Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[Mg].[CH:16]1([C:19](=[O:25])[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1>O>[BrH:6].[CH:16]1([C:19]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)([OH:25])[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1
Reactant: CN(C)CCC(=O)C1CC1
Reactant: COc1ccc(Br)cc1
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: Br
Product: COc1ccc(C(O)(CCN(C)C)C2CC2)cc1
Temperature: 25 °C

Procedure:
The stirred ether solution of the Grignard reagent prepared from 86 g. (0.46 mole) of 4-bromoanisole and 11.2 g. (0.46 mole) of magnesium in 200 ml. of dry ether was treated dropwise with a solution of 30 g. (0.23 mole) of 1-cyclopropyl-3-dimethylamino-1-propanone in 100 ml. of dry ether. After addition the mixture was allowed to warm to room temperature and was then hydrolyzed with water. The mixture was worked up as in Example 1 to give 16 g. (28%) of an oil which distilled at 110°-115°C./0.10 mm. The hydrobromide salt melted at 175°-177°C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([C:21]([F:24])([F:23])[F:22])([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.[OH2:40]>CN(C=O)C>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([O:8][C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([C:16]([F:17])([F:18])[F:19])([O:20][S:36]([C:33]3[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=3)(=[O:37])=[O:40])[C:21]([F:23])([F:22])[F:24])[CH:10]=2)([C:4]([F:7])([F:6])[F:5])[C:2]([F:25])([F:26])[F:1])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: O
Reactant: OC(c1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(OC(c1cccc(C(OS(=O)(=O)c2ccc(Cl)cc2)(C(F)(F)F)C(F)(F)F)c1)(C(F)(F)F)C(F)(F)F)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
4.1 g (10 mmol) of 1,3-bis-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-benzene were dissolved in 20 ml of dry DMF, and 0.75 g (25 mmol) of sodium hydride (80% strength dispersion) was added. The clear solution formed was stirred for a further 30 minutes. 5.25 g (25 mmol) of 4-chlorobenzenesulfonyl chloride in 15 ml of DMF were then added dropwise at 10° to 15° C. The mixture was stirred for 48 hours at room temperature and poured into water. The crystalline precipitate was filtered off, rinsed with water and dried. The residue was chromatographed over a silica gel column with methylene chloride. 4.2 g of 1,3-bis-[1-(4-chlorobenzenesulfonyloxy)-2,2,2-trifluoro-1-trifluoromethylethyl]-benzene were obtained (colorless crystals, m.p.: 125° C.).
Reaction SMILES: Br[C:2]1[N:6]([C@@H:7]2[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14][OH:15])[CH2:8]2)[C:5]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>C(O)C>[C:22]([NH:26][C:2]1[N:6]([C@@H:7]2[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14][OH:15])[CH2:8]2)[C:5]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N
Reactant: OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Solvent: CCO
Product: CC(C)(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1C[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 148 °C
Yield: 61 %

