Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]([C:21]1[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[C:23]([CH3:35])[CH:22]=1)([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=1)[CH2:11][CH3:12])[CH3:9].[C:36]([C:38]1([OH:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)#[CH:37]>C(#N)C>[CH2:8]([C:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=1)([C:21]1[CH:26]=[CH:25][C:24]([C:37]#[C:36][C:38]2([OH:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:23]([CH3:35])[CH:22]=1)[CH2:11][CH3:12])[CH3:9]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: C#CC1(O)CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCCCC2)c(C)c1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 63.3 %

Procedure:
Triethylamine (8.0 mL, 57.6 mmol), tetrakistriphenylphosphine palladium (2.2 g, 1.92 mmol) and cuprous iodide (0.36 g, 1.92 mmol) were added to a solution of trifluoromethanesulfonic acid 4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl ester (Example 1-(1); 8.0 g, 19.2 mmol) and 1-ethynyl-cyclohexanol (3.5 g, 28.8 mmol) in acetonitrile (96 mL), and the mixture was stirred at 110° C. for 1.5 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=4/1) to give the title compound (4.75 g, 63%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]3[O:17][C:15](=[O:16])/[C:14](=[CH:27]/[C:26]4[CH:29]=[CH:30][C:23]([O:22][C:21]([F:20])([F:31])[F:32])=[CH:24][CH:25]=4)/[N:13]=3)=[CH:18][CH:19]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Product: O=C1OC(c2ccc(OCCC3CC3)cc2)=N/C1=C\c1ccc(OC(F)(F)F)cc1

Procedure:
A reaction similar to that described in Example 1 (1c) was conducted using N-[4-(2-cyclopropylethoxy)benzoyl]glycine (150 mg) prepared in Example 1 (1b) and 4-(trifluoromethoxy)benzaldehyde (90 μL) to give (4Z)-2-[4-(2-cyclopropylethoxy)phenyl]-4-[4-(trifluoromethoxy)benzylidene]-1,3-oxazol-5(4H)-one (176 mg). A reaction similar to that described in Example 1 (1d) was conducted using 80 mg of this given compound to give 74 mg of 4-(2-cyclopropylethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide (white powder).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[C:14]1([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Ic1ccccc1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2ccc3[nH]ccc3c2)cc1
Temperature: 100 °C
Yield: 67.9 %

Procedure:
A mixture of indole-5-boronic acid (2.0 g, 12.4 mmole); iodobenzene (2.48 g, 12.2 mmole), tetrakis(triphenylphosphine) palladium (0) (288 mg, 0.25 mmole), sodium carbonate (4.34 g, 40.9 mmole) in water (20 ml), and dioxane (20 ml) was stirred under an argon atmosphere and heated to 100° C. for 5 hrs, cooled to room temperature, acidified with 1M HCl, extracted, washed, dried, and evaporated. The residue was purified by chromatography to give about 1.6 g of 5-phenyl-1H-indole, mp. 72-74° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([CH2:14][OH:15])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH:9]2[OH:23])=[CH:4][CH:3]=1.[C:24]1([C:30]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)Cl)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:13]([CH2:14][O:15][C:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:10][CH:9]2[OH:23])=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(c2ccc(Br)cc2)C(CO)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(O)C(c2ccc(Br)cc2)C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Yield: 84.1 %

