Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[CH2:13][C:12]2=[O:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO.CCOC(C)=O>[CH2:1]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:22])[CH2:13][CH:12]2[OH:23])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C1CC(O)C2(CCN(Cc3ccccc3)CC2)N1c1ccccc1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To a solution of 8-benzyl-1-phenyl-1,8-diazaspiro[4.5]decane-2,4-dione (2.3 g, 6.85 mmol) in methanol (50 mL) was added NaBH4 (0.78 g, 20.5 mmol) in portions at 15° C. The mixture was stirred for 1 h at 15° C. H2O (5 mL) was added slowly at 0° C. The solvent was removed under reduced pressure to give crude product, which was dissolved in EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated to give 8-benzyl-4-hydroxy-1-phenyl-1,8-diazaspiro[4.5]decan-2-one, which was used directly in the next step.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.[OH:17]O.Cl>C(OCC)C>[OH:17][C:4]1[C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][CH:3]=1
Reactant: OO
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: Cl
Solvent: CCOCC
Product: Oc1cccc2c1oc1ccccc12
Temperature: 0 °C

Procedure:
4-dibenzofuran boronic acid (4.02 g, 18.9 mmoles) is suspended in diethyl ether (50 mL). The suspension is cooled to 0° C. and hydrogen peroxide (30% in H2O) is added dropwise; the resulting mixture is heated to reflux for 1.5 hours to complete conversion of the starting material. The reaction mixture is then cooled to 0° C. and 1N HCl (4 mL) is added. The organic layer is washed with an aqueous solution containing 10% FeCl2, dried over Na2SO4 and evaporated to dryness to give 3.48 g of the desired compound which is employed in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=3[CH:25]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:38][O:37][C:35]([C:34]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=4[CH:25]=3)[C:10]([F:11])([F:13])[F:12])=[C:4]([Cl:27])[CH:3]=2)=[CH:30][C:29]=1[F:28])=[O:36]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cc1F
Temperature: 80 °C
Yield: 76 %

Procedure:
5-[2-(4-Bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (500 mg, obtained in Example 116, step 8), 3-fluoro-4-methoxycarbonyl-phenylboronic acid (320 mg, [CAS Reg. No. 505083-04-5]) and dichloro(1,1′-bis(diphenyl-phosphino)ferrocene)palladium(II)dichloromethane adduct (39 mg) were dissolved in dioxane (9 mL) and water (5 mL). To the reaction mixture was added 2.0 M aqueous Na2CO3 (0.81 mL). The mixture was heated to 80° C. for 2 hours. The reaction mixture was cooled, poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless foam (440 mg, 76%). MS (m/e)=555.2 [(M+NH4+)+], MS (m/e)=506.1 [(M−CH3O−)+].
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([CH2:15][CH2:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:22]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:40].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:40][C:7]1[C:6]2[N:22]=[C:3]([CH2:1][CH3:2])[N:4]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[C:5]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:15][CH2:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:10][C:9]=2[N:8]=1
Reactant: CCc1nc2cnc3cc(CCC(=O)N(C)C)ccc3c2n1CC(C)(C)O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cc(CCC(=O)N(C)C)ccc3c2n1CC(C)(C)O
Reaction time: 0.17 h

Procedure:
To a stirring solution of crude 3-[2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylpropanamide, (1.2 g, 3.3 mmol) in dichloromethane (75 mL) was added 3-chloroperoxybenzoic acid (60% pure, 941 mg, 3.6 mmol). After 18 hours concentrated ammonium hydroxide (50 mL) was added and the reaction was vigorously stirred for 10 minutes. p-Toluenesulfonyl chloride (690 mg, 3.6 mmol) was then added in one portion and the reaction was stirred for one hour. The fractions were separated and the aqueous fraction was extracted with chloroform (3×50 mL). The combined organic fractions were concentrated under reduced pressure. Purification of the residue by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-6% gradient of methanol in dichloromethane) followed by recrystallization from acetonitrile provided 651 mg of 3-[4-amino-2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylpropanamide as an off-white solid, mp 234-237° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[N:20]=[C:19]([N:17]2[CH:18]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[N:15]=[CH:16]2)[CH:24]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.4 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butylamide (example 278) (0.137 g, 0.24 mmol) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.100 g, 81%). MS (ISP) 519.2 [(M+H)+].
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9]O)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.C(Cl)(Cl)Cl.P(Br)(Br)[Br:19]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9][Br:19])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1
Reactant: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Temperature: -5 °C
Yield: 42.5 %

