Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1.Br[C:27]1[S:31][C:30]([C:32]#[N:33])=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:10]=[C:9]([C:27]2[S:31][C:30]([C:32]#[N:33])=[CH:29][CH:28]=2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1
Reactant: Cc1c2n(c3c(B4OC(C)(C)C(C)(C)O4)cc(F)cc13)CCNC2=O
Reactant: N#Cc1ccc(Br)s1
Product: Cc1c2n(c3c(-c4ccc(C#N)s4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light brown solid (25 mg, 38%), MS (ISP) m/z=326.5 [(M+H)+], mp 249° C., was prepared in accordance with the general method of example 171, step B from 8-fluoro-10-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (Example 171, step A) (68.8 mg, 0.2 mmol) and commercially available 5-bromothiophene-2-carbonitrile (56.4 mg, 0.3 mmol).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].[C:30]([OH:35])(=[O:34])[CH:31]([CH3:33])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH:31]([C:30]([OH:35])=[O:34])[CH3:33])=[O:26])=[CH:28][CH:29]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: CC(O)C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(=O)O)cc1

Procedure:
A flask containing 10.0 g. 4-(15-carbomethoxypentadecylamino)benzoic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4 A Linde molecular sieves. The solution is refluxed for 4 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon the product separates as off-white crystals.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:11][CH2:12][CH:13]1[CH2:16][CH2:15][CH2:14]1)=[O:5])C.[CH3:17][S:18]([NH:21][C:22]1[CH:37]=[CH:36][C:25]2[NH:26][C:27]([CH2:32][C:33](O)=[O:34])=[N:28][S:29](=[O:31])(=[O:30])[C:24]=2[CH:23]=1)(=[O:20])=[O:19].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+]>CN(C)C=O.C(O)C>[CH:13]1([CH2:12][N:11]2[C@@H:7]3[C@@H:6]([CH2:10][CH2:9][CH2:8]3)[C:4]([OH:5])=[C:32]([C:27]3[NH:26][C:25]4[CH:36]=[CH:37][C:22]([NH:21][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:23][C:24]=4[S:29](=[O:30])(=[O:31])[N:28]=3)[C:33]2=[O:34])[CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)C1CCCC1NCC1CCC1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(CC3CCC3)C1=O)N2
Yield: 29.2 %

Procedure:
2-(Cyclobutylmethyl-amino)-cyclopentanecarboxylic acid ethyl ester (0.22 g, 0.96 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.32 g, 0.96 mmol) was added followed by N-methylmorpholine (0.22 mL, 2.02 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.19 g, 1.01 mmol) was added and the mixture was stirred at 25° C. for 16 h. The reaction was quenched via addition of saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined and washed with saturated aqueous brine solution (20 mL). The resulting solution was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in ethanol (10 mL). A 21% w/w solution of sodium ethoxide in ethanol (1.08 mL, 2.88 mmol) was added. The reaction was refluxed for 16 h. The reaction was quenched via the addition of saturated aqueous ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The organic layer was further washed with saturated aqueous sodium bicarbonate solution (2×20 mL), saturated aqueous brine solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a clear oil. Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-5% methanol in dichloromethane) afforded the desired product, cis-N-[3-(1-cyclobutylmethyl-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (0.14 g, 0.28 mmol, 29%) as a pale yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.42-1.64 (4H, m), 1.72-1.87 (5H, m), 1.90-2.05 (2H, m), 2.08-2.19 (2H, m), 2.66 (1H, bs), 3.06 (3H, s), 3.74-3.79 (1H, m), 3.86 (1H, bs), 7.13-7.17 (2H, m), 7.49-7.57 (3H, m), 10.16 (1H, s). LC-MS (ESI) calcd for C21H26N4O6S2 494.58, found 495.4 [M+H+].
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:11]([CH3:21])[CH2:10][N:9]1[C:22](OC)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CCOC(C)=O>C(Cl)Cl>[CH2:14]([N:12]1[C@@H:11]([CH3:21])[CH2:10][N:9]2[C:22](=[O:23])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][C@@H:8]2[CH2:13]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)N1C[C@@H](C)N(Cc2ccccc2)C[C@@H]1Cc1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: C[C@H]1CN2C(=O)c3ccccc3C[C@@H]2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
A mixture of (2S,5R)-methyl 2,4-dibenzyl-5-methylpiperazine-1-carboxylate (0.28 g, 0.83 mmol), phosphorous oxychloride (5.0 ml) and phosphorous pentoxide (0.48 g, 1.6 mmol) was stirred at 100° C. under nitrogen overnight. The reaction was removed from the heat, quenched with ice, and brought to pH 7 to 8 with 1 N NaOH. Extraction with EtOAc (3×) and washing the combined organic layers with brine and drying over MgSO4 afforded 0.11 g of crude product after evaporation of the solvent. Flash chromatography (SiO2, CH2Cl2 to 60% EtOAc in CH2Cl2) afforded pure product (47 mg, 19% yield). MS (ESI) 307 (M+H).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:13]1=[O:31])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH2:23]2)[C:13]1=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](NC(=O)OCc3ccccc3)C2=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](N)C2=O)CC1
Yield: 77.9 %

