Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]2[CH2:11][C:10](OC)([O:12]C)[CH2:9][CH2:8][C:6]=2[N:7]=1.Cl.[OH-].[Na+]>O>[NH2:2][C:3]1[S:4][C:5]2[CH2:11][C:10](=[O:12])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: COC1(OC)CCc2nc(N)sc2C1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1nc2c(s1)CC(=O)CC2
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
21.9 g of the dimethoxy compound from example 2 was suspended in 205 ml of water and heated to 45° C. for dissolution. Then 7.3 ml of concentrated HCl was added and the solution was stirred at 60° C. for 30 minutes. Reaction mixture was cooled to ambient temperature and neutralised with 40% aqueous NaOH. Precipitated solid was filtered off, washed with water and dried to yield 10.9 g of the title product. For analytical purposes, the sample of the product was recrystalized from hot isopropanol.
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:27]([NH:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(N2CCc3ccncc3C2)cc1
Agent: Cl
Product: O=C(Nc1ccccc1)Nc1ccc(N2CCc3ccncc3C2)cc1
Yield: 60.2 %

Procedure:
In a manner similar to that described in Example 163, 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)aniline dihydrochloride (75.0 mg, 0.251 mmol) and phenyl isocyanate (0.041 mL, 0.377 mmol) were reacted to give the title compound as an off-white solid (52 mg, 60%). 1H NMR (DMSO-d6) δ 8.53 (s, 1H), 8.42 (s, 1H), 8.39 (s, 1H), 8.31 (d, J=4.7 Hz, 1H), 7.43 (d, J=7.6 Hz, 2H), 7.33 (d, J=9.1 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 7.18 (d, J=5.0 Hz, 1H), 6.99 (d, J=9.1 Hz, 2H), 6.94 (t, J=7.3 Hz, 1H), 4.33 (s, 2H), 3.47 (t, J=5.9 Hz, 2H), 2.91 (t, J=5.7 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[C:8](Br)[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[C:8]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CON=C1CCc2c(Br)cccc21
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CON=C1CCc2c1cccc2N1CCCCC1
Temperature: 170 °C

Procedure:
4-Bromoindan-1-one O-methyloxime (6.40 g, 26.7 mmol) was added to a mixture of piperidine (2.72 g, 31.9 mmol), sodium tert-butoxide (3.84 g, 40.0 mmol), Pd2(dba)3 (0.74 g, 0.81 mmol) and BINAP (1.49 g, 2.39 mmol) in dioxane (50 mL) under nitrogen atmosphere. The stirred mixture was heated at 170° C. for 5 minutes on the microwave. After cooling to ambient temperature, the reaction mixture was filtered through celite, then silica gel with 25% ethyl acetate in hexane. The filtrate was concentrated to a brown oil and chromatographed on silica gel with 4% ethyl acetate in hexane. Obtained 4-piperidin-1-ylindan-1-one O-methyloxime (4.33 g, 66%) as an orange oil. MS (ESI) m/z: 245.00 [M+H]+. 1H NMR (DMSO-d6) □: 1.55 (m, 2H), 1.64 (m, 4H), 2.79 (m, 2H), 2.91 (m, 6H), 3.87 (s, 3H), 6.94 (dd, 1H), 7.19 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.Cl.[CH2:17]([C:21]1[N:22]=[C:23]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[N:24]([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:25]=1)[CH:18]([CH3:20])[CH3:19].CN1CCCC1=O.C(N(C(C)C)CC)(C)C>O>[CH2:17]([C:21]1[N:22]=[C:23]([CH:33]2[CH2:38][CH2:37][N:36]([C:2]3[C:3]4[C@H:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:35][CH2:34]2)[N:24]([CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:25]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: C[C@@H]1CC(=O)Nc2ncnc(Cl)c21
Reactant: CC(C)Cc1cn(CCN2CCCC2)c(C2CCNCC2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)Cc1cn(CCN2CCCC2)c(C2CCN(c3ncnc4c3[C@H](C)CC(=O)N4)CC2)n1
Temperature: 200 °C
Yield: 23.7 %

Procedure:
Add (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.23 g, 1.18 mmol), 4-(4-isobutyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine trihydrochloride (0.64 g, 1.3 eq), N-methylpyrrolidinone (10 mL) and diisopropylethylamine (1.65 mL, 8.0 eq) in a microwave tube. Seal with crimp cap. Heat in a microwave reactor at 200° C. for 40 minutes. Dilute the reaction mixture with water and extract with ethyl acetate. Wash with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with hexanes to ethyl acetate to 5% methanol/ethyl acetate to 3% to 5% to 7% to 10% methanol/dichloromethane, to give the title compound (0.13 g, 23%). MS (ES) m/z=466 [M]+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:29]=[CH:28][C:22]4[N:23]([CH3:27])[C:24](=[O:26])[NH:25][C:21]=4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:40][N:41]1[CH2:46][CH2:45][CH:44](Br)[CH2:43][CH2:42]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.N1C=CC=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:29]=[CH:28][C:22]4[N:23]([CH3:27])[C:24](=[O:26])[N:25]([CH:44]5[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]5)[C:21]=4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)[nH]c(=O)n4C)sc2c1-c1ccc(Cl)cc1
Reactant: CN1CCC(Br)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)n(C3CCN(C)CC3)c(=O)n4C)sc2c1-c1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)benzo[d]thiazol-6-yl)acetate (47 mg, 0.083 mmol) in DMF (1 mL), pyridine (0.5 mL), was added N-methyl-4-bromopiperidine (26 mg, 0.146 mmol). The reaction was stirred at 85° C. overnight. Then Cs2CO3 (54 mg) was added, raised temp to 100° C. and stirred overnight. More N-methyl-4-bromopiperidine (50 mg 0.28 mmol), the mixture was heated at 100° C. for 2 days. The reaction was quenched by adding water, extracted by EtOAc, dried by MgSO4, filtered, concentrated down and purified by silica gel column, first 0-100% EtOAc in hexanes to elute (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)benzo[d]thiazol-6-yl)acetate , then switched to 0-20% MeOH in DCM to elute the product. LCMS-ESI+: calc'd for C36H41ClN4O4S: 661.2 (M+H+); found: 661.3.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:27])[CH2:22][O:23]C(=O)C)[CH2:17][CH2:16]1)=[O:2].C(=O)([O-])[O-].[K+].[K+].CO.O>ClCCl.CO>[OH:23][CH2:22][C:21]([N:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][CH2:12][C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[NH:4][C:3]=2[CH:1]=[O:2])[CH2:20][CH2:19]1)=[O:27]
Reactant: CC(=O)OCC(=O)N1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=Cc1[nH]c2c(c1CCCN1CCN(C(=O)CO)CC1)CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Each fraction of acetic acid 2-{4-[3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazin-1-yl}-2-oxo-ethyl ester was treated separately with potassium carbonate (3.0 eq.) in 6 ml of (methanol/ water 4/1). The two reactions were stirred at room temperature for overnight. Thin layer chromatography (dichloromethane: methanol 15:1) for both reactions showed the same spot and also LCMS showed that they have the same molecular weight. The two reactions were combined and the solvent was evaporated. The formed solid was washed with 30 ml of (dichloromethane/methanol 10/1) three times and sonicated. The liquid was collected and concentrated to give 268 mg of 3-{3-[4-(2-hydroxyacetyl)piperazin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[CH:7][C:6]=1[Cl:26].[OH-].[Na+]>CO.O1CCCC1.O>[Cl:11][C:10]1[CH:9]=[C:8]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:7]=[C:6]([Cl:26])[C:5]=1[C:4](=[O:27])[C:3]([OH:28])=[O:2]
Reactant: COC(=O)C(=O)c1c(Cl)cc(OCCOc2ccc3ccccc3c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1c(Cl)cc(OCCOc2ccc3ccccc3c2)cc1Cl
Yield: 91.4 %

Procedure:
A solution of 2,6-dichloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester(0.6 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from acetone-hexane provided 0.53 g of purified 2,6-dichloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 155°-156° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:57])[CH:45]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:46]6[CH2:51][CH2:50]O[CH2:48][CH2:47]6)=[N:37][CH:38]=5)=[CH:30][CH:29]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:58](=O)([O-])[O-].[K+].[K+].COC(NC(C1C=CC=CC=1)C(O)=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>CCO.[Pd].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4[CH:29]=[CH:30][C:31]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:57])[CH:45]([NH:52][C:53]([O:55][CH3:56])=[O:54])[C:46]6[CH:51]=[CH:50][CH:58]=[CH:48][CH:47]=6)=[N:37][CH:38]=5)=[CH:32][CH:33]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C1CCOCC1
