Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].S(Cl)([Cl:16])=O>>[CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:16])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: CNc1ccc(CO)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: CNc1ccc(CCl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
1.0 g (5.5 mmol) of 9 was dissolved in 25 ml thionylchloride at -78° C. cooled with dry ice/acetone bath. After it dissolved completely, the dry ice/acetone bath was removed and the reaction mixture allowed to warm up to room temperature and kept at room temperature for additional 1 hour. Thionylchloride was evaporated under vacuum at room temperature and the residue was washed with 5 ml cold diethylether and recrystallized from diethylether to yield 0.6 g (55%) of 10. Yellow, mp: 126°-128° C. 1H NMR: (DMSO-d6): δ 82.9 (s, 1H, NH), 8.15 (d, 1H, J=2.2 Hz, H-2), 7.60p, 1H, (dd, 1H, J=8.9, 2.2 Hz, H-6), 7.01 (d, 1H, J=9.0 Hz, H-5), 4.76 (s, 3H, CH2), 2.95 (s, 3H, CH3). Anal. Calcd for C8H9N2O2Cl: C, 47.89; H, 4.52; Cl, 17.67; N, 14.00; O, 15.95. found: C, 47.78; H, 4.49; Cl, 17.78; N, 13.82; O, 16.13.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:51][O:52][CH2:53][CH3:54])[C:15]([NH:17][CH:18]2[C:49](=[O:50])[N:20]3[C:21]([C:33]([O:35]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:34])=[C:22]([CH:25]=[CH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1.C(OC(C)C)(C)C>ClCCl.C1(OC)C=CC=CC=1>[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:51][O:52][CH2:53][CH3:54])[C:15]([NH:17][CH:18]2[C:49](=[O:50])[N:20]3[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH:25]=[CH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnc3)CS[C@H]12)c1nsc(N)n1
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=Cc3cccnc3)CS[C@H]12)c1nsc(N)n1
Reaction time: 2 h
Yield: 53.3 %

Procedure:
Trifluoroacetic acid (1.2 ml) was added to a suspension of benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (cis-trans mixture) (1.0 g) in dichloromethane (10 ml) and anisole (0.65 ml) at ambient temperature and stirred for 2 hours at the same temperature. To the resulting solution was added isopropyl ether (50 ml) and stirred. The precipitates, collected by filtration, were washed with diisopropyl ether. The precipitates were added to a mixture of ethyl acetate and water and adjusted to pH 7.5 with 20% aqueous potassium carbonate. The separated aqueous layer was adjusted to pH 3.5 with 10% hydrochloric acid under ice-cooling. The resulting precipitates were filtered off, washed with ice water and dried over phosphorus pentoxide in vacuo to give 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (cis-trans mixture) (0.4 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1B(O)O)(=[O:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: Cn1cnc(Nc2cc(Br)cn(C)c2=O)c1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cn(C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 90 °C
Yield: 94.3 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 268c (150 mg, 0.53 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (80.4 mg, 0.21 mmol), Pd(dppf)Cl2 (17.2 mg, 0.021 mmol), K3PO4 (89 mg, 0.42 mmol), sodium acetate (57.1 mg, 0.42 mmol), water (0.2 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 2.5 hrs. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (30:1 to 20:1) to afford 268d (110 mg, 37.2%) as brown solid. MS-ESI: [M+H]+ 556.4.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3]C1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:9]([C@H:5]1[C@@:4]([CH2:1][CH3:3])([OH:12])[CH2:8][CH2:7][N:6]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:23])([F:25])[F:24])[CH:15]=1)[CH3:11]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(C(F)(F)F)c2)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-diethylpyrrolidin-3-ol 0.5 oxalate (193 mg), 4-fluoro-2-(trifluoromethyl)benzonitrile (364 mg) and lithium carbonate (221 mg), the title compound was obtained as pale-yellow oil (yield: 219 mg, yield: 82%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19](#[N:21])[CH3:20]>O1CCCC1>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH2:20][C:19]#[N:21])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC#N
Reactant: CCOC(=O)CCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)CCCOCc1ccccc1
Temperature: 0 °C
Yield: 81.9 %