Procedure:
A solution of 735 mg (1.91 mmol) of tert-butyl (3RS,4RS,5SR)-4-(4-bromo-phenyl)-3-hydroxy-5-hydroxymethyl-piperidine-1-carboxylate, 766 mg (2.75 mmol) of triphenylchloromethane and 324 mg (3.20 mmol) of triethylamine in 8 ml of methylene chloride was stirred at room temperature for 15 hours. For the working-up, the reaction mixture was evaporated under reduced pressure and the crude product was chromatographed directly on silica gel using methylene chloride as the eluent. There were obtained 1.01 g (84.5% of theory) of tert-butyl (3RS,4RS,5SR)-4-(4-bromo-phenyl)-3-hydroxy-5-trityloxymethyl-piperidine-1-carboxylate as a colourless foam; MS: 646 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[C:17](=O)[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:46])([F:45])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39](=[O:44])/[CH:40]=[C:41](\[NH2:43])/[CH3:42])[CH2:35][CH2:34]1>C(O)(C)C>[F:46][C:24]([F:23])([F:45])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]([C:40]2[CH:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]([N+:20]([O-:22])=[O:21])=[C:17]([CH3:18])[NH:43][C:41]=2[CH3:42])=[O:44])[CH2:37][CH2:38]1
Reactant: C/C(N)=C/C(=O)N1CCN(CCc2ccccc2C(F)(F)F)CC1
Reactant: CC(=O)C(=Cc1ccccc1OCc1ccccc1)[N+](=O)[O-]
Solvent: CC(C)O
Product: CC1=C(C(=O)N2CCN(CCc3ccccc3C(F)(F)F)CC2)C(c2ccccc2OCc2ccccc2)C([N+](=O)[O-])=C(C)N1

Procedure:
2.97 g (10 mmol) of 1-(-2-benzyloxyphenyl)-2-nitro-1-buten-3-one and 2.96 g (mmol) of 3-aminocrotonic acid 4-(2-trifluoromethylphenylethyl)piperazide are heated in 15 ml of isopropanol at 60° C. for 4 hours. After cooling, a crude product is obtained, and this is recrystallized from a littel ethanol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:16]([F:27])[CH:15]=2)=[N:4][C:5]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[CH:6][N:7]=1.C(Cl)Cl.[H][H]>CO.[Pd]>[NH2:1][C:2]1[C:3]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[C:16]([F:27])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3=CCOCC3)cnc2N)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 29.8 %

Procedure:
To a suspension of tert-butyl 4-(3-amino-6-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoate (15 g, 40.4 mmol) in MeOH (800 mL) was added DCM (100 mL) until the suspension turned to a homogeneous solution. After degassed by N2 stream for 15 min, Pd/C (10 g, 9.40 mmol) was added to the reaction mixture. To this mixture, hydrogen balloon was equipped after flushed with hydrogen gas three times. The reaction mixture was stirred for 6 h. After the reaction mixture was filtered through Celite® pad, the volatile materials were removed in vacuo. The residue was dissolved in MeOH (200 mL) by heating and cooling down to room temperature and standing overnight. The brown precipitate was filtered off, which afforded 4.5 g of tert-butyl 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoate. The filtrate was concentrated and dissolved in EtOH (200 mL) by heating. The second brown precipitate was filtered off to afford 3.9 g of tert-butyl 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoate (55.7% combined yield). LCMS (m/z): 374.7 (MH+), 0.90 min.
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][OH:6].Cl[CH2:11][C:12](OCC)=[O:13].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH:7]([C@H:4]1[NH:3][C:12](=[O:13])[CH2:11][O:6][CH2:5]1)([CH3:9])[CH3:8]
Reactant: CC(C)[C@@H](N)CO
Reactant: CCOC(=O)CCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1COCC(=O)N1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
To an ice cold, stirred suspension of sodium hydride (60% in oil, 1.6 g, 40.0 mmol) in toluene (52 mL) was added dropwise a solution of (R)-2-amino-3-methylbutan-1-ol (1.8 g, 17.0 mmol) in toluene (38 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (8 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 40.0 mmol) added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 95:5 dichloromethane/methanol) to give (R)-5-isopropylmorpholin-3-one (1.7 g, 68%) as a light yellow solid.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[C:11]([Cl:15])[CH:12]=[CH:13][C:14]=3[C:6]=2[C:5]([OH:16])=[N:4][CH:3]=1.[CH3:17][N:18]1C(=O)CCC1>>[OH:16][C:5]1[C:6]2[C:14]3[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=3[NH:8][C:7]=2[C:2]([C:17]#[N:18])=[CH:3][N:4]=1
Reactant: Oc1ncc(Br)c2[nH]c3cc(Cl)ccc3c12
Reactant: CN1CCCC1=O
Product: N#Cc1cnc(O)c2c1[nH]c1cc(Cl)ccc12

