Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:34])[N:8](CC2C=CC(OC)=CC=2)[C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH:35](/B(O)O)=[CH:36]\[CH2:37][CH2:38][CH3:39].C([O-])(O)=O.[Na+].COCCOC.O>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>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:34])[NH:8][C:9]2[C:14]([C:15]=1[CH:35]=[CH:36][CH2:37][CH2:38][CH3:39])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2n(Cc2ccc(OC)cc2)c1=O
Reactant: CCC/C=C/B(O)O
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCCC=Cc1c(C(=O)OCC)c(=O)[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A solution of 11 (0.10 g, 0.19 mmol), E-penten-1-ylboronic acid (44.0 mg, 0.38 mmol), tetrakis(triphenylphosphine)palladium (22.0 mg, 0.023 mmol), and NaHCO3 (41.0 mg, 0.38 mmol) in 1:1 DME/H2O (3 mL) was heated at 100° C. for 1 h. The reaction was allowed to cool to room temperature, diluted with H2O, extracted with EtOAc, dried (Na2SO4), filtered, and concentrated. Chromatography (SiO2, 3:1 Hex/EtOAc) gave 12 (43.0 mg, 51%) as a colorless film.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.O[CH2:13][C:14]1[N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>Br.O>[N:16]1[CH:15]=[C:14]([CH2:13][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=3[N:3]=2)[N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=12
Reactant: Cc1ccc2nc(S)[nH]c2c1
Reactant: OCc1cnc2ccccn12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2[nH]c(SCc3cnc4ccccn34)nc2c1
Temperature: 25 °C

Procedure:
A mixture of 903 mg (5.5 mmole) of 2-mercapto-5-methylbenzimidazole and 805 mg (5.4 mmole) of 3-hydroxymethylimidazo[1,2-a]pyridine (prepared as in Example 1) was dissolved in 10 ml of 48% aqueous hydrobromic acid and 10 ml of acetic acid and heated to reflux. After being cooled to room temperature, the mixture was poured into water and made alkaline with potassium carbonate. The oil that separated was extracted into dichloromethane, washed with water, dried over magnesium sulfate, filtered, and concentrated to an oil that crystallized on standing. The solid was collected by filtration, washed with diethyl ether, and air dried to yield the title compound as 610 mg of analytically pure solid. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C(N(CC)CC)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:21]1[CH:22]=[CH:23][C:18]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:20]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: Oc1ccccc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Brc1ccccc1Oc1ccc(-c2ccccc2)cc1
Reaction time: 48 h

Procedure:
A mixture of 2-bromophenol (2.08 g, 12 mmol), 4-biphenylboronic acid (4.75 g, 24 mmol), Cu(OAc)2 (2.20 g, 12 mmol) and triethylamine (6.1 g, 60 mmol) in dioxane (100 mL) was stirred for 48 h. The crude mixture was evaporated onto silica gel and purified by column chromatography eluting with ethyl acetate/heptane 1:9. Yield: 0.73 g (19%). 1H NMR (CDCl3, 500 MHz) 7.65 (m, 1H) 7.55 (m, 4H), 7.43 (m, 2H), 7.25–7.38 (m, 2H), 7.00–7.08 (m, 4H); MS(m/z): 325.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[N:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[C:4]([C:8]3[N:12]4[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccncc1
Reactant: FC(F)(F)c1cnn2c(-c3cccc(Br)c3)cnc2n1
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cnn2c(-c3cccc(-c4ccncc4)c3)cnc2n1
Temperature: 65 °C
Reaction time: 12 h
Yield: 44.9 %