Procedure:
A solution of (1R, 2S, 3S, 5S)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol (500 mg, 1.26 mmole) was stirred in tert-butylamine (Aldrich, 98%, 20 mL) in a Parr bomb maintained at 148 ° C. (oil bath) for 48 hours. The bomb was cooled and the resulting pale yellow solution diluted with ethanol containing 1 N sodium hydroxide (1.2 mL). Volatiles were evaporated in vacuo and the residue was chromatographed on silica gel. Title compound was eluted with 10% methanol-chloroform as a colorless oil. The oil was dissolved in absolute ethanol, concentrated to an oil, and triturated with water (3 mL) to give (1R, 2S, 3S, 5S)-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol as white powder (303 mg, 61%), m.p.: collapses to glass at 116-150° C.; 1H-NMR(DMSO-d6) δ: 7.63 and 7.43 (both s, 2, aromatic CH), 6.15 (s, 1, NH), 5.08 (t, J=4.3 Hz, 1, OH), 4.85 (d,J=7.4 Hz, 1, OH), 4.71 (d, J=3.8 Hz, 1, OH), 4.7-4.5 (m, 1, NCH), 4.45-4.3 (m, 1, OCH), 3.80 (m, 1, OCH), 3.7-3.4 (m, 2, OCH2), 2.2-1.85 (m, 3, CH2 and CH of cyclopentane), 1.47 (s, 9, 3 CH3); mass spectrum (CI): 388(M+1); [α]20 589-4.0°, [α]20 578-4.3°, [α]20 546-6.0°, [α 20 436-22.6°, [α]20 365-82.1° (c=0.420, methanol). [See Examples 25-28, 30 and 31]
Reaction SMILES: [CH3:1][C:2]1[C:6]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][C:23]([N:26]6[CH2:30][CH2:29][CH2:28][CH2:27]6)=[N:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8]2=[O:32])=[CH:5][N:4]([CH2:33][C:34](O)=[O:35])[N:3]=1.CN(C=O)C.[Cl-].[CH2:43]([NH:45][CH2:46][CH3:47])[CH3:44]>ClCCl.C([O-])(O)=O.[Na+]>[CH2:43]([N:45]([CH2:46][CH3:47])[C:34](=[O:35])[CH2:33][N:4]1[CH:5]=[C:6]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][C:23]([N:26]6[CH2:30][CH2:29][CH2:28][CH2:27]6)=[N:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8]2=[O:32])[C:2]([CH3:1])=[N:3]1)[CH3:44]
Reactant: Cc1nn(CC(=O)O)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(N5CCCC5)nc4)cc3c21
Reactant: CCNCC
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)Cn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5cnc(N6CCCC6)nc5)cc4c32)c(C)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of {3-methyl-4-[3-methyl-2-oxo-8-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-acetic acid (Stage 247.1.1, 0.12 mmol) and DMF (0.007 ml) in dichloromethane (2 ml) was added oxallyl chloride (0.36 mmol) and the RM was stirred for 45 min at rt. The RM was quenched with diethylamine (Riedel-deHaën, Buchs, Switzerland, 2.4 mmol) and stirred for 5 min at it then diluted with saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with brine (2×), dried over Na2SO4, filtered and evaporated. The residue was taken in MeOH/DMF and purified by preparative HPLC. The fractions containing pure product were basified with NaHCO3, concentrated, cooled at 4° C. and the precipitate was filtered, washed with water and dried under vacuum to give the title compound as white solid. (HPLC: tR 2.63 min (Method A); M+H=540 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.57 (s, 2H), 8.07-8.04 (m, 2H), 7.87-7.84 (m, 1H), 7.67-7.65 (m, 1H), 5.21-5.04 (m, 2H), 3.57 (s, 3H), 3.52-3.46 (m, 4H), 3.42-3.34 (m, 2H), 3.32-3.34 (m, 2H), 1.96-1.90 (m, 4H), 1.94 (s, 3H), 1.18 (t, 3H), 0.99 (t, 3H))
Reaction SMILES: [Mg:1].C([Br:4])C.[CH3:5][C:6]#[CH:7]>O1CCCC1>[CH2:6]([Mg:1][Br:4])[CH3:7].[C:7]([Mg:1][Br:4])#[C:6][CH3:5]
Reactant: C#CC
Reactant: [Mg]
Reactant: CCBr
Solvent: C1CCOC1
Product: CC#C[Mg]Br
Product: CC[Mg]Br

Procedure:
Ethylmagnesium bromide was prepared in a similar manner to Example 1 from 12 g (0.5 mole) of metallic magnesium in 250 ml of tetrahydrofuran and 5.4 g (0.05 mole) of ethyl bromide instead of 54 g (0.5 mole). Then, 10 ml of a tetrahydrofuran solution containing 2 g (0.05 mole) of methylacetylene were added dropwise to the reaction mixture kept at 40° to 50° C. to form 1-propynylmagnesium bromide. Further, 57.2 g (0.4 mole) of chloromethyl dimethyl chlorosilane were added dropwise into the reaction mixture kept at 50° to 70° C. over a period of 4 hours followed by aging at 66° C. for 2 hours. The reaction mixture was subjected to hydrolysis with a saturated aqueous solution of ammonium chloride and the organic solution taken from the mixture by phase separation was distilled under reduced pressure to remove the solvent leaving 31 g of a viscous liquid residue as the reaction product.
Reaction SMILES: [H][H].[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][C:12](=O)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:17][NH2:18]>[Pt]=O.C(O)C>[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([NH:18][CH3:17])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: CN
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CNC1CCCN(Cc2ccccc2)C1