Agent: [Pd]
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: COC(=O)NC(C(=O)O)c1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.5 %

Procedure:
To a solution of 2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.36 mmol) in EtOH (3.5 mL) was added Palladium on carbon (10%, 0.42 g, 0.39 mmol) and Potassium Carbonate (0.10 g, 0.70 mmol). The slurry was stirred at room temperature under an atmosphere of H2 for 72 h. The slurry was filtered through celite and washed with EtOH. The filtrate was concentrated to an oil and diluted with CH2Cl2 (3 mL). Methoxycarbonylamino-phenyl-acetic acid (0.11 g, 0.54 mmol) and Potassium Phosphate (0.08 g, 0.35 mmol) were added and the resulting slurry was cooled to 0° C. (external, ice). COMU (0.19 g, 0.44 mmol) was added and the reaction was stirred at 0° C. for 2 h. The slurry was diluted with CH2Cl2 and filtered through celite. The filtrate was concentrated and purified by column chromatography (SiO2, 30→100% EtOAc (10% MeOH) in Hexanes to 60% MeOH in EtOAc) to provide 2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.20 g, 74%). LCMS-ESI+: calc'd for C45H47N7O5: 765.36 (M+); Found: 766.64 (M+H+).
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:12]([CH:13]2OCC[O:14]2)=[C:11]([F:18])[C:10]([O:19][CH2:20][CH3:21])=[CH:9][CH:8]=1.[B:22](OC)([O:25]C)[O:23]C>C1COCC1>[CH2:20]([O:19][C:10]1[CH:9]=[CH:8][C:7]([B:22]([OH:25])[OH:23])=[C:12]([CH:13]=[O:14])[C:11]=1[F:18])[CH3:21]
Reactant: CCOc1ccc(Br)c(C2OCCO2)c1F
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(B(O)O)c(C=O)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
Under a nitrogen atmosphere, n-BuLi (43.3 mL, 71.42 mmol) was slowly added dropwise, at −70° C. or lower, to a THF (200 mL) solution of compound (54) (19.8 g, 68.02 mmol). The reaction mixture was agitated at −70° C. or lower for 1 hour, and then trimethyl borate (10.6 g, 102.0 mmol) was slowly added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with 200 mL of 2N hydrochloric acid aqueous solution, and extracted with 100 mL of toluene three times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was washed with heptane, and thus (4-ethoxy-3-fluoro-2-formylphenyl)boronic acid (55) (9.85 g, yield 68.3%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[S:12][C:13]([CH:16]=[CH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:15]=1.[BH4-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[S:12][C:13]([CH:16]=[CH:17][CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:15]=1
Reactant: CCCCCC(=O)C=Cc1ccc(CCCCCCCC(=O)OC)s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCC(O)C=Cc1ccc(CCCCCCCC(=O)OC)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
1 G of 8-[5-(3-oxooct-1-enyl)thien-2-yl]octanoic acid methyl ester was dissolved in 25 ml of methanol and the solution was cooled to about 0° C. Under vigorous stirring, 0.9 g of sodium borohydride was added and the reaction mixture was warmed slowly to room temperature after a period of 30 minutes. After about 1 hour, the reaction mixture was diluted with water, adjusted to a pH of 5.5 to 6 with dilute hydrochloric acid and extracted with ether. The ether phase was washed with water, dried over sodium sulfate, and then concentrated to dryness under vacuum. The residue was purified by column chromatography (silica gel, using petroleum ether and ethyl acetate as eluants). The product was obtained as 0.9 g of an oil (90% yield); ir (film): 3450 (OH), 1740 (C=O), and 1645 cm-1 (C=C).