Procedure:
The title compound was prepared from 4-bromo-7-chloro-5H-pyrido[4,3-b]indol-1-ol using the same procedure as described in example 5 step 3 except that the reaction was refluxing in NMP for 2 h.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH:7]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH2:22])[C:16]=1[N+:23]([O-:25])=[O:24])C(OC(C)(C)C)=O)(C)(C)C.O>Cl.O1CCOCC1>[NH2:22][C:17]1[C:16]([N+:23]([O-:25])=[O:24])=[C:15]([CH2:7][C:6]([OH:26])=[O:5])[CH:20]=[C:19]([F:21])[CH:18]=1
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)cc(N)c1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(F)cc(CC(=O)O)c1[N+](=O)[O-]
Temperature: 40 °C

Procedure:
To the 2-(3-Amino-5-fluoro-2-nitro-phenyl)-malonic acid di-tert-butyl ester (140 g) in 500 mL of 4N HCl in dioxane was added 50 mL of water and heated to 40° C. for 2 days. The solution was extracted with ethyl acetate (3×'s) and the ethyl acetate washed with water (3×'s) and brine. The organic fraction was dried over MgSO4 and was concentrated to give 78 g of crude (66% pure by LC/MS); 1H NMR (500 MHz, DMSO) δ 12.40 (brs, 1H), 7.04 (s, 2H), 6.68 (dd, J=10.9 2.8 Hz, 1H), 6.47 (dd, J=10.9, 2.8 Hz, 1H), 3.80 (s, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[BH4-].ClCCl.[CH3:28][OH:29]>>[CH3:28][O:29][C:9]1[CH:8]=[CH:7][C:12]([CH2:4][NH:1][C@@H:2]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[CH:11][CH:10]=1
Reactant: CO
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Agent: [BH4-]
Solvent: ClCCl
Product: COc1ccc(CN[C@H](Cc2c[nH]c3ccccc23)c2nc(-c3ccccc3)c[nH]2)cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
2-{(1R)-1-Amino-2-[indol-3-yl]ethyl}-4-pheny-1H-imidazole (36.3 mg, 0.12 mmol) and panisaldehyde (12 μL, 0.1 mmol) in 1 mL of methanol were shaken for about 2 hours at about 22° C. Borohydride resin (76 mg, 2.5 mmol/g, AMBERLITE® IRA400) was then added and the slurry was stirred overnight before addition of dichloromethane (1 mL) and aldehyde Wang resin (31 mg, 3.22 mmol/g, Novabiochem). After about 8 hours of stirring, the slurry was then filtered and vaporated in vacuo to give a yellow solid (32.2 mg, 76%). 1H-NMR (CDCl3, 100 MHz) δ: 8.86 (br s, 1H); 7.73-6.68 (m, 15H); 4.62 (s, 1H); 4.33 (dd, J=4.7 and 8.5 Hz, 1H); 3.81 (s, 2H); 3.74 (s, 3H); 3.27 (ABX system, 2H); 2.26 (s, 1H). LC/MS: m/z=423 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1>C1COCC1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH2:12][CH2:13][S:14][CH2:15][CH2:16]1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(N2CCSCC2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(N2CCSCC2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenyl)thiomorpholine (4.00 g, 16.51 mmol) in THF (50 mL) was added Pd/C (1.30 g). The reaction mixture was stirred at rt under H2 for 12 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound as an offwhite solid (3.40 g, 97%).
Reaction SMILES: O=[C:2](C)CCC#CCCCCO.OS(O)(=O)=O.[O:18]=[C:19]([CH3:30])[CH2:20][CH2:21][C:22]#[C:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]>CO>[CH3:2][O:28][C:27](=[O:29])[CH2:26][CH2:25][CH2:24][C:23]#[C:22][CH2:21][CH2:20][C:19](=[O:18])[CH3:30]
Reactant: CC(=O)CCC#CCCCC(=O)O
Reactant: CC(=O)CCC#CCCCCO
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)CCCC#CCCC(C)=O

