Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:31][CH:32]([CH3:35])[CH2:33]O.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:31][CH:32]([CH3:35])[CH3:33])=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Reactant: CC(C)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 46 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (1.1 g, 3.1 mmol) dissolved in 30 mL of dichloromethane was reacted with 1.8 mL (3.6 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 2-methylpropanol (0.57 mL, 0.46 g, 6.2 mmol) and 0.50 mL of pyridine (0.49 g, 6.2 mmol) in 20 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:5) to provide 0.62 g (48% yield) of the title compound (30a) as a colorless oil. Rf=0.69 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=0.98 (d, J=6.4 Hz, 1H), 1.07 (s, 3H), 1.09 (s, 3H), 1.99 (septet, J=6.4 Hz, 1H), 2.25-2.34 (m, 2H), 3.22-3.26 (m, 2H), 3.64 (t, J=6.0 Hz, 2H), 3.86 (s, 1H), 3.89-4.01 (m, 3H), 4.23-4.25 (m, 1H), 4.35 (d, J=11.2 Hz, 1H), 4.64 (d, J=11.2 Hz, 1H), 7.29-7.39 (m, 5H) ppm. MS (ESI) m/z 435.16 (M+H)+, 457.11 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([C@@H:22]1[C@H:25](OC(=O)C)[N:24]([NH2:30])[C:23]1=[O:31])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([SH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>C1C=CC=CC=1.C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([C@H:22]1[C@H:25]([S:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:24]([NH2:30])[C:23]1=[O:31])=[O:21])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1ccccc1
Reactant: CC(=O)O[C@H]1[C@@H](C(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1N
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: NN1C(=O)[C@@H](C(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1Sc1ccccc1
Yield: 80.6 %

Procedure:
A mixture of (3S,4S)-3-(N-benzyloxycarbonyl-L-phenylalanyl)-amino-4-acetoxy-azetidin-2-one (500 mg, 1.18 mmol) obtained in example 7, thiophenol (117 mg, 1.07 mmol), and zinc acetate dihydrate (207 mg, 0.95 mmol) in a mixture of benzene (20 ml) and toluene (20 ml) was refluxed for 4 hrs using Dean-Stark water separator. After cooling, the reaction mixture was partitioned between ethyl acetate, containing a small volume of acetone, and water. The organic layer was washed with water, brine and dried over sodium sulfate. After removal of the solvent to dryness, a white solid was washed with dichloromethane and 410 mg of the title compound was obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.[C:12]1([C@@H:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[C:12]1([C@H:18]([NH:20][C@@H:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:3]2[C:2]([F:11])([F:10])[F:1])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCCCC1C(F)(F)F
Reactant: C[C@H](N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@H](N[C@@H]1CCCC[C@@H]1C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
To a 1,2-dichloroethane solution of 2-(trifluoromethyl)cyclohexanone (10.0 g) and [(1S)-1-phenylethyl]amine (7.29 g) was added NaBH(OAc)3(25.51 g) at ambient temperature. After stirring for 2 days at ambient temperature, 150 mL of saturated aqueous sodium hydrogencarbonate was added. After extraction with EtOAc, combined organic layer was dried over MgSO4, filtered and evaporated to dryness in vacuo. The crude residue was purified by silica gel column chromatography (n-hexane:EtOAc=8:1 to 2:1) to give (1R,2S)—N-[(1R)-1-phenylethyl]-2-(trifluoromethyl)cyclohexanamine (7.83 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:3].[H-].[Na+].[Cl:14][CH2:15][CH2:16][CH2:17]I>CN(C)C=O.CCCCCC.C(OCC)C>[Cl:14][CH2:15][CH2:16][CH2:17][O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:2](=[O:3])[CH3:1])=[CH:10][CH:9]=1
Reactant: ClCCCI
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)Cc1ccc(OCCCCl)cc1
Reaction time: 0.05 h