Reaction SMILES: O=C1C2NC(C(OC)=O)=CC=2CC1.[Br:14][C:15]1[CH:16]=[C:17]([Mg:21][Br:22])[CH:18]=[CH:19][CH:20]=1.[Br:23][C:24]1[CH:25]=[C:26]([C:30]2(O)[C:34]3[NH:35][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:37][C:33]=3[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.[Mg].BrC1C=CC=C(Br)C=1.C1(CC2C3C=C(C(O)=O)NC=3CC2)CCCCC1>C1COCC1.CO>[Br:23][C:24]1[CH:25]=[C:26]([CH:30]2[C:34]3[NH:35][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:37][C:33]=3[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.[Br:14][C:15]1[CH:16]=[C:17]([Mg:21][Br:22])[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc2c([nH]1)C(O)(c1cccc(Br)c1)CC2
Agent: Br[Mg]c1cccc(Br)c1
Agent: COC(=O)c1cc2c([nH]1)C(=O)CC2
Agent: O=C(O)c1cc2c([nH]1)CCC2CC1CCCCC1
Solvent: CO
Solvent: C1CCOC1
Solvent: Brc1cccc(Br)c1
Product: COC(=O)c1cc2c([nH]1)C(c1cccc(Br)c1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The title compound was synthesized in two steps. First, methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.503 g, 2.81 mmol) and (3-bromophenyl)magnesium bromide (synthesized in situ) were reacted according to General Procedure 3 to give the carbinol-containing compound methyl 6-(3-bromophenyl)-6-hydroxy-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate. (Note: (3-Bromophenyl)magnesium bromide was synthesized as follows: Activated magnesium (0.308 g, 12.67 mmol) was placed in a flask and anhydrous THF (50 mL) was added. 1,3-dibromobenzene (1.6 mL, 13.2 mmol) and a catalytic amount of 12 was added. The solution was stirred gently at ambient temperature for 30 min. Additional anhydrous THF (25 mL) was added and the solution refluxed for 3 h, and then allowed to cool to ambient temperature). Methyl 6-(3-bromophenyl)-6-hydroxy-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate was hydrogenated according to General Procedure 6 (with Pt2O), and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-30% EtOAc/heptane affording the product as a slightly yellow solid: 0.213 g (83% yield). 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.27 (ddt, J=13.19, 8.32, 5.23, 5.23 Hz, 1H), 2.58-2.67 (m, 1H), 2.71-2.79 (m, 1H), 2.90-3.01 (m, 1H), 3.73 (s, 3H), 4.30 (dd, J=8.64, 5.17 Hz, 1H), 6.62-6.65 (m, 1H), 7.10-7.14 (m, 1H), 7.21-7.26 (m, 1H), 7.28-7.30 (m, 1H), 7.35-7.40 (m, 1H), 10.67 (br. s, 1H); LCMS (ESI+) 344.0 (M+Na).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.[Li].BrC1C=CC=CC=1.[Cl:28][C:29]1[CH:43]=[CH:42][C:32]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[O:34])=[CH:31][CH:30]=1.[Cl-].[Na+]>O1CCCC1.C(OCC)C>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:33]([C:32]1[CH:42]=[CH:43][C:29]([Cl:28])=[CH:30][CH:31]=1)([C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[OH:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cn2ccnc2)cc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Brc1ccccc1
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1nccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 17.4 g (0.11 mol) of N-benzylimidazole in 40 ml. of anhydrous tetrahydrofuran was added dropwise in the course of one hour, at -20° to -30° C. and under a nitrogen atmosphere, to a phenyl lithium solution, prepared from 1.67 g (0.24 gr. at.) of lithium and 18.8 g (0.12 mol) of bromobenzene in 80 ml. of anhydrous diethyl ether. The mixture was heated for about one hour until a brightly red, homogenous solution was obtained. Subsequently a solution of 25.1 g (0.1 mol) of 4,4'-dichlorobenzophenone in 60 ml. of anhydrous tetrahydrofuran was added in the course of one hour at a temperature between -25° and -15° C. The reaction mixture was stirred for 15 hours at room temperature, under the nitrogen atmosphere and it was then poured on 200 g of ice. The aqueous phase was saturated with sodium chloride and the organic phase was separated off and concentrated. The residue was dissolved in a small amount of acetone and the solution was acidified with 2 N hydrochloric acid. Then some toluene was added and the precipitate formed was filtered off. The product was thrice crystallised from a mixture of isopropyl alcohol and petroleum ether (boiling range 28°-40° C.). 1-Benzyl-α,α-bis(p-chlorophenyl)imidazole-2-methanol was obtained. Melting point 167°-168° C.
