Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.CCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:11]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]=2[C:4]2[C:12]1=[CH:13][CH:14]=[C:2]([Cl:1])[CH:3]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CCCc2[nH]c3ccc(Cl)cc3c21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C1CCCc2c1c1cc(Cl)ccc1n2Cc1ccccc1
Reaction time: 0.45 h
Yield: 92.5 %

Procedure:
6-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.4010 g, 0.0018 mol) is added to a slurry of pentane-washed NaH (0.0902 g, 0.0023 mol) in DMF (2 mL) and after stirring for 27 min, benzyl bromide (0.26 mL, 0.0022 mol) is added. After stirring for 2.5 h at room temperature, the mixture is partitioned between aq. sodium bicarbonate and ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (200 mL) using dichloromethane/heptane (60/40 and 100/0) to give 0.5158 g (91%) of the title compound. An aliquot (0.0625 g) is recrystallized from ethyl acetate/heptane to give 0.0415 g of product; mp 196.5-197° C.; MS (ESI+) for C19H16ClNO m/z 310.1 (M+H)+; 1H NMR (CDCl3) δ2.24, 2.58, 2.87, 5.31, 6.99, 7.16, 7.29, 8.28. Anal. Calcd for C19H16ClNO: C, 73.66; H, 5.20; N, 4.52. Found: C, 73.18; H, 5.19; N, 4.58.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[O:19]1[CH2:20][CH2:21][N:16]([C:7]([C:6]2[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:8])[CH2:17][CH2:18]1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)N1CCOCC1
Reaction time: 2 h

Procedure:
A solution of 17.4 g. (0.075 mol.) of 3,4 dinitrobenzoylchloride in 250 ml of methylene chloride is treated at 0°-20° C. with a solution of 13 g. (0.15 mol.) of morpholine in 100 ml. of methylene chloride. The solution is kept at 20°-25° C. for 2 hrs., the solvent is evaporated and the residue triturated with water. Recrystallization from methanol affords 4-morpholinocarbonyl-1,2-dinitrobenzene (m.p. 136°-137° C.). 17.0 G. of 4-morpholinocarbonyl-1,2-dinitrobenzene in 340 ml. of methanol is hydrogenated for 3 hrs. at 45-50 psi in the presence of 1.7 g of 5% palladized charcoal. The resulting solution of 1,2-diamino-4-morpholinocarbonylbenzene is filtered and concentrated to ~170 ml. 14.0 G. of 1,3-bis-methoxycarbonyl-S-methyl isothiourea, 170 ml. of water and 4 ml. of acetic acid are added to the diamine solution and the mixture is refluxed for 3 hrs. The solution is concentrated and cooled. Filtration and recrystallization from methanol-chloroform affords 5(6)-morpholinocarbonyl-2-carbomethoxyaminobenzimidazole (m.p. 224° C. dec.).
Reaction SMILES: [H-].[Na+].C(OC(=O)[NH:9][CH2:10][CH2:11][SH:12])(C)(C)C.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](F)[N:16]=1>O1CCCC1.C(Cl)Cl>[F:14][C:15]1[N:16]=[C:17]([S:12][CH2:11][CH2:10][NH2:9])[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(F)n1
Reactant: CC(C)(C)OC(=O)NCCS
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: NCCSc1cccc(F)n1
Temperature: 0 °C
Yield: 127.6 %

