Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:44]([OH:46])=O)[CH2:33][C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25].Cl.[CH3:48][C:49]1[N:53]=[C:52]([CH:54]([NH2:62])[CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:51][N:50]=1.C(N(CC)CC)C>CN(C)C=O>[C:24]([O:28][C:29](=[O:30])[NH:31][C@@H:32]([C:44](=[O:46])[NH:62][C@@H:54]([C:52]1[O:51][N:50]=[C:49]([CH3:48])[N:53]=1)[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:33][C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1)([CH3:26])([CH3:27])[CH3:25]
Reactant: Cc1noc(C(N)Cc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)n1
Yield: 80.3 %

Procedure:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (6.3 g, 32.9 mmol) and 1-hydroxybenzotriazole monohydrate (5.0 g, 32.9 mmol) were added to a solution of (R) N-tert-butoxycarbonyl-3-(2-naphthyl)-alanine (10.4 g, 32.9 mmol) in N,N-dimethylformamide (140 ml). After 1 h at 20° C. a mixture of 1-(3-methyl-[1,2,4]oxadiazole-5-yl)-2-phenylethylamine hydrochloride (5.6 g, 23.5 mmol) and triethylamine (2.37 g, 23.5 mmol) in N,N-dimethylformamide (100 ml) were added. After 18 h at 20° C. the reaction mixture was poured onto water (1.4 L) and extracted several times with ethyl acetate (total 1.4 L). The combined organic phases were washed with aqueous citric acid (10%, 200 ml), a saturated solution of sodium hydrogencarbonate (200 ml) and water (3×200 ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and crystallized from ethyl acetate and heptane to give 9.45 g of {(1R)-1-{(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl}-2-(2-naphthyl)ethyl}carbamic acid tertbutyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: Fc1ccc(-c2noc(C(F)(F)F)c2-c2cn(-c3ccc(C(F)(F)F)cc3)cn2)cc1
Yield: 34 %

Procedure:
As described for Example 24, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (100 mg, 0.34 mmol), using 4-fluorobenzotrifluoride instead of 4-fluoroacetophenone, was converted to the title compound (50 mg, 34%) which was obtained as a white solid. MS: m/e=442.1 [M+H]+.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[CH3:22][O:23][C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:32](=[O:36])[CH2:31][CH2:30][CH2:29][C:28]=2[CH:27]=1)=[O:25].CO>C1(C)C=CC=CC=1.C1COCC1>[OH:36][C@H:32]1[CH2:31][CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([C:24]([O:23][CH3:22])=[O:25])[CH:35]=[CH:34][C:33]1=2
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)CCC[C@@H]2O
Temperature: -10 °C

Procedure:
To an oven-dried 2 L round-bottomed flask equipped with an argon inlet/outlet and magnetic stirring was added (R)-2-methyl-CBS-oxazaborolidine (7.4 mL of a 1M solution in toluene, 7.4 mmol, Aldrich). Toluene (190 mL) was added and the reaction mixture was cooled in an ice-salt bath (bath temp.=−10° C.). BH3—SMe2 was added (17 mL, 180 mmol, Aldrich), then 5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (30 g, 150 mmol, Albany Molecular) in 200 mL of THF was added over 5 h using a syringe pump. After the addition was complete, the reaction mixture was stirred for an additional 1 h. The reaction mixture was poured into an addition funnel, and then added to 200 mL of MeOH, cooled in a ice-salt bath, over 30 min at such a rate that the internal temperature was kept below 0° C. The mixture was concentrated in vacuo. Et2O (1 L) was added, and the mixture was washed with 1M H3PO4 (3×), 5% NaHCO3, and brine (ca. 400 mL each wash). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in Et2O again (500 mL), and the mixture was washed with 1M H3PO4 (3×200 mL), satd NaHCO3, and brine. After drying the organic layer over MgSO4, the mixture was filtered and concentrated in vacuo, which gave the title compound as a white-yellow solid. MS (+ion ESI) m/z =207 (MH+), 189 (MH+-H2O).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.I[CH2:22][C:23]([NH2:25])=[O:24].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:22][C:23](=[O:24])[NH2:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)CI
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCN(CC(N)=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.7 %

