Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Brc1ccc(Br)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 74.2 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g, 10 mmol), and 1,4-dibromobenzene (11.8 g, 50 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.02 g (74%) of the product 4-(3-bromo-phenyl)-1H-indole as a white solid.
Reaction SMILES: C([N:14]1[N:18]=[N:17][C:16]([C:19]2[CH:24]=[C:23]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([CH3:35])=[CH:27][CH:26]=3)[CH:22]=[C:21]([C:36]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:39]([CH3:46])=[CH:38][CH:37]=3)[CH:20]=2)=[N:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:46][C:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:36]([C:21]2[CH:20]=[C:19]([C:16]3[N:15]=[N:14][NH:18][N:17]=3)[CH:24]=[C:23]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([CH3:35])=[CH:27][CH:26]=3)[CH:22]=2)=[CH:37][CH:38]=1
Reactant: Cc1ccc(-c2cc(-c3nnn(C(c4ccccc4)c4ccccc4)n3)cc(-c3ccc(C)c4ccccc34)c2)c2ccccc12
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cc(-c3nn[nH]n3)cc(-c3ccc(C)c4ccccc34)c2)c2ccccc12
Reaction time: 8 h
Yield: 95.5 %

Procedure:
2-Benzhydryl-5-(3,5-bis(4-methylnaphthalen-1-yl)phenyl)-2H-tetrazole (0.32 g, 0.54 mmol) was dissolved in dichloromethane (2 mL). Anisole (0.3 mL, 2.76 mmol) and TFA (1 mL) were added sequentially. The reaction was stirred overnight, and then concentrated. The residue was purified by flash chromatography (hexane:ethyl acetate:AcOH=30:10:1) to afford 0.22 g (95.5%) of product as a white solid, 1H NMR (DMSO, 500 MHz) δ 8.24 (d, J=1.55 Hz, 2H), 8.25 (d, J=8.15 Hz, 2H), 8.03 (d, J=8.20 Hz, 2H), 7.72 (s, 1H), 7.65 (t, J=7.58 Hz, 2H), 7.60 (t, J=7.44 Hz, 2H), 7.56 (d, J=7.15 Hz, 2H), 7.51 (d, J=7.29 Hz, 2H), 2.74 (s, 6H); 13C NMR (DMSO, 125 MHz) δ 141.58, 136.38, 134.51, 133.81, 132.43, 130.72, 127.15, 127.03, 126.51, 126.32, 126.11, 125.61, 124.76.19.21.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[C:5]=1[F:19].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]([F:19])=[C:6]2[C:7]([CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[NH:10]2)=[CH:8][CH:9]=1)=[O:20]
Reactant: COC(=O)c1cccc(N=Cc2cccc(Br)c2)c1F
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1F)NC(c1cccc(Br)c1)C(C)(C)C2O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a stirred mixture solution of 3-[(3-bromo-benzylidene)-amino]-2-fluoro-benzoic acid methyl ester (51.7 g, 153.8 mmol) and ytterbium(III) triflate hydrate (14.3 g, 23.1 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (14 mL, 153.8 mmol) and water (2.8 mL, 153.8 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-8-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (63.0 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrFNO3 (M+H)+: 409.27, observed: 390.0 & 392.0.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3](Cl)=[O:4].[CH2:9]([O:11][C:12]#[CH:13])[CH3:10].C(N(CC)CC)C>CCOCC>[CH2:12]([O:11][C:9]1[C:2]([CH3:1])([CH2:6][CH2:7][CH3:8])[C:3](=[O:4])[CH:10]=1)[CH3:13]
Reactant: CCCC(C)C(=O)Cl
Reactant: C#COCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCC1(C)C(=O)C=C1OCC
Yield: 77 %

