Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.[O:35]1[CH2:39][CH2:38][CH:37]([C:40](O)=[O:41])[CH2:36]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][C@H:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([C:40]([CH:37]5[CH2:38][CH2:39][O:35][CH2:36]5)=[O:41])[CH2:23][CH2:24]4)[C@H:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: O=C(O)C1CCOC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)C2CCOC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
A mixture of 2-methyl-1-{8-[2-(4-phenyl piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (75 mg, 0.16 mmol), tetrahydro-3-furoic acid (18 mg, 0.16 mmol) and triethylamine (48 mg, 0.48 mmol) in dimethylformamide (0.5 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (68 mg, 0.18 mmol) and the resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with water and extracted with dichloromethane. The residue from the dichloromethane layer was purified by chromatography on silica gel eluting with 1:20 methanol:dichloromethane to give 2-methyl-1-((1R,5S)-8-{2-[4-phenyl-1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-1H-benzimidazole as a clear oil (0.019 g, 23%). 1H NMR (400 MHz, DMSO-d6) δ 7.46 (m, 1H), 7.36 (m, 5H), 7.21 (m, 1H), 7.09 (m, 2H), 4.49 (m, 1H), 3.58-3.87 (m, 7H), 3.12-3.35 (m, 6H), 2.28-2.39 (m, 2H), 1.89-2.12 (m, 5H), 1.58-1.86 (m, 10H), 1.53-1.60 (m, 2H). HRMS C33H42N4O2 m/z 527.3386 (M+H)Cal., 527.3397 (M+H)Obs..
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3[N:15]=[C:16]([CH2:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:22])=[O:21])[S:17][CH:18]=3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1>CN(C=O)C.O=[Mn]=O>[C:23]1([S:20]([CH2:19][C:16]2[S:17][CH:18]=[C:14]([C:8]3[C:9](=[O:13])[NH:10][C:11]4[C:6]([CH:7]=3)=[CH:5][CH:4]=[C:3]([CH:2]=[O:1])[CH:12]=4)[N:15]=2)(=[O:22])=[O:21])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=c1[nH]c2cc(CO)ccc2cc1-c1csc(CS(=O)(=O)c2ccccc2)n1
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Product: O=Cc1ccc2cc(-c3csc(CS(=O)(=O)c4ccccc4)n3)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 7-(hydroxymethyl)-3-(2-((phenylsulfonyl)methyl)-1,3-thiazol-4-yl)-2(1H)-quinolinone (Example 8723, 1.7 g, 4.12 mmol) in 150 mL of DMF was added 25 g of MnO2. The mixture was stirred at RT for 24 h. The solids were filtered off through Celite®. 20 mL of DMF was used to rinse the solid. The combined filtrate containing the intermediate aldehyde was stored in refrigerator until being used for the next step without further purification. MS m/z: 411.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[NH2:19])[CH:7]=1.[I:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:10]=2[NH:19][S:27]([C:24]2[CH:25]=[CH:26][C:21]([I:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1
Product: O=S(=O)(Nc1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1)c1ccc(I)cc1
Yield: 61.8 %

Procedure:
Using the method of Example 17.4, 4-(3-chloro-5-pyridyloxy)-3-aminobenzotrifluoride (0.41 g) and 4-iodobenzenesulfonyl chloride (0.30 g) were combined to provide the title compound (0.34 g) as crystals directly from the reaction mixture. mp 192-193° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].N#N.[CH2:23]1[CH2:27]OCC1>>[CH3:9][N:1]1[CH2:23][CH2:27][C:3]2([C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[CH2:3][CH2:2]1
Reactant: O=C1Cc2ccccc2N1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#N
Agent: [Na+]
Product: CN1CCC2(CC1)C(=O)Nc1ccccc12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 57 %

Procedure:
A solution of oxindole 9 (6.25 g, 47 mmol) in THF (500 ml) was cooled to −78° C. and to it a solution of sodium hexamethyldisilazide (43 g, 235 mmol) in THF (300 ml) was added drop wise under N2 atmosphere. After stirring at −78° C. for 45 min, N-methylbis(2-chloromethyl)amine hydrochloride (9 g, 47 mmol) was added, as a solid. The reaction mixture was stirred at −78° C. for 1 h and at room temperature for 24 h. After quenching with H2O (90 ml), the mixture was extracted with ethyl acetate (3×100 ml). The organic extracts were washed with brine (25 ml), dried and the solvent removed in vacuo. Silica gel chromatography (5-50% MeOH/CH2Cl2, gradient) gave 6 g (57%) of 10 as a solid. 1HNMR (CD3OD, 400 MHz) δ 1.84 (m, 2H); 2.51 (m, 2H); 2.62 (s, 3H); 3.02 (m, 2H); 3.37 (m, 2H); 6.82 (d, 1H, J=7.68 Hz); 6.94 (t, 1H, J=7.58 Hz); 7.12 (t, 1H, J=7.7 Hz); 7.26 (d, 1H, J=9 Hz); 9.27 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]3[CH2:13][S:12][CH2:11][C:10]3=[C:6]2[N:5]=[C:4]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[C:3]=1[C:23]#[N:24].Cl.CO>O1CCCC1>[NH2:24][CH2:23][C:3]1[C:4]([C:14]2[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[N:5][C:6]2[N:7]([N:8]=[C:9]3[CH2:13][S:12][CH2:11][C:10]=23)[C:2]=1[NH2:1]
Reactant: Cc1cc(C)c(-c2nc3c4c(nn3c(N)c2C#N)CSC4)c(C)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C)c(-c2nc3c4c(nn3c(N)c2CN)CSC4)c(C)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A suspension of 81 mg (0.24 mmol) of 4-amino-2-mesityl-7H,9H-thieno[3′,4′:3,4]pyrazolo[1,5-a]pyrimidine-3-carbonitrile from Step A in 1.2 mL of anhydrous tetrahydrofuran was stirred under nitrogen in an ultrasound bath as 1.2 mL (1.2 mmol) of 1M borane-tetrahydrofuran complex in tetrahydrofuran was added gradually by syringe. The mixture was stirred overnight with intermittent sonication. Next, the mixture was quenched by cautious gradual addition of 0.36 mL (4.32 mmol) of concentrated hydrochloric acid (gas evolution) followed by addition of 1.2 mL of methanol. The resulting solution was stirred in a sealed tube with heating in an oil bath at 80° C. for 4 h. The solution was evaporated to dryness and re-concentrated twice from methanol. The residue was converted to free base form by passage through a pre-washed SCX ion exchange cartridge. After flushing the column with methanol to remove trifluoroacetic acid, elution with 1M ammonia in methanol afforded the crude product. Further purification by flash chromatography on silica gel (elution with 98:2:0.4 dichloromethane:methanol:concentrated ammonium hydroxide) yielded the title compound. LC-MS 340 (M+1).
Reaction SMILES: [C:1]([CH2:4][C@@H:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:29])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][C:18]=2[Cl:28])[CH2:8][CH2:7][CH2:6]1)([OH:3])=O.[CH:30]([NH2:33])([CH3:32])[CH3:31].P(C#N)(OCC)(OCC)=O.O>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[CH:30]([NH:33][C:1]([CH2:4][C@@H:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:29])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][C:18]=2[Cl:28])[CH2:8][CH2:7][CH2:6]1)=[O:3])([CH3:32])[CH3:31]
Reactant: CC(C)N
Reactant: O=C(O)C[C@H]1CCCN(C(=O)c2ccc(N3CCCC3)cc2Cl)c2ccccc21
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)NC(=O)C[C@H]1CCCN(C(=O)c2ccc(N3CCCC3)cc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R)-5-carboxymethyl-1-[4-(1-pyrrolidinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (21 g) in dimethylformamide (400 ml) are added isopropylamine (21.7 ml) and diethyl cyanophosphate (10 g) at room temperature, and the mixture is stirred at room temperature for two hours. To the reaction solution are added water and ethyl acetate--n-hexane (10:1), and the mixture is extracted twice. The organic layer is washed successively with a 5% citric acid, a saturated aqueous sodium hydrogen carbonate solution, and water, and dried over anhydrous magnesium sulfate. The mixture is concentrated under reduced pressure to remove the solvent, and the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol:ammonium hydroxide=1000:5:0.2→1000:15:0.5), and recrystallized from acetone--n-hexane to give (5R)-5-isopropylaminocarbonylmethyl-1-[4-(1-pyrrolidinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (12.5 g).