Procedure:
A suspension of 0.30 g. of platinum oxide in 20 ml. of absolute ethanol was shaken under 35 psi of hydrogen for 1 hour. To this was added a solution of 12.44 g. (65.9 mmoles) of 1-benzyl-3-piperidone and 4.1 g. (132 mmoles) of methylamine in 40 ml. of absolute ethanol. The mixture was then shaken under ca. 50 psi of hydrogen until uptake ceased. Filtration and evaporation afforded 1-benzyl-3-methylaminopiperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([Cl:20])[CH:22]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cccc(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of 6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 6b supra), 3-chlorobenzyl bromide (0.15 g, 0.7 mmol)(Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 4 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(3-chloro-benzyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.18 g, 75.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1.C1C(=O)N([Br:25])C(=O)C1.C(N(CC)C(C)C)(C)C.[C:35](=O)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[O:36]C(C)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:25][C:10]1[N:11]([C:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:36])[C:6]2[C:7](=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)Cc1c[nH]c2ccc(OC)nc12
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1c(Br)n(C(=O)OC(C)(C)C)c2ccc(OC)nc12
Temperature: 0 °C
Yield: 25.8 %

Procedure:
Ethyl 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetate (1.0 g, 4.26 mmol) was dissolved in methylene chloride (40 mL) and cooled to 0° C. with ice-water bath. NBS (760 mg, 4.26 mmol) was added in small portions over 1 hour. The reaction mixture was allowed to stir at 0° C. for two more hours. Then, to the reaction mixture were added N,N-diisopropylethylamine (1.86 mL, 8.52 mmol), di-tert-butyl carbonate (1.86 g, 8.52 mmol) and 4-dimethylaminopyridine (52 mg, 0.42 mmol). The resulting mixture was allowed to stir overnight at ambient temperature. More methylene chloride was added and washed with water and half-brine. The organic layer was separated and dried over MgSO4. The mixture was filtered and the filtrate was concentrated to dryness, and the residue was purified by silica gel chromatography (loading with toluene, eluting with EtOAc/hexanes) then RP HPLC eluting with acetonitrile/water to afford 455 mg of tert-butyl 2-bromo-3-(2-ethoxy-2-oxoethyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate and 131 mg of side product. MS (m/z): 415.0 [M+H]+; HPLC retention time 4.68 min (5-99% acetonitrile:water with 0.05% formic acid).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[Cl:5][C:6]1[C:7]([C:17]([O:19][CH3:20])=[O:18])=[N:8][C:9]([C:13]([F:16])([F:15])[CH3:14])=[CH:10][C:11]=1Cl.CO.[BH4-].[Na+]>CN(C)C=O.O>[NH2:1][C:11]1[CH:10]=[C:9]([C:13]([F:16])([F:15])[CH3:14])[N:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:6]=1[Cl:5]
Reactant: COC(=O)c1nc(C(C)(F)F)cc(Cl)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(C(C)(F)F)cc(N)c1Cl
Temperature: 50 °C
Reaction time: 5 h
Yield: 56.8 %

Procedure:
Sodium azide (26.5 mg, 0.41 mmol) was added to a solution of methyl 3,4-dichloro-6-(1,1-difluroethyl)pyridine-2-carboxylate (100 mg, 0.37 mmol) in dimethylformamide (2 mL) and water (0.2 mL). After the reaction mixture was stirred at 50° C. for 5 hours, it was quenched with water and extracted with ethyl ether. The orgainc phase was dried and concentrated to provide the crude 4-azide compound. It was immediately taken up into methanol (2 mL) and sodium borohydride (21 mg, 0.55 mmol) was carefully added. After stirring for 10 minutes, water was added and the mixture concentrated. Ethyl acetate was added and the mixture washed with brine. The organic layer was dried (MgSO4), filtered and concentrated to dryness. The crude product was purified by column chromatography (20% ethyl acetate in hexane) to give methyl 4-amino-3-chloro-6-(1,1-difluroethyl)pyridine-2-carboxylate (53 mg, 0.21 mmol) as an oil; 1H NMR (CDCl3): δ 7.04 (s, 1H), 4.92 (b.s, 2H), 3.98 (s, 3H), 1.97 (t, d=18.7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:16]1([NH2:21])[CH:20]=[CH:19][CH:18]=[CH:17]1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[ClH:1].[N:16]1([NH:21][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: Nn1cccc1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cl
Product: FC(F)(F)c1ccc2c(Nn3cccc3)ccnc2c1
Yield: 35.4 %