Reaction SMILES: C(O[C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)C.C(NC(C)C)(C)C.C([Li])CCC.[CH2:22]([SnH:26]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>C1COCC1.C(Cl)Cl>[CH2:31]([Sn:26]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:27][CH2:28][CH2:29][CH3:30])[C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CCOC1=CC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)C1=CC(=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
3-Ethoxy-cyclopent-2-enone (1.0 g, 7.9 mmol) was dissolved in THF (2 ml) and was placed in an addition funnel atop a flask equipped with stirring and a cooling bath. The flask was charged with THF (10 ml) and diisopropylamine (0.88 g, 8.7 mmol) and cooled to 0° C. To the solution was added n-butyllithium (1.9M, 4.6 ml) and the resulting solution stirred for five minutes. While still at 0° C., tributyltinhydride (2.35 ml, 8.7 mmol) was added to give a yellow solution, then after 15 minutes at 0° C., the solution was cooled to -70° C. At -70° C. the 3-ethoxy-cyclopent-2-enone was added dropwise, and after addition was complete, the reaction was stirred at -20° for one hour. The cooling bath was removed and the reaction quenched with NH4Cl solution and diluted with ether. The organic layer was separated, dried (MgSO4), filtered, and evaporated to give an oil. Chromatography on silica gel with CH2Cl2 gave the title compound (1.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=O)[NH:11][CH2:10][CH:9]2[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1.F[B-](F)(F)F.C[O+](C)C.[BH4-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1
Reactant: O=C(O)CCC1CNC(=O)CC1c1ccc(F)cc1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: ClCCl
Product: O=C(O)CCC1CNCCC1c1ccc(F)cc1
Temperature: 16 °C
Reaction time: 60 h
Yield: 75 %

Procedure:
4-(4-fluorophenyl)-3-carboxyethylpiperidin-6-one (12.0 g, 0.045 mol, trans/cis-ratio˜1:1) was added in one portion to a solution of trimethyloxonium fluoroborate (12.0 g, 0.081 mol) in dichloromethane (80 ml) and the resulting solution stirred, at 14-18° C., for 60 hours under an argon atmosphere. The solvent was removed in vacuo, and then the residue was dissolved in absolute ethanol (100 ml), heated to 45° C. and treated with sodium borohydride (10.0 g, 0.26 mol) in 1.0 g portions, allowing the mixture to boil under reflux. Most of the solvent was evaporated and the residue quenched with water (60 ml) followed by concentrated hydrochloric acid. After neutralization with 10% sodium bicarbonate solution the products were extracted with dichloromethane (150 and 50 ml). The extracts were dried with anhydrous sodium sulphate, filtered, and evaporated to afford the title compound as a cis/trans mixture (1:1). Yield 75%. A portion of the product was purified by column chromatography (silica gel, eluted with ethyl acetate-triethylamine, 98:2).
Reaction SMILES: [C:1]1([C:7]2[NH:23][C:10]3[N:11]=[CH:12][N:13]=[C:14]([O:15][C:16]4[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(#N)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:14]3[C:9]4[CH:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[NH:23][C:10]=4[N:11]=[CH:12][N:13]=3)=[CH:17][CH:18]=2)=[O:33])=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1
Reaction time: 1 h

Procedure:
After dissolving 40 mg of 4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine in 4.5 ml of toluene and 4.5 ml of acetonitrile at 110° C., 4-fluorophenylisocyanate (16.6 μl) was added and the mixture was stirred for 1 hour. After returning the mixture to room temperature, the precipitated crystals were filtered out and dried to obtain 37 mg of the title compound.