Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:24]([Mg]Br)[CH3:25]>C1COCC1>[C:16]1([NH:15][C:6]2[C:5]([C:4](=[O:22])[CH2:24][CH3:25])=[CH:10][CH:9]=[C:8]([C:11]([F:12])([F:13])[F:14])[N:7]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
In a 250 mL round-bottomed flask, N-methoxy-N-methyl-2-phenylamino-6-trifluoromethyl-nicotinamide (1.73 g, 5.32 mmol) was combined with THF (20 mL) to give a brown solution and the solution was cooled to 0° C. Ethylmagnesium bromide (1.0 M in THF) (16 mL, 16.0 mmol) was added dropwise at 0° C. over 5 min. The reaction mixture was stirred in an ice bath for 2.5 hr and 1 hr at room temperature. Additional ethylmagnesium bromide (1.0 M in THF) (6 mL, 6.00 mmol) was introduced over 3 min and the mixture was stirred for 2 hr at room temperature. The reaction mixture was cautiously quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (1×50 mL), dried over MgSO4 and concentrated in vacuo to give 1.56 g of crude product as a yellow solid. The crude material was purified by flash chromatography (silica gel, 150 g, 15% ethyl acetate in hexanes) to give 1-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-propan-1-one (1.35 g, 86.3% yield) as a yellow solid. 1H NMR (DMSO-d6) δ ppm 11.13 (s, 7H) 8.67 (d, J=8.2 Hz, 1H) 7.74 (d, J=7.8 Hz, 2H) 7.20-7.54 (m, 3H) 6.81-7.19 (m, 1H) 3.19 (q, J=7.2 Hz, 2H) 1.12 (t, J=7.1 Hz, 3H). MS calcd. for C15H13F3N2O [(M+H)+] 295.0, obsd. 295.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:15]#[N:16])[C:11]=1[N:12]([CH3:14])[CH3:13])[N:8]=[C:7]([CH2:17][OH:18])[CH:6]=[CH:5]2.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:15]#[N:16])[C:11]=1[N:12]([CH3:14])[CH3:13])[N:8]=[C:7]([CH2:17][O:18][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24])[CH:6]=[CH:5]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)c1c(Br)cc2ccc(CO)nc2c1C#N
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN(C)c1c(Br)cc2ccc(CO[Si](C)(C)C(C)(C)C)nc2c1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
The 6-bromo-7-dimethylamino-2-(hydroxymethyl)quinoline-8-carbonitrile (2 g, 6.5 mmol, 1 eq), TBDMSCl (1.4 g, 7.3 mmol, 1.1 eq) and imidazole (623 mg, 7.3 mmol, 1.1 eq) were added to DMF (20 mL). The resulting solution was stirred at room temperature for 3 hours, and then the solvent was removed under high reduced pressure. Cyclohexane was added and the mixture was washed twice with water, and then with brine. The organic layer was then dried over MgSO4, and concentrated under reduced pressure. The product was obtained pure as a yellow powder (1.9 g, 68%).