Procedure:
A solution of 4-chloro-7-(trifluoromethyl)quinoline (5 g) and 1H-pyrrol-1-amine (2.1 g) in 100 ml of isopropanol containing 1 ml saturated ether/HCl was stirred for thirty minutes at reflux, and thereafter was cooled, stirred with water, basified with sodium carbonate and extracted with ether. The organic extract was washed successively with water and saturated sodium chloride solution, dried (anhy. MgSO4), filtered and concentrated to 6.5 g solid. This was converted to the hydrochloride salt and recrystallized twice from methanol/ether to give 2.4 g white crystals, 260° dec.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[OH:1]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1O
Temperature: 25 °C

Procedure:
To a MeOH solution (200 ml) of 2-hydroxy-4-nitro-benzoic acid (18 g) was added concentrated sulfuric acid. The resulting mixture was heated to reflux for 24 h. After it was cooled to rt, volatile was removed in vacuo. The residue was then partitioned between water and EtOAc. The EtOAc layer was washed with water (2×), NaHCO3 (sat.), NaCl (sat.), dried over Na2SO4 and concentrated. The crude product was purified on a silica gel column with 20% EtOAc in hexane to give 14.5 g of 2-hydroxy-4-nitro-benzoic acid methyl ester as a solid (M+: 197).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1(C[C@H](N2CC3C(=C([F:48])C=CC=3)C2=O)C(O)=O)CCCCC1.NC1SC=CN=1.[CH:56]1([CH2:62][C@H:63]([N:72]2[CH2:80][C:79]3[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=3)[C:73]2=[O:81])[C:64]([NH:66][C:67]2[S:68][CH:69]=[CH:70][N:71]=2)=[O:65])[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>>[CH:56]1([CH2:62][C@H:63]([N:72]2[CH2:80][C:79]3[C:74](=[CH:75][CH:76]=[CH:77][C:78]=3[F:48])[C:73]2=[O:81])[C:64]([NH:66][C:67]2[S:68][CH:69]=[CH:70][N:71]=2)=[O:65])[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2cccc(F)c2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1nccs1
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2c(F)cccc2C1=O
Yield: 30 %

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic and (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (499 mg; 1.63 mmol, as a 1:1 mixture of regioisomers) and 2-aminothiazole (376 mg; 3.64 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Biotage 40M; eluent: 30% ethyl acetate/hexanes) (S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (221 mg): EI-HRMS calcd for C20H22FN3O2S (M+) 387.1417, found 387.1422; and impure (S)-3-Cyclohexyl-2-(7-fluoro-1-oxo-1,3dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide which was further purified by radial chromatography (eluent:35% ethyl acetate/hexanes) providing 48 mg of pure (S)-3-Cyclohexyl-2-(7-fluoro-1-oxo-1,3dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamideas a white foam: EI-HRMS m/e calcd for C20H22FN3O2S (M+) 387.1417, found 387.1415.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH:17]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[CH:17]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:37])=[CH:34][CH:33]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(Cl)cc1)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
To a solution of 6.4 g. 4-chlorophenol and 7.6 g. triethylamine in 500 ml. methylene chloride is added 10.4 g. 4-(8-cyclohexyloctylamino)benzoyl chloride hydrochloride in 250 ml. methylene chloride. After four hours at reflux, the solution is cooled, washed with water and dilute phosphoric acid, and dried. After passing the solution through a column of alumina, the solvent is evaporated an the residue is crystallized from diisopropyl ether.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([NH2:24])(=[O:23])[CH2:21][CH3:22].CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>CC(O)C>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[CH2:11][CH2:10][C:9]=1[NH:24][C:20](=[O:23])[CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(N)=O
Reactant: O=C1CCc2ccc(Br)cc2C1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCC(=O)NC1=C(Cc2ccccc2)c2cc(Br)ccc2CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
In a three-necked flask equipped with a Dean-Stark apparatus, heating mantle and magnetic stirrer were charged 1-benzyl-7-bromo-3,4-dihydronaphthalen-2(1H)-one (23.50 g, 74.6 mmol), propionamide (13.62 g, 186 mmol) and 4-methylbenzenesulfonic acid (1.284 g, 7.46 mmol) followed by toluene (200 ml). The resulting solution was heated to reflux overnight and monitored by HPLC (<6% starting material remained). The reaction mixture was cooled to r.t. and a suspension formed. To the mixture was added IPA and the resulting suspension was cooled to 0° C., stirred at 0° C. for 2 hours and filtered. The filtrate was concentrated and the residue was suspended in IPA/EtOH (50 ml/50 ml) at 0° C. for 1 hr and filtered to give additional product as a white solid. HPLC analysis indicated that both crops have similar purity. The solids were combined and further dried to give 22.5 g product as white solid.
Reaction SMILES: [Li].[O:2]([CH2:5][CH3:6])CC.IC.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2(C(O)=O)[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:18]2)=[CH:12][CH:11]=1>O>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2([C:5](=[O:2])[CH3:6])[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:21][CH2:22]2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(NC2(C(=O)O)CCN(CCc3ccccc3)CC2)cc1
Reactant: CCOCC
Agent: [Li]
Solvent: O
Solvent: CI
Product: CC(=O)C1(Nc2ccc(C)cc2)CCN(CCc2ccccc2)CC1
Reaction time: 0.75 h
Yield: 62.4 %

