Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:12]([CH3:21])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>C1(O)CCCCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:22]([O:24][CH:25]2[CH2:4][CH2:3][CH2:2][CH2:7][CH2:26]2)=[O:23])[N:12]([CH3:21])[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: OC1CCCCC1
Product: Cn1c(C(=O)OC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole-2-carboxylate (28 mg, 0.07 mmol) from Example 36, Step A (Method B) in cyclohexanol (2 mL) and methylene chloride (1 mL) was added a catalytic amount of sodium hydride (60% in mineral oil, <5 mg). The mixture was stirred at rt for 2 hr and then poured into aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (3×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH:5]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH:14]=[CH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)[CH2:4]1.[CH3:25][C:26]([CH3:30])=[CH:27][CH2:28]Br.O>CN(C)C=O>[CH3:25][C:26]([CH3:30])=[CH:27][CH2:28][N:3]1[CH2:8][CH2:7][O:6][CH:5]([CH2:9][N:10]2[C:11]3[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=3[CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=3)[CH2:4]1
Reactant: CC(C)=CCBr
Reactant: C1=Cc2ccccc2N(CC2CNCCO2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCN1CCOC(CN2c3ccccc3C=Cc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.05 g) in dimethylformamide was added a solution of 5-(2-morpholinylmethyl)-5H-dibenz[b,f]azepine (0.2 g) in dimethylformamide under ice cooling, and the resulting mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of 3,3-dimethylallyl bromide (0.12 g) in dimethylformamide, and the reaction mixture was stirred at room temperature for 3 hours, cooled, admixed with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-{4-(3,3-dimethylallyl)-2-morpholinylmethyl}-5H-dibenz[b,f]azepine. M.P. 99°-100° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[NH2:39][C:35]1[CH:34]=[C:33]([C:2]2[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:6]([CH:16]=2)[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:38]=[CH:37][N:36]=1
Reactant: CC1(C)OB(c2ccnc(N)c2)OC1(C)C
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1
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: C1COCCO1
Product: Nc1cc(-c2ccc(OCc3ccccc3)c(C(=O)Nc3cccnc3)c2)ccn1
Temperature: 100 °C

Procedure:
To a microwave vial was added 5-bromo-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in example 2; 200 mg, 0.52 mmol), 1,4-dioxane (2 ml), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinamine (201 mg, 0.78 mmol), 1M sodium carbonate (1.04 ml, 1.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (36.2 mg, 0.03 mmol). The vial was sealed and heated to 100° C. for 30 minutes under microwave conditions. The mixture was evaporated in vacuo and the residue was purified using the MDAP to yield the title compound. 41 mg.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=1[Cl:27])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:3])=[O:23])=[CH:20][C:19]=1[Cl:27])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Thionyl chloride (5 ml) and dimethylformamide (1 drop) were added to a solution of (R)-4-(1-benzyloxycarbonylaminoethyl)-3-chlorobenzoic acid (680 mg) in dichloromethane (7 ml), and the mixture was stirred at room temperature for 4 hours. After the reaction, the solvent was evaporated under reduced pressure to give (R)-4-(1-benzyloxycarbonylaminoethyl)-3-chlorobenzoyl chloride as crystals. Then, the crystals were dissolved in dichloromethane (12 ml). The solution was dropwise added to a solution of 4-aminopyridine (187 mg) and diispropylethylamine (267 mg) in dichloromethane (5 ml) at room temperature, and the mixture was stirred for 1 hour. After the reaction, water was added to the reaction mixture. The mixture was extracted with chloroform, washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 650 mg of (R)-4-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)-3-chlorobenzamide.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4](C)[CH:5]([O:8][CH3:9])[O:6][CH3:7].C1N2CN3CN(C2)CN1C3.[Cl-].[Na+].[CH:23]([O:26]C(C)C)(C)C>O>[CH3:9][O:8][CH:5]([O:6][CH3:7])[CH:4]=[C:3]([CH3:2])[CH:23]=[O:26]
Reactant: CC(C)OC(C)C
Reactant: COC(OC)C(C)=CCBr
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(C=C(C)C=O)OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 64 %

