Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7](O)=[N:8][CH:9]=1)([O-:3])=[O:2].O=S(Cl)[Cl:17].CN(C=O)C>>[Cl:17][C:7]1[C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1cnc(O)c(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
To a solution of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (1 g, 4.81 mmol) in SOCl2 (10 mL, 137 mmol) was added DMF (0.372 mL, 4.81 mmol). The resulting mixture was stirred at 80° C. for 16 h. After TLC analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in DCM (60 mL) and washed with aq NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE/EA=20/1) to yield a yellow solid of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (0.8 g, 3.53 mmol, 73.5% yield): 1H NMR (400 MHz, CD3OD) δ 9.42 (d, J=2.8 Hz, 1H), 8.91 (d, J=2.4 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][CH:37]=[C:38]([CH:41]=2)[CH:39]=[O:40])O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:20]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:11][C:2]([C:34]2[CH:35]=[N:36][CH:37]=[C:38]([CH:41]=2)[CH:39]=[O:40])=[N:3]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (2 g, 5.7 mmol) in 1,4-dioxane (40 mL) and H2O (8 mL) under nitrogen was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde (1.48 g, 6.30 mmol), and potassium carbonate (2.39 g, 17.0 mmol). Upon completion of addition, the reaction mixture was degassed with nitrogen for 15 min and then (1,1′-bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (0.46 mg, 0.050 mmol) was added. The reaction mixture was again degassed for 10 min with nitrogen. At the conclusion of this period, the reaction mixture was stirred at 90° C. for 16 h, then allowed to cool to room temperature and quenched by the addition of water. The reaction mixture was transferred to a separation funnel and the aqueous layer was extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by silica gel column chromatography using 2.7% MeOH in DCM as eluent to afford 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinaldehyde (1.8 g, 100% yield) as an off-white solid. LCMS Method Y: retention time 1.99 min; [M+1]=418.4.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][S:12]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCSc1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCS(=O)c1ccncc1
Yield: 79 %

Procedure:
To a solution of 4.03 g (15.0 mmol) of 4-[3-(t-butoxycarbonylamino)propylthio]pyridine in 100 ml of methylene chloride, 3.05 g (15.0 mmol) of m-chloroperbenzoic acid was added with stirring under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed two times with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol =10 : 1) to give 3.37 g of the desired compound (78.9% yield, colorless crystals).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][C:23]1[CH:28]=[CH:27][C:26](N)=[CH:25][CH:24]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].F[B-](F)(F)F.[H+].N([O-])=O.[Na+].P(P(O)(O)=O)(O)(O)=O.N>O.[Cu-]=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(Oc4ccc(N)cc4)c3c2c1COC
Agent: O=[Cu-]
Agent: F[B-](F)(F)F
Agent: N
Solvent: O
Product: CCOC(=O)c1ncc2[nH]c3cccc(Oc4ccccc4)c3c2c1COC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
978 mg of 5(-4-aminophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester is suspended in 2 ml of water and 10 ml of a 50% tetrafluoroboric acid. After cooling to 0° C., it is mixed drop by drop with a solution of 224 mg of sodium nitrite in 2 ml of water and stirred at 0° C. for 1/2 hour. Then it is mixed at the same temperature with a 60% hypophosphoric acid and 150 mg of copper(I) oxide, diluted with 10 ml of water and afterwards heated for 1/2 hour on the steam bath. After adjustment of the pH to 8 with soda and addition of ammonia, it is extracted with ethyl acetate. The ethyl acetate phase is evaporated and the residue chromatographed over silica gel with acetone: hexane=1:1 as eluant. 540 mg (57% of theory) of 5-phenoxy-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester with a melting point of 174°-176° C. is obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][NH:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][N:11]([CH3:10])[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CNCCO
Reactant: N#Cc1ccccc1F
Product: CN(CCO)c1ccccc1C#N