Procedure:
A 500-mL three-necked round-bottomed, flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was purged with nitrogen and charged with (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol (37.0 g, 148 mmol) and chloroform (160 mL). The reaction was cooled to −5° C. using an ice/acetone bath and phosphorous tribromide (40.0 g, 148 mmol) was added portionwise. The cooling bath was removed and the reaction stirred at reflux for 2 h. After this time, the reaction was cooled to −5° C. and saturated aqueous sodium bicarbonate (250 mL) was added until a pH of 8.5 was reached. The mixture was extracted with ethyl acetate (3×150 mL) and the combined organic layers were washed with saturated aqueous sodium carbonate (2×50 mL), brine (75 mL), dried over sodium sulfate and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to afford a yellow residue that was dissolved with gentle heating in methylene chloride (60 mL). Hexanes (approximately 20 mL) was added and the solution became cloudy. The mixture was heated until a solid precipitate formed, methylene chloride (9 mL) was added and the solution became clear. The solution was left to cool to room temperature and after 4 h the resulting crystals were collected by vacuum filtration. The filter cake was washed with a ice cold 1:2 mixture of methylene chloride:hexanes (2×20 mL) to afford 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (19.7 g). The combined filtrates were evaporated and the procedure was performed again to afford an additional 9.70 g of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole. The solids were combined and dried under high vacuum for 18 h to afford a 57% yield (26.0 g) of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole as white crystals: mp 95-97° C.; 1H NMR (300 MHz, CDCl3) δ 6.93 (s, 1H), 4.63 (t, 2H, J=6.0 Hz), 4.54 (s, 214), 3.86 (t, 2H, J=6.0 HZ).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(OC)c(OC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cc(OC)c(OC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5,6-dimethoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: C([O:3][C:4](=[O:34])[C@H:5]([OH:33])[CH2:6][C@H:7]([NH:22][C:23]([C:25]1[CH:29]=[C:28]([C:30](=[O:32])[CH3:31])[NH:27][N:26]=1)=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)C.[Li+].[OH-].O.CCO>>[C:30]([C:28]1[NH:27][N:26]=[C:25]([C:23]([NH:22][C@H:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)=[CH:13][CH:14]=2)[CH2:6][C@@H:5]([OH:33])[C:4]([OH:34])=[O:3])=[O:24])[CH:29]=1)(=[O:32])[CH3:31]
Reactant: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(C(C)=O)[nH]n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cc(C(=O)N[C@H](Cc2ccc(-c3cccc(Cl)c3)cc2)C[C@@H](O)C(=O)O)n[nH]1
Yield: 16.8 %

Procedure:
(2R,4R)-4-[(5-Acetyl-1H-pyrazole-3-carbonyl)amino]-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-pentanoic acid ethyl ester (72 mg, 150 μmol) was stirred at room temperature with LiOH (10.8 mg, 450 μmol) in water (450 μL, 25 mmol) and EtOH (450 μL, 7.7 mmol), overnight. The solvent was removed and the remaining material was purified by preparative HPLC to yield the title compound (11.5 mg) as a TFA salt.
Reaction SMILES: [C:1]1([CH:7]([CH3:18])[CH2:8][C:9]([O:11]C2C=CC=CC=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1(C)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH2:26]>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:26][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:9](=[O:11])[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:18]
Reactant: CC(CC(=O)Oc1ccccc1)c1ccccc1
Reactant: O
Reactant: Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CC(CC(=O)c1ccccc1O)c1ccccc1
Temperature: 130 °C
Yield: 38 %