Procedure:
The title compound was prepared using a modification of the method of Wasserman, H. H. et al [J. Org. Chem, 38, 1451-1455, (1973)]; to a solution of 2-methyl pentanoyl chloride (3.91 ml) and ethyl ethynylether (5 g, 40% solution in hexanes, 28.6 mmol) in Et2O (35 ml) at room temperature was added triethylamine (9.9 ml), with stirring. The reaction was warmed to 50° and stirred for 72 h prior to cooling and filtration. The filtrate was concentrated in vacuo and the residual oil chromatographed (SiO2; hexanes 80:EtOAc 20) to give the title compound as a colourless oil (3.71 g, 17.9 mmol, 77%). δH (CDCl3, 300K), 4.84 (1H, s), 4.24-3.98 (2H, m), 2.04 (3H, s), 1.56-1.43 (4H, m), 1.30-1.26 (3H, m), 0.91 (3H, t, J 7.3 Hz). m/z (ES+, 70V) 178.1 (MH+).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([NH:17]C(=O)C)[CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[C:7](=[O:21])[CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[C:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([NH2:17])[CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[C:7](=[O:21])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(NC(C)=O)c2c1CC(NC(C)=O)CC2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(N)c2c1CC(NC(C)=O)CC2=O
Temperature: 60 °C

Procedure:
102 mg of the compound prepared in (4) above was charged into 20 ml of 3N hydrochloric acid aqueous solution, and the mixture was heated at 60° C. for 2 hours while stirring. After cooling to 0° C., the reaction mixture was neutralized with sodium carbonate and extracted with chloroform. The extract was dried over magnesium sulfate, and subjected to silica gil column chromatograghy using an chloroform-methanol (40:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 66 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=2[CH:13]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>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.CCO>[OH:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=3[CH:13]=2)=[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=1
Reactant: Oc1ccc(-c2cc3cc(O)ccc3o2)c(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: Oc1ccc(-c2cc3cc(O)ccc3o2)c(-c2ccccc2)c1
Yield: 47.9 %

Procedure:
Compound 102 (0.2 g, 0.69 mmol) in a solution consisting of Tol/EtOH/2M Na2CO3 aq (5/1/5) was treated with phenylboronic acid (0.12 g, 1.0 mmol) and cat Pd(PPh3)4 and heated to reflux until TLC analysis indicated complete reaction. The reaction was worked up by acidifying with 2 N HCl aq and extracting with EtOAc. The organic layer was washed with saturated NaHCO3 aq, brine, and dried over MgSO4. After filtering and concentrating, the crude material was chromatographed on silica gel (1:9 EtOAc/hexanes to 4:6 EtOAc/hexanes) and then triturated with hexanes to yield 0.10 g of the desired material: Mp=167-170° C.; 1H NMR (DMSO-d6) δ 9.98 (br s, 1 H), 9.07 (br s, 1 H), 7.68 (d, 1 H, J=8.5 Hz), 7.4-7.38 (m, 3 H), 7.26-7.22 (m, 2 H), 7.18 (d, 1H, J=8.7 Hz), 6.90 (dd, 1 H, J=8.5 Hz, 2.5 Hz), 6.72 (d, 1 H, J=2.5 Hz), 6.67 (d, 1 H, J=2.3 Hz), 6.62 (dd, 1 H, J=8.7 Hz, 2.4 Hz), 5.81 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=1.[C:17](#[N:21])[CH:18]([CH3:20])[CH3:19].C(#N)C.C(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[CH3:15][C:13]1([CH3:16])[CH2:12][O:11][C:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([C:18]([CH3:20])([CH3:19])[C:17]#[N:21])=[CH:7][C:2]=2[F:1])=[N:14]1
Reactant: CC(C)C#N
Reactant: Cc1cc(F)cc(F)c1C1=NC(C)(C)CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1cc(C(C)(C)C#N)cc(F)c1C1=NC(C)(C)CO1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
A flask containing a solution of 2-(2,4-difluoro-6-methylphenyl)-4,4-dimethyl-4,5-dihydrooxazole (14.84 g, 65.9 mmol) and isobutyronitrile (9.11 g, 132 mmol) in dry tetrahydrofuran (130 ml) was cooled to −15 to −20° C. (acetonitrile/dry ice bath) under an argon atmosphere. A solution of potassium bis(trimethylsily) amide (171 ml, 0.5M in toluene) was added via slow drop-wise addition. The mixture was stirred for 30 minutes at −15° C. and then gradually warmed to 15° C. over about 1.5 hours. The material was quenched via the addition of a saturated solution of aqueous ammonium chloride (100 ml). Water (80 ml) and diethyl ether (50 ml) were added and the material was transferred to a reparatory funnel and the organic phase was collected. This was washed with an equal volume of water and the organic phase was collected. The aqueous phases were back extracted with ether (2×100 ml) and the combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The material was purified by chromatography on silica gel eluting with 60% ethyl acetate/hexane to provide semi-pure product as a golden yellow oil (18 g, 75% pure). This material was used “as is” in subsequent steps. (M+H)+=275 m/e.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[C:18](=[O:28])[C@H:19]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH3:20]>CS(C)=O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[C:18]1([C@H:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:20])[CH2:2][O:28]1
Reactant: C[C@@H](OC1CCCCO1)C(=O)c1cc(F)c(F)cc1F
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H](OC1CCCCO1)C1(c2cc(F)c(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 101.6 %