Procedure:
4-Bromo-1,1-dimethoxy-2-methyl-2-butene (2 g) was added to a solution of hexamine (1.7 g) and water (10 ml), and the mixture was stirred at room temperature for 14 hours. Dowex 50×8 (type H)(3 g) was previously treated with sodium chloride to convert it to type Na. Then isopropyl ether (20 ml) was added to the above reaction mixture, the type Na resin was added, and the mixture was stirred at 70° C. for 6 hours. The isopropyl ether layer was separated, concentrated and purified by column chromatography to give 4,4-dimethoxy-2-methyl-2-buten-1-al (0.92 g, 64%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:21](=[O:22])[C:20]5=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]5[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH:21]([OH:22])[CH:20]5[C:19](=[CH:26][CH:25]=[CH:24][CH2:23]5)[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C1C2=CC=CCC2C(O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a suspension of N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimide (7.8 g, 19.8 mmol) in methanol (250 ml) and DCM (30 ml) was added NaBH4 (1.7 g, 45.5 mmol) at room temperature under nitrogen. After stirring for 0.5 hours the homogeneous reaction mixture was concentrated. The remaining solid was purified on a flash chromatography column (SiO2, 1:1 EtOAc/DCM, increased to 10% MeOH) to give 7.0 g (90%) of the desired product as a solid which was recrystallized from EtOAc, m.p.=172-173° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=[O:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:32][C:33]([CH3:39])([CH3:38])[CH2:34]C(Cl)=O>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:24])[CH2:32][C:33]([CH3:39])([CH3:38])[CH3:34])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:30][CH:31]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(S(C)(=O)=O)cc3)nc2)CC1
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)N1CCC(c2ccc(COc3ccc(S(C)(=O)=O)cc3)nc2)CC1

Procedure:
The title compound was prepared from tert-butyl 4-[2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 1) (30 mg, 0.067 mmol) and 3,3-dimethylbutyryl chloride (14 μL, 0.1 mmol) following a procedure analogous to that in Example 41 as a white crystal (28 mg, yield 94%).
Reaction SMILES: [CH3:1][C:2]([CH:5]=[O:6])([CH3:4])[CH3:3].[NH2:7][C:8]1[C:9](O)=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].C>>[C:2]([C:5]1[O:6][C:9]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=[CH:17][C:8]=2[N:7]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)C=O
Reactant: COC(=O)c1cccc(N)c1O
Agent: C
Product: COC(=O)c1cccc2nc(C(C)(C)C)oc12
Temperature: 120 °C
Yield: 59.6 %

Procedure:
A mixture of pivaldehyde (1.65 mL, 15.4 mmol), methyl 3-amino-2-hydroxybenzoate (501 mg, 3.0 mmol) and Darco KB-B (375 mg) in xylenes (8 mL) was heated under an oxygen atmosphere at 120° C. for 12 h. The reaction mixture was cooled to room temperature, filtered through a celite pad. The filtrate was concentrated and the crude material was purified by column chromatography (silica gel, 7:3 hexanes/ethyl acetate) to afford the desired methyl 2-tert-butylbenzoxazole-7-carboxylate (417 mg, 60%) as a light orange oil: 1H NMR (500 MHz, CDCl3) δ 7.94 (dd, J=7.8, 0.9 Hz, 1H), 7.88 (dd, J=7.8, 0.9 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 4.01 (s, 3H), 1.54 (s, 9H); MS (ESI+) m/z 234 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:27][C:28]([F:31])([F:30])[F:29]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][C:28]([F:31])([F:30])[F:29])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)CI
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCC(F)(F)F)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (65 ml). To the suspension were added potassium carbonate (100 mg, 0.7 mmol) and 2-iodo-1,1,1-trifluoroethane (0.07 ml, 0.73 mmol) in order. The mixture was stirred at room temperature for 8 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (20 mg, yield 12%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[CH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])=[O:18])[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc2c1ccn2S(=O)(=O)c1ccccc1

Procedure:
3-[1-(Benzenesulphonyl)-1H-indol-4-yl]acrylic acid ethyl ester (2.48 g, 6.98 mmol) was hydrogenated over 10% Pd-C (500 mg) in ethyl acetate-ethanol (4:1; 75 ml), under an atmosphere of hydrogen. The catalyst was removed by filtration after 4 h, and the solvents were removed to obtain the title compound as a colourless oil which crystallised on standing (2.47 g, 100%); δH (CDCl3, 360 MHZ) 1.10 (3H, t, J=6.8 Hz), 2.57 (2H, t, J=7.5 Hz), 3.06 (2H, t, J=7.5 Hz), 4.02 (2H, q, J=7.2 Hz), 6.66 (1H, d, J=0.72 Hz), 6.98 (1H, d, J=7.5 Hz), 7.14-7.18 (1H, m), 7.34-7.38 (2H, m), 7.43-7.48 (1H, m), 7.50 (1H, d, J=3.9 Hz), 7.77-7.82 (3H, m).
Reaction SMILES: B(O)(O)O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:16])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1.C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O.[OH:32][CH2:33]C(CO)O>>[OH:16][C:8]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=[C:6]([CH3:5])[C:7]=1[CH:33]=[O:32]
Reactant: OCC(O)CO
Reactant: Cc1cc(O)c2c(c1)CCCC2
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Agent: OB(O)O
Product: Cc1cc2c(c(O)c1C=O)CCCC2
Temperature: 170 °C
Reaction time: 0.25 h