Procedure:
Titanium(IV) chloride (7.89 g, 41.6 mmol) was dissolved in 1,2-dichloroethane (30 ml). To this solution was added dropwise at room temperature the solution of phenyl 3-phenylbutanoate (10 g, 41.6 mmol) in 1,2-dichloroethane (20 ml). The resulting dark brown solution was heated to 130° C. for 6 h, then cooled to 90° C. and toluene (40 ml) was added. The mixture was cooled to 5° C. and water (40 ml) was added carefully to keep the temperature below 10° C. The mixture was then transferred into a separatory funnel, the phases separated and the organic layer washed twice with water, then twice with 1 N aq. NaOH-solution (100 ml), followed by six washes with half saturated brine. The organic layer was dried with MgSO4 and the solvent removed in a rotary evaporator and the residue thoroughly dried to yield 3.82 g (38%) of a dark oil, which was bulb-to-bulb distilled at 170-180° C./0.05 mbar to yield 1.74 g (17%), which was further purified by column flash chromatography on silica to obtain 1.2 g (12%) of product, which was finally recrystallized from hexane/toluene 2:1 to yield 1.1 g (11%) of product as white crystals, melting point 76.8° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH:35]=[CH:34][CH:33]=1
Reactant: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2cccc(Cl)c2)CC1
Yield: 43 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone (example 21), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (43%).
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.C(OCC)(=O)C>CS(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: BrCCCCCBr
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(N(CCCCCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,5-dibromopentane (5 mL) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca. 5 cm). The silica was washed with more diethyl ether (ca 100 mL) to remove the excess of 1,5-dibromopentane. The crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a white solid. Yield: 1.01 g (609%). 1H-NMR (400 MHz, d6-DMSO) δ=1.40-1.52 (m, 2H), 1.75-1.85 (m, 2H), 3.52 (t, J=6.6 Hz, 2H), 3.78-3.89 (m, 2H), 6.64 (d, J=9.0 Hz, 2H), 7.72 (d, J=9.0 Hz, 2H), 8.97 (s, 2H). LRMS (FAB+): 334.1 (100, [M+H]+).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][NH:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:26]=O>C(O)=O>[CH3:26][N:18]1[CH2:19][C:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])([NH:15][S:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=2)(=[O:14])=[O:13])[CH2:17]1
Reactant: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CNC2)cc1
Reactant: C=O
Solvent: O=CO
Product: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CN(C)C2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Ethyl 2-(3-(4-pentylphenylsulfonamido)azetidin-3-yl)acetate (35 mg, 0.095 mmol) was dissolved into formic acid (2 mL). The solution was treated with formaldehyde (16 mg of 36% solution, 0.19 mmol). The mixture was stirred at 110° C. for 2 h. Solvent was removed under vacuum. The residue was added CH2Cl2(10 mL) and washed with saturated sodium bicarbonate (3×5 mL) and H2O (10 mL) dried over MgSO4 and concentrated. The residue was loaded onto a silica gel column and eluted with EtOAc/hexane (30% to 50%) to obtain the title compound as a white powder (20 mg, 55%). 1H NMR (400 MHz, CDCl3) δ 7.76 (d, 2H, J=7.6 Hz), 7.30 (d, 2H, J=7.6 Hz), 4.03 (q, 2H, J=7.2 Hz), 3.36 (d, 2H, J=7.2 Hz), 3.23 (d, 2H, J=7.2 Hz), 2.95 (s, 2H), 2.68 (t, 2H, J=7.6 Hz), 2.30 (s, 3H), 1.67-1.60 (m, 2H), 1.33 (br, 4H), 1.19 (t, 3H, J=7.2 Hz), 0.92 (m, 3H); MS ESI 383.2 [M+H]+, calcd for [C19H30N2O4S+H]+383.20.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O=S(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:26]2[CH2:27][CH2:28][CH:23]([N:20]3[CH2:21][CH2:22][CH:17]([CH2:16][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:18][CH2:19]3)[CH2:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(N2CCC(Cc3ccccc3)CC2)CC1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc(C2=CCC(N3CCC(Cc4ccccc4)CC3)CC2)cc1

Procedure:
4-Fluorophenyl magnesium bromide (10 mmole) and 4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanone (7.38 mmole) were reacted by the method described in Example 13 to give the intermediate mixture of cis and trans alcohols. This crude mixture was then dehydrated using SOCl2 in CH2Cl2 by the method described in Example 35 to give the crude product which was purified by chromatography on silica gel using ethyl acetate as the eluent. The pure product was converted the HCl salt in acetone using 12N HCl (23.3% overall, mp: 214-217° C.). Calc'd for C24H28NF.HCl.0.25H2O: C, 73.83%; H, 7.62%; N, 3.59%. Found: C, 73.85%; H, 7.61%; N, 3.56%.
Reaction SMILES: C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]1[S:27][C:26](=[O:28])[NH:25][CH:24]1[C:29]([OH:31])=O.[N+]([O-])(O)=O.[N+:36]([O:39][CH2:40][CH2:41][NH2:42])([O-:38])=[O:37]>O1CCCC1>[N+:36]([O:39][CH2:40][CH2:41][NH:42][C:29]([CH:24]1[CH:23]([C:19]2[O:18][CH:22]=[CH:21][CH:20]=2)[S:27][C:26](=[O:28])[NH:25]1)=[O:31])([O-:38])=[O:37]
Reactant: O=C1NC(C(=O)O)C(c2ccco2)S1
Reactant: NCCO[N+](=O)[O-]
Agent: CCOP(=O)(C#N)OCC
Solvent: O=[N+]([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2ccco2)S1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 56.6 %

