17]1[CH:27]=[CH:26][CH:25]=[C:19]2C(N[C:23](=[O:24])[C:18]=12)=O)(OCC)=[O:13].C(N(CC)CC)C>O1CCCC1>[C:23]1(=[O:24])[N:1]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[C:12](=[O:13])[C:17]2=[CH:27][CH:26]=[CH:25][CH:19]=[C:18]12
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Yield: 77.9 %

Procedure:
A mixture of 10 g of 4-aminomethylbenzoic acid, 14.5 g of carbethoxyphthalimide, 9.2 ml of triethylamine and 140 ml of tetrahydrofuran is maintained for 72 hours at reflux temperature. The precipitate formed is isolated at room temperature; after washing with an aqueous acidic solution and drying, 14.5 g of product are obtained. M.p.=264° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:24][CH2:23]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[O:26]1[CH2:30][CH:29]=[N:28][C:27]1=[O:31]>>[CH:22]1([C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:28]5[CH2:29][CH2:30][O:26][C:27]5=[O:31])=[CH:3][C:4]=4[F:25])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:24][CH2:23]1
Reactant: O=C1N=CCO1
Reactant: O=C(c1ccc(Br)cc1F)N1CCN(c2ccc(C3CC3)cn2)CC1
Product: O=C(c1ccc(N2CCOC2=O)cc1F)N1CCN(c2ccc(C3CC3)cn2)CC1
Yield: 74.4 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2-fluorophenyl)[4-(5-cyclopropylpyridin-2-yl)piperazin-1-yl]methanone (404 mg) described in Preparation Example 188 and oxazolin-2-one (104 mg), the title compound (305 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH:14]([CH3:16])[CH3:15])=[CH:7][CH:6]=1)(OC)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.[OH-].[Na+]>O1CCCC1>[OH:2][CH2:1][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH:14]([CH3:16])[CH3:15])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2ccn(C(C)C)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1ccc2ccc(CO)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.3 %

Procedure:
A solution of 0.250 g (1.15 mmole) of 6-carbomethoxy-1-(2-propyl)indole in 2 mL of anhydrous tetrahydrofuran was added dropwise to a stirring slurry of lithium aluminum hydride (52.4 mg 1.38 mmole) in 7 mL of anhydrous tetrahydrofuran under argon at 0° C. and then stirred at 25° C. for 45 min. The solution was cooled to 0° C. and 0.340 mL of methanol was added dropwise, followed by 0.58 mL of 1N sodium hydroxide solution. The slurry was stirred at 25° C. for 15 min. The white precipitate was filtered through celite, and the solution concentrated. The residue was suspended in 20 mL of ethyl acetate and 20 mL of water. The layers were separated. The aqueous layer was back-extracted with ethyl acetate and both ethyl acetate layers were combined and dried over magnesium sulfate. Concentration gave 6-hydroxymethyl-1-(2-propyl)indole as an oil (214 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:34]C(=O)OC(C)(C)C)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]=[C:20]4[NH:30][CH:31]=[C:32]([CH3:33])[C:19]=34)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[NH2:34][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][N:21]=[C:20]3[NH:30][CH:31]=[C:32]([CH3:33])[C:19]=23)[CH2:14][CH2:13]1)=[O:11]
Reactant: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@H](N)Cc4ccc(Cl)cc4)CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
(R)-tert-Butyl 3-(4-chlorophenyl)-1-(4-(3-methyl-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.029 g, 0.051 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, and the resulting residue was dissolved in minimal DCM. The solution was added dropwise to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether, and dried to give (R)-2-amino-3-(4-chlorophenyl)-1-(4-(3-methyl-5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)propan-1-one (0.020 g, 72% yield) as the dihydrochloride salt. MS APCI (+) m/z 475 detected.