Procedure:
To a solution of 1.25 g (7.8 mmole) of N-(t-butoxycarbonyl)ethylenediamine in 10 mL of acetonitrile was added 1.36 mL (7.8 mole) of DIEA followed by 1.44 g (7.8 mmole) of iodoacetamide at room temperature. After 90 min most of the solvent was removed in vacuo and the residue was taken up in 12 mL of CH2Cl2 and was treated with 1.36 mL (7.8 mmole) of DIEA and then 1.1 mL (7.8 mmole) of benzyl chloroformate. The resulting solution was stirred at room temperature for 2 days, and was then concentrated partly in vacuo. The residue was treated with 100 mL of ethyl acetate and 20 mL of 1M aqueous tartaric acid and the layers were separated. The organic layer was washed with 2×15 mL of water, the tartaric acid layer was extracted with 30 mL of ethyl acetate, this extract was washed with 2×10 mL of water, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on 131 g of silica gel eluting with 2.5 L of 100:4 CH2Cl2 :methanol to provide 1.5 g (55%) of an oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:19]Br.C(OCC)(=O)C>C(O)(=O)C>[BrH:19].[Br:19][C:12]1[CH:13]=[C:14]([C:15]([F:18])([F:16])[F:17])[C:9]([NH:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:10][CH:11]=1
Reactant: BrBr
Reactant: FC(F)(F)c1cccnc1NCCN1CCCC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Br
Product: FC(F)(F)c1cc(Br)cnc1NCCN1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 142.4 %

Procedure:
To the solution of N-(2-(pyrrolidin-1-yl)ethyl)-3-(trifluoromethyl)pyridin-2-amine (1030 mg, 4 mmole) in 10 ml of acetic acid, bromine (203 ul, 4 mmole) was added. The reaction solution was stirred at room temperature for 1.5 hr and then concentrated under vacuo to give an orange solid. The crude product was dissolved with 40 ml of ethyl acetate to give a yellow milky mixture that was then filtered and washed to give an ivory powder as HBr salt of 5-bromo-N-(2-(pyrrolidin-1-yl)ethyl)-3-(trifluoromethyl)pyridin-2-amine (963 mg). ES/MS m/z 335.9, 337.9 (MH+).
Reaction SMILES: O[C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N+](=[CH2:21])=[N-].[CH3:22][OH:23]>CCOCC>[CH3:22][O:23][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([O:12][CH3:21])=[O:11])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CO
Reactant: O=C(O)CCC1OC(=O)C(O)=C1c1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CCC1OC(=O)C(OC)=C1c1ccccc1
Reaction time: 8 h

Procedure:
3-(4-Hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionic acid (100 mg) was dissolved in methanol (2 ml), and a solution of diazomethane in ether was added thereto until the yellow color did not vanish any longer. The mixture was allowed to stand at room temperature overnight. The solvent was then distilled off to give methyl 3-(4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate (110 mg).
Reaction SMILES: [NH2:1][C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[N:3]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[Cl:41][CH2:42][C:43](Cl)=[O:44].O>O1CCCC1>[Cl:41][CH2:42][C:43]([NH:1][C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[N:3]=1)=[O:44]
Reactant: Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCl)Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A 500 mg amount of 5-amino-8-[3-(trifuoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (prepared as described in Example 29) was suspended and stirred in 30 ml of dry tetrahydrofuran, then 1 equivalent (0.322 g) of [1,8-bis(dimethylamino)-naphthalene,N,N,N',N'-tetramethyl-1,8-naphthalenediamine] (Proton Sponge® was added followed by 1.1 equivalents (0.187 g) of chloroacetyl chloride. The reaction mixture was heated at reflux for 16 hours, then allowed to cool to room temperature. The mixture was poured into 200 ml of water and the resulting precipitate was collected by filtration to give 423 mg of the product of the example as a brown solid, m.p. 189°-192° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[CH2:6][CH2:7][OH:8].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:32].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[CH2:6][C:7]([OH:32])=[O:8]
Reactant: COC(=O)CC(CCO)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Reaction time: 20 h
Yield: 64.4 %

Procedure:
5-Hydroxy-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]pentanoic acid methyl ester (70 mg, 0.17 mmol) is dissolved in DMF (1.5 mL) at room temperature and pyridinium dichromate (250 mg, 0.66 mmol) is added into it. The mixture is stirred for 20 hr and water (25 mL) is added. The pH of the solution is adjusted to pH 5 by adding acetic acids and the mixture is extracted with EtOAc (3×50 mL). The organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC using 80% EtOAc in Hexanes with 1% acetic acid affords 48 mg (66%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-pentanedioic acid monomethyl ester. LCMS (ESMS): m/z 439.17 (M+H+).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C>C([O-])(O)=O.[Na+].O>[C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 83.6 %

