Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[OH:31].Br[CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[O:31][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(O)c3)nc2-c2ccc3ncccc3c2)n1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(OCCNC(=O)OC(C)(C)C)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 60 °C
Reaction time: 20 h
Yield: 91.4 %

Procedure:
To a stirred solution of 2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol (Example 81) (100 mg, 0.244 mmol) in acetone (5 mL) were added tert-butyl 2-bromoethylcarbamate (109 mg, 0.488 mmol) and K2CO3 (67 mg, 0.488 mmol) and the mixture was stirred at 60° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with H2O (20 mL), and extracted with CH2Cl2 (5 mL, 3 times). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC on NH silica gel (MeOH:CH2Cl2=1:50 (v/v)) to give tert-butyl 2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethylcarbamate (123.5 mg, 91%). This compound was dissolved in CH2Cl2 (5 mL), and p-anisole (224 uL, 2.23 mmol) and trifluoroacetic acid (1 mL) were added. The mixture was stirred for 1 hour, then concentrated, diluted with H2O (10 mL), and neutralized by addition of aqueous NH4OH solution to pH 7˜8. The aqueous solution was saturated with NH4Cl solid, extracted with CH2Cl2 (5 mL, 3 times), and then the organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC on NH silica gel (MeOH:CH2Cl2=3:100 (v/v)) to afford the title compound (70.2 mg, 69%). 1H NMR (300 MHz, CDCl3) δ 2.50 (3H, s), 3.09 (2H, t), 4.04 (2H, t), 4.16 (2H, s), 6.85-6.90 (1H, m), 6.95-7.07 (3H, m), 7.24 (1H, s), 7.36 (1H, d), 7.41 (1H, dd), 7.97 (1H, dd), 8.09-8.18 (3H, m), 8.92 (1H, dd), 10.40 (1H, bs). MS (ESI) m/z 454 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[CH3:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][C:26](=[O:32])[NH:27]2>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:25]3\[C:26](=[O:32])[NH:27][C:28]4[C:24]\3=[C:23]([CH3:22])[CH:31]=[CH:30][CH:29]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cccc(C)c43)c(C)c2C1=O
Yield: 44.1 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 4-methyl-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-5-(2-diethylamino-ethyl)-3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 16 (25 mg, yield 44.1%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>O1CCCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([B:26]([OH:27])[OH:25])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCOc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 73.8 %

Procedure:
4-Bromo-octyloxybenzene (Compound 6, 31.5 g, 0.111 mol) was dissolved in 300 mL tetrahydrofuran. The solution was cooled to −78° C. in a cooling bath and n-butyllithium (55.3 mL of 2.5M solution, 0.138 mol) was added to it. After stirring for 25 minutes at −78° C., triisopropylborate (36.4 g, 0.194 mol) was added quickly with a syringe. The cooling bath was removed, and 90 minutes later, the solution was re-cooled to 0° C. 150 mL of a dilute HCl solution was added. After 30 minutes, ethyl ether was added to the reaction mixture and the organic layer was washed with water (2 times), dried with MgSO4, and concentrated to provide an oil, which slowly crystallized over time. This crystallized product was re-crystallized once from acetonitrile to provide a colorless solid, 4-octyloxy-phenylboronic acid (Compound 7, 20.5 g, 74%).
Reaction SMILES: [Cl-].[NH4+].O.[I:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[O:14][CH2:15][CH2:16][O:17][CH3:18]>C(O)C.[Fe]>[I:4][C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[O:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: COCCOc1ccc([N+](=O)[O-])cc1I
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COCCOc1ccc(N)cc1I
Temperature: 25 °C
Yield: 58.8 %