Procedure:
In a stream of argon, 248 ml of tetrahydrofuran was added to 26 g (0.65 mole) of 60% sodium hydride, and a solution of 72.2 g (0.325 moles) of ethyl 4-benzyloxybutyrate and 26.7 g (0.65 mole) of acetonitrile in 94 ml of anhydrous tetrahydrofuran was added dropwise over the course of 40 minutes, and the mixture was heated under reflux for 2.5 hours. After cooling, the reaction mixture was poured into ice water, and washed with a 1:1 mixture of hexane and ether. The aqueous layer was acidified with concentrated hydrochloric acid, and extracted with ether. The ether layer was washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting crude 6-benzyloxy-3-ketohexanenitrile was subjected to silica gel column chromatography. The column was eluted with a 1:1 mixture of hexane and ether to give 57.8 g (81.2%) of a pale yellow oily product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl.[NH:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[NH2:21]>C(O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:20]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:9][C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[N:21]1)[CH3:27]
Reactant: COc1ccc(CC=Cc2ccc(Br)cc2)cc1
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CN1N=C(c2ccc(OC)cc2)CC1c1ccc(Br)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of ([1-(4-bromophenyl)-3-(4-methoxypheyl)-propene]) (3.17 g, 10 mmol) and ethyl hydrazinoacetate hydrochloride (1.54 g, 10 mmol) in ethanol (50 mL) was heated to reflux for 4 h. After cooling to room temperature, the solution was concentrated, diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (5-10% ethyl acetate in heptane) provided [5-(4-bromo-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-acetic acid ethyl ester (3.25 g, 78%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[CH:20]=[CH:19][C:12]([O:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>COCCOC.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:20]=[CH:19][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:21][CH:22]=1
Reactant: COC(=O)COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(=O)c2ccc(OCC(=O)O)cc2)cc1
Reaction time: 3 h

Procedure:
9.0 g of the methyl ester (Example 1) are dissolved in 120 ml of 1,2-dimethoxyethane/water (4:1, v:v), and 15 ml of 2N NaOH are added. The mixture is stirred for three hours, and the pH is adjusted to 3 with 3N HCl. The organic solvent is evaporated off in vacuo, and the precipitated product is filtered off, washed with water and dried under high vacuum.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O1CCCC1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:20][S:21]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (10 g) and tetrahydrofuran (100 mL) were successively added methanesulfonyl chloride (5.98 g) and triethylamme (5.53 g) at 0° C. The mixture was stirred at room temperature for 2 hrs., and the reaction mixture was diluted with ethyl acetate and washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give tert-butyl 4-(methylsulfonyl)oxypiperidine-1-carboxylate as crystals. Recrystallization from ethyl acetate-hexane gave white prism crystals (13.2 g, yield 95%). melting point: 94–95° C.
Reaction SMILES: Cl.COC(=O)CCCCCN.[C:12]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])(=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[C@@H:25]2[C@@H:20]([NH:21][C:22]([NH:24]2)=[O:23])[CH2:19][S:18]1.NC1C=C2C(C([Cl:57])=C(OCCC3C=CC=CC=3)OC2=O)=CC=1.CCN(CC)CC>S(Cl)(Cl)=O.O>[C:12]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])(=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[C@@H:25]2[C@@H:20]([NH:21][C:22]([NH:24]2)=[O:23])[CH2:19][S:18]1.[C:12]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([Cl:57])=[O:35])(=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[C@@H:25]2[C@@H:20]([NH:21][C:22]([NH:24]2)=[O:23])[CH2:19][S:18]1
Reactant: Nc1ccc2c(Cl)c(OCCc3ccccc3)oc(=O)c2c1
Agent: COC(=O)CCCCCN
Agent: Cl
Agent: O=C(O)CCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cl)CCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(Biotinylamino)caproic acid was prepared from N-hydroxysuccinimido biotinate (Jasiewicz et al., Exp. Cell Res. 100, pp 213-217 (1976)) and 6-aminocaproic acid methyl ester hydrochloride by a previously described method (Hofmann et al., Biochemistry 23, pp 2547-2553 (1984)). 6-(Biotinylamino)caproic acid chloride was prepared by incubating 6-(biotinylamino)caproic acid (0.36 g, 1 mmole) in 4 ml of thionyl chloride at 25°-35° C. for 1 h, and excess thionyl chloride was removed under reduced pressure. The residue was dissolved in DMF and 7-amino-4-chloro-3-(2-phenylethoxy)isocoumarin (0.34 g, 1 mmole) and Et3N (0.1 g, 1 mmole) were added and the reaction mixture was stirred at r.t. overnight. The product was purified from column chromatography and eluted with CH2Cl2 :MeOH=10:1, yield, 28%, mp 163°-167° C., NMR was consistent with the assigned structure, mass spectra (FAB+) m/e=655 (M+1). Anal. Calc. for C33H39N4O6ClS.H2O: C, 58.87; H, 6.14; N, 8.32; Cl, 5.27. Found: C, 58.72; H, 6.22; N, 8.90; Cl, 5.50.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:32][CH:33]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CC(C)(C)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, yellow solid (110 mg, 90%), MS (ISP) m/z=487.5 [(M+H)+], mp 180° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-tert-butyl-benzoic acid.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7](O)(=[O:11])/[CH:8]=[CH:9]/[CH3:10]>O>[CH3:10][CH:9]1[C:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=2[C:7](=[O:11])[CH2:8]1
Reactant: C/C=C/C(=O)O
Reactant: C1=CCCCC1
Solvent: O
Product: CC1CC(=O)C2=C1CCCC2
Yield: 65.8 %