Procedure:
A suspension of boric acid (5.88 g) in glycerol (20 ml) was heated at 170° C. for 30 minutes. Temperature of the reaction mixture was lowered at 155° C. and 5,6,7,8-tetrahydro-3-methyl-1-naphthol (5.00 g) was added dropwise over 10 minutes. After 15 minutes, hexamethylenetetramine (4.35 g) was added dropwise below 180° C. and stirred at 170° C. for 30 minutes. The mixture was cooled to 110° C. and 24% aqueous sulfuric acid (20 ml) was added. The mixture was steam distilled and AcOEt was added to the distillate. The organic phase was washed with brine and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give 5,6,7,8-tetrahydro-1-hydroxy-3-methylnaphthalene-2-carbaldehyde as a solid (2.15 g). A pure sample was obtained by recrystallization from EtOH-H2O.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[C:15]1[N:16]([CH2:34][CH2:35][O:36]C2CCCCO2)[C:17]2[C:22]([C:23]=1[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[CH:21][CH:20]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:18]=2.Cl>CO.O1CCCC1>[CH:24]1([C:23]2[C:22]3[C:17](=[CH:18][C:19]([C:30]([O:32][CH3:33])=[O:31])=[CH:20][CH:21]=3)[N:16]([CH2:34][CH2:35][OH:36])[C:15]=2[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[OH:4])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COCOc1ccc(-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2CCOC2CCCCO2)c(OCOC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(O)cc3O)n(CCO)c2c1
Reaction time: 10 h
Yield: 68 %

Procedure:
To a solution of methyl 2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indole-6-carboxylate in methanol (525 ml) and tetrahydrofuran (30 ml) was added 6N hydrochloric acid (105 ml) and the mixture was stirred for 10 hr. The reaction mixture was concentrated and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give methyl 3-cyclohexyl-2-(2,4-dihydroxyphenyl)-1-(2-hydroxyethyl)-1H-indole-6-carboxylate (10.3 g, yield 68%).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[H-].[Na+].[CH:21]1[C:26]([C:27]([CH2:29]Br)=[O:28])=[CH:25][CH:24]=[C:23]([Cl:31])[CH:22]=1>CN(C)C=O>[CH2:11]([C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH2:29][C:27]([C:26]1[CH:25]=[CH:24][C:23]([Cl:31])=[CH:22][CH:21]=1)=[O:28])[C:4]([OH:3])=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)c1ccc(Cl)cc1)(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
5.0 g (20 mmol) of benzylmalonic acid diethyl ester were added dropwise at room temperature to a suspension of 0.87 g of sodium hydride dispersion (55% in oil) in 20 ml of dimethylformamide. Subsequently, the reaction mixture was stirred at room temperature for 20 minutes and thereafter 4.67 g (20 mmol) of omega-bromo-4-chloroacetophenone in 25 ml of dimethylformamide were added dropwise. After completion of the addition, the deep brown colored reaction mixture was stirred at room temperature overnight and thereafter evaporated in a high vacuum. The residue was dissolved in methylene chloride, washed with water and dried over sodium sulfate. Thereafter, the solvent was evaporated under reduced pressure and the residue, for purification, was chromatographed on silica gel with a 6:1 mixture of hexane and ether, to obtain 5.17 g (64%) of 2-(RS)-benzyl-2-carbethoxy-4-(4-chloro-phenyl)-4-oxobutyric acid as a yellowish solid. MS: 357 (M-OC2H5)+, 311 (M-benzyl)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23](Br)=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:35]([O:39][C:40]([N:42]1[C:46](B(O)O)=[CH:45][C:44]([CH3:50])=[N:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>O1CCOCC1.O>[C:35]([O:39][C:40]([N:42]1[C:46]([C:23]2[CH:24]=[CH:25][C:20]3[N:21]([C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)[N:19]=3)[CH:22]=2)=[CH:45][C:44]([CH3:50])=[N:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(Br)cn4c3-c3ccccc3)cc2)CCC1
Reactant: Cc1cc(B(O)O)n(C(=O)OC(C)(C)C)n1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccc3nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)n3c2)n(C(=O)OC(C)(C)C)n1
Temperature: 110 °C