Procedure:
(S)-tert-butyl 3-(benzyloxycarbonylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (20.9 g, 48.4 mmol) was dissolved in methanol (250 mL). 10% Pd/C (500 mg) was added and stirred under balloon pressure hydrogen overnight. The reaction was filtered through celite and concentrated. The residue was purified over silica gel (50-100% EtOAc in hexanes followed by 5% ammoniated methanol in CH2Cl2) to afford (S)-tert-butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (11.2 g, 37.7 mmol, 77.8% yield) as white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[S:23][C:22]([CH3:24])=[N:21][C:20]=3[CH3:25])[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)=[O:4].[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[CH3:24][C:22]1[S:23][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)=[CH:7][CH:8]=3)[N:18]=2)=[C:20]([CH3:25])[N:21]=1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CCl)cc3)n2)s1
Reactant: c1c[nH]cn1
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)Cn4ccnc4)cc3)n2)s1

Procedure:
By treatment of 2-chloro-N-{4-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-acetamide with 1H-imidazole. 1H-NMR (DMSO-D6) δ: 2.61 (s, 3H, CH3), 2.63 (s, 3H, CH3), 4.86 (s, 2H, CH2), 6.88 (s, 1H, Aryl-H), 7.04 (d, 1H, J=5.9 Hz, pyrimidinyl-H), 7.15 (s, 1H, Aryl-H), 7.50 (d, 2H, J=7.8 Hz, Ph-H), 7.62 (s, 1H, Aryl-H), 7.68 (d, 2H, J=7.8 Hz, Ph-H), 8.48 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.60 (s, 1H, NH), 10.18 (brs, 1H, NH). MS (ESI+) m/z 406.02 [M+H]+ (C20H19N7OS requires 405.48).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1>C(#N)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:12]2[CH2:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: C1CNC1
Solvent: CC#N
Product: Nc1nc(N2CCC2)c2nc[nH]c2n1
Temperature: 62 °C
Reaction time: 24 h