Procedure:
A suspension of iron (3.89 g, 69.7 mmol), ammonium chloride (5.0 g, 93.5 mmol), in 100 mL of ethanol and 28 mL of water was heated to reflux. 2-Iodo-1-(2-methoxyethoxy)-4-nitrobenzene (7.5 g, 23.2 mmol) was added and the reaction was heated at reflux for 3 hours. The mixture was cooled to room temperature and filtered through Celite, washed with ethanol. The filtrate was concentrated in vacuo until a precipitate appeared. The precipitate was removed by filtration through Magnesol and the filtrate was concentrated in vacuo to provide 4.0 g of [3-iodo-4-(2-methoxyethoxy)phenyl]amine as an oil; 1H NMR (300 MHz, DMSO-d6) δ 3.33 (s, 3H), 3.62 (t, 2H), 3.95 (t, 2H), 5.01 (d, 2H), 6.55 (d, 1H), 6.73 (d, 1H), 7.03 (s, 1H); MS (ES) m/z294.0 (M+H)
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH3:3].[H-].[Na+].[CH2:17](Br)[CH:18]=[CH:19][CH3:20]>CN(C=O)C>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)/[CH:18]=[CH:19]/[CH3:20]
Reactant: CCCNC(=O)OCc1ccccc1
Reactant: CC=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C/C=C/CN(CCC)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Cbz Protection A solution of propylamine (9.0 g, 152.4 mmol) and triethylamine (15.4 g, 152.4 mmol) in methylene chloride (350 mL) was cooled to 0° C. and treated with benzyl chloroformate (20.0 g, 117.2 mmol). Upon stirring at 0° C. for 1 hour the reaction was warmed to ambient temperature and quenched with 1N HCl. The reaction was partitioned between 1N HCl and methylene chloride. The organics were washed with 1N HCl, water and brine. The combined organics were dried over sodium sulfate, filtered and evaporated in vacuo to give benzyl propylcarbamate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 5H), 5.10 (s, 2H), 4.77 (bs, 1H), 3.16 (q, J=6.5 Hz, 2H), 1.52 (m, 2H), 0.92 (t, J=7.5 Hz, 3H). Step B: Alkylation A solution of benzyl propylcarbamate (20.8 g, 107.9 mmol) in DMF (200 mL) was cooled to 0° C. and treated with sodium hydride (4.6 g, 194.2 mmol). The reaction was stirred to 0° C. for 15 minutes and subsequently treated with crotyl bromide (17.5 g, 129.5 mmol). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with ammonium chloride solution and partitioned between water and ether. The organics were washed with water (4×) and brine, dried over sodium sulfate, filtered and evaporated in vacuo. Flash chromatography (silica, 0-10% EtOAc/hexanes) gave benzyl (2E)-but-2-enyl(propyl)carbamate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.57 (bt, 1H), 5.42 (bs, 1H), 5.13 (s, 2H), 3.82 (bm, 2H), 3.19 (bs, 2H), 1.68 (bs, 3H), 1.54 (bs, 2H), 0.87 (bs, 3H). Step C: Cyclopropanation A solution of benzyl (2E)-but-2-enyl(propyl)carbamate (5.0 g, 20.2 mmol) in methylene chloride (120 mL) was cooled to 0° C. and treated with diethylzinc (12.48 g, 101 mmol) followed by diiodomethane (54.1 g, 202 mmol). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with saturated ammonium chloride solution and partitioned between methylene chloride and saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and evaporated in vacuo. Flash chromatography (10% EtOAc/hexanes) gave 5.16 g (96%) of benzyl (2-methylcyclopropyl)methyl(propyl)carbamate as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.13 (s, 2H), 3.16 (bm, 4H), 1.59 (bm, 2H), 1.01 (bs, 3H), 0.88 (bs, 3H), 0.68 (bs, 2H), 0.34 (bd, 1H), 0.22 (bs, 2H). Step D: Hydrogenation
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH:16]3[C:23]4[CH:22]=[C:21]([C:24]([O:26]C)=[O:25])[NH:20][C:19]=4[CH2:18][CH2:17]3)[CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Li+].CO>C1COCC1>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH:16]3[C:23]4[CH:22]=[C:21]([C:24]([OH:26])=[O:25])[NH:20][C:19]=4[CH2:18][CH2:17]3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccc(CO)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccc(CO)cc2)c1

