Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]#[CH:5])([CH3:3])[CH3:2].C([Li])CCC.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21]>C1COCC1>[NH2:11][C:12]1[C:13]([C:19]([OH:24])([C:5]#[C:4][CH:1]([CH3:3])[CH3:2])[C:20]([F:23])([F:21])[F:22])=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1
Reactant: C#CC(C)C
Reactant: Nc1ccc(F)cc1C(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)C#CC(O)(c1cc(F)ccc1N)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To an ice-cooled solution of 1.89 mL of isopropylacetylene in 35 mL of dry THF was added dropwise over 5 min, 10.0 mL of 1.6 M n-butyllithium. The reaction mixture was stirred at 0° for 30 min after which time 828 mg of 1-(2-amino-5-fluorophenyl)-2,2,2-trifluoroethanone was added. The reaction mixture was stirred at 0° for 1.25 h after which time it was quenched with saturated aqueous ammonium chloride and poured onto water. This mixture was extracted twice with ether and the combined extracts were washed with brine dried and evaporated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate/hexanes) affording 220 mg of the title compound as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[Li]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([C:14]1[S:13][CH:17]=[CH:16][CH:15]=1)([C:14]1[S:13][CH:17]=[CH:16][CH:15]=1)[OH:6]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: [Li]c1cccs1
Product: Nc1ccc(Br)cc1C(O)(c1cccs1)c1cccs1

Procedure:
Prepared from methyl 2-amino-5-bromobenzoate and 2-thienyllithium using the procedure similar to example 6. 1H-NMR (CDCl3) δ 7.35 (dd, J=5.3, 1.1 Hz, 2H), 7.26 (dd, J=8.4,2.3 Hz, 1H), 6.98 (m, 2H), 6.82 (d, J=2.3 Hz, 1H), 6.79 (m, 2H), 6.62 (d, J=8.4 Hz, 1H), 5.45 (br s, 1H), 3.86 (br s, 2H); Anal. Calc. For C15H12BrNOS2: C, 49.18; H, 3.30; N, 3.82. Found: C, 49.62; H, 3.47; N, 3.60.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([CH2:11][CH2:12][O:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:8][CH2:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl.ClCCl>C(O)C>[ClH:29].[Cl:29][C:25]1[CH:24]=[C:23]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:14][O:13][CH2:12][CH2:11][N:7]2[CH2:8][CH2:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]2)[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)C1=CCCN(CCOC=C(c2cccc(Cl)c2)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccccc1C(=COCCN1CCC=C(C(=O)O)C1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
1-(2-((2-(3-Chlorophenyl)-2-(2-methylphenyl)ethenyl)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic methyl ester (0.60 g, 0.0014 mol, prepared similarly to the method described in Example 70) was dissolved in ethanol (5 ml) and 12 N sodium hydroxide solution (0.35 ml) was introduced. After stirring the solution at room temperature for 3 h, 37% hydro chloric acid solution was added, until the pH 1. Dichloromethane (200 ml) was introduced, and the mixture was dried (Na2SO4), filtered and evaporated to a residue, which was co-evaporated twice with acetone. The residue was recrystallized from acetone/ethyl acetate to give the title compound (0.33 g, 55%) as white crystals.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([C:12]([O:14]C)=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24].[Li+].[OH-]>C1COCC1.CO.O>[F:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24]
Reactant: COC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cnc2c(F)c(Nc3ccc(I)cc3F)c(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-fluoro-5-(2-fluoro-4-iodophenylamino)-1-methyl-1H-benzo[d]imidazole-6-carboxylate (2.15 g, 4.8 mmoles) is dissolved in a mixture of THF (30 ml), MeOH (10 ml) and H2O (5 ml) and LiOH (1.16 g, 4.8 mmoles) is added. The mixture is stirred at room temperature for 2 hours. Solvents are removed under reduced pressure and 1N HCl is added. The aqueous layer is extracted with chloroform. The organic layers are combined, washed with brine, dried (Na2SO4) and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[C:17]([Cl:22])[CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][N:13]=1>>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[N:15]=[CH:14][N:13]=[C:12]2[N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: Clc1ncnc2c(Cl)cccc12
Product: Clc1ccc2c(c1)N(c1ncnc3c(Cl)cccc13)CC2
Yield: 47 %