Procedure:
A 4.50 g portion of p-hydroxyphenylacetone, prepared above, was dissolved in 80 mL of anhydrous dimethylformamide under a dry nitrogen atmosphere. With stirring 1.26 g of sodium hydride (as a 60% dispersion in oil) was added to the solution. After 3 minutes, 9.40 g of 1-chloro-3-iodopropane was quickly added. After stirring for approximately 18 hours, the reaction was diluted with 300 mL hexane and 100 mL diethyl ether. The resulting mixture was washed with distilled water, 5% sodium hydroxide solution, and brine. The remaining organic phase was dried and evaporated to dryness in vacuo. The yellow oil was purified by column chromatography over silica gel, using 22% ethyl acetate and 78% hexane. Appropriate fractions were pooled and solvents removed in vacuo to yield 3.06 g of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11]C)=[C:6]([CH:9]=1)C=O.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([OH:18])[CH:9]=1
Reactant: CCOc1ccc(Br)cc1C=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
A solution of 5-bromo-2-ethoxy-benzaldehyde (50 g, 233 mmol), in CH2Cl2 (150 mL) at 0-5° C., was treated with a solution of 3-chloroperoxybenzoic acid (70-75% purity) (68.1 g, 276 mmol) in CH2Cl2 (500 mL) and the reaction mixture allowed to warm slowly to room temperature and stirred for 72 h. The resulting precipitate was filtered and the filtrate then stirred for 2 h with a 2 N aqueous Na2SO2O3 solution (200 mL). The organic layer was then concentrated, dissolved in diethyl ether, and washed with an aqueous 1 N Na2SO3 followed by a half saturated NaHCO3 solution. The organic phase was extracted with a 2 N aqueous NaOH solution and the combined basic extract acidified (pH ˜3-4) with concentrated HCl. The acidified mixture was extracted with diethyl ether, dried over MgSO4, filtered, and evaporated to afford intermediate 5-bromo-2-methoxy-phenol (43.5 g, 90%). 1H NMR (CDCl3) 7.06 (br s, 1H), 6.96 (dd, J=8.6, 2.3, 1H), 6.70 (d, J=8.6, 1H), 5.67 (s, 1H), 4.05 (q, J=7.1, 2H), 1.44 (t, J=7.1, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH3:17])[CH2:10][C:11]1[S:15][C:14](Cl)=[N:13][CH:12]=1.[OH-].[NH4+]>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH3:17])[CH2:10][C:11]1[S:15][CH:14]=[N:13][CH:12]=1
Reactant: CC(O)(Cc1cnc(Cl)s1)c1ccc(Cl)cc1Cl
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(O)(Cc1cncs1)c1ccc(Cl)cc1Cl
Yield: 56 %