Procedure:
The Heather synthesis of 2-(6-carboxy-2-cis-hexynyl)-cyclopentane-1,3,4-trione implicitly includes a process for preparing 9-oxo-5-decynoic acid (I; n=3, R=H). Table A provides a synopsis of that synthesis which consists of: first treating 2-methyl-2-(3-butynyl)-1,3-dioxolane, III, with lithium amide in liquid ammonia and then with 1-bromo-4-tetrahydropyranyloxybutane, IV, in tetrahydrofuran to obtain 2-methyl-2-(8-pyranyloxy-3-oxtynyl)-1,3-dioxolane, V; hydrozyling V to 9-oxo-5-decyn-1-ol, VI; oxidizing VI with Jones's reagent (CrO3, H2SO4) to 9-oxo-5-decynoic acid; esterifying the latter with methanol under acidic catalyss to obtain methyl-9-oxo-5-decynoate, VII; hydrogenating VII over Pd/BaSO4 (Lindlar's catalyst) in quinoline to get methyl 9-oxo-5-cis-decenoate, VIII; condensing VIII with diethyl oxalate in the presence of sodium ethoxide in ethanol to obtain 2-(6-carbomethoxy-2-cis-hexenyl)-5-(ethoxyalkyl)-cyclopentane-1,3,4-trione, IX; and hydrolyzing IX under acidic conditions to obtain 2-(6-carboxy-2-cis-hexenyl)-cyclopentane-1,3,4-trione (II: n=3: R= H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH2:14][C:15](OCC)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH2:14][CH2:15][OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1nccn1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCCCc1nccn1Cc1ccccc1
Yield: 105.7 %

Procedure:
A solution of 1-benzyl-2-(2-carbethoxyethyl)imidazole (5.2 g) in dry ether (150 ml) is added, dropwise, to a stirred suspension of aluminum lithium hydride (1.0 g) in dry ether (150 ml) at gentle reflux. The suspension is subsequently heated under reflux for 2 hours, and then cooled during the successive addition of water (1 ml), 15% sodium hydroxide (1 ml) and water (3 ml). After heating under reflux for 0.5 hour and filtration, the insoluble solid is extracted with hot methanol (3 × 100 ml). The combined organic extracts are concentrated under reduced pressure and the residue dissolved in 2N hydrochloric acid. Following extraction with chloroform, the solution is basified with solid potassium carbonate. Chloroform extracts of the basic solution are dried over sodium sulphate and concentrated under reduced pressure, affording 1-benzyl-2-(3-hydroxypropyl) imidazole as a colourless viscous liquid (4.6 g). The carbinol (4.4 g) is dissolved in benzene (40 ml) and added to thionyl chloride (20 ml) at reflux temperature. After complete addition, water (four drops) is added and the mixture is heated under reflux for 0.5 hour. Concentration followed by the addition of cyclohexane yields a yellow solid. Recrystallization from ethanol-ether yields 1 -benzyl-2-(3-chloropropyl)imidazole hydrochloride, m.p. 162°-164° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[S:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[F:15][C:16]1[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>>[F:15][C:16]1[CH:25]=[C:24]([NH:26][C:12]([C:6]2[S:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: CC(C)c1cc(C(=O)O)sc1C(C)C
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cc1F
Yield: 32.8 %

Procedure:
In the same manner as that of Example 24, 4,5-diisopropylthiophene-2-carboxylic acid (80 mg, 0.377 mmol) and methyl 2-fluoro-4-aminobenzoate (115 mg, 0.680 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [n-hexane-ethyl acetate (40:1)] and recrystallized to obtain methyl 2-fluoro-4-[(4,5-diisopropylthiophene-2-carbonyl)amino]benzoate (45 mg, 33%) as colorless prisms.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([S:21][CH3:22])[O:20][C:16]=2[CH:15]=1.O>CN(C=O)C>[N:1]1[C:5]2[C:4](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:3]([CH2:13][C:14]2[CH:24]=[CH:23][C:17]3[N:18]=[C:19]([S:21][CH3:22])[O:20][C:16]=3[CH:15]=2)[CH:2]=1
Reactant: CSc1nc2ccc(CCl)cc2o1
Reactant: c1cnc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cccnc43)cc2o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38.4 %