Procedure:
Suspend sodium hydride (138 mg, 5.46 mmol) in tetrahydrofuran (6 mL) and cool to 0° C. in an ice bath. Add (2-mercaptoethyl)carbamic acid tert-butyl ester (0.461 mL, 2.73 mmol) dropwise over 5 minutes. Stir reaction for 30 minutes, add 2,6-difluoropyridine (0.495 mL, 0.546 mmol), remove ice bath and stir an additional hour. Re-cool reaction and quench with water. Extract with 1/1 hexanes/ethyl acetate. Dry organics over magnesium sulfate, filter and evaporate. Perform flash column chromatography (ethyl acetate/hexanes). Dissolve resulting orange oil in trifluoroacetic acid (3 mL) and stir for 15 minutes. Concentrate the reaction with a stream of dry nitrogen, re-dissolve in dry methylene chloride and evaporate to give 120 mg of the title compound as an orange oil. 1H NMR (d MeOH): 7.70 (m, 1H), 7.22 (m, 1H), 6.78 (m, 1H), 3.44 (m, 2H), 3.34 (m, 2H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:14][OH:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[CH3:16][O:15][CH2:14][C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a stirred solution of 463 mg (2.43 mmol) of BOC-leucinol in 2 ml of tetrahydrofuran at -78° C. under argon is added 2.4 mL (2.4 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran. After 10 minutes, 0.3 ml (4.8 mmol) of methyliodide was added and the resulting mixture is allowed to warm to room temperature. It is then heated to reflux for 1 hour and then cooled. The mixture is partitioned between 40 ml of dichloromethane and 30 ml portions of dichloromethane. The combined residue is chromatographed on silica gel with 15% ethyl acetate in hexane to give 405 mg (1.75 mmol, 83%) of BOC-leucinol methyl ether. 1H-NMR (CDCl3): δ0.9 d (d, d×3H, J=6 Hz), 1.44, 3.33.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:28])[CH2:17][CH2:16][CH:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([CH:15]1[CH2:16][CH2:17][C:12]([F:28])([F:11])[CH2:13][CH2:14]1)[C:21]1[CH:22]=[N:23][C:24]([CH3:27])=[N:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Cc1ncc(C(CN)C2CCC(F)(F)CC2)cn1
Product: Cc1ncc(C(CNC(=O)c2ccccc2Cl)C2CCC(F)(F)CC2)cn1

Procedure:
From 2-chlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=394.1, tR (minutes, Method F)=2.1
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH:12]([CH3:14])[CH3:13].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:41])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:41])=[CH:6][C:5]=1[O:11][CH:12]([CH3:13])[CH3:14]
Reactant: COC(=O)c1ccc(C)cc1OC(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC(C)C
Temperature: 70 °C
Yield: 50.8 %

