Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:12]3[C:13]([O:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:14][CH:15]=[CH:16][C:11]=3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:44][CH:45]1[CH2:48][O:47][CH2:46]1>>[O:47]1[CH2:48][CH:45]([NH:44][C:2]2[CH:7]=[C:6]([C:8]3[C:12]4[C:13]([O:17][CH:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)=[N:14][CH:15]=[CH:16][C:11]=4[NH:10][N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:46]1
Reactant: NC1COC1
Reactant: Clc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccnc(OC4CCOCC4)c23)ccn1
Agent: Cl
Product: c1cc(-c2n[nH]c3ccnc(OC4CCOCC4)c23)cc(NC2COC2)n1
Yield: 19 %

Procedure:
Prepared according to the procedure described in Example 111, by reacting 3-(2-chloropyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine with 3-aminooxetane hydrochloride for 70 minutes in Step 1 to give the title compound (13.3 mg, 19% over two steps). LC-MS (Method G): m/z=368.1 [M+H]+; 2.93 min. 1H-NMR (400 MHz, DMSO): δ 13.68 (s, 1H), 8.24 (d, J=7.1, 1H), 7.96-7.91 (m, 1H), 7.63 (s, 1H), 7.54 (d, J=7.1, 1H), 7.24 (d, J=5.4, 1H), 5.55-5.40 (m, 2H), 3.91-3.81 (m, 2H), 3.68-3.46 (m, 5H), 2.18-1.99 (m, 2H), 1.91-1.78 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([OH:23])=[CH:8][C:9]([C:14]3[S:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)=[N:10]2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26](=[O:40])[C@@H:27]1[CH2:31][C@@H:30](O)[CH2:29][N:28]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:23][C@@H:30]3[CH2:29][N:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:27]([C:26]([O:25][CH3:24])=[O:40])[CH2:31]3)=[CH:8][C:9]([C:14]3[S:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: COc1ccc2c(O)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
The 7-methoxy-8-methyl-2-(4-(trifluoromethyl)thiazol-2-yl)quinolin-4-ol BO (10.0 g, 1 eq.), the N-Boc-trans-4-hydroxyproline methyl ester BP (7.20 g, 1 eq.), and the triphenylphosphine (11.56 g, 1.5 eq.) in suspension in THF (250 mL) under N2 were cooled down to 0° C. The DIAD (8.70 mL, 1.5 eq.) was added dropwise. The reaction mixture was allowed to warm up and stir at room temperature for 1.25 hrs, then cooled again at 0° C. and additional 1 more eq. of DIAD was added. The reaction mixture was stirred for 2 hrs at room temperature, and then concentrated in vacuo to 50 mL. Water and ethyl acetate were added and the phases were separated. The aqueous layer was further extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to yield compound BQ (16.75 g, 87% purity). MS (ESI, EI+) m/z=568.3 (MH+); 626.5 (M+OAc−).
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:10]2[NH:9][C:8](=[O:13])[C:7]([CH3:15])([CH3:14])[CH2:6][O:5][C:4]=2[CH:3]=1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][C:7]1([CH3:15])[CH2:6][O:5][C:4]2[CH:3]=[C:2](/[CH:18]=[CH:17]/[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]=[N:11][C:10]=2[NH:9][C:8]1=[O:13]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC1(C)COc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)OCC(C)(C)C(=O)N2
Yield: 87.3 %

Procedure:
A solution of 8-bromo-3,3-dimethyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one (1 g, 3.6 mmol), t-butyl acrylate (1.38 g, 10.8 mmol) and DIPEA (1.86 mL, 10.1 mmol) in DMF (10 mL) was purged with Ar for 10 min. Pd(OAc)2 (81 mg, 0.36 mmol) and P(o-tol)3 (218 mg, 0.72 mmol) were added and the mixture purged again then refluxed overnight. The crude mixture was evaporated in vacuo and chromatographed over silica eluting with methanol/dichloromethane to afford the title compound (1.0 g, 87%). 1H NMR (300 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.26 (s, 1H), 7.77 (s, 1H), 7.47 (d, J=16.1 Hz, 1H), 6.53 (d, J=16.1 Hz, 1H), 4.05 (s, 2H), 1.53 (s, 9H), 1.47 (s, 6H)
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([F:10])[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)=[N+]=[N-].[C:18](Cl)(=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.N1C=CC=CC=1.[Pd]>[CH2:20]([O:19][C:18]([NH:1][C@H:4]1[C@@H:9]([F:10])[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H](N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
A mixture of cis-tert-butyl 3-azido-4-fluoropiperidine-1-carboxylate (1.40 g, 5.73 mmol) and 10% Pd/C (0.61 g, 0.57 mmol) in MeOH (20 mL) was charged 1 atmosphere H2 and stirred at room temperature for 1 hour. The catalyst was removed by filtration and washed with methanol. The filtrate was concentrated in vacuo. The residue obtained was dissolved in pyridine (10 mL) and benzyl carbonochloridate (1.61 mL, 11.46 mmol) was added. The reaction was stirred at room temperature for 2 hours. The pyridine was removed in vacuo, and the residue was dissolved in ethyl acetate (30 mL), washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (hexane:ethyl acetate 3:1) to give cis-tert-butyl 3-(benzyloxycarbonylamino)-4-fluoropiperidine-1-carboxylate (0.44 g, 22%) as a solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:29]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:31]3[CH:32]=[CH:33][S:29][CH:30]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccsc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccsc4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and thiophene-3 carbaldehyde. MS (ESI) m/z 475.
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)[CH3:4].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[CH3:1][NH:2][CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)[CH3:4]
Reactant: CC(C/C=C/c1cccc(F)c1)N(C)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C/C=C/c1cccc(F)c1
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 89.9 %