Procedure:
To a stirred solution of 4-azabenzimidazole (304 mg, 2.55 mmol) in anhydrous DMF (10 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 107 mg, 2.68 mmol) and the mixture was stirred at 0° C. for 20 min. The mixture was allowed to warm to rt and stirred for a further 20 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (600 mg, 2.81 mmol) from Step 3 of this Example in DMF (5 mL). The mixture was stirred at rt for 15 h. To the reaction mixture was added water and the mixture was extracted with DCM. The combined organic layers were washed with brine. The organic layer was separated, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography eluting with 100% DCM followed by 1% MeOH in DCM to afford 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (290 mg, 38%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.38 (dd, J=1.2, 4.6 Hz, 1H), 8.10 (dd, J=1.2, 8.0 Hz, 1H), 7.69 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.25-7.41 (m, 2H), 5.61 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 297 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].Br[C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][C:39]=1[O:45][C:46]([F:49])([F:48])[F:47].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:36])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:38]3[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][C:39]=3[O:45][C:46]([F:47])([F:48])[F:49])=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
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
Reactant: Nc1ccc(Br)c(OC(F)(F)F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(N)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C
Yield: 53 %

Procedure:
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 (1.80 g, 3.63 mmol) and 4-bromo-3-trifluoromethoxy-phenylamine (1.00 g, 3.90 mmol) dissolved in toluene (5.4 mL) and water (2.7 mL) was added potassium carbonate (2.50 g, 18.1 mmol). The reaction mixture was sparged with nitrogen. Tetrakis(triphenylphosphine)-palladium(0) (0.21 g, 0.18 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 100° C. in a sealed tube overnight, diluted in ethyl acetate (100 mL) and washed with water, brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to produce a red paste (6.5 g), which was purified by silica gel chromatography (120 g silica, 0-3% MeOH/DCM) to provide the title intermediate (1.05 g) and a second fraction which was purified by reverse phase HPLC to provide the di-TFA salt of the title intermediate (800 mg). (Total yield 80%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:14].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(N(CC)CC)C.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[N:4]=[C:3]1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: Cc1ccc(N2CC(C)C(=O)N2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(N2CC(C)C(O[Si](C)(C)C(C)(C)C)=N2)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a stirred solution under nitrogen of 4-methyl-1-p-tolyl-3-pyrazolidinone (19.0 g, 0.10 mole) and t-butyldimethylsilyl chloride (16.6 g, 0.11 mole) in 200 ml toluene, was added sequentially triethylamine (10.6 g, 0.11 mole), 1,8-diazabicyclo- [5.4.0]-undec-7-ene (0.1 g), and 4-(N,N-dimethylamino) pyridine (0.1 g). The mixture was refluxed for 16 hours, cooled to room temperature and filtered. The salts were washed with ether and the solvents of the combined filtrate were removed under reduced pressure. The resulting residue was treated with 200 ml adhydrous ether, filtered to remove salts, and dried over anhydrous magnesium sulfate. Removal of the solvent yielded 29.8 g (98% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:15])=[O:4].[C:16](=O)([O-])[O-].[K+].[K+].IC.CN(C=O)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7]([CH3:16])[C:6]=1[CH3:15])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(C)[nH]c2cc(Cl)ccc12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)n(C)c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A mixture of 6-chloro-2-methyl-1H-indole-3-carboxylic acid methyl ester (2.76 g, 12.3 mmol), potassium carbonate (6.80 g, 49.2 mmol), iodomethane (1.07 mL, 17.2 mmol) and DMF (36 mL) is stirred overnight at room temperature. The mixture is diluted with ethyl acetate, washed twice with water, washed with brine and dried (MgSO4) and concentrated. The residue is triturated in 25 mL of 1:3 ethyl acetate-heptane and filtered to provide 1.63 g (55%) of pure title product. Additional material can be obtained through further trituration of the mother liquor. ES/MS m/e 238.0 (M+1).