Procedure:
Utilizing a procedure analogous to that described in Example 24, this product was prepared in 47% yield from 6-chloro-indoline and 4,8-dichloro-quinazoline. (M.P. 190° C.; LC-MS: 316 (MH+)).
Reaction SMILES: [Cl:1][CH:2]([C:7](=O)[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].C([O-])(=O)C.[NH4+:15]>CO>[NH2:15][C:7]([CH2:8][CH3:9])=[C:2]([Cl:1])[C:3]([O:5][CH3:6])=[O:4]
Reactant: [NH4+]
Reactant: CCC(=O)C(Cl)C(=O)OC
Agent: CC(=O)[O-]
Solvent: CO
Product: CCC(N)=C(Cl)C(=O)OC
Reaction time: 4 h
Yield: 94.7 %

Procedure:
A solution of 576.1 g (3.5 mol) of methyl 2-chloro-3-oxovalerate and 674.5 g (8.75 mol) of ammonium acetate in 1.2 l of methanol is heated at 65° C. with stirring for a period of 4 h. After cooling, the solvent is removed in vacuo, the residue is taken up in 2.5 l of diisopropyl ether, and the solid is removed. The solid is dissolved in a little water and subsequently extracted with ethyl acetate. The organic fractions are combined, dried over MgSO4 and evaporated in vacuo. Yield: 94.7% [GC]
Reaction SMILES: [I:1][C:2]1[C:6]([C:7](O)=[O:8])=[CH:5][N:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[N:3]=1.B.C1COCC1>CC(=O)OCC>[I:1][C:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[N:3]=1
Reactant: O=C(O)c1cn(C2CCCCO2)nc1I
Agent: B
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cn(C2CCCCO2)nc1I
Yield: 83.5 %

Procedure:
A solution of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylic acid (34 g, 105 mmol) in BH3-THF (340 mL, 340 mmol, 1M in THF) was stirred at rt overnight. Solvent was evaporated under vacuum and the residue dissolved in DCM (340 mL), washed with water (340 mL×3), dried and concentrated. The residue was purified by SGC using Hex: EA (0%-70%) as eluent to afford (3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methanol (27 g, yield: 83%). LCMS (method C): RT=1.74 min, m/z=309.1 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14]1.[Br:25][C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[Cl:34].[Cl-].[NH4+]>C1COCC1>[Br:25][C:26]1[CH:31]=[C:30]([CH2:32][CH:17]([CH:13]2[CH2:14][CH2:15][CH2:16]2)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:29]=[CH:28][C:27]=1[Cl:34]
Reactant: Clc1ccc(CBr)cc1Br
Reactant: CC(C)(C)OC(=O)CC1CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C(Cc1ccc(Cl)c(Br)c1)C1CCC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Under argon, 2.9 ml (20.8 mmol) of diisopropylamine were dissolved in 30 ml of dry THF, and the mixture was cooled to −20° C. 8.3 ml (20.8 mmol) of n-butyllithium solution (2.5 M in hexane) were added dropwise, and the resulting mixture was stirred to −20° C. for 30 min and then cooled to −78° C. At this temperature, a solution of 2.60 g (about 15.3 mmol, crude) of tert-butyl cyclobutylacetate in 10 ml of THF was added. After 4 h of stirring at −78° C., a solution of 3.95 g (13.9 mmol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 10 ml of THF was added. The reaction mixture was slowly warmed to RT overnight, and saturated aqueous ammonium chloride solution was then added. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The solid that remained was triturated with 30 ml of cyclohexane/dichloromethane (1:1) and filtered off. The solid was once more triturated with 10 ml of cyclohexane/dichloromethane (1:1) and again filtered off; this procedure was repeated once more. All filtrates were collected, combined and concentrated under reduced pressure. This residue was then purified further by chromatography on silica gel (mobile phase from pure cyclohexane to cyclohexane/dichloromethane 20:1 to 10:1). This gave 2.24 g of the title compound (43.2% of theory).
Reaction SMILES: C([O:4][C:5]([CH3:10])([CH3:9])[C:6](Cl)=[O:7])(=O)C.[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH2:21])=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH:21][C:6](=[O:7])[C:5]([OH:4])([CH3:9])[CH3:10])=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
1-Chloro-2-methyl-1-oxopropan-2-yl acetate (215 mg, 1.30 mmol) in dry dichloromethane (2 mL) was added dropwise to a solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (250 mg, 1.087 mmol; Example 1, Step H) and triethylamine (550 mg, 0.757 mL, 5.43 mmol) in dry dichloromethane (10 mL) cooled on an ice-bath. The resulting solution was stirred at room temperature for 1 hour. The solvent was evaporated. The residue was then stirred in THF (10 mL), treated with an aqueous 2N LiOH solution (3 mL), and stirred at room temperature for 18 hours. The mixture was evaporated under reduced pressure, and the residue dissolved in EtOAc and washed with water (3×20 mL). The organic layer was dried over MgSO4, filtered and concentrated to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxy-2-methylpropanamide (289 mg, 84% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.03 (br s, 1H), 9.27 (s, 1H), 8.36 (d, 1H), 7.69 (d, 1H), 5.84 (s, 1H), 1.37 (s, 6H); LCMS (APCI+) m/z 317.9 (M+H)+, Retention time=2.51 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13](C3C4C(=CC=C(C(F)(F)F)C=4)NN=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:29][C:30]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([N+:39]([O-:41])=[O:40])=[CH:38][C:30]=3[Cl:29])=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C(Nc1cccc(F)c1)c1ccc(-c2n[nH]c3ccc(C(F)(F)F)cc23)[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Nc1cccc(F)c1)c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 7.1 %