Procedure:
A mixture of 7-(3-bromophenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (21 mg, 0.06 mmol), 4-pyridylboronic acid (11 mg, 0.09 mmol) and 2 M Na2CO3 (0.09 ml) in 1,2-dimethoxyethane (1.5 ml) was degassed with a stream of nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) was added and the mixture was stirred under nitrogen at 65° C. for 12 h. After allowing to cool to room temperature, the mixture was diluted with ethyl acetate and partitioned between water (20 ml) and ethyl acetate (30 ml). The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) and triturated with diethyl ether to give 9.2 mg (44%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.58 (2H, m), 7.70 (1H, t, J 7.3 Hz), 7.74-7.77 (1H, m), 8.13 (1H, dt, J 7.3, 1.6 Hz), 8.39 (1H, t, J 1.6 Hz), 8.68 (1H, s), 8.72 (2H, m), 8.83 (1H, s); MS (ES+) m/z 342 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1)C>>[Cl:28][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][C:18]([OH:29])=[O:17])[CH:26]=[CH:25][C:24]=1[O:27][CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Product: O=C(O)CCc1ccc(OCc2cccnc2SC2CCCC2)c(Cl)c1
Yield: 80.5 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (28 mg, 0.13 mmol) obtained in Step C of Preparation Example 8 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (33 mg, 0.14 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (41 mg, 91%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]([CH3:28])([CH3:27])[C:22](OCC)=[O:23])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22][OH:23])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(C)(C)CC1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CO)CC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
Into a solution of 2.7 g of lithium aluminum hydride in tetrahydrofuran (200 ml) was slowly dropped at 0° C. a solution of 21.5 g of ethyl 3-(1-benzylpiperidin-4-yl)-2,2-dimethylpropanoate in tetrahydrofuran (20 ml) and the resulting mixture was stirred at room temperature for 30 minutes. After adding water and a 10% aqueous solution of sodium hydroxide to the reaction mixture, the insoluble matters were filtered off. After distilling off the solvent under reduced pressure, 19 g of crude 3-(1-benzylpiperidin-4-yl)-2,2-dimethylpropanol was obtained as a yellow oily substance. This oily substance was dissolved in 300 ml of ethanol. After adding 20 ml of acetic acid, the mixture was subjected to hydrogenation at ordinary temperature under atmospheric pressure for 12 hours. After filtering off palladium-carbon, the solvent was concentrated under reduced pressure to thereby give 23 g of crude 3-(piperidin-4-yl)-2,2-dimethylpropanol as a yellow oily substance. This crude product was further dissolved in 200 ml of dichloromethane and 23 ml of pyridine was added thereto. Then 15.5 g of di-tert-butyl dicarbonate was dropped thereinto at 0° C. and the resulting mixture was reacted at room temperature for 2 hours. After adding water, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 14.9 g of the title compound as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[N:43]([CH3:44])[C:29]2=[N:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=[C:28]2[N:27]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:28]6[N:27]=[C:26]([O:25][CH3:24])[N:43]([CH3:44])[C:29]6=[N:30][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COc1nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2n1C
Product: COc1nc2cc(-c3ccc4ncc5c(c4c3)n(-c3cn(C)nc3C)c(=O)n5C)cnc2n1C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-methoxy-3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine (Stage 71.1.1) to give the title compound as a white solid. (HPLC: tR 2.62 min (Method A); M+H=455 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.24-8.20 (m, 1H), 8.17-8.13 (m, 1H), 8.13-8.08 (m, 1H), 7.97-7.92 (m, 1H), 7.87-7.83 (m, 1H), 7.55-7.53 (m, 1H), 4.16 (s, 3H), 3.91 (s, 3H), 3.57 (s, 6H), 1.97 (s, 3H))
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:14][C:15]([O:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:17]
Reactant: OC1CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cl)OC1CCCC1
Reaction time: 2.5 h