Procedure:
To a stirred solution of 17.4 parts of lithium in 140 parts of dry 1,1'-oxybisethane is added dropwise a small amount of a solution of 193.7 parts of iodomethane in 210 parts of dry 1,1'-oxybisethane. After the reaction is started by heating, there are added 420 parts of dry 1,1'-oxybisethane. The remainder of the solution is added dropwise at reflux temperature. Stirring at reflux is continued for 45 minutes. Then there are added portionwise (quickly) 41.8 parts of 4-[(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinecarboxylic acid (exothermic reaction: reflux temperature is maintained). Upon completion, stirring at reflux is continued for 1 hour. The reaction mixture is cooled in an ice-bath and decomposed by the dropwise addition of 1000 parts of water. The organic layer is separated and discarded. The aqueous phase is extracted with 1,1'-oxybisethane. The extract is dried, filtered and evaporated. The solid residue is crystallized from 2,2'-oxybispropane. The product is filtered off and recrystallized from 2,2' -oxybispropane, yielding 26 parts (62.4%) of 1-{4-[(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinyl} ethanone; mp. 133.7° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[CH:7][CH:6]=[CH:5]2.[C:13]1([CH3:23])[C:14]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1>>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:23])(=[O:21])=[O:20])=[CH:7][CH:6]=[CH:5]2
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc2c(O)cccc2c1
Product: Cc1ccccc1S(=O)(=O)Oc1cccc2cc(N)ccc12

Procedure:
Additional substituents can be added to the naphthol ring by reacting a 6-aminonaphth-1-ol (SM11) with toluene sulfonyl chloride in the manner disclosed above to yield the 6-amino-1-(methylphenylsulfonyloxy)naphthalene (NN). The 6-amino-1-(methylphenylsulfonyloxy)naphthalene (NN) was then reacted with t-butyl nitrite in a solvent, for example at 0° C. followed by a copper (II) halide, for example, copper (II) chloride, to yield the appropriate 6-halo-1-(methylphenylsulfonyloxy)naphthalene (PP). The 6-amino-1-(methylphenylsulfonyloxy)naphthalene (NN) was also reacted with an excess of a copper (II) halide, for example, copper (II) chloride, in a solvent followed by t-butylnitrite in the manner disclosed above to form the appropriate 5,6-dihalo-1 -(methylphenylsulfonyloxy)naphthalene (QQ). The appropriately substituted naphthalene (QQ) or (PP) can then reacted with a base, for example, potassium hydroxide, and an alcohol, for example, ethanol, in a mixture of a solvent, for example, THF, and water to yield the appropriately substituted naphthol (RR), for example 5,6-dichloronaphthol. When the naphthol was a 5,6-dihalonaphthol (RR) it was reacted with either the appropriately substituted benzaldehyde (BB), alcohol (CC), toluene (DD), or hydrochloride (EE) and a borane-pyridine complex under acidic conditions, or a base, for example, sodium hydride or triethylamine, in a solvent, for example DMF, or a phosphine complex, for example n-butylphosphine, and DPAD in a solvent, for example, THF, to form the targeted 1-substitutedalkylthio or alkoxy-4-((5,6-substituted naphth-1-yl)oxyalkyl)benzene (Ia), for example, (2-(4-((5,6-dichloronaphthyloxy)methyl)phenoxy)ethyl)diethylamine.