Procedure:
The mixture of 2-isopropoxy-4-methyl-benzoic acid methyl ester (1.0 g, 4.8 mmol), dibenzoyl peroxide (100 mg), and NBS (0.85 g, 4.8 mmol) in CCl4 (20 mL) is heated at 70° C. overnight. The solid is filtered off and the filtrate is concentrated to a residue. The residue is purified by flash chromatography to afford the title compound as white solid (0.7 g, 51%). LC-ES/MS m/e 287.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH2:34]([O:36][C:37]1[CH:43]=[C:42]([CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]2)[CH:41]=[CH:40][C:38]=1[NH2:39])[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([CH2:44][CH2:45][N:46]4[CH2:47][CH2:48][N:49]([CH3:52])[CH2:50][CH2:51]4)=[CH:43][C:37]=3[O:36][CH2:34][CH3:35])[N:7]=2)[CH:18]=1
Reactant: CCOc1cc(CCN2CCN(C)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOc1cc(CCN2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 52.9 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(ethyloxy)-4-[2-(4-methyl-1-piperazinyl)ethyl]aniline (Example 146, step D) (46 mg, 0.17 mmol), and p-toluenesulfonic acid (99 mg, 0.52 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (67 mg, 0.09 mmol, 56%); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.21 (s, 1H), 9.34 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.46 (s, 1H), 7.38 (s, 1H), 7.18 (s, 2H), 6.96 (s, 2H), 6.72 (s, 1H), 6.46 (s, 1H), 4.02-4.11 (m, 2H), 2.60-2.71 (m, 2H), 2.25-2.32 (m, 10H), 2.12 (s, 3H), 1.26 (s, 3H). MS (ESI): 689 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([Br:18])=[CH:13][N:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>O1CCCC1.CO>[Br:18][C:14]1[CH:15]=[C:16]([CH3:17])[C:11]([C:5]2([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[N:12][CH:13]=1
Reactant: COC(=O)C1(c2ncc(Br)cc2C)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Br)cnc1C1(C(=O)O)CCOCC1
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 4-(5-bromo-3-methylpyridin-2-yl)tetrahydro-2H-pyran-4-carboxylic acid methyl ester (745 mg) in tetrahydrofuran (5 ml) and methanol (5 ml) was added 4 N aqueous solution of sodium hydroxide (5 ml) at room temperature, and stirred overnight. After completion of the reaction, the organic solvent was evaporated, diluted with 1 N aqueous solution of sodium hydroxide and water, diethyl ether was added thereto, and the aqueous layer was separated. The aqueous layer was ice-cooled, concentrated hydrochloric acid was added thereto to adjust the layer to pH 4, extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to give 4-(5-bromo-3-methylpyridin-2-yl)tetrahydro-2H-pyran-4-carboxylic acid (421 mg) as a white solid. MS (ESI) m/z: 300, 302 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[O:12][C:11](=[O:13])[CH:10]=[C:9]([OH:14])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([C:28]1[CH:33]=[C:32]([OH:34])[C:31]([CH3:35])=[CH:30][C:29]=1[S:36]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:24]([C:28]1[CH:33]=[C:32]([OH:34])[C:31]([CH3:35])=[CH:30][C:29]=1[S:36][C:10]1[C:11](=[O:13])[O:12][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:8][C:9]=1[OH:14])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(C2CCCCC2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(C3CCCCC3)OC2=O)c(C(C)(C)C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 from 6-cyclohexyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example NN; 210 mg, 0.664 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxy-5-methyl-phenyl) ester (prepared in Example RRR; 256 mg, 0.730 mmol), K2CO3 (367 mg, 2.655 mmol), and DMF (4 mL). The reaction was stirred at room temperature overnight and then worked up in the usual fashion. The crude product was flash chromatographed using CH2Cl2 :MeOH (98:2) to give the desired product as a solid, m.p. 100°-103° C. 1H NMR (DMSO-6) δ 1.0-2.1 (m, 13 H), 1.45 (s, 9 H), 1.80 (s, 3 H), 2.5-2.6 (2 H+DMSO), 2.7 (d, 1 H), 2.9 (d, 1 H), 6.6-6.7 (d, s, 3 H), 6.77 (s, 1 H), 6.9 (d, 2 H), 9.01 (s, 1 H), 9.13 (s, 1 H).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][S:9][C:8]=2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[C:20]12[C:28](=[O:29])[O:27][C:25](=[O:26])[C:21]=1[CH2:22][CH2:23][CH2:24]2>C1COCC1>[C:1]1([C:7]2[CH:11]=[CH:10][S:9][C:8]=2[NH:12][C:28]([C:20]2[CH2:24][CH2:23][CH2:22][C:21]=2[C:25]([OH:27])=[O:26])=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1sccc1-c1ccccc1
Reactant: O=C1OC(=O)C2=C1CCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)C1=C(C(=O)Nc2sccc2-c2ccccc2)CCC1
Temperature: 25 °C
Yield: 36 %

Procedure:
3-Phenyl-thiophen-2-ylamine (73 mg, 417 μmol, Int1.1), NEt3 (84.3 mg, 116 μL, 833 μmol) and 1-cyclopentene-1,2-dicarboxylic anhydride (144 mg, 1.04 mmol) were dissolved in dry THF (3 mL). The green-yellow suspension was stirred at RT over the week-end and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC (MeOH/H2O with 0.1% formic acid) to give the title compound as a yellow oil (47 mg, 32%, purity estimated at 90%). MS (ESI): m/z=312.2 [M−H]−.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][O:5][CH2:4][C@@H:3]1[OH:7].CCN(C(C)C)C(C)C.[C:17](=O)(OC(Cl)(Cl)Cl)[O:18]C(Cl)(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:7]1[C@H:3]2[CH2:4][O:5][CH2:6][C@H:2]2[NH:1][C:17]1=[O:18]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@@H]1COC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1N[C@@H]2COC[C@@H]2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 121.9 %