Procedure:
A mixture of uridine (14; 13.25 g, 54.5 mmol), diphenyl carbonate (15.48 g, 72.5 mmol), anhydrous NaHCO3 (349 mg, 4.15 mmol), and hexamethylphosphoric triamide (50 mL) was heated with stirring at 150° C. under nitrogen for 20 min, and then cooled to room temperature. The mixture was poured into cold water (400 mL), and washed with CHCl3. Et3N (25 mL) was added, and the aqueous solution was heated at 70° C. for 5 h. The solvent was evaporated in vacuo, and the residue was crystallized from MeOH/water to give the title compound 15 as a white solid (11.13 g, 84%). 1H NMR (DMSO-d6) δ 11.2 (s, 1H, NH), 7.60 (d, J=7.5 Hz, 1H, H-6), 5.95 (d, 1H, H-1′), 5.51 (d, J=7.5 Hz, 1H, H-5), 6.30-5.30 (br, 2H, 2 OH), 4.10-3.50 (m, 6H, H-2′, H-3′, H-4′, H-5′, OH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:12][CH:11]=1.Cl>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:14][CH:15]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1ccc(F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(F)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3-{1-[6-(4-chlorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.22 (s, br, 1H), 7.74–6.68 (m, 12H) 5.04–4.92 (m, 1H), 3.66–3.50 (m, br, 2H), 3.00–2.82 (br, 2H), 2.80–2.58 (m, br, 4H), 2.58–2.40 (m, br, 2H), 2.001.68 (m, br, 6H), 1.66–1.46 (m, br, 1H), 1.46–1.36 (br, 3H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 551.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH:5][CH:6]=[C:7]([C:21]#[N:22])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=1[Cl:20])=O.CO.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:20][C:12]1[CH:13]=[C:14]([Cl:19])[C:15]([O:17][CH3:18])=[CH:16][C:11]=1[NH:10][C:8]1[C:23]2[C:4](=[CH:3][C:2]([F:1])=[C:25]([O:26][CH3:27])[CH:24]=2)[N:5]=[CH:6][C:7]=1[C:21]#[N:22]
Reactant: COc1ccc(NC=C(C#N)C(=O)Nc2cc(OC)c(Cl)cc2Cl)cc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CO
Product: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reaction time: 2 h
Yield: 54.8 %

Procedure:
To a suspension of 3-fluoro-4-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (360 mg, 0.88 mmol) in 40 mL of acetonitrile was added 0.1 mL of methanol. The reaction mixture was heated to reflux and phosphorous oxychloride (0.65 mL, 7.0 mmol) was added dropwise, via syringe. After 2 hours the mixture became a clear orange solution. This solution was heated at reflux overnight. After 24 hours, the reaction mixture was cooled in an ice-bath and the solid was collected by filtration, washed with cold acetonitrile (20 mL) and then suspended in tetrahydrofuran (50 mL). To both the acetonitrile filtrate and the tetrahydrofuran suspension were added concentrated ammonium hydroxide (2×25 mL) and the mixtures were stirred for 1 hour. Water (2×400 mL) was added and stirring was continued for 2 hours. The resulting solids were combined, washed with hot water and dried under reduced pressure at ˜40° C., overnight, to provide 189 mg (55%) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile as orange crystals, mp 219-221° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.87 (s, 3H), 4.02 (s, 3H), 7.36 (s, 1H), 7.65-7.80 (m, 2H), 8.08 (d, J=9 Hz, 1H), 8.48 (s, 1H), 9.85 (s, 1H); MS (ES) m/z392.0, 394.0 (M+H)+
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>COCCOC>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:3]=2[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:15]4[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=4[N:13]=3)=[CH:8][CH:7]=2)=[CH:40][CH:39]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(Cl)ccc3Br)cc1)n2C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(Cl)ccc3-c3ccc(Cl)cc3)cc1)n2C1CCCCC1
Yield: 85.1 %

Procedure:
Ethyl 2-[4-(2-bromo-5-chlorobenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate (49 g) obtained in Example 4, 4-chlorophenylboronic acid (18 g) and tetrakis-(triphenylphosphine)palladium (10 g) were suspended in 1,2-dimethoxyethane (600 ml). Saturated aqueous sodium hydrogencarbonate solution (300 ml) was added and the mixture was refluxed under heating for 2 hr. Chloroform was added to the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution, waiter and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (developing solvent, chloroform:methyl acetate=97:3). Ethyl acetate and diisopropyl ether were added to the resulting oil for crystallization and the resulting crystals were collected by filtration to give the title compound (44 g, yield 85%).
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].B(Cl)([C@H]1[C@H](C)C2C(C)(C)C(CC2)C1)[C@H]1[C@H](C)C2C(C)(C)C(CC2)C1.CO.C(CN)O>C1COCC1>[I:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([OH:11])[CH3:10]
Reactant: CC(=O)c1cccc(C)c1I
Agent: C[C@@H]1C2CCC(C[C@H]1B(Cl)[C@@H]1CC3CCC([C@H]1C)C3(C)C)C2(C)C
Solvent: C1CCOC1
Solvent: CO
Solvent: NCCO
Product: Cc1cccc([C@H](C)O)c1I
Temperature: -20 °C
Reaction time: 6 h
Yield: 23.8 %