Procedure:
To a mixture of 1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide (1 g, 4.9 mmol) (Example 55) and 2-chloro-4-nitro-benzoyl chloride (1.5 g, 6.8 mmol) (Aldrich, Milwaukee, Wis.) in benzene (10 mL) at room temperature, was added a solution of tin (IV) chloride (1.4 mL). After stirring at room temperature for 5 hours and the usual work-up, the residue was purified on a silica gel column to give 135 mg of 5-(2-chloro-4-nitro-benzoyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH:5]=[C:6]([C:13]([O:15]C)=O)[NH:7]2.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH:5]=[C:6]([C:13](=[O:15])[NH:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[NH:7]2
Reactant: NCCN1CCCC1
Reactant: COC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Product: Cl
Product: O=C(NCCN1CCCC1)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1

Procedure:
Treatment of methyl 5,7-dichloro-4-oxo-1,4-dihydroquinoline-2-carboxylate (2 g) with 1(2-aminoethyl-pyrrolidine (10 ml) as described in Example 39 gave 5,7-dichloro-2-[2-(1-pyrrolidinyl) ethyl]carbamoyl-4-oxo-1,4-dihydroquinoline dihydrochloride (1.5 g).,m.p.>280° C. δ (360 MHz, D2O) 2.02 and 2.16 (4H, 2m, pyrrolidinyl-3,4-H), 3.16 (2H, m, CH2N), 3.49 (2H, t, CONHCH2), 3.80 (4H, m, pyrrolidinyl-2,5-H), 6.70 (1H, s, 3-H), 7.43 (1H, d, 6-H) and 7.64 (1H, d, 8-H). (Found: C, 45.02; H, 4.52; N, 9.90%. C16H17Cl2N3O2.2HCl requires C, 44.99; H, 4.48; N, 9.84%).
Reaction SMILES: [Cl-].[Al+3:2].[Cl-].[Cl-].[C:5]([OH:17])(=[O:16])[CH2:6][C:7]([CH2:12][C:13]([OH:15])=[O:14])([C:9]([OH:11])=[O:10])[OH:8]>>[C:5]([O-:17])(=[O:16])[CH2:6][C:7]([CH2:12][C:13]([O-:15])=[O:14])([C:9]([O-:11])=[O:10])[OH:8].[Al+3:2].[Al:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [Al]

Procedure:
combining the aluminum chloride solution with an aqueous solution of citric acid containing up to about 50% (w/w) citric acid while providing vigorous agitation to form a solution of aluminum citrate containing from 1 to about 3 weight % aluminum and having a mole ratio of aluminum ion to citric acid molecule of from about 1.5:1 to about 2:1; and
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:12])[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:13](=O)([O-])[O-].[Cs+].[Cs+].[Br:19][CH2:20]CBr>CN(C=O)C.CCOC(C)=O>[Br:19][CH2:20][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[O:12][CH3:13]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: BrCCBr
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1OCCBr
Temperature: 80 °C
Reaction time: 18 h
Yield: 42.6 %