Reaction SMILES: C(O[NH:6][C@H:7]([C:27]([OH:29])=[O:28])[CH2:8][C:9]1[CH:16]=[C:14]([I:15])[C:13]([O:17][C:18]2[CH:25]=[C:23]([I:24])[C:22]([OH:26])=[C:20]([I:21])[CH:19]=2)=[C:11]([I:12])[CH:10]=1)(C)(C)C.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH2:6][C@H:7]([C:27]([OH:29])=[O:28])[CH2:8][C:9]1[CH:10]=[C:11]([I:12])[C:13]([O:17][C:18]2[CH:19]=[C:20]([I:21])[C:22]([OH:26])=[C:23]([I:24])[CH:25]=2)=[C:14]([I:15])[CH:16]=1
Reactant: CC(C)(C)ON[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.23 g (1.4 mmoles) of N-(tert-butoxy)-L-thyroxine and 0.16 g (1.4 mmoles) of N-hydroxysuccinimide are dissolved in 20 mL dimethylformamide. 0.31 g (1.5 mmoles) of dicyclohexyl carbodiimide is added to the solution which is then stirred at room temperature for 18 h. The urea precipitated during the reaction is removed by filtration and the filtrate, containing the active ester, is stored at -20° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][C:14]2([C:17]([F:20])([F:19])[F:18])[CH2:16][O:15]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2].[CH3:21][C:22]1[CH:31]=[CH:30][C:29]2[C:28]([NH2:32])=[CH:27][CH:26]=[CH:25][C:24]=2[N:23]=1>>[CH2:1]([C:3]1([CH2:13][C:14]([CH2:16][NH:32][C:28]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:29]=2[CH:30]=[CH:31][C:22]([CH3:21])=[N:23]3)([OH:15])[C:17]([F:20])([F:19])[F:18])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: Cc1ccc2c(N)cccc2n1
Reactant: CCC1(CC2(C(F)(F)F)CO2)CCCc2ccccc21
Product: CCC1(CC(O)(CNc2cccc3nc(C)ccc23)C(F)(F)F)CCCc2ccccc21

Procedure:
Similar reaction of 2-[(1-ethyl-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]-2-(trifluoromethyl)oxirane (D2, racemic diastereomer 2) (Intermediate 15) with 2-methyl-5-quinolinamine afforded Example 5-D2 (racemic diastereomer 2).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:13][CH:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:15]([OH:19])[C:16]([OH:18])=O)=[O:12].[CH:31]1([NH2:34])[CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:31]1([NH:34][C:16](=[O:18])[CH:15]([OH:19])[CH:14]([NH:13][C:11]([C@H:6]2[CH2:7][CH2:8][C:9](=[O:10])[N:5]2[CH2:4][C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=2[F:1])=[O:12])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:33][CH2:32]1
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F

Procedure:
The reaction was carried out in analogy to reaction step 20.3 by reacting 3-((R)-1-(2-fluorobenzyl)-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoic acid with cyclopropanamine using HATU (1.2 equivalents) as coupling reagent and DIPEA (3 equivalents) as base. ESI-MS [M+H]+=454.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[N+:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([O-:22])=[O:21]>ClCCl>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
A solution of 4-amino benzoic acid ethyl ester (1.95 g, 11.8 mmol) in dry dichloromethane (20.0 ml) was treated with triethylamine (1.31 g, 13.0 mmol) and cooled to 0° C. 3-Nitrobenzoyl chloride (2.00 g, 10.8 mmol) was added portion wise over 5 min. The mixture was stirred at 0° C. for 5 min, then at room temperature for 10 min. The reaction was quenched by addition of 20 ml of saturated NaHCO3. The organic phase was separated and filtered washing with dichloromethane. Drying of the solid under high vacuum yielded 4-(3-nitro-benzoylamino)-benzoic acid ethyl ester as a white solid (2.52 g, 74%), MS (ISP): m/e=315.1 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([NH2:11])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH:13]([CH3:24])[C:14]([C:16]1[S:20][CH:19]=[C:18]([C:21]([NH2:23])=[O:22])[CH:17]=1)=[O:15].CC(=O)CC>CCOC(C)=O>[CH3:1][CH:2]([N:11]=[C:13]([CH3:24])[C:14]([C:16]1[S:20][CH:19]=[C:18]([C:21]([NH2:23])=[O:22])[CH:17]=1)=[O:15])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(N)CCc1ccccc1