Procedure:
2-Amino-6-chloropurine (Sigma, lot #69F4064, 1.0 g, 5.8 mmol) was suspended in 50mL acetonitrile. Azetidine (Aldrich, lot #05606HV, 1.0 g, 17.5 mmol) was added and the reaction stirred at 62° C. for 24 hours. The solvents were evaporated to give a white solid which was recrystallized from methanol to yield 0.71 g (3.7 mmol, 65%); mp=280° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][N:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[NH:5][CH2:4]1.[CH3:19][S:20]([C:23]1[N:28]=[C:27]([C:29](Cl)=[O:30])[CH:26]=[CH:25][N:24]=1)(=O)=O.[OH-].[Na+]>ClCCl>[CH3:18][N:2]([CH3:1])[CH:3]1[CH2:7][N:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:5]([C:29]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([S:20][CH3:19])[N:28]=2)=[O:30])[CH2:4]1
Reactant: CN(C)C1CNN(C(=O)Cc2ccc(F)cc2)C1
Reactant: CS(=O)(=O)c1nccc(C(=O)Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CSc1nccc(C(=O)N2CC(N(C)C)CN2C(=O)Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(4-dimethylamino-pyrazolidin-1-yl)-2-(4-fluorophenyl)-ethanone, 22, (2.5 g, 10 mmol) in dichloromethane (20 mL) is added 2-methylsulfonyl-pyrimidine-4-carbonyl chloride (3.7 g, 20 mmol) followed by dropwise addition of a 1.0 N aqueous solution of sodium hydroxide (35 mL). The mixture is vigorously stirred at room temperature for 12 hours. The reaction is diluted with dichloromethane (100 mL) and washed with water (100 mL). The aqueous layer is back-extracted with dichloromethane (100 mL). The combined organic layers are washed with a saturated aqueous solution of sodium bicarbonate (100 mL) and brine (100 mL), dried, filtered and concentrated in vacuo. The resulting crude material is purified over silica (1:1 hexane/ethyl acetate to 100% ethyl acetate) to afford the desired product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].NC(N)=O.[CH3:9][C:10]1([CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[CH2:11]1>>[CH3:9][C:10]1([CH3:20])[C:18]2[C:13](=[CH:14][C:15]([N+:1]([O-:4])=[O:2])=[CH:16][CH:17]=2)[C:12](=[O:19])[CH2:11]1
Reactant: CC1(C)CC(=O)c2ccccc21
Reactant: O=[N+]([O-])O
Agent: NC(N)=O
Product: CC1(C)CC(=O)c2cc([N+](=O)[O-])ccc21
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A mixture of nitric acid (90% fuming, 35 mL) and urea (0.17 g) was cooled to -10° C. and purged with air for 20 minutes; 3,3-dimethyl-1-indanone (8.68 g, 54.2 mmoles) was added and the reaction was stirred for two hours at -10° C. to 5° C. The reaction mixture was poured into ice/H2O and extracted with ethyl acetate. The combined extracts were washed with distilled H2O, saturated NaHCO3 solution, saturated NaCl solution, and dried over MgSO4. The solvent was recovered under vacuum to obtain 10.0 g of a yellow solid. The crude product was recrystallized from methanol in two crops to obtain 8.08 g (71%) of the title D compound as yellow needles. MS: M- @ 205.
Reaction SMILES: [Cl:1][C:2]([Cl:14])([Cl:13])[CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:12][CH:3]([C:2]([Cl:13])([Cl:14])[Cl:1])[C:4]2[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(O)cc1
Reactant: COc1ccc(C(O)C(Cl)(Cl)Cl)cc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc(OC(c2ccc(OC)cc2)C(Cl)(Cl)Cl)cc1
Reaction time: 8 h