Procedure:
4-Nitroguaiacol (1.0171 g, 6.0134 mmol) was dissolved in anhydrous DMF (20 mL). Cesium carbonate (3.9207 g, 12.0268 mmol) and 1,2-dibromoethane (2.07 mL, 24.0534 mmol) were added. The reaction was heated to 80° C. and stirred for 18 h. The mix was then cooled to RT and diluted with EtOAc (100 mL), washed with water (3×100 mL), and the organics dried over MgSO4, filtered and concentrated. The residue was filtered through a 3″ plug of basic alumina (100% CH2Cl2) to give 0.7075 g (2.5634 mmol, 42%) of the product as a white solid. 1H NMR (CDCl3) δ 7.90 (d, 1H, J=8.8 Hz), 7.78 (s, 1H), 6.92 (d, 1H, J=8.8 Hz), 4.42 (t, 2H, J=6.4 Hz), 3.96 (s, 3H), 3.70 (t, 2H, J=6.5 Hz).
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][N:8]([C:12](=[O:24])[CH:13]([S:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:14])[CH:9]1[CH2:11][CH2:10]1)(C)(C)C.C1CCC(NC2CCCCC2)CC1>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.CCOCC>[C:16]([S:15][CH:13]([CH3:14])[C:12]([N:8]([CH:9]1[CH2:11][CH2:10]1)[CH2:7][C:6]([OH:25])=[O:5])=[O:24])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(SC(=O)c1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1CC1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(SC(=O)c1ccccc1)C(=O)N(CC(=O)O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude N-(2-benzoylthiopropanoyl)-N-cyclopropylglycine tert-butyl ester (17.1 g) was dissolved in a mixture of anisole (25 ml) and trifluoroacetic acid (100 ml). The resulting solution was stirred at room temperature for two hours. Trifluoroacetic acid was removed in vacuo and the residue was distributed between ethyl acetate and saturated sodium bicarbonate. The aqueous bicarbonate phase was separated and washed twice with ethyl acetate and then acidified cautiously to pH 4-6 with concentrated hydrochloric acid. The precipitated product was extracted into chloroform and washed twice with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give crude product as a pale yellow oil. The product was characterized as its DCHA salt which was prepared in ether to give colorless crystals, m.p. 140°-143° C.
Reaction SMILES: C1(C)C(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=CC=1.N12CCCN=C1CCCCC2.ClCCl.[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[O:36])[CH:32]=[N:33][CH:34]=1>O>[Br:28][C:29]1[CH:30]=[C:31]([C:35]2[O:36][CH:12]=[N:11][CH:10]=2)[CH:32]=[N:33][CH:34]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Brc1cncc(-c2cnco2)c1
Reaction time: 5 h
Yield: 79.3 %

Procedure:
Toluenesulfonylmethylisocyanide (126 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (122 mg) were added to a dichloromethane (4 ml) solution containing 5-bromo-3-pyridinecarboxaldehyde (100 mg) at room temperature, followed by stirring for 5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 5:2), and a white solid of 5-(5-bromopyridin-3-yl)oxazole (96 mg) was thus obtained.
Reaction SMILES: O[C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.CCN(S(F)(F)[F:28])CC.C(OCC)(=O)C>C(Cl)Cl>[F:28][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](O)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (MG Bursavich et al; Organic Letters 2001, 3, 2317, 150 mg, 0.51 mmol) in 5 mL of DCM at −78° C. under nitrogen was added DAST (0.2 mL, 1.5 mmol). The mixture was allowed to warm up to rt with stirring over 3 h. To the mixture was added 100 mL of ethyl acetate and the organic layer was separated, washed with a saturated NaHCO3 solution, and then evaporated under vacuum. The residue was purified via silica gel chromatography eluting with 0-100% ethyl acetate/hexanes to give (3R,4R)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (120 mg, 0.41 mmol); LCMS (Method T) RT 3.09 min, m/z 294.3. (M−H)−; 1H NMR (500 MHz, chloroform-d) δ 7.11 (d, J=8.5 Hz, 2H), 6.93 (br. s., 1H), 6.89-6.82 (m, 2H), 4.56-4.47 (m, 1H), 4.45-4.38 (m, 1H), 4.16 (d, J=7.2 Hz, 1H), 2.89-2.69 (m, 3H), 1.89-1.83 (m, 1H), 1.76-1.65 (m, 1H), 1.53 (s, 9H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([S:6]([NH2:9])(=[O:8])=[O:7])=[CH:2]1.C=O.C[O:13][P:14]([O:17]C)[O:15]C.Br[Si](C)(C)[CH3:21]>>[O:1]1[CH:5]=[CH:4][C:3]([S:6]([NH:9][CH2:21][P:14](=[O:17])([OH:15])[OH:13])(=[O:8])=[O:7])=[CH:2]1
Reactant: COP(OC)OC
Reactant: C[Si](C)(C)Br
Reactant: NS(=O)(=O)c1ccoc1
Agent: C=O
Product: O=P(O)(O)CNS(=O)(=O)c1ccoc1