Procedure:
The 2-(2,4-dichlorophenyl)-1-(2-chlorothiazol-5-yl)propan-2-ol (6.4 g) obtained in Example 1 was dissolved in acetic acid (80 ml) and the mixture brought to reflux whereupon zinc dust (3.5 g) was added and the mixture was stirred under reflux for a further 2 hours and then cooled. Dilute ammonium hydroxide solution was added until the reaction mixture was basic and the mixture was then extracted into ethyl acetate (2×200 ml). The combined extract was washed with brine (50 ml), dried and then concentrated under reduced pressure. Flash chromatography of the residue on a silica gel column using petroleum ether-ethyl acetate as eluant gave 2-(2,4-dichlorophenyl)-1-(thiazol-5-yl)propan-2-ol (3.2 g) as a white solid, m.pt. 164° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1.Cl[Sn]Cl>CC(O)=O.Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2c(F)cccc2F)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Product: Nc1ccc(/C=C/c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
The procedure described for the preparation of 7 was repeated using 300 mg (1.15 mmol) of 8 in 20 mL of glacial HOAc and 1.85 g (9.76 mmol, 8.5 equiv) of SnCl2 in 3 mL of conc HCl to afford, after stirring ca. 12 h at 25° C. and quenching with water, a precipitate. The precipitate was collected by filtration, washed with 5 mL of glacial acetic acid and suspended in 80 mL of water. The aqueous suspension was adjusted to pH 9-10 with NaOH and was extracted with Et2O. The combined ethereal extracts were washed with water, dried over anhydrous MgSO4, and concentrated. The product was recrystallized from hexane to afford 220 mg (83%) of 9 as colorless crystals: mp 74-75° C. 1H NMR (DMSO-d6): δ 7.28 (d, 2H, J=8.8 Hz), 7.27-7.22 (m, 1H), 7.21 (d, 1H, J=16.8 Hz), 7.13-7.06 (m, 2H), 6.77 (d, 1H, J=16.8 Hz), 6.57 (d, 2H, J=8.8 Hz), 5.43 (s, 2H). 13C NMR (DMSO-d6): δ 160.35 (dd, J1=246.8 Hz, J2=8.0 Hz, two C), 150.06, 136.41 (t, J=7.9 Hz), 128.42 (two C), 127.99 (t, J=10.3 Hz), 124.68, 115.31 (t, J=15.1 Hz), 114.29 (two C), 112.33 (dd, J1=19.1 Hz, J2=6.3 Hz, two C), 108.84. MS: m/z (%) 232 (18), 231 (100), 183 (13). Anal. Calcd for C14H11F2N: C, 72.72; H, 4.79. Found: C, 72.77; H, 4.83.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[SH:9].[CH3:10][C:11]1[CH:12]=C[C:14](S(O)(=O)=O)=[CH:15][CH:16]=1.C1(C)C=CC(C)=CC=1.C=C1CC(C(Cl)=O)C1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:10]([CH:11]3[CH2:16][C:15](=[CH2:14])[CH2:12]3)[S:9][C:3]=2[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1ccc(Br)cc1S
Agent: C=C1CC(C(=O)Cl)C1
Solvent: Cc1ccc(C)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: C=C1CC(c2nc3ccc(Br)cc3s2)C1
Temperature: 50 °C
Yield: 250.1 %

Procedure:
The product of Example 1A (1.0 g, 4.90 mmole) was weighed into a 100 ml round bottom flask and pyrridium p-toluenesulfonate (0.37 g, 1.47 mmole) was added. The flask was placed on high vacuum overnight. Para-xylene (50 ml) was added followed by tiethylamine (0.68 ml, 4.9 mmole). The mixture was rapidly stirred at 50° C. to give an almost clear solution. A solution of 3-methylene-cyclobutanecarbonyl chloride (0.64 g, 4.9 mmole) (prepared according to literature procedure, JACS, 1959, 81, 2723-2728) in 10 ml xylene was then added dropwise over 15 minutes. The temperature was raised to 140° C. for 7 hours. The mixture was cooled to room temperature, followed by the addition of ethyl acetate (100 ml). The resulting solution was washed with saturated sodium bicarbonate, and the organic layer was dried (Na2SO4), and concentrated to give an oil. The crude product was purified by chromatography (20% hexane in dichloromethane) to give the title compound (1.03 g, 75%). 1H NMR (300 MHz, CDCl3) δ ppm 7.98 (d, J=2.03 Hz, 1H), 7.83 (d, J=8.82 Hz, 1H), 7.55 (dd, J=8.82, 2.03 Hz, 1H), 4.83-4.98 (m, 2H), 3.83-4.04 (m, 1H), 3.10-3.35 (m, 4H). MS: (M+H)+=279/281.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[CH:14]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]1.[BH4-].[Na+]>CO>[O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:19][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=Cc1cccc(OCC2CO2)c1
Reactant: NC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cc(CNC2CCCC2)cc(OCC2CO2)c1
Reaction time: 4 h
Yield: 79 %