Procedure:
Cyclohexene (27.3 g, 0.33 mol), crotonic acid (28.7 g, 0.33 mol) and polyphosphoric acid (300 ml) were mechanically stirred under a nitrogen atmosphere at 60° C. for 30 minutes. The slurry was poured into water and the aqueous solution extracted with diethyl ether. The diethyl ether extract was washed successively with a 10 percent NaHCO3 solution and a saturated NaCl solution. The organic extract was then dried over anhydrous MgSO4. The solution was then filtered and the solvent removed under reduced pressure. The crude product was then purified via vacuum distillation (bp 87°-92° C. at 5 mm) to give 32.6 g (66 percent) of purified material.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH:11]=[O:12].[CH:13]1([Mg]Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl-].[NH4+].C[N+]1([O-])CCOCC1>O1CCCC1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C>[CH:13]1([C:11]([C:3]2[S:4][C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:10]3[C:2]=2[CH3:1])=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1c(C=O)sc2ncccc12
Reactant: Br[Mg]C1CCCCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1c(C(=O)C2CCCCC2)sc2ncccc12
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution (60 mL) of 3-methylthieno[2,3-b]pyridine-2-carbaldehyde (2.07 g) synthesized above in tetrahydrofuran was added a 1.0M solution (17.6 mL) of cyclohexylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-50% ethyl acetate/hexane) to give a yellow solid. To a mixture of the obtained solid, 4-methylmorpholine N-oxide (1.81 g) and acetonitrile (40 mL) was added tetrapropylammonium perruthenate (238 mg), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% ethyl acetate/hexane) to give the title object compound (1.50 g, 85%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]([F:16])[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:17][CH3:18])=[CH:9][CH:10]=3)[C@@:5]3([CH2:22][O:21][C:20]([NH2:23])=[N:19]3)[C:4]=2[CH:3]=1.C([Li])CCC.N#N.[O:31]1[CH2:34][C:33](=[O:35])[CH2:32]1>C1COCC1>[NH2:23][C:20]1[O:21][CH2:22][C@:5]2([N:19]=1)[C:6]1[CH:7]=[C:8]([O:17][CH3:18])[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:4]2=[CH:3][C:2]([C:33]2([OH:35])[CH2:34][O:31][CH2:32]2)=[CH:15][C:14]=1[F:16]
Reactant: COc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(Br)cc(F)c1O2
Reactant: O=C1COC1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(C3(O)COC3)cc(F)c1O2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a RBF was added (S)-2′-bromo-4′-fluoro-7′-methoxy-5H-spiro[oxazole-4,9′-xanthen]-2-amine (2.17 g, 5.72 mmol, prepared as described in Method BB40 but using 4-bromo-2-fluorophenol and 2-bromo-5-methoxybenzoic acid) and THF (30 mL). The resulting mixture was then cooled to −78° C. and butyllithium solution, 2.5M in hexanes (8.01 mL, 20.03 mmol, Aldrich) was added drop wise under N2. The resulting mixture was then stirred at −78° C. for 15 min. Then, oxetan-3-one (1.031 g, 14.31 mmol, Molbridge LLC) in THF (3 mL) was added slowly. After addition, the mixture was stirred at −78° C. for 1.5 h under N2. Then, the mixture was quenched with saturated sodium bicarbonate solution (5 mL) at 0° C. and the mixture was extracted with EtOAc (2×30 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was then dissolved in MeOH (30 mL) and silica gel was added. The solvent was removed and the solid mixture was purified by silica gel flash column chromatography using ISCO instrument (solid loading, 50%-100% EtOAc/hexane, then 10% MeOH in DCM) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 373 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[C:9]1([CH2:15][CH2:16][C:17]2[N:18]=[C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[S:20][CH:21]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.O>ClCCl>[C:9]1([CH2:15][CH2:16][C:17]2[N:18]=[C:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:24][CH2:23]3)[S:20][CH:21]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCC(=O)Cl
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCC(=O)N1CCC(c2nc(CCc3ccccc3)cs2)CC1
Reaction time: 8 h