Procedure:
A mixture of {1-[4-(6-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (50 mg) and 1-tert-butoxycarbonyl-3-methylpyrazole-5-boronic acid (44 mg) in dioxane (1 mL) and water (0.43 mL) was placed under argon and [1,1-bis-(diphenylphosphino)-ferrocene]-dichloropalladium-dichlormethane-complex (7.9 mg) added. The mixture was heated at 110° C. under microwave irradiation for 60 minutes. On cooling the mixture was partitioned between DCM and water and extracted. The organic portion was dried and concentrated in vacuo to give the crude title compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6](COCC[Si](C)(C)C)[N:5]=[C:4]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[NH:20][C:21](=O)OC(C)(C)C)[CH:3]=1.FC(F)(F)C(O)=O.COC(OC)N(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[N:5]([CH:21]=[N:20][C:19]3[CH:18]=[CH:17][S:16][C:15]=32)[N:6]=1
Reactant: Cc1cc(-c2sccc2NC(=O)OC(C)(C)C)nn1COCC[Si](C)(C)C
Agent: COC(OC)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c3sccc3ncn2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl [2-(5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-3-thienyl]carbamate (3.2 g, 7.8 mmol) in methylene chloride (23 mL) was added trifluoroacetic acid (23 mL). After stirring at room temperature for 5 h, the solvent was removed. The residue was dissolved in THF (40 mL) and treated with 1,1-dimethoxy-N,N-dimethylmethanamine (1.56 mL, 11.7 mmol). The resulting solution was heated at 80° C. for 1 h. The solvent was removed under reduced pressure. The crude was purified with flash chromatography (eluting with a gradient of 0-20% ethyl acetate in hexanes) to give the desired product as white solid. 1H NMR (300 MHz, CD3OD) δ 9.09 (1H, s), 7.81 (1H, d, J=5.3 Hz), 7.45 (1H, d, J=5.3 Hz), 6.60 (1H, s), 2.49 (3H, s) ppm. LCMS calculated for C9H8N3S (M+H)+: m/z=190.0. Found: 190.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9](C(OC(C)(C)C)=O)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:11])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)Nc1cc(F)ccc1F
Reaction time: 1 h
Yield: 64.1 %

Procedure:
Di-tert-butyl (2,5-difluorophenyl)imidodicarbonate (1.48 g, 4.49 mmol) was dissolved in DCM (15.0 mL) at rt. TFA (0.48 mL, 6.28 mmol) was added to the reaction and the contents were stirred for 1 h. LC/MS at this time shows that starting material has been consumed. The solution was then washed with saturated aqueous sodium bicarbonate. The organics were dried over MgSO4 filtered and concentrated. The crude product was purified on silica gel, eluting with 0-50% EtOAc in hexanes over 32 minutes to afford the title compound (758 mg, 2.88 mmol) as a pale yellow oil. MS (ESI): m/z=174.2 (M+H-[t-Bu]).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH3:34][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:34])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
{2′-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester (0.408 g, 0.88 mmol) was dissolved in THF (4 mL) and cooled to −78° C. Sodium bis(trimethylsilyl)amide (1M in THF; 1.06 mL, 1.06 mmol) was added, followed by iodomethane (0.06 mL, 0.97 mmol), and the reaction was stirred at −78° C. for 30 minutes. The mixture was quenched with saturated aqueous NH4Cl and warmed to room temperature. The mixture was extracted three times with EtOAc, and the combined organic layers were dried, concentrated, and purified by silica gel chromatography (10-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[Br:16])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC([F:25])=CC=1O.BrCC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([F:25])[CH:12]=[CH:11][C:10]=1[Br:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cc(F)ccc1Br
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Agent: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COc1cc(F)ccc1Br
Yield: 95 %

Procedure:
Following the general method as outlined in Intermediate 1, starting from 2-bromo-5-fluorophenol and tert-butyl bromoacetate (Aldrich), the title compound was obtained as a white solid in 95% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14][O:15]CC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[CH:42][C:41]([CH2:44]Br)=[C:40]([F:46])[CH:39]=1>>[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:40]([F:46])[CH:39]=1
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Product: COC(=O)c1ccc(COCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 26, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 1, intermediate c) and 4-bromomethyl-3-fluorobenzoic acid methyl ester (commercially available) to give the compound as light yellow solid (34%). MS (Turbo Spray): m/z=557.4 [M+H].