Procedure:
To a solution of 3-(oxiran-2-ylmethoxy)benzaldehyde (1.0 g, 5.61 mmol) in MeOH (15 mL) was added cyclopentanamine (502 mg, 5.89 mmol) at room temperature. After 4 h, sodium borohydride (318 mg, 8.42 mmol) was added in portions and the mixture was stirred for another 1 h. The reaction mixture was quenched by adding aqueous 1 N HCl until the pH was adjusted to 4-5. The resulting solution was diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered and concentrated. The crude product was used in the next step without further purification. (1.1 g, yield 79%) MS (ESI+) e/z: 248.2 [M+1]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)([O:3]C(C)(C)C)=O.[CH2:15]([N:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)CC(O)=O)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:13]([C@H:9]1[NH:8][C:1](=[O:3])[CH2:15][N:17]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:12])[CH3:14]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(CC(=O)O)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H]1NC(=O)CN(Cc2ccccc2)C1=O
Temperature: 12.5 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (R)—N-BOC-2-aminobutyric acid (3.36 g) and ethyl N-benzylglycine (4.52 g) in dichloromethane (50 ml) at 15° C. was added dicyclohexylcarbodiimide (3.59 g). The temperature was maintained at 10-15° C. for a further 2 h and then allowed to stir at ambient temperature for a further 16 h. The mixture was filtered and the mother liquor collected and solvent evaporated under reduced pressure. The residue was re-dissolved in dichloromethane (20 ml) and hydrogen chloride gas passed through the mixture for 20 minutes. The mixture was quenched with aq. saturated sodium bicarbonate solution and extracted with ethyl acetate, collected, dried (MgSO4) and solvent evaporated under reduced pressure to leave a colourless oil. This was purified by crystallisation from ether/iso-hexane mixtures to give the subtitle compound as a white solid. Yield: 1.35 g
Reaction SMILES: [Cu][C:2]#[N:3].I[C:5]1[CH:10]=[C:9]([C:11]([N:13]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:14]2)=[O:12])[CH:8]=[CH:7][C:6]=1[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1>CS(C)=O>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH:15]2[CH2:16][CH2:17][N:13]([C:11]([C:9]3[CH:10]=[C:5]([C:2]#[N:3])[C:6]([C:24]4[CH:25]=[C:26]([C:34]([F:35])([F:36])[F:37])[CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=4)=[CH:7][CH:8]=3)=[O:12])[CH2:14]2)[CH:19]=1
Reactant: N#C[Cu]
Reactant: O=C(c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(I)c1)N1CCC(c2cccnc2)C1
Solvent: CS(C)=O
Product: N#Cc1cc(C(=O)N2CCC(c3cccnc3)C2)ccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C

Procedure:
Copper(I) cyanide (42.9 mg, 0.479 mmol) was added to a stirred solution of 4b (200 mg, 0.368 mmol) in DMSO (4.00 mL), and the resulting mixture was heated to 180° C. for 12 h. The reaction mixture was cooled to rt, quenched with satd. aq. NH4Cl and extracted with EtOAc. The combined organics were washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. The resulting crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (CH3CN/H2O as eluent, 0.05% TFA as modifier), followed by lyophilization of the purified fractions to afford the title compound 6a. m/z (ES) 490 (MH)+.
Reaction SMILES: C([S:4][C:5]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]([N:9]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:10][C:11]([OH:13])=[O:12])=[O:8])(=O)C.[OH-].[Na+]>>[SH:4][C:5]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]([N:9]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:10][C:11]([OH:13])=[O:12])=[O:8]
Reactant: COc1cccc(C(=O)N(CC(=O)O)C2CCCC2)c1SC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(C(=O)N(CC(=O)O)C2CCCC2)c1S