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 2-fluorobenzonitrile and N-methylethanolamine.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C@H:10]3[CH2:13][C@H:12]([N:14]4[CH2:18][CH2:17][CH2:16][CH:15]4[CH3:19])[CH2:11]3)=[N:7][C:6]=2[CH:20]=1.[F-].[K+].[CH3:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[C:26]([CH3:39])[N:25]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[OH-].[NH4+]>ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.O1CCOCC1>[CH3:23][C:24]1[C:29]([C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([C@H:10]4[CH2:13][C@H:12]([N:14]5[CH2:18][CH2:17][CH2:16][CH:15]5[CH3:19])[CH2:11]4)=[N:7][C:6]=3[CH:20]=2)=[CH:28][CH:27]=[C:26]([CH3:39])[N:25]=1
Reactant: CC1CCCN1[C@H]1C[C@H](c2nc3cc(Cl)ccc3s2)C1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(-c2ccc3sc([C@H]4C[C@H](N5CCCC5C)C4)nc3c2)c(C)n1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
In a 4 ml vial, the product of Example 91E (30 mg, 0.098 mmole), potassium fluoride (19 mg, 0.323 mmole) and tris(dibenzylideneacetone)dipalladium (5.3 mg, 0.0075 mmole) were charged and dried on high vacuum for 30 min. The product of Example 2A (34 mg, 0.147 mmole) was added followed by dioxane (1 ml) under nitrogen atmosphere. Tri-t-butylphosphine (10 wt % in hexane, 45 ul, 0.0147 mmole) was added last and the vial was sealed and heated at 85° C. overnight then 95° C. for 7 h. TLC (TLC conditions: 1% ammonium hydroxide and 10% methanol in dichloromethane on silica gel) showed a new spot besides the starting material. The reaction mixture was quenched with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluted by 0.35% ammonium hydroxide and 3.5% methanol in dichloromethane) to give 6 mg (16% yield) of title compound. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 7.93 (d, J=1.36 Hz, 1H), 7.89 (d, J=8.14 Hz, 1H), 7.47 (d, J=7.80 Hz, 1H), 7.30 (dd, J=8.48, 1.70 Hz, 1H), 7.08 (d, J=7.80 Hz, 1H), 3.80-3.94 (m, 1H), 3.46-3.60 (m, 1H), 3.02-3.15 (m, 1H), 2.66-2.84 (m, 3H), 2.60-2.61 (s, 3H), 2.50-2.54 (s, 3H), 2.26-2.40 (m, 2H), 1.62-2.04 (m, 4H), 1.43-1.58 (m, 1H), 1.15 (d, J=5.76 Hz, 3H). (M+H)+=378.
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH2:26][C:27]([O:29]C)=[O:28])[CH2:19][CH2:18]1)=[O:16].[OH-].[Li+]>O1CCCC1.O.C(OCC)(=O)C.O>[CH3:1][CH2:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:19][CH2:18]1)=[O:16]
Reactant: CCOCCn1c(C(=O)C2CCN(CCOCC(=O)OC)CC2)nc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCCn1c(C(=O)C2CCN(CCOCC(=O)O)CC2)nc2ccccc21
Temperature: 60 °C

Procedure:
Dissolve 1-[[(2-ethoxy)ethyl]-1H-benzimidazol-2-yl][1-(carbomethoxy methoxy ethyl)-4-piperidinyl]methanone (0.9 g, 2.15 mmol) in tetrahydrofuran/water (20 mL, 1/1). Add lithium hydroxide monohydroate (932 mg, 8.5 mmol). Seal the flask and warm to 60° C. for 3 hours. Dilute with ethyl acetate/water, acidify and separate the organic phase. Dry (MgSO4), evaporate the solvent in vacuo, and purify by ion-exchange chromatography to give the title compound.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(O)(=O)C.O[C@@H:10]1[C@@:34]2([CH3:35])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13][C@@H:12]([OH:37])[CH2:11]1.[OH-].[K+].C(O)(=O)C.O>C(OCC)C.CO>[C:1]([O:4][C@@H:10]1[C@@:34]2([CH3:35])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13][C@@H:12]([OH:37])[CH2:11]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CC(=O)O[C@H]1C[C@H](O)CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@]21C
Yield: 107.8 %

Procedure:
A solution of 600 mg of 1α-hydroxycholesterol diacetate (16) in 1.6 ml of diethyl ether was cooled to ice-bath temperature and 1.6 ml of 0.1 N KOH in methanol was added slowly with stirring. After stirring for 2.5 hours, acetic acid (0.25 ml) and water was added, the mixture was extracted with ether (3×), combined extracts were dried (Na2SO4) and evaporated to dryness to give 0.55 g of 1α-acetoxycholesterol (17), homogeneous on tlc. nmr (CDCl3) δ5.55 (1H, broad, C-6), 5.00 (1H, m, C-1), 3.62 (1H, m, C-3), 2.10 (3H, s, OAc).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[CH3:12][S:13](Cl)(=[O:15])=[O:14].Cl>O>[CH3:12][S:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: NCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
6-aminohexanoic acid (904 mg, 6.89 mmol) and NaOH (415 mg, 10.34 mmol) were dissolved in H2O (30 mL) and cooled to 0–5° C. Methanesulfonyl chloride (0.586 mL, 7.58 mmol) was added dropwise and the reaction mixture stirred for 2 h, then warmed to ambient temperature and stirred for an additional 2 h. The mixture was acidified with HCl (1 N) and extracted with EtOAc (3×15 mL). The extracts were combined, washed with H2O, then brine, dried over MgSO4, and filtered. Evaporation under reduced pressure gave 69 as a white crystalline solid (207 mg, 0.99 mmol, 14%). 1H-NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 6.91 (t, 1H), 2.90 (dt, 2H), 2.87 (s, 3H), 2.20 (t, 2H), 2.48 (m, 2H), 2.43 (m, 2H), 1.27 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([Cl:11])[S:9][CH:10]=1)=[O:5])C.[Li+].[OH-]>C1COCC1>[Cl:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1csc(Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1csc(Cl)n1
Temperature: 65 °C