Procedure:
To a solution of (3R,4R)-4-aminotetrahydrofuran-3-ol (1.1 g, 7.88 mmol) and DIEA (4.54 ml, 26.0 mmol) in CH2Cl2 (30 mL) was added (bis(trichloromethyl) carbonate (1.75 g, 5.91 mmol) dissolved in CH2Cl2 (5 mL) at RT over a period of 30 min. After stirring for 0.5 h at 25° C., the reaction mixture was added to aqueous K2CO3 solution, stirred for 1 h and the CH2Cl2 was evaporated. The aqueous phase was washed with Et2O and afterwards evaporated to dryness. The residue was triturated with EtOH/THF 1:1, the inorganic salts removed by filtration through a plug of silica gel, and the filtrate was concentrated to provide the title compound as a beige solid (930 mg, 90%): ESI-MS: 147 [M+NH]+.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[F:18][CH2:19][C:20]#[N:21].Cl>O1CCCC1>[F:18][CH:19]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:20]#[N:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#CCF
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)C(F)C#N
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A solution of lithium hexamethyldisilazide (LHMDS) in tetrahydrofuran (THF) (1M, 33.9 mL, 2 equiv) was added dropwise to a chilled (−78° C.) solution of pivaloyl chloride (2.04 g, 1 equiv) and FCH2CN (1.00 g, 1 equiv) in THF (50 mL). The mixture was allowed to warm to room temperature and 1 N HCl was added dropwise until the solution was pH=2. The mixture was concentrated in vacuo to provide the title compound (2.40 g, 99% yield).
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.Cl[Si](C)(C)C.[C:17]1([CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>C(Cl)Cl.C(N(CC)CC)C>[C:7]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([OH:9])=[O:8]
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccccc1)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(Aminomethyl)benzoic acid (3.6 g) is suspended in methylene chloride (100 mL), to which 15 mL triethylamine is added. Chlorotrimethylsilane (10 mL) is then added and the mixture allowed to stir at room temperature for 1 hr. The mixture is then cooled in an ice bath and 4-phenylbutyryl chloride (5.3 g) in methylene chloride (10 mL) is added dropwise and the resulting mixture stirred for 30 min at 0° C., followed by an additional 3 hrs at ambient temperature. The mixture is treated with 75 mL 1N HCl, after which the organic layer is separated and extracted with 1N HCl. The precipitate which had formed is recovered by filtration and recrystallized two times from methanol/l N HCl to give pure N-(4-carboxybenzyl)-4-phenylbutyramide. M.p. 178°-179° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:42])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13].[NH2:43][C:44]1[C:45]([Cl:55])=[CH:46][C:47](Br)=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1>C1(C)C=CC=CC=1.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>[CH3:7][O:8][C:9](=[O:42])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:28]=[CH:29][C:30]([C:47]3[CH:46]=[C:45]([Cl:55])[C:44]([NH2:43])=[CH:49][C:48]=3[C:50]([F:52])([F:53])[F:51])=[CH:31][CH:32]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13]
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1Cl
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(N)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
Potassium carbonate (280 mg, 2.0 mmol) was added to a solution of [(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (200 mg, 0.40 mmol) and 5-amino-2-bromo-4-chlorobenzotrifluoride (110 mg, 0.40 mmol; Preparation 51) dissolved in toluene (1.3 mL) and water (0.43 mL). The reaction mixture was sparged under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (56 mg, 0.48 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 100° C. for 4 h. The reaction mixture was diluted in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to produce a red solid, which was purified by silica gel chromatography (0-100% ethyl acetate:hexanes) to produce the desired product as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:10][C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)c(C#N)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1cc(CBr)ccc1F
Temperature: 25 °C
Yield: 33.6 %