Procedure:
3-Furylsulfonamide (x) was treated with paraformaldehyde and trimethylphosphite, followed by treatment with bromotrimethylsilane, according to the procedure described in Example 46, steps 2 and 3, to produce the title compound: 1H NMR (300 MHz, CD3OD) δH 8.13 (dd, J=1.5, 0.6 Hz, 1H), 7.71 (t, J=1.8 Hz, 1H), 6.78 (dd, J=1.8, 0.6 Hz, 1H), 3.21 (d, J=13.5 Hz, 2H); 13C NMR (75 MHz, CD3OD) δC 147.2, 146.4, 128.0, 109.3, 40.7 (d, J=158 Hz).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:17].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C=O.[C:25](OCC)(=O)C.Cl>C(OCC)(=O)C>[ClH:17].[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:16])[CH:14]([CH3:25])[CH2:15][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(=O)c1ccc(C2CCCCC2)cc1
Reactant: CCOC(C)=O
Reactant: C1CCNC1
Agent: C=O
Agent: Cl
Product: CC(CN1CCCC1)C(=O)c1ccc(C2CCCCC2)cc1

Procedure:
A solution of 5.10 g of 4'-cyclohexylpropiophenone in 15 ml of ethyl acetate, 2.50 g of pyrrolidine hydrochloride, 1.30 g of paraformaldehyde and 0.5 ml of 22% hydrogen chloride-ethyl acetate were treated in the same manner as that described for Example 3 to give 3.65 g of hydrochloride of the desired compound, which were recrystallized from a mixture of ethanol and ether as colorless needles, mp 186°-187°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:27])[C:16]2[CH:25]=[CH:24][C:19]3[C:20](=[O:23])[O:21][CH2:22][C:18]=3[C:17]=2[CH3:26])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>O1CCOCC1>[Cl-:28].[OH:27][CH:15]([C:16]1[CH:25]=[CH:24][C:19]2[C:20](=[O:23])[O:21][CH2:22][C:18]=2[C:17]=1[CH3:26])[CH2:14][NH+:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1COC2=O
Reactant: Cl
Solvent: C1COCCO1
Product: Cc1c(C(O)C[NH+]2CCNCC2)ccc2c1COC2=O
Product: [Cl-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl-4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate (800 mg, 2.1 mmol, 1.0 eq) was treated with 4 N HCl in dioxane (4 mL). The reaction was stirred at r.t. for 3 h and then concentrated. The product was dried under high vacuum pump for 6 hr. The intermediate is often converted to the corresponding free base prior to use by partitioning between saturated Na2CO3 solution and CHCl3-IPA (3:1). LC-MS (IE, m/z): 277.1 [M+1]+; tR=0.4 min.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C:20]2[C:21]([O:26][C:27]3[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>C(O)=O.CO.CN(C)C=O.[Pd]>[CH3:34][S:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][C:21]2[C:20]([C:18]([NH:17][C@@H:14]3[CH2:13][CH2:12][C@H:11]([C:9]([OH:10])=[O:8])[CH2:16][CH2:15]3)=[O:19])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:32][CH:31]=1
Reactant: CSc1ccc(Oc2ncccc2C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O=CO
Product: CSc1ccc(Oc2ncccc2C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)cc1
Reaction time: 2.5 h
Yield: 76.5 %

Procedure:
cis-4-{[2-(4-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic acid benzyl ester (4.35 g, 9.13 mmol) was dissolved in a solution of 4.4% formic acid in methanol (100 ml) and dimethylformamide (25 ml) and this was added to a suspension of palladium black (5 g) in 4.4% formic acid in methanol (300 ml) at room temperature under nitrogen. The mixture was stirred for 2.5 h, then filtered through arbocel washing with methanol (4×200 ml). The filtrates were concentrated under reduced pressure and the residue was azeotroped with toluene (2×50 ml). The residue was then diluted with water (50 ml) and basified to pH10 with 1M sodium hydroxide pellets. The aqueous phase was extracted with diethylether (2×50 ml) then acidified to pH1 with concentrated hydrochloric acid. After extraction with diethylether (5×50 ml) the combined organic extracts were washed with water (20 ml), dried over MgSO4 and the solvent removed under reduced pressure to give cis-4-{[2-(4-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic acid (2.7 g) as a white solid.