Procedure:
The title compound was synthesized from methyl 4-((4′-(hydroxymethyl)biphenyl-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.012 g, 0.033 mmol) and lithium hydroxide (0.016 g, 0.38 mmol in 0.5 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (1 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound: 4.5 mg, 39% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.10-2.18 (m, 1H), 2.52-2.63 (m, 3H), 2.79-2.91 (m, 2H), 3.33 (d, J=1.61 Hz, 1H), 4.64 (s, 2H), 6.39 (s, 1H), 7.19 (s, 1H), 7.34 (s, 2H), 7.42 (s, 3H), 7.56 (d, J=8.30 Hz, 2H); LCMS-MS (ESI−) 346.2 (M−H); HPLC (UV=93.1%), (ELSD=100%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[O:4].[I-:20].[Na+]>CC(C)=O.O>[I:20][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[O:4]
Reactant: COc1ccccc1OCC1SCCN1C(=O)CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccccc1OCC1SCCN1C(=O)CI
Yield: 75.7 %

Procedure:
A solution of 3-α-chloroacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine (6 g) in acetone (80 ml) is heated to reflux temperature in the presence of sodium iodide (5 g) for 3 hours and then poured in ice and water (400 ml). The precipitate is collected, dissolved in methylene dichloride and washed with water, 5% aqueous NaHCO3, 2N sodium thiosulphate, water and dried on Na2SO4. After the usual work-up, the residue is crystallized from acetone and isopropanol to give 5.92 g of 3-α-iodoacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p. 81°-83° C. Using this procedure sodium bromide, the 3-α-bromoacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine is obtained, m.p. 82°-84° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][N:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) in dioxane (1.0 mL) at room temperature was added 2-chloro-5-trifluoromethyl-pyridine (0.11 g, 0.6 mmol) and diisopropylethyl amine (0.21 mL, 1.2 mmol). The reaction mixture was stirred at 150° C. in a microwave for 180 minutes, concentrated under reduced pressure and purified by flash chromatography with 30% ethyl acetate in hexane to provide (4-methyl-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester. MS (CI) m/z 394 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.38 (d, 1H), 7.61 (d, d 1H), 7.40-7.30 (m, 5H), 6.66 (d, 1H), 5.07 (s, 2H), 4.71-4.67 (m, 1H), 3.93 (m, 2H), 3.36 (m, 2H), 2.10 (m, 2H), 1.68 (m, 2H), 1.42 (s, 3H).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:9]=2)=[CH:6][C:5]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]2)=[CH:4][N:3]=1.[CH3:45][N:46]1[C:50]2=[N:51][CH:52]=[C:53]([NH2:55])[CH:54]=[C:49]2[N:48]=[CH:47]1>>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:55][C:53]3[CH:54]=[C:49]4[N:48]=[CH:47][N:46]([CH3:45])[C:50]4=[N:51][CH:52]=3)=[N:3][CH:4]=[C:5]([CH2:34][N:35]3[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]3)[CH:6]=2)[N:9]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Reactant: Cn1cnc2cc(N)cnc21
Product: Cc1nc(N)nc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2Nc2cnc3c(c2)ncn3C)n1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 197 (starting from Step 2) using 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (388 mg, 0.624 mmol) and 3-methyl-3H-imidazo[4,5-b]pyridin-6-amine (Adesis) as starting materials. 1H NMR (400 MHz, d6-DMSO) δ 12.00 (s, 1H); 8.73 (d, J=2.3 Hz, 1H); 8.67 (m, 2H); 8.36 (s, 1H); 8.26 (d, J=2.5 Hz, 1H); 7.93 (br, 1H); 7.74 (br, 1H); 3.84 (s, 3H); 3.50 (s, 2H); 3.11 (m, 4H); 2.87 (s, 3H); 2.48-2.49 (m, 4H); 2.49 (m, 3H). m/z (ESI, +ve ion) 510 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:15][C:16]1[CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][C:21]=1F>CS(C)=O.C(OCC)(=O)C>[F:15][C:16]1[CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][C:21]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1COCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Temperature: 60 °C
Yield: 103.1 %