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[OH:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[OH:6]
Reactant: [N-]=[N+]=NCC(O)c1cccc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCC(O)c1cccc(Br)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 2-Azido-1-(3-bromo-phenyl)-ethanol (3.38 g, 13.8 mmol) in THF (40 mL) was added water (2.48 ml, 138 mmol) and triphenylphosphine (7.26 g, 27.7 mmol). The mixture stirred for 2 hours at 50° C. and was then cooled to room temperature, diluted with water and extracted with ethyl acetate. The organics were washed with 1M HCl (2×) and the aqueous washes were combined and neutralized with 1N sodium hydroxide. The aqueous mixture was extracted with ethyl acetate and the organics were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The title compound was isolated as a yellow oil (2.53 g, 85%). 1H NMR (300 MHz, CDCl3): 7.55 (s, 1H), 7.41 (d, 1H), 7.31-7.20 (m, 2H), 4.62 (m, 1H), 3.02 (d, 1H), 2.79 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=[CH:13][C:12]=2[NH:22]C(=O)OCCCC)=[O:9])=[CH:4][CH:3]=1.[CH2:30]([NH:32][C:33]([N:35]1[C:39]2([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36]1)=[O:34])[CH3:31].CCN(CC)CC>CS(C)=O>[NH2:22][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:16][C:11]=1[NH:10][C:8]([C:5]1[CH:4]=[CH:3][C:2]([N:42]2[CH2:41][CH2:40][C:39]3([N:35]([C:33]([NH:32][CH2:30][CH3:31])=[O:34])[CH2:36][CH2:37][CH2:38]3)[CH2:44][CH2:43]2)=[N:7][CH:6]=1)=[O:9]
Reactant: CCNC(=O)N1CCCC12CCNCC2
Reactant: CCCCOC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCNC(=O)N1CCCC12CCN(c1ccc(C(=O)Nc3cc(-c4cccs4)ccc3N)cn1)CC2
Reaction time: 1 h

Procedure:
A solution of intermediate F (82 mg, 0.19 mmol), N-ethyl-1,8-diazaspiro[4.5]-decane-1-carboxamide (73 mg, 0.35 mmol), and NEt3 (43 μL, 0.31 mmol) in 5 mL of DMSO was stirred at 90° C. for 12 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO3, the organic layer was dried (MgSO4), filtered and concentrated. The residue was stirred in 2 mL of TFA and 2 mL of CH2Cl2 for 1 h at room temperature and concentrated. Reverse-phase chromatography (10 to 100% MeCN/water with 0.05% TFA) followed by neutralization with EtOAc/saturated NaHCO3 extraction and drying with MgSO4 gave the title compound: MS (ESI+): cal'd [M+H]+ 505.2, obs'd 505.2.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>>[CH2:13]([N:15]([CH2:16][CH3:17])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:14]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCNCC
Product: CCCCCCC/C=C/C(=O)N(CC)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and diethylamine as starting materials to give the aimed compound.
Reaction SMILES: [Br:1][C:2]1[C:20]([O:21][CH3:22])=[CH:19][C:5]2[O:6][C:7]([C:14]([O:16]CC)=[O:15])=[C:8]([C:9]([O:11]CC)=[O:10])[C:4]=2[CH:3]=1.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[C:20]([O:21][CH3:22])=[CH:19][C:5]2[O:6][C:7]([C:14]([OH:16])=[O:15])=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1oc2cc(OC)c(Br)cc2c1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc2oc(C(=O)O)c(C(=O)O)c2cc1Br
Yield: 84.9 %

Procedure:
Diethyl 5-bromo-6-methoxybenzo[b]furan-2,3-dicarboxylate (D11) (1.26 g, 3.4 mmoles) in ethanol (20 ml) and water (5 ml) was treated with 20% sodium hydroxide solution (5 ml) and heated under reflux for 3 hrs. The mixture was cooled and the ethanol removed in vacuo. The mixture was acidified to pH1 with hydrochloric acid. Filtration of the solid and drying gave the title compound (D12) (0.91 g, 85%)
Reaction SMILES: O1CCN(S(F)(F)[F:8])CC1.[CH3:11][O:12][CH2:13][O:14][CH2:15][C:16]1[N:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>ClCCl>[F:8][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][CH2:13][O:12][CH3:11])=[N:21][CH:20]=1
Reactant: FS(F)(F)N1CCOCC1