Procedure:
N-(2-Acetylthio-3-methoxybenzoyl)-N-cyclopentylglycine (4.4 g, 12.5 mmol) was stirred with excess sodium hydroxide solution for 2 hours at 25° C., then acidified and extracted with ethyl acetate. The extract was washed with water and brine, then dried and concentrated. The amorphous product was obtained by column chromatography of the residue.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1ccc(F)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,5 difluorobenzaldehyde. MS (ESI) m/z 505.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:25][C@H:26]2[CH2:46][CH2:45][C:28]3([O:32][C@H:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@@H:30]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:29]3)[CH2:27]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:51].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:51][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:15][CH:14]=2)[CH2:25][C@H:26]2[CH2:46][CH2:45][C:28]3([O:29][C@H:30]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C@@H:31]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:32]3)[CH2:27]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2ccccn2)cc1Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3ccccn3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-6-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]-1-(pyridin-2-yl)hexane-1,4-dione (698 mg) in acetic acid (5 mL) was added ammonium acetate (1.31 g), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (580 mg, yield 85%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C[O:2][C:3]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:5][N:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[S:5][N:4]=1
Reactant: COc1nsc(-c2ccccc2)c1C#N
Agent: Br
Solvent: CC(=O)O
Product: N#Cc1c(O)nsc1-c1ccccc1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A mixture of 20 g of 3-methoxy-4-cyano-5-phenyl-isothiazole [prepared by the method of U.S. Pat. No. 3,476,765] and 200 ml of a solution of 25 parts by weight of hydrobromic acid in 75 parts by weight of acetic acid was heated at 80°C with stirring for 1 hour and the resulting suspension was evaporated to dryness under reduced pressure. The residue was empasted with ethanol and the mixture was vacuum filtered to obtain 16 g of 3-hydroxy-4-cyano-5-phenyl-isothiazole in the form of white crystals melting at 234°C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[NH:16][C:17]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[N:19]=2)([CH3:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)(=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:17]2[NH:16][C:15]([C:11]3([CH3:14])[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[N:19][C:18]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(C)(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Yield: 40.8 %

Procedure:
To a stirring solution of 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-4-methylpiperidine-1-carboxylic acid tert-butyl ester (0.14 mmol, 60 mg) in THF (2.0 mL) was added lithium aluminum hydride (0.56 mmol, 0.56 mL of a 1M solution). The reaction was heated to reflux for 6 h, cooled, diluted with ethyl acetate (20 mL) and quenched with water (0.5 mL). The suspension was filtered and the filtrates washed with water (20 mL), dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The resulting solid was triturated with diethyl ether and filtered to give 20 mg of the title compound as a white powder.
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24]Cl)[CH3:21]>>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][S:1][C:2]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:21]
Reactant: CCN(CC)CCCl
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Agent: Cl
Product: CCN(CC)CCSc1nc2ccccc2c(=O)n1-c1ccccc1
Yield: 32.7 %

Procedure:
The title compound was prepared in a yield of 32.7%, using 2-mercapto-3-phenyl-4(3H)-quinazolinone in place of 3-isobutyl-2-mercapto-4(3H)-quinazoline and β-diethylaminoethyl chloride hydrochloride in place of 2-chloromethylpyridine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:4]=1[NH2:5].Cl.Cl[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH-].[Na+]>C(O)CCC.O>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:4]=1[N:5]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: ClCCNCCCl
Reactant: COc1ccc(C(F)(F)F)cc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Solvent: O
Product: COc1ccc(C(F)(F)F)cc1N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.7 %

Procedure:
A mixture of 6.65 g of 2-methoxy-5-trifluoromethylaniline, 6.21 g of bis-(2-chloroethyl)amine hydrochloride, 4.71 g of anhydrous potassium carbonate and 0.34 g of anhydrous potassium iodide in 70 mL of n-butanol was refluxed for 50 hours. The solvent was removed at reduced pressure and the residue was taken up in 400 mL of diethyl ether. The suspension was acidified with 3N anhydrous hydrogen chloride in diethyl ether and stirred at room temperature for 3 hours. The solid was collected by filtration and dissolved in 50 mL of water. The solution was acidified with 36% hydrochloric acid, washed with 3×50 mL of diethyl ether, alkalinised with excess 36% sodium hydroxide and extracted with 2×70 mL of diethyl ether. The organic layer was dried over sodium sulphate and evaporated to dryness at reduced pressure to give a residue which was purified twice by flash chromatography, first using chloroform/3N methanolic ammonia 100:3 and subsequently using the upper layer of a 4:5:1 mixture of water, n-butanol and glacial acetic acid. The solvents were removed by evaporation in vacuo to give a residue which was dissolved in water. The mixture was alkalinised with 2N sodium hydroxide and extracted with chloroform; the organic layer was dried over sodium sulphate and the solvent was removed under reduced pressure to afford 1.42 g (16%) of Compound 17A as an oil.