Procedure:
1-(2-Iodo-3-methylphenyl)ethanone (500 mg, 1.92 mmol) (prepared according to the procedure of Buchwald, et al., J. Am. Chem. Soc. 1987, 109, 7137-7141) was added slowly over a period of 5 minutes to a cooled (−25° C.) solution of (−) DIP-Chloride™ (691 mg, 2.15 mmol) in THF (2 mL). The reaction was stirred at −20° C. for 6 hours. MeOH (0.8 mL) was added, then the reaction was warmed to ambient temperature and concentrated in vacuo. The resultant residue was taken up in ethyl acetate (1 mL) and ethanolamine (0.4 mL, 4.2 mmol) was added. As the solution stirred vigorously, a precipitate formed. The precipitate was filtered off; the liquors were diluted with hexane (1 mL) and filtered again. The liquors were concentrated in vacuo and the resultant residue was purified by flash column chromatography on silica, eluting with 10% ethyl acetate/isohexane, followed by recrystallisation with isohexane to give the title compound as a white solid (120 mg). SFC (10% MeOH, chiralpak AD-H) e.e. 100%; 1H NMR (400 MHz, d6-DMSO): δ 7.33 (1H, dd, J=1.6, 7.3 Hz); 7.27 (1H, t, J=7.5 Hz); 7.21 (1H, dd, J=1.5, 7.2 Hz); 5.36 (1H, d, J=4.1 Hz); 4.92-4.88 (1H, m); 2.40 (3H, s); 1.26 (3H, d, J=6.3 Hz).
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:14]([O-])=O)=[C:7]([B:11]([OH:13])[OH:12])[CH:8]=[CH:9][CH:10]=1)(=O)C.O[C:18]([C:21](O)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>Cl.O1CCOCC1.C(O)(=O)C.[Pd]>[NH2:14][C:6]1[C:7]([B:11]2[O:12][C:21]([CH3:23])([CH3:22])[C:18]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:9]=[CH:10][C:5]=1[NH2:4]
Reactant: CC(=O)Nc1cccc(B(O)O)c1[N+](=O)[O-]
Reactant: CC(C)(O)C(C)(C)O
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC1(C)OB(c2cccc(N)c2N)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (3-acetamido-2-nitrophenyl)boronic acid (300 mg) in 2M aqueous hydrochloric acid solution (4 mL) was heated at 80° C. for 20 min. After cooling to room temperature, the solvent was reduced in vacuo to give a brown solid which was redissolved in 1,4-dioxane (5 mL). Pinacol (316 mg) was added and the mixture heated at 100° C. for 30 min. After cooling to room temperature the solvent was reduced in vacuo to give a beige solid which was dissolved in acetic acid (5 mL). Palladium on carbon (100 mg) was added and the mixture stirred under an atmosphere of hydrogen at 40° C. for 1 h. The reaction mixture was then filtered through Celite and the filtrate reduced in vacuo. Purification by column chromatography gave 2-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[N:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=1>COC(O)C>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=3)[N:20]=2)=[CH:11]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Nc1ccc(CCO)cc1
Agent: COC(C)O
Product: OCCc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Temperature: 160 °C
Yield: 84.2 %

Procedure:
A mixture of compound 1f (4.00 g) and 2-(4-aminophenyl)-ethanol (2.96 g) in 1-methoxyethanol (30 mL) was heated at 160° C. for 17 hrs in a pressure tube. The mixture was then cooled, quenched with water and extracted with mixed THF and ethyl acetate. The combined organic phase was washed with brine and concentrated. The residue was subjected to silica column and eluted with 2-6% methanol in dichloromethane to give compound 1 (3.01 g, yield 84%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.89 (d, J=8.0 Hz, 1H), 8.26 (dd, J=5.2 Hz, 2.0 Hz, 2H), 8.22 (s, 1H), 7.59 (m, 2H), 7.20 (m, 4H), 3.78 (t, J=7.2 Hz, 2H), 2.83 (t, J=7.2 Hz, 2H). MS (ESI) m/z: 332 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[F:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[CH:33]2>>[F:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=1)[CH:34]=[CH:33]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: O=S(=O)(Nc1nccnc1-c1ccc(Cn2ccc3cc(F)ccc32)cc1)c1ccccc1C(F)(F)F
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzene sulfonamide (Intermediate 9), and 5-fluoro-indole, the title compound was isolated as a yellow solid in 69% yield (99% purity by HPLC).