Procedure:
To a stirred solution of 2-chlorothiazole-4-carboxylic acid ethyl ester (20.49 g, 0.107 mol) in THF (180 mL) at RT, a 1M solution of LiOH (aq) (160 mL, 0.160 mol) was added. The resulting solution was heated to 65° C. for 1 h. The solvent was evaporated in vacuo. The residue was treated with brine (100 mL) and acidified to pH 1 with 1M HCl (aq). The precipitate was filtered off, washed with H2O (2×50 mL) and Et2O (2×50 mL) and dried in a vacuum oven at 60° C. for 62 h to yield the title compound as a pale yellow solid. MS m/z: 164.1 (M+H). Calc'd. for C4H2ClNO2S-163.58.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=1.[Cl-].[NH4+]>CN(C)C=O>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=1
Reactant: OCC(F)(F)F
Reactant: N#Cc1cc(Cl)ccn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#Cc1cc(OCC(F)(F)F)ccn1
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
Into 7 ml of N,N-dimethylformamide was suspended 0.2 g of sodium hydride (60% oily), and 0.43 g of trifluoroethyl alcohol was added at 10° C. After stirring for 10 minutes, 0.5 g of 4-chloropyridine-2-carbonitrile was added, the mixture was stirred for 1 hour, and the reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert-butyl=methyl=ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.65 g of 4-(2,2,2-trifluoroethoxy)pyridine-2-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[N:12]1([C:18]2([CH2:28][NH2:29])[CH2:21][N:20]([S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])[CH2:19]2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C.C(O)(=O)C(O)=O>ClCCl.C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][CH2:28][C:18]1([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:21][N:20]([S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])[CH2:19]1)=[O:5]
Reactant: CCCS(=O)(=O)N1CC(CN)(N2CCOCC2)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCS(=O)(=O)N1CC(CNC(=O)c2ccc(Cl)cc2Cl)(N2CCOCC2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 4 %

Procedure:
tert-butyl {[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}carbamate (0.98 g, 2.6 mmol) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (2 eq) was added. The reaction was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue treated with saturated aqueous sodium carbonate. The product was extracted into dichloromethane. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give {[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}amine which was used without further purification. 2,4-dichlorobenzoyl chloride (0.14 ml, 1.0 mmol) was added to {[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}amine in dichloromethane (2 ml) and triethylamine (0.22 ml, 1.6 mmol) at 0° C. The reaction was stirred at 0° C. for 15 mins, before warming to room temperature. After 30 mins, lc-ms showed complete consumption of starting material. The reaction was quenched and the resulting mixture was partitioned between dichloromethane and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. Purification by preparative tlc led to 2,4-dichloro-N-{[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}benzamide as an oil (15 mg, 4%). This was dissolved in hot ethanol (1 ml) and oxalic acid (2 eq) in ethanol (minimum amount) was added. The ethanol was evaporated and the residue triturated with ether to give the oxalate salt of 2,4-dichloro-N-{[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}benzamide as a white solid (15 mg, 4%). Analytical LCMS: single peak (214 nm), 4.35 min. 1H NMR (400 MHz, DMSO): δ 8.70 (t, J=6.3 Hz, 1 H); 7.71 (d, J=2.0 Hz, 1 H); 7.54-7.46 (m, 2 H); 3.81-3.69 (m, 4 H); 3.59 (d, J=6.3 Hz, 6 H); 3.10-3.04 (m, 2 H); 2.56 (t, J=7.4 Hz, 4 H); 1.74-1.66 (m, 2 H); 0.97 (dd, J=7.4, 7.4 Hz, 3 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.[CH2:16]([O:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1)=[O:21])[CH:17]=[CH2:18]>>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([C:20]([O:19][CH2:16][CH:17]=[CH2:18])=[O:21])=[CH:23][CH:24]=3)=[O:30])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Reactant: C=CCOC(=O)c1ccc(CC(=O)O)cc1
Product: C=CCOC(=O)c1ccc(CC(=O)Nc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 4(c), by reaction of 2 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine with 2.2 g (10 mmol) of 4-(allyloxycarbonyl)phenylacetic acid, 3.7 g (92%) of the expected ester, melting point 49°-50° C., are obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].[CH2:16](I)[CH2:17][CH3:18]>CS(C)=O>[CH2:16]([O:1][C:2]1[C:3]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:17][CH3:18]
Reactant: Cc1cnc(CCCC#N)c(O)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCOc1cc(C)cnc1CCCC#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-hydroxy-2-(3-cyanopropyl)-5-methylpyridine from Example 3(a) (1.5 g), in dimethyl sulphoxide (11 ml) was first treated with sodium hydride (0.2 g) and then with n-propyl iodide in dimethyl sulphoxide (3 ml) at 17°-20° C. After stirring for four hours at room temperature, the solvent was removed in vacuo and the residue partitioned between chloroform and water, the chloroform extract was evaporated to dryness to give 3-n-propyloxy-2-(3-cyanopropyl)-5-methylpyridine (1.79 g) N.M.R. (CDCl3), assignment, δ(p.p.m.), multiplicity; O(CH2)2CH3, 1.07, t; OCH2CH2CH3, 1.86, m; CH2CH2CN, 2.12, m; CH2CN, 2.40, m; 5--CH3, 2.30, s; CH2 (CH2)2CN, 3.94, m; OCH2, 3.91, t; 4--H pyridyl, 6.96, m; 6--H pyridyl, 7.91, m;
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:17](Cl)(=[O:19])[CH3:18].Cl>ClC(Cl)C>[CH:11]1([C:5]2[CH:6]=[CH:7][C:8]([C:17](=[O:19])[CH3:18])=[CH:9][CH:10]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CC(=O)Cl
Reactant: c1ccc(C2CCCCC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc(C2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
Anhydrous aluminium chloride (1.65 g, 0.012 mol) is added to a solution of cyclohexyl benzene (1 g, 0.006 mol) and acetyl chloride (0.7 mL, 0.009 mol) in dichloroethane (10 mL) at −5° C. to 0° C. temperature. The reaction mixture is stirred at this temperature for 30 minutes and then treated with 2N hydrochloric acid (7 mL). It is extracted with dichloromethane (2×20 mL) and the combined extract is dried over sodium sulfate. After removing the solvent under reduced pressure the residue is purified by column chromatography (silica gel, 230-400 mesh, ethyl acetate:n-hexane 7:93) to get 1-(4-cyclohexylphenyl)ethanone.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].[CH3:9][O:10][C:11]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([S:24][CH3:25])[C:12]=1[C:13](O)=[O:14]>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:13](=[O:14])[C:12]1[C:16]([S:24][CH3:25])=[CH:17][C:18]([C:20]([F:23])([F:21])[F:22])=[CH:19][C:11]=1[O:10][CH3:9]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Reactant: N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1CCCC[C@@H]1N