Procedure:
A suspension of morpholine (4.72 mL, 4.72 g, 54.2 mmol) and dibasic potassium phosphate (9.44 g, 54.2 mmol) in DMSO (27 mL) was treated with 3,4-difluoronitrobenzene (3.0 mL, 4.31 g, 27.1 mmol) was warmed at 60° C. for 18 h. The solution was cooled and diluted with ethyl acetate and extracted with water (3×) and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded the title compound (6.32 g, ca. 100%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.00 (ddd, J=9.0, 2.6, 0.9 Hz, 1H), 7.92 (dd, J=13.1, 2.6 Hz, 1H), 6.92 (t, J=8.8 Hz, 1H), 3.88 (m, 4H), 3.29 (dd, J=5.5, 4.0 Hz, 4H). MS+DCI m/z (rel abundance) 227 (10, M+H), 244 (100, M+NH4).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([C:17]3[CH:21]=[CH:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:18]=3)=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:9]1=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([CH:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]3)=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:9]1=[O:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1ccc(-c2cccc3c2n(C(=O)OC(C)(C)C)c(=O)n3Cc2ccccc2)c1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc3c2n(C(=O)OC(C)(C)C)c(=O)n3Cc2ccccc2)C1
Reaction time: 95 h
Yield: 52.8 %

Procedure:
To a Parr vessel flushed with nitrogen was added a 5% dispersion of platinum on charcoal (15 mg) followed by a solution of 3-benzyl-7-(1-tert-butoxycarbonyl-1H-pyrrol-3-yl)-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (0.150 g., 0.307 mmol) in 10 mL methanol. The Parr vessel was vacuum-purged with hydrogen at atmospheric pressure and stirred for 95 hours. The reaction mixture was then vacuum-purged with nitrogen, filtered through a plug of celite to remove catalyst, and concentrated in vacuo. The resulting residue was purified by flash chromatography (5 to 10% gradient ethyl acetate in hexanes) to give 80 mg of racemic 3-benzyl-7-(1-tert-butoxycarbonyl-pyrrolidin-3-yl)-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester as a clear oil. MS: 516 (M+Na)+.
Reaction SMILES: Cl[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]([C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>CCCCO.CO>[C:29]([C:33]1[CH:34]=[CH:35][C:36]([NH:37][C:2]2[C:12]3[CH2:11][CH2:10][N:9]([C:13]4[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=4)[CH2:8][CH2:7][C:6]=3[N:5]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)=[CH:38][CH:39]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: FC(F)(F)c1cccnc1N1CCc2nc(N3CCOCC3)nc(Cl)c2CC1
Solvent: CCCCO
Solvent: CO
Product: CC(C)(C)c1ccc(Nc2nc(N3CCOCC3)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Temperature: 180 °C
Yield: 92.6 %