Procedure:
Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(3-fluorophenyl)-4-penten-2-amine (0.83 g, 2.82 mmol) in anisole (11 mL) was treated drop-wise over 30 min with trifluoroacetic acid (13.32 g, 116.8 mmol). The resulting solution was stirred for 45 min at 0-5° C. The solution was then concentrated by rotary evaporation followed by further drying under high vacuum. The resulting residue was cooled (0-5° C.), basified with 10% NaOH solution (10 mL), treated with saturated NaCl solution (10 mL) and extracted with CHCl3 (5×10 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation, and the residue was further dried under high vacuum to produce a light-yellow oil. The crude product was purified by column chromatography on silica gel (32 g), eluting with CH3OH—MeOH (3:1, v/v) containing 2% Et3N. Selected fractions containing the product (Rf 0.49) were combined and concentrated on a rotary evaporator to give 0.49 g of a light-yellow oil. The oil was purified by column chromatography on silica gel (31.5 g), eluting with CH3OH—NH4OH (100:2, v/v). Selected fractions containing the product (Rf 0.28) were combined and concentrated on a rotary evaporator to a light-yellow oil. The residue was dissolved in CHCl3. The CHCl3 solution was dried (Na2SO4), filtered, concentrated by rotary evaporation and dried under high vacuum to give 262 mg (48.1%) of a light-yellow oil.
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1[C:11](=O)[CH2:12][NH:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[F:23][C:22]([F:25])([F:24])[O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[S:37][C:11]([CH:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[S:1]3)=[CH:12][N:13]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(NCC(=O)C1C=Cc2ccccc2S1)c1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(-c2ncc(C3C=Cc4ccccc4S3)s2)cc1
Yield: 88.4 %

Procedure:
In a manner similar to Step E of Example 1, the reaction of 1.0 g (0.0026 mole) of N-[2-(thianaphthalene-2-yl)-2oxoethyl]-4-trifluoromethoxybenzamide with 0.53 g (0.0013 mole) of Lawesson's reagent in 25 ml of toluene yielded 0.45 g of 2-(4-trifluoromethoxyphenyl)-5-(thianaphthalene-2-yl)thiazole as a solid, mp 65-69, compound 40 of Table 1.
Reaction SMILES: C(Br)(Br)(Br)[Br:2].[C:6]1([C:12]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21]O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:6]1([C:12]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH:20]([Br:2])[CH3:21])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(Br)OCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of carbon tetrabromide (8.3 g, 25 mmol) and 10 g of 2-[2-(2-triphenylmethoxyethoxy)ethoxy]ethanol are stirred together in 75 mL dichloromethane at 0° C. To this solution is added a solution of 6.7 g triphenylphosphine (25 mmol) in 75 mL dichloromethane dropwise over 1½ hours at 0° C. After stirring for an additional 2 hours, the solution is evaporated to dryness and the residual solids are resuspended in 150 mL diethyl ether. The triphenylphosphine by-product is removed via vacuum filtration and the product is then purified via column chromatography over silica gel, eluting with dichloromethane.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]1([CH2:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:16])[CH:13]=[CH:12][N:11]=[CH:10]1>CCOCC.O1CCCC1>[OH:16][C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:14][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=C1CCc2cc(C(=O)Cn3ccnc3)ccc2N1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1CCc2cc(C(O)(Cn3ccnc3)c3ccccc3)ccc2N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3 ml of 3M phenylmagnesium bromide in ether was added to a suspension of 1.0 g of 6-(imidazol-1-yl acetyl)-3,4-dihydrocarbostyril in 25 ml of tetrahydrofuran at 0° C., the mixture stirred for 30 minutes at 0° C., then at 25° C. for 18 hours. The reaction was quenched with 10 ml of water and extracted with 10% methanol in methylene chloride. The organic extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield a gum which was chromatographed on silica gel, eluting with 5% methanol in methylene chloride, to give 6-[1-hydroxy-1-phenyl-2-(imidazol-1-yl)ethyl]-3,4-dihydrocarbostyril as a foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:16]([CH2:20][C:21](Cl)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:7][CH2:8][N:9]([C:21](=[O:22])[CH2:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CCOC)CCN(C(=O)CC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
To a solution of 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.646 g) under an argon atmosphere were added triethylamine (0.668 g, 0.92 ml) and tert-butyl acetyl chloride (0.44 g, 0.45 ml) under ice cooling. The reaction mixture was stirred at RT for 3 h. It was then partitioned between methylene chloride and aqueous 1M HCl, the layers were separated and the aqueous layer washed with 2M aqueous KHCO3 and dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 50%) to give 1-(3,3-Dimethyl-butyryl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, (0.46 g) as a light yellow solid. MS (ESI): 314 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14](Cl)=[O:15].[OH:22][CH2:23][CH2:24][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([O:22][CH2:23][CH2:24][CH2:25][C:26](=[O:27])[N:28]([CH3:30])[CH3:29])=[O:15]
Reactant: CC(OCc1ccc2ccccc2c1)(C(=O)Cl)C(F)(F)F
Reactant: CN(C)C(=O)CCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)CCCOC(=O)C(C)(OCc1ccc2ccccc2c1)C(F)(F)F
Reaction time: 48 h
Yield: 34.5 %