Procedure:
α-trichloromethyl-p-methoxybenzyl alcohol, 5.0g, and p-methoxyphenol, 2.48g, were added to a mixture of phosphorus pentoxide, 18g, and phosphoric acid, 12 ml, and heated for 1 hr. on the steam bath. After standing overnight, ice was added and the mixture extracted with ether. The product was purified by column chromatography on silica gel and eluted with 5% ether in petroleum ether (60°-68°C) to give α-trichloromethyl-p-methoxybenzyl p-methoxyphenyl ether, mp 90°C. This method of synthesis is referred to in Table I as method B.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)=[O:4].[CH3:18][O:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:18][O:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:2]([CH3:17])[C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)=[O:4])=[CH:24][CH:23]=1
Reactant: COCOc1ccc(O)cc1
Reactant: CC(Br)C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCOc1ccc(OC(C)C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.91 g (9.3 mmol) of 2-bromo-N-(4-(trifluoromethoxy)phenyl)propanamide, 1.58 g (10 mmol) of 4-(methoxymethoxy)phenol, 1.52 g (11 mmol) of powdered, anhydrous potassium carbonate and 35 ml of acetonitrile was warmed, under N2, at reflux for a period of 5.5 hours and then stirred at room temperature overnight. The resulting mixture was poured into water and extracted with two portions of ether. The combined organic layers were washed twice with 5 percent aqueous NaOH, treated with charcoal and MgSO4, filtered and the filtrates evaporated to dryness. The residue was recrystallized from hexane to leave 1.77 g (49 percent of theoretical) of the above-named product as a colorless solid, m.p. 115°-116° C. The product is identified on the basis of IR and NMR analyses.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:13](Cl)(=[O:16])[CH:14]=[CH2:15]>C(Cl)Cl.O>[N:1]1([C:13](=[O:16])[CH:14]=[CH2:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCCC1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
To a stirred solution of pyrrolidine (2 g, 28.16 mmol) in anhydrous DCM (30 ml) was added triethylamine (15.56 ml, 111.88 mmol) and acryloyl chloride (3.04 g, 33.77 mmol) at 0° C. The reaction mixture was stirred at 20-35° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers was washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get the desired compound as a brown liquid (1.1 g, 31%). 1H NMR (400 MHz, DMSO-d6) δ 6.49-6.33 (m, 2H), 5.66 (dd, J=9.8, 2.4 Hz, 1H), 3.54 (dt, J=6.8, 3.9 Hz, 4H), 2.02-1.91 (m, 2H), 1.90-1.82 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[OH:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC.[OH-].[Na+]>C(Cl)Cl>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCCC2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(=O)C2CCCC2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
To a solution of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclopentyl-methanol (44,5 mg, 0.077 mmol) in methylene chloride (1.0 mL) at room temperature was added Dess-Martin periodinane reagent (35.7 mg, 0.084 mmol). The mixture was stirred at room temperature for 1.5 hours. Ether and 1N sodium hydroxide was added. The mixture was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to yield a pale yellow oil (41.6 mg, 94%). 1H NMR (400 MHz, CDCl3) δ ppm 1.58-1.72 (m, 4H) 1.75-1.88 (m, 4H) 3.48-3.58 (m, 1H) 4.18 (s, 3H) 4.81 (s, 2H) 4.88 (s, 2H) 7.53 (s, 1H) 7.57 (d, J=8.30 Hz, 1H) 7.66 (s, 2H) 7.71 (d, 1H) 7.73 (s, 1H). MS (ES+) Calc: 579.2, Found: 580.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][CH:15]=[CH:16][N:17]=1.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:17][CH:16]=[C:15]([N+:18]([O-:20])=[O:19])[N:14]=1
Reactant: FC(F)(F)c1cc(Cl)c(-c2ncc[nH]2)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1c[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 70 °C

Procedure:
A mixture of 2-(2,6-dichloro-4-trifluoromethylphenyl)imidazole (5.62 g, 0.02 mol), nitric acid (70% w /w, 5.6 ml) and sulphuric acid (98% w /w, 5.6 ml) was stirred and heated at 70° C. for a total of 51 hours. After cooling the reaction mixture was poured into a mixture of ice and water (approximately 75 ml) and the precipitated solid was filtered off. It was purified by mplc on silica eluted with a mixture of ethyl acetate and dichloromethane (1:20) to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-nitroimidazole (4.21 g), m.p. 254°-255° C., as a cream crystalline solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]1[CH2:12]C1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.CO>[CH2:1]([NH:8][CH:9]1[CH2:10][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCC2CC2)cc1
Solvent: ClCCl
Solvent: CO
Product: c1ccc(CNC2CC2)cc1