Procedure:
1.58 ml of triethylamine and 0.47 ml of diethyl cyanophosphonate were added, whilst ice-cooling and stirring, to a suspension of 500 mg of 5-(furan-2-yl)-2-oxothiazolidine-4-carboxylic acid and 476 mg of N-(2-nitrooxyethyl)amine nitrate in 50 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 3.5 hours, after which the solvent was removed by distillation under reduced pressure. The crystals which precipitated were triturated with diisopropyl ether and collected by filtration. These crystals were recrystallized from methylene chloride, to give 400 mg of the title compound as colorless crystals, melting at 117°-118° C.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[B-](F)(F)(F)F.[CH3:22][CH2:23][O+](CC)CC>C(Cl)Cl>[CH2:1]([O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](=[NH:12])[O:11][CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC[O+](CC)CC
Reactant: CCCCCCOc1ccccc1C(N)=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCCCCOc1ccccc1C(=N)OCC
Reaction time: 48 h

Procedure:
To a solution of 2-hexyloxybenzamide (64 g; prepared as described by E. M. Bavin, F. J. Macrae, D. E. Seymour and P. D. Waterhouse, J.Pharm.Pharmacol., 1952, 4, 872) in anhydrous methylene chloride (830 ml.) was added, dropwise during 10 minutes with stirring, a solution of triethyloxonium borofluoride (55.2 g.) in anhydrous methylene chloride (170 ml.). The solution was stirred for a further 105 minutes, and allowed to stand at room temperature for 2 days. The solution was concentrated to 350 ml., and anhydrous diethyl ether (1750 ml.) was added. The precipitated solid was filtered off and washed with anhydrous diethyl ether to give ethyl 2-hexyloxybenzimidate borofluoride (62 g.), m.p. 68°-70° C., which was pure enough to use for the next stage of the synthesis. A pure sample, m.p. 73°-74° C., was obtained by recrystallisation of an aliquot from a mixture of anhydrous methylene chloride and anhydrous diethyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[CH:6][C:3]=1[CH:4]=[O:5].[C:15](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[CH3:15][O:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(-n2cnnn2)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1ccc(-n2cnnn2)cc1C=O
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 2-hydroxy-5-tetrazol-1-yl-benzaldehyde (2.63 mmol) in dimethylformamide (5 ml) was added potassium carbonate (3.95 mmol) and iodomethane (3.95 mmol) and the mixture was stirred under nitrogen atmosphere for 2 h. The mixture was poured into water (100 ml) and the white solid formed filtered to afford the title compound in a 67% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12](=[O:15])[CH2:13]Br)=[CH:4][C:3]=1[Cl:16].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH:12]([CH2:13][N:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[OH:15])=[CH:4][C:3]=1[Cl:16]
Reactant: Nc1c(Cl)cc(C(=O)CBr)cc1C(F)(F)F
Reactant: c1ccc(CNCCCCCCOCCc2ccccn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C(O)CN(CCCCCCOCCc2ccccn2)Cc2ccccc2)cc1C(F)(F)F
Reaction time: 1 h
Yield: 43.6 %

Procedure:
1-[4-Amino-3-chloro-5-(trifluoromethyl)phenyl]-2-bromoethanone (2.1 g), N-[6-[2-(2-pyridinyl)ethoxy]hexyl]benzenemethanamine (2.20 g) and N,N-diisopropylethylamine (0.94 g) were stirred together in tetrahydrofuran (45 ml) for 24 h at room temperature under nitrogen. The mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in methanol (80 ml) and sodium borohydride (0.63 g) was added portionwise to the solution at 0° under nitrogen. The mixture was stirred for 1 h and then 2N hydrochloric acid (40 ml) was added. The solvent was evaporated in vacuo, the residue partitioned between 8% sodium bicarbonate solution (150 ml) and ethyl acetate (100 ml). The organic phase was separated, and the aqueous phase re-extracted with ethyl acetate (100 ml). The combined organic extracts were dried and evaporated in vacuo to give a yellow oil. Purification by FCC eluting with toluene-ethanol-triethylamine (98:2:1) afforded the title compound as a yellow oil (1.59 g).