Procedure:
Pentanoyl chloride (133 mg) is added to a solution of 4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg) and triethylamine (0.7 ml) in dichloromethane (3 ml). The mixture is stirred overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulphate and concentrated. The residue is purified. This gives 1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}pentan-1-one (179 mg).
Reaction SMILES: [ClH:1].O1CCOCC1.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:17]([OH:34])[C@@H:18]([NH:26]C(OC(C)(C)C)=O)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:1].[NH2:26][C@@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:17]([C:9]1[S:8][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)[OH:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(O)c1nc2ccccc2s1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(O)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 4 N hydrogen chloride/dioxane solution (6.3 ml) is added to (1RS,2S)-1-(2-benzothiazolyl)-2-(tert-butoxycarbonyl)amino-3-phenyl-1-propanol (0.64 g, Reference compound No. 9-1) under ice cooling, then the temperature is raised to room temperature, and the mixture is stirred for 30 minutes. The reaction mixture is concentrated under reduced pressure, diethyl ether is added to the residue, and precipitated crystals are filtered off to give the titled reference compound (0.56 g).
Reaction SMILES: Cl([O-])=O.[Na+].[OH:5]P([O-])(O)=O.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH:23]=[O:24])=[CH:21][N:20]=[C:19]2[C:25]2[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=2[F:33])=[CH:14][CH:13]=1.CC(=CC)C>O.C(O)(C)(C)C.C(OCC)(=O)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:22]([C:23]([OH:5])=[O:24])=[CH:21][N:20]=[C:19]2[C:25]2[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=2[F:33])=[CH:16][CH:17]=1
Reactant: O=Cc1cnc(-c2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: O=C(O)c1cnc(-c2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
A solution of sodium chlorite (80%, 2.53 g, 22.5 mmol), sodium phosphate mono-basic (210.6 mg, 1.76 mmol) in water was added to a solution of 1-(4-fluorophenyl)-2-(2,3,6-trifluorophenyl)-1H-imidazole-5-carb aldehyde (26) (720 mg, 2.25 mmol) and 2-methyl-2-butene (2M in THF, 7.53 mL, 15.1 mmol) in tert-butanol and the reaction was stirred for 15 minutes. Water and ethyl acetate were added and the layers were separated. The organic layer was washed with saturated sodium bicarbonate. The aqueous layer was acidified to pH 6 with 2N HCl and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-(4-fluorophenyl)-2-(2,3,6-trifluorophenyl)-1H-imidazole-5-carboxylic acid (27).
Reaction SMILES: O=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[C:24]1([C@@H:30]([NH2:32])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[B-](F)(F)(F)[O+](C)C>C1(C)C=CC=CC=1>[C:24]1([C@@H:30]([N:32]=[C:2]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:5]3([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:4][CH2:3]2)[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)c3ccccc32)CC1
Reactant: C[C@H](N)c1ccccc1
Agent: C[O+](C)[B-](F)(F)F
Solvent: Cc1ccccc1
Product: C[C@H](N=C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21)c1ccccc1

Procedure:
A solution of tert-butyl 4-oxo-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (A4) (5.0 g, 15.8 mmol), (S)-1-phenylethanamine (3.0 ml, 23.8 mmol) and boron trifluoride dimethyl etherate (0.5 ml, 5 mmol) in dry toluene (150 ml) was heated at 140° C. under a Dean-Stark trap for 24 hours. The solvent was distilled and the residue was cooled with an ice bath, dissolved in ethyl acetate, washed with saturated NaHCO3, and water. The organic phase was dried over Na2SO4, filtered and concentrated to give (S)-tert-butyl 4-(1-phenylethylimino)-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (B1) as a gum. LC-MS analysis of the crude indicated that there is trace of starting material (A4). LC-MS: m/e=419.37 (M+H). Rt=2.24 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:30])[CH2:10][CH2:9]1)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:30])[CH2:12][CH2:13]1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 41.8 %

Procedure:
To a solution of 540 mg (1.22 mmol) of 3-[1-(3-nitrobenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)quinazolinone in 50 mL of ethanol was added 826 mg (3.66 mmol) of SnCl2.2H2O, and the mixture was stirred for 12 hours at 60° C. After being cooled, the reaction mixture was filtered through cerite, and the filtrate was concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:19 methanol:chloroform) to give 210 mg (0.51 mmol) of the title compound.