Procedure:
To a solution of 4-chloro-2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (30 mg, 0.08 mmol) in n-BuOH (2 mL) was added 4-tert-butylaniline (23 μL, 0.15 mmol). The mixture was heated in the microwave at 180° C. for 90 min, then was cooled to rt, diluted with MeOH, and filtered through quaternary amine resin, carbonate form (500 mg). The filtrate was concentrated and the residue was purified (FCC) to give the title compound (39 mg, 99%). MS (ESI): mass calcd. for C28H33F3N6O, 526.27; m/z found, 527.2 [M+H]+. 1H NMR (CDCl3): 8.40-8.37 (m, 1H), 7.87 (d, J=1.8 Hz, 1H), 7.48-7.43 (m, 2H), 7.37-7.31 (m, 2H), 6.96-6.89 (m, 1H), 6.35 (s, 1H), 3.80-3.70 (m, 8H), 3.64-3.54 (m, 4H), 3.11-3.04 (m, 2H), 2.88-2.82 (m, 2H), 1.33 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][NH2:15])[O:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:27]=[C:28]2[CH:34]=[C:33]([C:35](O)=[O:36])[NH:32][C:29]2=[CH:30][N:31]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:14][NH:15][C:35]([C:33]3[NH:32][C:29]4=[CH:30][N:31]=[C:26]([Cl:25])[CH:27]=[C:28]4[CH:34]=3)=[O:36])[O:10][CH2:11][CH2:12][O:13]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(CN)OCCO2)cc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C2(CNC(=O)c3cc4cc(Cl)ncc4[nH]3)OCCO2)cc1
Reaction time: 0.03 h

Procedure:
To a solution of [2-(4-methoxyphenyl)-[1,3]-dioxolan-2-yl]methylamine (Preparation 45, 0.117 g, 0.56 mmol) in dichloromethane (5 mL) was added DIPEA (213 μL, 1.22 mmol), 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 0.100 g, 0.51 mmol) and HOBT (0.076 g, 0.56 mmol). The resulting solution was stirred for 2 min then EDCI (0.117 g, 0.61 mmol) was added and stirring was continued for 18 h at rt. The reaction mixture was partitioned between dichloromethane (30 mL) and water (20 mL) and the layers separated. The aqueous phase was extracted with dichloromethane (3×20 mL) then the combined organics were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. Recrystallisation from methanol/dichloromethane gave the title compound as an orange solid. δH (CDCl3): 3.81 (3H, s), 3.84-3.91 (4H, m), 4.05 (2H, m), 6.56 (1H, t), 6.76 (1H, s), 6.89 (2H, d), 7.44 (2H, d), 7.57 (1H, s), 8.68 (1H, s), 9.94 (1H, br s).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:12]#[CH:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl>[C:1]([NH:8][C@@H:9]([C:12]#[CH:13])[CH2:10][O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C#C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
(S)-N-Boc-2-amino-1(-tert-butyldimethylsilyloxy)-but-3-yne was prepared by the treatment of (S)-N-Boc-2-amino-but-3-yn-1-ol (120 mg, 0.65 mmol) (Example 115A above) with imidazole (110 mg, 1.29 mmol) (Aldrich) and tert-butyldimethylsilyl chloride (120 mg, 0.77 mmol) (Fluka) in CH2Cl2 (10 mL) according to the procedure described above in Example 104B. (Yield 190 mg, 98%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:36]Br>C(Br)CBr>[Br:36][CH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6]
Reactant: BrBr
Reactant: COc1ccc(C(=O)c2cccc(C)c2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: BrCCBr
Product: COc1ccc(C(=O)c2cccc(CBr)c2)cc1
Reaction time: 17 h
Yield: 60.8 %

Procedure:
A solution of the benzophenone (17.5 g, 77.4 mmole) of Step A in ethylene bromide (26.5 mL) (containing a small amount of benzoyl peroxide) is heated at reflux. A solution of bromine (12.7 g, 79.6 mmole) in ethylene bromide (15 mL) is added dropwise over 30 minutes while the mixture is irradiated with a Photolamp (300 W). Reflux is continued for 17 hours (TLC, 9:1 petrolether-ethylacetate, traces of starting material still present). The solvent is removed in vacuo and the residue (brown oil, 39.22 g) is purified by flash chromatography (on silica Merck-60, preabsorbed in dichloromethane, eluted with 9:1 petrolether-ethyl acetate) to give unreacted starting material (2.59 g, ca. 15%) along with the desired product (14.36 g, 61% or 71.5% based on recovered unreacted starting material) and some mixed fraction (ca. 5.20 g). The light yellow solid melts at 58°-61° C. and it is used as such in the next step.