Procedure:
A solution of (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride (3.0 g.) in tetrahydrofuran (70 ml.) is added, dropwise at 0° C., to a stirred solution of 4-hydroxy-N,N-dimethylbutyramide (1.20 g.) and triethylamine (2.1 g.) in tetrahydrofuran (35 ml.). The mixture is stored for two days. The solid is filtered off and washed with ether, and the filtrate and washings are evaporated. The residue is dissolved in ether and the solution is washed with water, 0.4 N aqueous sodium hydroxide, and water, dried with magnesium sulphate, and evaporated. The residue is crystallised from a mixture of light petroleum (b.p. 40°-60° C.) and ether to give (±)-3-dimethylcarbamoylpropyl 2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate (1.3 g.) m.p. 42°-43° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]#[N:16].C(=O)(O)[O-:18].[Na+]>OS(O)(=O)=O>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:8]([F:14])=[CH:9][CH:10]=[CH:11][C:12]=2[F:13])=[N:4][C:3]=1[C:15]([NH2:16])=[O:18]
Reactant: O=C([O-])O
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1Br
Yield: 94 %

Procedure:
A solution of 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (0.010 g, 0.04 mmol) in concentrated H2SO4 (0.4 mL) was stirred at room temperature for 4 hours. The reaction was neutralised with saturated sodium bicarbonate solution and extracted with EtOAc. The organic phase was dried over MgSO4 and the solvent removed in vacuo to afford 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.010 g, 0.03 mmol, 94%) as a white solid. 1H NMR (CDCl3) δ 5.79 (1H, br. s), 6.95 (1H, br. s), 7.07 (2H, t), 7.49 (1H, m). LCMS (1) Rt: 1.59 min; m/z (ES+) 303/305.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Br:14][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(F)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)C(Br)c1ccc(F)cc1Cl
Temperature: 80 °C