Reactant: CC(Br)C(=O)c1cc(C(N)=O)cs1
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CC(=NC(C)CCc1ccccc1)C(=O)c1cc(C(N)=O)cs1
Reaction time: 48 h

Procedure:
A solution of 1-methyl-3-phenylpropylamine (9.0 g) and 5-(2-bromo-1-oxopropyl)thiophene-3-carboxamide (7.6 g) was stirred for 2 h; butanone (75 ml) was added and stirring continued for 48 h. The resulting mixture was filtered and the filtrate evaporated to small volume (ca. 30 ml) and added to vigorously stirred light petroleum (b.p. 60°-80°: 500 ml) to precipitate a yellow gum (ca. 9 g) which was separated on a short path silica (7736H; 300 g) column eluted with ethyl acetate/2% isopropanol/20% triethylamine to give three products. TLC SiO2 (EtOAc/20% i-PrOH/2% Et3N) Rf 0.26, 0.39 and 0.5 respectively.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][CH:4]=1.C([O:19][C:20]1[CH2:25][CH2:24][CH2:23][C:22](=O)[CH:21]=1)C.Cl>C1COCC1.CCOCC>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([C:22]2[CH2:23][CH2:24][CH2:25][C:20](=[O:19])[CH:21]=2)=[CH:4][CH:5]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOC1=CC(=O)CCC1
Reactant: CCCCCCCCc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCc1ccc(C2=CC(=O)CCC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
To a suspension of magnesium (1.477 g, 60.8 mmol) in THF (56 mL) was added 1-bromo-4-octylbenzene (15.00 g, 55.7 mmol). After stirring for about 6 h the reaction mixture was added with filtering to a solution of 3-ethoxycyclohex-2-enone (7.10 g, 50.6 mmol) in THF (28.0 mL) at 0° C. Following the addition the reaction mixture was allowed to warm to room temperature. After 1 h 1N HCl was added until a pH of 1 was obtained. The reaction mixture was diluted with Et2O and the organic layer was separated, washed with NaHCO3, and brine, dried with (Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/Hep) to provide 3-(4-octylphenyl)cyclohex-2-enone (9.5 g, 33.4 mmol, 65.9% yield) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([S:10][CH3:11])[N:7]([C:12](Cl)=[O:13])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>CCOCC>[CH2:15]([N:17]([CH2:18][CH3:19])[C:12]([N:7]1[C:8]([S:10][CH3:11])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]1)=[O:13])[CH3:16]
Reactant: CSc1cc(C(C)(C)C)nn1C(=O)Cl
Reactant: CCNCC
Solvent: CCOCC
Product: CCN(CC)C(=O)n1nc(C(C)(C)C)cc1SC
Yield: 54 %

Procedure:
3-t-butyl-1-chlorocarbonyl-5-(methylthio)pyrazole (4.0 g) in ether (25 ml) was added dropwise with stirring to a solution of diethylamine (3.9 g, 5.5 ml) in ether (25 ml) at room temperature. The reaction mixture was refluxed for 1/2 hour and then filtered, and the ether layer washed with water, dried and evaporated to give crude product. Recrystallisation from petrol gave 1-(diethylcarbamoyl)-3-t-butyl-5-(methylthio)pyrazole, melting point 55°-6°. Yield 54%.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11](I)[N:10]=[CH:9]2)C=CC=CC=1.C([Mg]Br)C.[CH3:30][O:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][CH2:37][C:38]2=O)=[CH:34][C:33]=1[CH3:42].[Cl-].[NH4+]>C(Cl)Cl>[NH:8]1[C:12]([C:38]2[C:39]3[C:35](=[CH:34][C:33]([CH3:42])=[C:32]([O:31][CH3:30])[CH:40]=3)[CH2:36][CH:37]=2)=[CH:11][N:10]=[CH:9]1
Reactant: COc1cc2c(cc1C)CCC2=O
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1cc2c(cc1C)CC=C2c1cnc[nH]1
Temperature: 23 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