Procedure:
Cyclopentanol (0.431 mL, 4.75 mmol, 17.4 equiv) was dissolved in dry CH2Cl2 (25 mL). Triethylamine (0.662 mL, 4.75 mmol, 17.4 equiv) and triphosgene (0.507 g, 1.71 mmol, 6.26 equiv) were added sequentially. The reaction solution was stirred 2.5 hours to provide a stock solution of cyclopentyl chloroformate (0.19 M). A portion of this solution (2.87 mL, 0.545 mmol, 2 equiv) was added to a solution of crude ethyl-3-[H2N-L-ValΨ[COCH2]-L-(p-F)Phe-L-(Tr-Gln)]-E-propenoate•HCl(from above) and 4-methylmorpholine (0.120 mL, 1.09 mmol, 4 equiv) in dry CH2Cl2 (4 mL). The reaction mixture was stirred for 1.75 hours, then poured into water (30 mL), and extracted with CH2Cl2 (3×30 mL). The combined organic phases were dried over Na2SO4, concentrated, and the residue was chromatographed on silica gel (gradient elution 40-50% EtOAc in hexanes) to afford ethyl-3-[CyPentylOCO-L-ValΨ[COCH2]-L-(p-F)Phe-L-(Tr-Gln)]-E-propenoate (0.077 g, 35%) as a colorless glass: 1H NMR (CDCl3) δ 0.68 (d, 3H, J=6.8), 0.93 (d, 3H, J=6.8), 1.29 (t, 3H, J=7.2), 1.50-1.86 (m, 10H), 1.93-2.04 (m, 2H), 2.52 (d, 1H, J=15.9), 2.64 (dd, 11H, J=12.1, 5.6), 2.73-2.90 (m, 2H), 2.29 (dd, 1H, J=17.0, 9.8), 4.10-4.22 (m, 3H), 4.40-4.51 (m, 1H), 4.92 (d, 1H, J=8.1), 4.95-5.03 (m, 1H), 5.38 (d, 1H, J=15.9), 6.06 (d, 1H, J=8.4), 6.60 (dd, 1H, J=15.9, 4.8), 6.92-7.00 (m, 2H 7.04-7.11 (m, 211), 7.16-7.32 (m, 15H).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[S:25]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26]1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:30][C:27]3[CH:28]=[CH:29][S:25][CH:26]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: O=Cc1ccsc1
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=Cc1ccsc1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with thiophene-3-carbaldehyde (0.5 g, 4.5 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.077 g, 63%).
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.I[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[C:2]1([C:1](=[O:8])[CH2:9][C:10](=[O:12])[CH2:11][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCI
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCC(=O)CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 1 g (6.1 mmol) of benzoylacetone in 6 mL of THF at −78° C. was added 8.2 mL (12.3 mmol) of a 1.5 M LDA solution in THF. Warmed to 0° C. over 2 h, then 2.6 mL (12.3 mmol) of 1-iodohexane was added. The mixture was stirred at rt for 3 h before quenching with saturated aqueous NH4Cl solution and dilution with Et2O. The organics were dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (15/1 hexanes/Et2O) to yield Intermediate 19: TLC Rf=0.52 (1/10 Et2O/Hexanes); 1H NMR (400 MHz, CDCl3, enol form) δ7.88 (m, 2H), 7.54-7.43 (m, 3H), 6.17 (s, 1H), 2.42 (t, 2H, J=7.6), 1.66 (m, 2H), 1.4-1.25 (m, 8H), 0.85 (m, 3H); low resolution MS(ES+) m/e 269.0 (M+Na+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:30][C@H:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]([S:26][CH:27]([CH3:29])[CH3:28])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][S:40]([NH2:43])(=[O:42])=[O:41].Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:38][C@H:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][N:8]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:24])=[C:19]([S:26][CH:27]([CH3:29])[CH3:28])[CH:18]=2)=[CH:15][CH:16]=1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(N)(=O)=O
Reactant: CC(C)Sc1cc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)Sc1cc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(C)(=O)=O
Reaction time: 72 h
Yield: 6.7 %

Procedure:
To a solution of 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylthio)-4-biphenycarboxylic acid (131 mg) in N,N-dimethylformamide (2.6 ml) were added methanesulfonamide (24.9 mg), 4-(dimethylamino)pyridine (43.7 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (91.4 mg) at room temperature and the mixture was stirred at the same temperature for 72 hours. The mixture was poured into aqueous hydrochloric acid solution (0.3N) and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/3) to give tert-butyl [(2R)-2-hydroxy-2-phenylethyl](2-[3′-(isopropylthio)-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]-carbamate (10 mg).
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29]([F:32])([F:31])[F:30])=[CH:4][CH:3]=1.[F:33]C1C=CC2SC(I)=NC=2C=1C(F)(F)F>>[F:33][C:4]1[CH:3]=[CH:2][C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]=1[C:29]([F:30])([F:31])[F:32]
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Reactant: Fc1ccc2sc(I)nc2c1C(F)(F)F
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)c(F)ccc2s1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 5-fluoro-2-iodo-4-trifluoromethyl-1,3-benzothiazole and conducting the Suzuki coupling at 80° C. for 2 h, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=9.02-8.92 (brm, 1H), 8.80-8.70 (brm, 1H), 8.58 (dd, J=4.8, 9.2 Hz, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.37 (s, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.17 (brs, 1H), 8.05 (s, 1H), 7.64 (dd, J=9.2, 11.2 Hz, 1H), 4.56-4.47 (mc, 1H), 3.40 (brd, J=12.8 Hz, 2H), 3.11 (brq, J=11.4 Hz, 2H), 2.30-2.11 (m, 4H). MS(ES+): m/z=463.07 (95) [MH+], 380.02 (100) [MH+-piperidine]. HPLC: tR=2.28 min (polar—5 min, ZQ2).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:14][CH:13]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:14][CH:13]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCC1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A solution of 1-fluoro-4-nitrobenzene (0.61 g, 4.32 mmol) and tert-butyl azetidin-3-ylmethylcarbamate (0.886 g, 4.76 mmol) in dimethylformamide (8.65 ml) was treated with potassium carbonate (0.896 g, 6.48 mmol) and the suspension was heated at 55° C. (12 pm) for 3 hours and at ambient temperature for 16 hours. The reaction was poured into water and the suspension was filtered. The solid was washed with water and dried to provide the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](=O)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:13][C:14]([S:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.[Cl-].[Na+].O>[Si:1]([O:8][CH2:9]/[C:10](=[N:19]/[S:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])/[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)CO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)S(N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C/C(CO[Si](C)(C)C(C)(C)C)=N\S(=O)C(C)(C)C
Temperature: 70 °C
Yield: 65.2 %