Reactant: COCOCc1ccc(CO)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCOCc1ccc(CF)cn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 70% HF-pyridine complex (0.3 ml) is added to a solution of morpholinosulfur trifluoride (2 ml, 1.63×10−2 mol) in dichloromethane (32 ml) cooled to −78° C. and maintained under an inert atmosphere, followed by dropwise addition of 1 g (5.4 mmol) of compound (3) as a solution in CH2Cl2 (10 ml). The mixture is stirred for 2 hours at −78° C. and then poured into saturated NaHCO3 solution (75 ml). The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue is bulb-to-bulb distilled (P: 4.7×10−2 mb, b.p.: 110-130° C.). The title compound is isolated in the form of a colorless oil (0.3 g), which is used directly in the following step.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:44]([NH:46][CH2:47][C:48]([CH2:54][NH:55][C:56]1[CH:64]=[C:63]([CH3:65])[CH:62]=[C:61]2[C:57]=1[CH:58]=[N:59][N:60]2[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([OH:53])[C:49]([F:52])([F:51])[F:50])[CH3:45]>CN(C)C=O>[CH2:44]([N:46]([CH2:47][C:48]([OH:53])([CH2:54][NH:55][C:56]1[CH:64]=[C:63]([CH3:65])[CH:62]=[C:61]2[C:57]=1[CH:58]=[N:59][N:60]2[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:49]([F:52])([F:51])[F:50])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH3:45]
Reactant: Cc1ccccc1C(=O)O
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To a solution of 2-methylbenzoic acid (12.7 mg, 0.09 mmol) in N,N-dimethylformamide (100 μl) was added a solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (34 mg, 0.09 mmol) in dimethylformamide (150 μl) followed by N,N-diisopropylethylamine (36 μl, 0.21 mmol). The mixture was shaken for 5 minutes and then a solution of 3-(ethylamino)-1,1,1-trifluoro-2-{[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol (27 mg, 0.07 mmol) in N,N-dimethylformamide (150 μl) was added. The mixture was again shaken for 5 minutes and then left to stand at room temperature for 18 hours. The crude reaction was purified by mass-directed autopreparation (System A) to give the title compound (21.1 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:5][N:4]=1.[CH3:15][C:16]1([CH3:26])[C@H:18]([CH:19]=[C:20]([CH3:22])[CH3:21])[C@H:17]1[C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].O1CCOCCOCCOCCOCCOCC1>C(C(C)=O)C>[CH3:15][C:16]1([CH3:26])[C@H:18]([CH:19]=[C:20]([CH3:21])[CH3:22])[C@H:17]1[C:23]([O:25][CH2:2][C:3]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:5][N:4]=1)=[O:24]
Reactant: ClCc1nsc(Oc2ccccc2)n1
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)=C[C@@H]1[C@@H](C(=O)OCc2nsc(Oc3ccccc3)n2)C1(C)C
Yield: 30.9 %

Procedure:
A mixture of 4.5 g of 3-chloromethyl-5-phenoxy-(1,2,4)-thiadiazole, 3.7 g of (1R,3R) 2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-1-carboxylic acid, 50 ml of methyl ethyl ketone, 3.2 g of potassium carbonate and 0.1 gof 1,4,7,10,13,16-hexaoxacyclooctadecane was refluxed for 18 hours and was cooled and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution withbenzene yielded 2.2 g of [5-phenoxy-(1,2,4)-thiadiazol-3-yl]-methyl (1R,3R)2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-1-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:25]2([OH:28])[CH2:26][CH2:27][N:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCN(Cc3ccccc3)CC2)c1
Reaction time: 1 h

Procedure:
3-Bromoanisole (50.0 g, 0.264 mol) was dissolved in 150 mL of THF and then chilled to −78° C. n-Butyllithium (1.6M, 175 mL, 0.276 mol) was then added while maintaining the reaction temperature at −70° C. or below. After complete addition, the reaction mixture was stirred for an additional 60 min. 1-Benzyl4-piperidone in 150 mL of THF was then added at such a rate as to maintain the reaction temperature at −70° C. or below. The reaction was stirred at −70° C. for an additional 15 min, then the dry ice-acetone bath was removed, and the reaction was allowed to come to room temperature. Brine (400 mL) was added, and the organic layer was separated and washed with an additional 300 mL of brine. The organic layer was separated, dried (K2CO3), and concentrated in vacuo. 