Procedure:
The title compound is prepared analogously as described for benzyl-cyclopropylmethylamine. TLC, Rf (CH2Cl2/MeOH 95:5)=0.1, MS (LC-MS): 148.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:20]=[C:19]([F:29])[CH:18]=2)=[CH:7][CH:6]=1.[OH:31][CH2:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:29][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:20]=1)[C:16]([NH:15][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([O:4][CH2:3][CH2:2][N:36]2[CH2:37][CH2:38][CH:33]([CH2:32][OH:31])[CH2:34][CH2:35]2)=[CH:6][CH:7]=1)=[O:30]
Reactant: OCC1CCNCC1
Reactant: O=C(Nc1ccc(OCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Product: O=C(Nc1ccc(OCCN2CCC(CO)CC2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from N-[4-(2-chloroethoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and 4-hydroxymethylpiperidine according to conditions described in general procedure N. 1H NMR 300 MHz (CDCl3) 8.32 (dd, 1H, J=1.5 and 8.4 Hz), 7.88 (s, 1H), 7.83 (d, 1H, J=8.4 Hz), 7.73 (d, 1H, J=8.1Hz), 7.54 (m, 2H), 7.31 (s, 1H), 6.98 (d, 1H, J=8.4 Hz), 6.84 (d, 1H, J=7.8 Hz), 6.76 (d, 1H, J=11.7 Hz), 4.32 (t, 2H, J=5.7 Hz), 3.51 (d, 2H, J=6.3 Hz), 3.28 (m, 4H), 3.1 (m, 2H), 2.99 (t, 2H, J=5.7 Hz), 2.23 (dt, 2H, J=2.7 and 11.4 Hz), 1.32-1.8 (m, 11H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:35])[CH:5]([CH:24](O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:6]([CH:8]=[CH:9][CH:10]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.CN(C1C=CC=CN=1)C.CS(Cl)(=O)=O.C(OCC)(=O)C>ClCCl>[CH3:1][S:2][C:3]1[C:4](=[O:35])[C:5](=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:6]([CH:8]=[CH:9][CH:10]([O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1
Reactant: CCCCCC(C=CC1C=C(SC)C(=O)C1C(O)CCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCC(C=CC1C=C(SC)C(=O)C1=CCCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 15 h
Yield: 64.2 %

Procedure:
To a solution of 3.47 g of 2-methylthio-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-(3-t-butyldimethylsilyloxy-1-octenyl)-2-cyclopentenone obtained in Example 6 in dichloromethane (30 ml) was added dimethylaminopyridine (1.54 g) and the mixture was cooled to 0° C. To the solution was dropwise added 0.59 ml of methanesulfonyl chloride, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture were added ethyl acetate and an aqueous potassium hydrogensulfate, and the product was extracted into an organic layer. The extract was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride, dried over anhydrous magnesium sulfate, and filtered, followed by concentration. The concentrate was subjected to silica gel chromatography to give 2.15 g (yield 64%) of 2-methylthio-5-(6-methoxycarbonylhexylidene)-4-(3-t-butyldimethylsilyloxy-1-octenyl)-2-cyclopentenone.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH2:10][CH3:11])[CH:5]=[C:4]([Br:12])[C:3]=1[CH3:13].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>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].C1(C)C=CC=CC=1>[CH2:14]([NH:21][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH2:10][CH3:11])[CH:5]=[C:4]([Br:12])[C:3]=1[CH3:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOCc1cc(Br)c(C)c(Br)c1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOCc1cc(Br)c(C)c(NCc2ccccc2)c1
Temperature: 80 °C
Yield: 88.4 %

Procedure:
A mixture of 1,3-dibromo-5-ethoxymethyl-2-methyl-benzene (1.322 g, 4.29 mmol), benzylamine (0.49 mL, 4.507 mmol), Pd2(dba)3 (409 mg, 0.447 mmol), rac-BINAP (811 mg, 1.302 mmol), NaOtBu (618 mg, 6.435 mmol) and toluene (30 mL) was heated at 80° C. for 1 h 45 minutes. The reaction was cooled, poured onto water and extracted with EtOAc (×3). The organics were washed with water, brine and dried (Na2SO4). Chromatography (Hexanes/EtOAc) afforded benzyl-(3-bromo-5-ethoxymethyl-2-methyl-phenyl)-amine (1.268 g) as a yellow liquid. 1H NMR (400 MHz, d6-DMSO) δ: 1.24 (t, 3H), 2.32 (s, 3H), 3.50 (q, 2H), 4.04 (bs, 1H), 4.41 (s, 4H), 6.61 (s, 1H), 7.00 (s, 1H), 7.35 (m, 5H) ppm.