Procedure:
1-(tert-butyldimethylsilyloxy)propan-2-one (188 mg, 1.0 mmol) and Ti(OEt)4 (0.52 mL, 2.5 mmol) were dissolved in THF (5 mL). Then 2-methylpropane-2-sulfinamide (121 mg, 1.0 mmol) was added to the mixture under nitrogen atmosphere. The mixture was heated to 70° C. for 2 h. The mixture was poured into brine and filtered through a plug of Celite. The organic layer was concentrated and purified by silica gel chromatography using PE/EA (5/1) to give product the title compound (190 mg, 65%). EDI-MS (M+1): 292. 1H NMR (300 MHz, CDCl3) δ 4.152 (s, 2H), 2.248 (s, 3H), 1.156 (s, 9H), 0.839 (s, 9H), 0.001 (s, 6H).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32](OC(F)(F)F)=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:40]C1C=CC(B(O)O)=CC=1>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([Cl:40])=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(Cl)cc2)CC1

Procedure:
(R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-chlorophenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one was synthesized as per (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 220) in 76% yield using 4-chlorophenylboronic acid as the reagent.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][S:20][C:21]2[NH:25][C:24]3[CH:26]=[C:27]4[C:31](=[CH:32][C:23]=3[N:22]=2)[CH2:30][CH2:29][CH2:28]4)=[N:17][CH:18]=1>C(OCC)(=O)C.C(Cl)Cl>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][S:20]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]4[C:31](=[CH:32][C:23]=3[N:22]=2)[CH2:30][CH2:29][CH2:28]4)=[O:9])=[N:17][CH:18]=1
Reactant: Cc1ccc(CSc2nc3cc4c(cc3[nH]2)CCC4)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(CS(=O)c2nc3cc4c(cc3[nH]2)CCC4)nc1
Reaction time: 3 h
Yield: 65.1 %

Procedure:
50 ml of a 10% solution of m-chloroperbenzoic acid in ethyl acetate were added dropwise with intensive stirring and at 0°-5° C. to 6.7 g of 1,5,6,7-tetrahydro-2-[[(5-methyl-2-pyridyl)-methyl]thio]indeno(5,6-d)imidazole, dissolved in 200 ml of methylene chloride. After stirring at 0°-5° C. for 3 hours, the mixture was poured into 1 l of methylene chloride, it was washed twice with 250 g of 2 N soda, then neutral with water, dried over sodium sulfate and evaporated in vacuo. 6.5 g of crude product were recrystallized from acetonitrile. There were obtained 4.6 g (65.1% of theory) of 1,5,6,7-tetrahydro-2-[[(5-methyl-2-pyridyl)methyl]sulfinyl]indeno(5,6-d)imidazole of melting point 190°-191° C.
Reaction SMILES: [Cl-].[CH3:2][Zn+].Cl[C:5]1[N:10]=[C:9]2[N:11](S(C3C=CC=CC=3)(=O)=O)[CH:12]=[CH:13][C:8]2=[CH:7][CH:6]=1>C1COCC1.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>[CH3:2][C:5]1[N:10]=[C:9]2[C:8]([CH:13]=[CH:12][NH:11]2)=[CH:7][CH:6]=1
Reactant: C[Zn+]
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccc(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc2cc[nH]c2n1
Temperature: 0 °C
Yield: 88 %

Procedure:
A solution of methylzinc chloride in THF (2 M) (9 mL, 12 mmol) was added to 6-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.600 g, 2.05 mmol) and Pd(PPh3)4 (0.095 g, 0.08 mmol) in THF (30 mL). The mixture was refluxed for 40 h, cooled to 0° C., quenched with water and extracted with Et2O. The organic layer was concentrated and the residue was purified over a silica gel column eluting with EtOAc/hexane (1:5) to give N-protected 6-methyl-7-azaindole (0.495 g, 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:38])[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:21]=2[N:20]([CH3:36])[C:19]1=[O:37])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:38])[N:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:22]3[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:21]=3[N:20]([CH3:36])[C:19]2=[O:37])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2)c2cc(Cl)ccc2N(C)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(c2ccccc2)c2cc(Cl)ccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-C), the title compound was prepared as a white solid having a melting point of 126.5-130° C.