6N HCl (250 mL) was added to the oily residue which was then washed with EtOAc. The aqueous layer was separated, basified with 50% NaOH, and extracted with EtOAc. The EtOAc layer was separated, dried (K2CO3), and concentrated in vacuo to give 75.7 g of 4-(3-methoxyphenyl)-1-benzyl4-piperidinol as an orange oil. A sample was chromatographed on silica gel using hexane/EtOAc (7:3) mixtures as the eluent to afford a yellow oil which was dissolved in ether and treated with ethereal hydrochloric acid to give 4-(3-methoxyphenyl)-1-benzyl-4-piperidinol hydrochloride as a white solid (mp 195-197° C.). 1H NMR (CDCl3) (free base) 5 (ppm) 1.64-1.75 (m, 2H), 2.09-2.21 (m, 2H), 2.41-2.51 (m, 2H), 2.71-2.80 (m, 2H), 3.51 (s, 2H), 3.80 (s, 3H), 6.77-6.81 (m, 1H), 7.06-7.09 (m, 2H), 7.23-7.35 (m, 6H). Anal. Calcd for C19H23NO2 HCl.1/2 H2O: C, 66.56; H, 7.06; N, 4.09. Found: C, 66.41; H, 7.31; N, 4.33.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CN(C)C=O>[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCCOc1cccnc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
3-Hydroxypyridine (262 mg) was added to a suspension of 60% sodium hydride (128 mg) in N,N-dimethylformamide (5 ml) and the mixture was stirred at 60° C. for 30 minutes. After cooling in ice a solution of N-(tert-butoxycarbonyl)-6-bromo-hexylamine (770 mg) (Helv. Chim. Acta 76 891 (1993) in N,N-dimethylformamide (3 ml) was added dropwise and stirring was continued overnight at room temperature. Ice and water were added and the mixture was extracted three times with diethyl ether. The organic phases were washed with saturated sodium chloride, dried and evaporated to leave a yellow oil which after purification by chromatography on silica gel with diethyl ether as eluent gave the desired compound as a colourless oil.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]=C)=[CH:19][CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])C.C[N+]1([O-])CC[O:30]CC1>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:11]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:25])=[CH:18][CH:19]=1)=[O:30]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc(CN(CCCCCCC(=O)OCC)S(C)(=O)=O)cc1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)N(CCCCCCC(=O)O)Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of ethyl-7-[(4-vinyl-benzyl)-methanesulfonyl-amino]-heptanoate (2.2 g, 6.0 mmol) in dioxane (45 mL) was added to a solution of N-methylmorpholine N-oxide (1.47 g, 12.5 mmol) in water (45 mL). Osmium tetroxide (4.6 mL, 2.5 wt % in 2-methyl-2-propanol) was added and the mixture was stirred at room temperature for 1 h. The reaction was quenched with 1N HCl (50 mL) and the aqueous solution was extracted with CH2Cl2. The organic layer was washed with water (1×) followed by brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in 35% aqueous THF (100 mL) and NalO4 (1.41 g, 6.59 mmol) was added. The mixture was stirred at room temperature for 2 h and was diluted with EtOAc and water. The organic solution was washed with water (1×) followed by brine (1×), dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound (1.9 g) which was used without further purification. 1H NMR (400 MHz, CDC13) δ 10.0 (s, 1H), 7.82-7.90 (d, 1H), 7.50-7.59 (d, 2H), 5.30 (s, 2H), 4.45 (s, 2H), 4.05-4.18 (m, 2H), 3.12-3.22 (m, 2H), 2.86 (s, 3H), 2.19-2.30 (m, 2H), 1.42-1.62 (m, 6H), 1.18-1.80 (m, 3H); MS 387 (M+18).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.[CH:24]1[CH:29]=[CH:28][CH:27]=CC=1>>[CH3:1][C:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4]([O:6][CH2:27][CH:28]1[CH2:24][CH2:29]1)=[O:5]
Reactant: CC(=CC(=O)O)CCCC(C)CCCC(C)C
Reactant: c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: CC(=CC(=O)OCC1CC1)CCCC(C)CCCC(C)C
Reaction time: 2 h

Procedure:
To 1.56 g. of 3,7,11-trimethyldodec-2-enoic acid, under nitrogen, is added dry benzene and oxalyl chloride (2.4 g.). The mixture is stirred 2 hours and then concentrated in vacuo. To the concentrate is added fresh dry benzene and 1.6 g. of cyclopropylmethyl alcohol and the mixture stirred overnight at room temperature. The reaction is worked up by pouring into water and extracting with ether. The organic phase is washed with brine, stirred over neutral alumina (Act. III), concentrated under reduced pressure and purified by distillation to yield cyclopropylmethyl 3,7,11-trimethyldodec-2-enoate, b.p. 90° (bath) at 0.005 mm.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.5 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butylamide (example 162) (0.2 g, 0.34 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 purified by flash chromatography (heptane/ethyl acetate) to yield the title compound as an off-white solid (0.12 g, 67%). MS (ISN) 529.3 [(M−H)−]; mp 262° C.
Reaction SMILES: Cl.Cl.[N:3]1([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:14])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:15]1([C:18]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:19]=2[C:20](O)=[O:21])[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:19]=2[C:20]([NH:14][C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:8]2[N:3]2[CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:21])[CH2:17][CH2:16]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Agent: Cl
Product: O=C(N[C@@H]1CCCC[C@@H]1N1CCCC1)c1ccc(C(F)(F)F)cc1C1CC1

Procedure:
The title compound, white solid, MS: m/e=381.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclohexylamine dihydrochloride (intermediate F) and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate K).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:32]2[O:36][C:35]([Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])=[N:34][CH:33]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[O:36][C:35]([Si:37]([CH:41]([CH3:43])[CH3:42])([CH:44]([CH3:46])[CH3:45])[CH:38]([CH3:39])[CH3:40])=[N:34][CH:33]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)[Si](c1ncc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)o1)(C(C)C)C(C)C

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-triisopropylsilanyl-oxazole following a procedure analogous to that described for Intermediate 15. LC (method 10): tR=2.02 min; Mass spectrum (ESI+): m/z=528 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(CC2(c3cccc(OC)c3)C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 6b supra), 4-methoxybenzyl chloride (0.15 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 4 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(4-methoxy-benzyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.19 g, 80.4%).
Reaction SMILES: [Br:1][C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[C:5]([CH2:11]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-:14].[K+].[K+]>O>[Br:1][C:2]1[C:7]2[C:6](=[N:10][S:9][N:8]=2)[C:5]([CH2:11][OH:14])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)c2nsnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OCc1ccc(Br)c2nsnc12
Temperature: 110 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
A mixture of 4-bromo-7-bromomethyl-benzo[1,2,5]thiadiazole (Example 5.1) (29.05 g), potassium carbonate (65.2 g) and water (400 ml) was stirred at 110° C. for 16 hours. The reaction mixture was cooled to ambient temperature and quenched by addition of aqueous hydrochloric acid (2M) (400 ml). Ethyl acetate (600 ml) was added to the mixture. The phases were separated and the organic layer was washed successively with aqueous hydrochloric acid (2M) (400 ml), water (250 ml) and brine (250 ml), dried over sodium sulfate and concentrated to give (7-bromo-benzo[1,2,5]thiadiazol-4-yl)-methanol (20.22 g) as a orange solid. 1H-NMR (400 MHz, CDCl3): 7.87 (d, 1H), 7.57 (d, 1H), 5.14 (s, 2H) ppm.