Procedure:
Trimethylsulfoxonium iodide (697 mg, 1.2 eq) was added portionwise to a stirred mixture of sodium hydride [60% mineral oil dispersion] (122 mg, 1.15 eq) and dry dimethyl sulfoxide (7 ml) at 0° C. The resulting mixture was stirred at room temperature for 40 min and then cooled in an ice bath. A solution of (2R)-2′,4′,5′-trifluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (760 mg) in dry dimethyl sulfoxide (2 ml) was added to the mixture and stirring was continued for 2 h at room temperature. The mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 2-(2,4,5-trifluorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane ( 810 mg) as a pale yellow oil, which was a mixture of 4 diastereomers and was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[Se:10](=O)=O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][Se:10][N:9]=[C:4]2[CH:3]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=[Se]=O
Solvent: CCO
Product: Clc1ccc2n[se]nc2c1
Temperature: 25 °C

Procedure:
A solution of 4-chlorobenzene-1,2-diamine (1.50 g, 10.5 mmol) in EtOH (15 mL) was heated to reflux and selenium dioxide (1.28 g, 11.5 mmol) was added. The reaction was refluxed for 30 min and cooled to ambient temperature. The precipitated solid was filtered, washed thoroughly with H2O and dried under high vacuum to give the title compound. MS: m/z=219(M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:32]=[CH:31][C:13]3[N:14]([CH3:30])[C:15]([C:17]4[N:27]([CH2:28][CH3:29])[C:20]5=[N:21][CH:22]=[C:23]([O:25]C)[CH:24]=[C:19]5[CH:18]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:3]1.B(Br)(Br)Br>ClCCl.CS(C)=O>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:32]=[CH:31][C:13]3[N:14]([CH3:30])[C:15]([C:17]4[N:27]([CH2:28][CH3:29])[C:20]5=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]5[CH:18]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:3]1
Reactant: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](N)C4)ccc3n2C)cc2cc(OC)cnc21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](N)C4)ccc3n2C)cc2cc(O)cnc21
Reaction time: 4 h
Yield: 114.7 %

Procedure:
A solution of (R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone (11 mg, 0.025 mmol) in dichloromethane (DCM) (3 mL) was cooled to 0° C. using an ice-water bath under nitrogen. Boron tribromide (8 μL, 0.085 mmol) was added to the reaction dropwise with vigorous stirring. The reaction mixture was allowed to return to room temperature with stirring, over 4 hours. The reaction mixture was partitioned with water (5 mL), the organic layer was isolated using a hydrophobic frit, and the aqueous layer was re-extracted with DCM (2×10 mL). The combined organic layers were evaporated in vacuo but LCMS showed there was no product. The aqueous layer was neutralised by the dropwise addition of NaHCO3, partitioned with DCM and separated. The aqueous was re-extracted with DCM (2×15 mL) and the combined organic layers were concentrated in vacuo to give the crude product. The residue was dissolved in DMSO 1 mL and purified by MDAP with an ammonium bicarbonate modifier (Method E). The appropriate fraction was evaporated in vacuo to give the title compound as a yellow gum (12 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23](OC)=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[NH3:27]>CO>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23]([NH2:27])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: COC(=O)c1cccc2nc(-c3ccc(-c4ccccn4)cc3F)oc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(-c4ccccn4)cc3F)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 84 %