Procedure:
Methyl 2-chloro-4-fluorophenylacetate (3.15 g, 15.6 mmol), N-bromosuccinimide (2.77 g, 15.6 mmol) and AIBN (255 mg, 1.56 mmol) were suspended in benzene (50.0 mL) and degassed via N2 stream. The resulting mixture was heated to 80° C. for 12 h. After cooling to rt, the mixture was partially concentrated in vacuo and partitioned between ether and water. The layers were separated, and the organic layer was washed with water and brine. The organics were dried (MgSO4), filtered and concentrated in vacuo. The resulting crude oil was purified by flash chromatography on silica gel (gradient elution; 0%-20% EtOAc/hexanes as eluent) to afford the title compound i-1a. 1HNMR (500 MHz, CDCl3): δ 7.82 (dd, 1H, J=6.0, 8.8 Hz), 7.17 (dd, 1H, J=2.6, 8.3 Hz), 7.08 (m, 1H), 5.88 (s, 1H), 3.84 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:48]([C:51]1[CH:56]=[CH:55][C:54]([N:57]2[CH2:61][CH2:60][CH:59]([C:62](O)=[O:63])[C:58]2=[O:65])=[CH:53][CH:52]=1)([CH3:50])[CH3:49]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:62]([CH:59]1[CH2:60][CH2:61][N:57]([C:54]2[CH:55]=[CH:56][C:51]([CH:48]([CH3:49])[CH3:50])=[CH:52][CH:53]=2)[C:58]1=[O:65])=[O:63]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CC(C)c1ccc(N2CCC(C(=O)O)C2=O)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CC(C)c1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1
Yield: 32.3 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.036 g; 0.146 mmol), PyBOP (0.113 g; 0.219 mmol), N,N-diisoprpylethylamine (0.075 mL; 0.437 mmol) and 1-(4-isopropylphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.425 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.020 g (32%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[OH:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17].Cl>[N+](C1C=CC=CC=1)([O-])=O>[OH:9][C:7]1[CH:8]=[C:2]([OH:1])[C:3]([OH:4])=[CH:5][C:6]=1[C:14]([CH2:15][CH:16]([CH3:18])[CH3:17])=[O:19]
Reactant: CC(C)CC(=O)Cl
Reactant: Oc1ccc(O)c(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)CC(=O)c1cc(O)c(O)cc1O
Temperature: 25 °C
Yield: 87 %

Procedure:
In a vessel fitted with a calcium chloride tube, 12.61 g (100.0 mmol) of hydroxyhydroquinone (2) was suspended in 110 ml of nitrobenzene and stirred at room temperature. Into this, 40.0 g (300 mmol, 3.00 equivalents) of granular aluminum chloride was added piecemeal. They were further stirred for one hour and then 12.06 g (100.0 mmol, 1.00 equivalent) of isovaleryl chloride was slowly added dropwise. As the reaction mixture became a reddish purple amorphous solid 10 hours after the addition, it was mechanically crushed into fine fragments. The fine fragments were poured into 500 ml of a cold 2 M hydrochloric acid solution, stirred for 30 minutes, and extracted from ether. The ether layer was washed with water, distilled to remove the solvent, combined with a large volume of water, and distilled water under reduced pressure to remove nitrobenzene by steam distillation method. The residue of the distillation was dissolved in ether, washed with saturated brine, dried over sodium sulfate, distilled under a reduced pressure to remove ether and obtain a crude reaction product. By recrystallizing the crude product from hexane-petroleum ether (2:1), 18.3 g (yield 86.6%) of the product (7) was obtained in the form of reddish purple crystals of thin needles.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][N:10](C(OCC)=O)[CH2:9][C@H:8]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)N1CC[C@H](Oc2ccc(Br)cc2)[C@H](c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Product: Brc1ccc(O[C@H]2CCNC[C@H]2c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 7.28 g of cis-4-(4-bromophenoxy)-1-ethoxycarbonyl-3-phenylpiperidine, 48 ml of 20% aqueous sodium hydroxide solution and 90 ml of absolute ethanol is refluxed overnight under nitrogen. The mixture is cooled and partitioned between 50 ml of water and 100 ml of ether. The aqueous phase is extracted with ether (100 ml), and the combined organic phases are concentrated in vacuo. The resulting solid is dissolved in dichloromethane (100 ml) and washed with saturated sodium chloride solution. After drying over anhydrous sodium sulfate, filtration and concentration in vacuo affords a nearly colorless solid. The solid is dissolved in 200 ml of boiling hexane and the solution is reduced after boiling down in volume to about 150 ml. The solution is filtered, allowed to cool to room temperature and refrigerated overnight to afford product as a nearly colorless, crystalline solid, mp 113°-115° C.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[N:11][C:10]=2[CH:9]=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1.CN1CC[N:30]([C:33](=O)[CH:34]=[CH:35]C2C3N(C4C=CC=CC=4)C=NC=3C=C(C(F)(F)F)C=2)CC1>>[C:15]1([N:13]2[C:14]3[C:6]([CH:5]=[CH:4][C:3]([NH:30][CH2:33][CH2:34][CH3:35])=[O:2])=[CH:7][C:8]([C:21]([F:22])([F:23])[F:24])=[CH:9][C:10]=3[N:11]=[CH:12]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN1CCN(C(=O)C=Cc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)CC1
Reactant: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Product: CCCNC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12

Procedure:
This was prepared from 3-(3-phenyl-6-trifluoromethyl-3H-benzoimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one. The oily residue was purified by preparative LCMS to afford, after removal of the solvent, the title compound as a white solid (16 mg, 6%), m/z 374.0 (M+H)+.