Procedure:
The title compound, yellow foam, MS: m/e=385.1 [(M+H)+], was prepared in accordance with the general method of intermediate G from cis-1,2-diaminocyclohexane and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate A).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[NH2:15][C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[CH:17]=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:15][C:16]2[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[CH:17]=2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(N)n(C)n1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1Nc1cc(C)nn1C
Temperature: 80 °C
Yield: 79.7 %

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (4.6 g, 19.6 mmol) in ethanol (90 mL) is added 5-amino-1,3-dimethylpyrazole (4.4 g, 39.2 mmol). The mixture is heated for 22 hours at 80° C. The reaction is cooled to room temp and concentrated in vacuo. The solid which remains is dissolved in CHCl3 and washed with aqueous saturated NaHCO3 solution. The organic phase is dried (MgSO4), filtered and concentrated in vacuo and the resulting residue is purified over silica (50% EtOAc//hexanes, followed by 100% EtOAc) to afford 4.8 g of the desired product: 1H NMR (300 MHz, CDCl3) δ10.29 (s, NH), 8.82 (s, 1H), 6.30 (s, 1H), 4.43 (q, J=7.2 Hz, 2H), 3.77 (s, 3H), 2.53 (s, 3H), 2.30 (s, 3H), 1.45 (t, J=7.2 Hz, 3H); ESI+ MS: m/z (rel intensity) 308.0 (100, M++H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:15][CH2:16]Cl)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1)([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:2][N:3]([CH2:15][CH2:16][S:27][C:24]1[CH:25]=[CH:26][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CN(CCCl)CCc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCSc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Yield: 92.7 %

Procedure:
2-[N-Methyl-N-(4-nitrophenethyl)amino]ethyl chloride hydrochloride (3.0 g), 4-nitrothiophenol (1.7 g) and potassium carbonate (4.0 g) in acetonitrile (100 ml) were stirred at reflux for 16 hours. After evaporation, the residue was partitioned between water and ethyl acetate. The organic liquors were washed with saturated aqueous brine, dried (MgSO4), filtered and evaporated to give an orange oil (3.6 g). Chromatography on silica ("Kieselgel 60"-Trade Mark) eluting with ethyl acetate followed by collection of suitable fractions gave on evaporation the title compound as a yellow solid, (3.05 g), m.p. 56°-7°.