Procedure:
Methyl 2-(2-fluoro-4-(pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxylate (500 mg, 1.40 mmol) was added to ammonia in methanol (30 ml) and the mixture was stirred at room temperature for 3 days. The solid was filtered, washed with methanol and ammonium hydroxide, dried in vacuum. 400 mg of 2-(2-fluoro-4-(pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide as a solid was obtained, yield 84%. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.5-7.54 (m, 2H), 7.87-8.04 (m, 5H), 8.21-8.23 (m, 3H), 8.47 (s, 1H), 8.76 (s, 1H); LC-MS (ESI) m/z: 334 (M+1)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([CH3:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:18]I>CN(C)C=O.O.[Cl-].[Na+].O>[CH3:18][O:3][C:4]1([CH3:17])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% dispersion on mineral oil) (198 mg, 4.95 mmol) was added portionwise to tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (21) (710 mg, 3.30 mmol) in N,N-dimethylformamide (12 mL) at ambient temperature over a period of 30 seconds under an air atmosphere. The resulting suspension was stirred at 25° C. for 20 minutes. Methyl iodide (0.411 mL, 6.60 mmol) was then and the resulting suspension was stirred at 25° C. for 18 hours. The reaction mixture was diluted with water (150 mL) and saturated brine (25 mL), then washed sequentially with dichloromethane (3×100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, which was used directly in the next stage.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:19]=[O:20])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[N:7]2.O1CCC[CH2:22]1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:19]([OH:20])[CH3:22])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[N:7]2
Reactant: C1CCOC1
Reactant: O=Cc1cc2c(Cl)cccc2nc1-c1cccc(F)c1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1cc2c(Cl)cccc2nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring hetereogeneous mixture of 5-chloro-2-(3-fluorophenyl)quinoline-3-carbaldehyde (1.0120 g, 3.542 mmol) in tetrahydrofuran (35.42 mL, 3.542 mmol) was added methylmagnesium bromide 3 M in diethyl ether (3.542 mL, 10.63 mmol) dropwise at 0° C. (started at 11:10 am), and the mixture was then stirred at room temperature. After 3 h, the reaction was quenched with saturated aq. NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined orgainc layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(5-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethanol as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (1 H, s), 8.00-8.05 (1 H, m), 7.73-7.85 (2 H, m), 7.54-7.63 (1 H, m), 7.41-7.47 (2 H, m), 7.33-7.40 (1 H, m), 5.56 (1 H, d, J=4.3 Hz), 4.98-5.06 (1 H, m), 1.27 (3 H, d, J=6.7 Hz); LC-MS (ESI) m/z 302.0 [M+H]+.
Reaction SMILES: Cl.[C:2]([CH2:4][C:5](=[NH:10])[O:6][CH:7]([CH3:9])[CH3:8])#[N:3].[N:11]#[C:12]N>>[C:12]([N:10]=[C:5]([O:6][CH:7]([CH3:9])[CH3:8])[CH2:4][C:2]#[N:3])#[N:11]
Reactant: CC(C)OC(=N)CC#N
Reactant: N#CN
Agent: Cl
Product: CC(C)OC(CC#N)=NC#N
Yield: 68.5 %