Procedure:
A solution of 2-fluoro-5-methylbenzonitrile (3.00 g, 22 mmol), N-bromosuccinimide (4.12 g, 23 mmol) and benzoyl peroxide (1.07 g, 4.4 mmol) in CCl4 (100 mL) was heated at reflux 6 h. The reaction mixture was cooled to room temperature and then combined with water. The separated organic phase was dried over MgSO4, filtered through a Celite™ pad, and evaporated under reduced pressure. Purification by flash chromatography (Hex/EtOAc, 20:1) gave 5-(bromomethyl)-2-fluorobenzonitrile (1.58 g, 33% yield) as an oil. 1H NMR (CDCl3, 400 MHz): δ 4.45 (s, 2H), 7.21 (m, 1H), 7.65 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].C([Li])CCC.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.[Cl-].[NH4+]>O1CCCC1>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([NH:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[B:22]([OH:27])[OH:23])=[O:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)c(NC(=O)C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(NC(=O)C(C)(C)C)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a stirred solution of N-(2-bromo-5-methoxyphenyl)-2,2-dimethylpropanamide (2.82 g, 9.85 mmol) in tetrahydrofuran (20 mL) at −78° C. was added slowly a solution of n-butyllithium in hexanes (2.5 M, 8.30 mL, 20.7 mmol). The solution was stirred for 30 minutes in a −40° C. bath, then was cooled back to −78° C. Triisopropyl borate (6.82 mL, 29.6 mmol) was added slowly. The solution was stirred for 1 hour at −40° C., then was stirred at 0° C. for 30 minutes. Saturated aqueous ammonium chloride was added. The mixture was extracted with diethyl ether. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to afford a residue that was triturated with hexanes. The hexanes were decanted and the residue was stirred in methanol/water to precipitate a white solid that was isolated by filtration, washed with water, and dried to yield 1.36 g of 2-[(2,2-dimethylpropanoyl)amino]-4-methoxyphenylboronic acid, m.p. 256-257° C. The material was used in the next step without further purification.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)(=O)=O.C(#N)C>>[CH3:44][O:43][C:37]1[CH:36]=[C:35]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[CH2:21]2)[CH:40]=[CH:39][C:38]=1[O:41][CH3:42]
Reactant: COc1ccc([C@@]2(CCOS(C)(=O)=O)CCN(C(=O)c3ccccc3OC)C2)cc1OC
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: COc1ccc([C@]2(CCN3CCC(N4CCCCC4)CC3)CCN(C(=O)c3ccccc3OC)C2)cc1OC

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dimethoxyphenyl)-1-(2-methoxybenzoyl)pyrrolidine (3.17 g), prepared essentially as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[I:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.O>CN(C=O)C>[I:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][C:8]1[S:9][CH:10]=[CH:11][N:12]=1
Reactant: Oc1cccc(I)c1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1cccc(Oc2nccs2)c1
Temperature: 135 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
Cesium carbonate (4.52 g, 13.87 mmol) was added to 2-bromo-1,3-thiazole (1.90 g, 11.6 mmol) and 3-iodophenol (2.54 g, 11.5 mmol) in anhydrous DMF (30 mL). The reaction was heated to 135° C. and stirred at this temperature overnight. The reaction was allowed to cool, then was poured into water (100 mL), and extracted with EtOAc (3×100 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated. The crude product was purified via flash chromatography using a Varian SF15-24 g column and an eluent of EtOAc in hexanes (0-10%) to afford the title compound as a yellow oil (2.52 g, 71.8%). MS (LCMS) m/z 304.1 (M+1).