Procedure:
3.25 g of isopropyl cyanoacetimidate hydrochloride and 1.26 g of cyanamide were treated with the same manner as in Example 1 and 2.07 g of isopropyl N-cyanocyanoacetimidate was obtained (yield 68.5%) mp 66.5°C. Analysis calculated for C7H9N3O (%) C 55.62, H 6.00, N 27.80, found C 55.41, H 5.91, N 27.66.
Reaction SMILES: [B].[C:2]1([C:8]2[O:14][C@H:13]3[C@H:10]([C:11](=[O:15])[NH:12]3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][CH2:17][C:18]#[C:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21].C([O-])(O)=O.[Na+]>O1CCCC1>[C:8]([NH:9][C@@H:10]1[C@@H:13]([O:16][CH2:17][C:18]#[C:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[NH:12][C:11]1=[O:15])(=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C#CCO)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C1N[C@H]2OC(c3ccccc3)=N[C@@H]12
Agent: O=C([O-])O
Agent: [B]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C#CCO[C@H]1NC(=O)[C@@H]1NC(=O)c1ccccc1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
10 μl of boron trifuloride etherate were sprayed into a stirred suspension of 376 mg (2mmols) of (1R, 5S)-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one and 941 mg (4 mmols) of 4-nitrobenzyl 4-hydroxy-2-butinoate in 8 ml of anhydrous tetrahydrofuran at room temperature. After a short time, a clear, light yellow solution formed, and was stirred at room temperature for 0.5 hour. Thereafter, the solution was poured into dilute NaHCO3 solution, the mixture was extracted with methylene chloride and the extract was washed with water and dried over MgSO4. After the solvent had been evaporated off in vacuo and the residue had been chromatographed on 60 g of silica gel (toluene:ethyl acetate 35:65), 557 mg (66%) of 4-nitrobenzyl 4-[3(R)-benzoylamino-2-azetidinon-4(R)-yloxy]-2-butinoate were obtained as a colorless rigid foam.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.[OH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH:20]1([N:17]2[CH2:18][CH2:19][CH:15]([CH2:14][C:10]3[C:11]([Cl:13])=[CH:12][C:7]([C:34]4[CH:35]=[CH:36][C:31]([OH:30])=[CH:32][CH:33]=4)=[CH:8][C:9]=3[Cl:27])[C:16]2=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Product: O=C1C(Cc2c(Cl)cc(-c3ccc(O)cc3)cc2Cl)CCN1C1CCCCC1
Yield: 90.8 %

Procedure:
Using the procedure to synthesize Example 81 and using reagents 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (750 mg, 1.58 mmol) and 4-hydroxyphenylboronic acid (650 mg, 4.7 mmol) affords 600 mg (91%) of the title compound: Mass spectrum (apci) m/z=418.2 (M+H—HCl).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7]Cl)[C:3](Br)=[O:4].[NH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.[OH-].[Na+]>C(#N)C>[Br:1][CH:2]1[CH2:6][CH2:7][N:9]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[C:3]1=[O:4]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(Br)C(Br)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N#Cc1ccc(N2CCC(Br)C2=O)cc1

Procedure:
2-Bromo4-chlorobutyryl bromide (BCBB, 145.7 g, 0.540 mole) was added via an addition funnel to a cold (5° C.), well stirred slurry of 4-aminobenzonitrile (4-ABN, 55.0 g, 0.466 mole), Na3PO4 (42 g, 0.256 mole) and acetonitrile (550 mL) in a 1 liter flask while maintaining a temperature below 30° C. during the addition. The addition funnel was rinsed with acetonitrile (55 mL). Upon completion of the coupling (determined by LC), a 50 wt % solution of NaOH (56 mL, 1.061 mole) was added via an addition funnel while maintaining the reaction temperature below 30° C. Upon completion of the reaction (determined by LC), the slurry was filtered through a pressure filter (10 micron polypropylene filter cloth). The flask and the cake were washed with acetonitrile (256 mL). The filtrate and the wash were combined to afford a solution of 4-(3-bromo-2-oxopyrrolidin-1-yl)benzonitrile in acetonitrile (of about 17 wt %). Qualitative LC analysis showed the product with 91.8 to 95 area % purity.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10]1>>[C:18]([O:17][C:16](=[O:22])[NH:15][CH:11]1[CH2:12][CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:10]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccnc(Cl)n2)C1

Procedure:
tert-butyl(1-(2-chloropyrimidin-4-yl)piperidin-3-yl)carbamate was prepared using the procedure similar to COMPOUND 54 using 2,4-dichloropyrimidine and tert-butyl piperidin-3-ylcarbamate. MS (ES+) C14H21ClN4O2 requires: 312. found: 313 [M+H]+