A stirred solution of 5.0 grams (0.012 mole) of 1-(triphenylmethyl)-4-iodoimidazole (vii) in about 200 mL of anhydrous methylene chloride was cooled to about 21° C., and 3.84 mL (3.0M in diethyl ether: 0.012 mole) of ethylmagnesium bromide was added. Upon completion of addition, the reaction mixture was stirred for about one hour at 23° C., and then a solution of 2.0 grams (0.012 mole) of 6-methoxy-5-methylindan-1-one (ii) (prepared in a manner analogous to Step D of Example 1) in 50 mL of methylene chloride was added in one portion. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time, the reaction mixture was poured into a separatory funnel containing an aqueous saturated solution of ammonium chloride. The organic layer was separated and the aqueous layer was extracted with two portions of methylene chloride. The combined extracts and organic layer were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in methanol and aqueous 4N hydrochloric acid was then added to the solution. Upon completion of addition, the mixture was stirred at ambient temperature for about 18 hours. After this time, the methanol was removed from the mixture under reduced pressure, leaving an aqueous residue. The residue was washed with three portions of diethyl ether, then the pH of the residue was adjusted to about 8-9 by the addition of solid sodium carbonate. The mixture was then extracted with methylene chloride, and the extract was dried with sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to a residue. The residue was again treated with aqueous 4N hydrochloric acid, and the mixture was washed with diethyl ether. The pH of the aqueous layer was adjusted to about 8-9 by the addition of solid sodium carbonate. The mixture was then extracted with methylene chloride, and the extract was dried with sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure, yielding about 0.5 gram of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.[CH:16]#[C:17][CH2:18][CH2:19][CH2:20][CH3:21].O.C(=O)(O)[O-].[Na+]>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:16]([C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1)#[C:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CCCCC
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCC#Cc1cncc(OC[C@@H]2CCCN2C)c1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (272 mg, 1.00 mmol), bis(triphenylphosphine)palladium(II) chloride (18 mg, 0.025 mmol) and copper (I) iodide (2 mg, 0.025 mmol) in NEt3 (6.0 mL) was added 1-hexyne (0.237 mL, 2.00 mmol). The mixture was refluxed overnight and cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH4OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (174 mg, 64%). MS (CI/NH3) m/z 273 (M+H(+. 1H NMR (CDCl3, 300 MHz) δ 0.96 (t, J=7.0 Hz, 3H), 1.42-2.10 (m, 8H), 2.26-2.37 (m, 1H), 2.43 (t, J=7.0 Hz, 2H), 2.48 (s, 3H), 2.63-2.71 (m, 1H), 3.08-3.16 (m, 1H), 3.88-4.03 (m, 2H), 4.47-4.55 (m, 1H), 7.17-7.21 (m, 1H), 8.19-8.23 (m, 2H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br:15][C:16]1[C:23]([F:24])=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[F:25]>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:15][C:16]1[C:23]([F:24])=[CH:22][C:19]([CH:20]2[O:12][CH2:11][CH:10]([CH:7]3[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)[CH2:13][O:14]2)=[CH:18][C:17]=1[F:25]
Reactant: O=Cc1cc(F)c(Br)c(F)c1
Reactant: CCCC1CCC(C(CO)CO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCC1CCC(C2COC(c3cc(F)c(Br)c(F)c3)OC2)CC1
Yield: 60 %

Procedure:
6.0 g (0.03 mol) of 2-(4'-propylcyclohexyl)propane-1,3-diol, 6.6 g (0.03 mol) of 4-bromo-3,5-difluorobenzaldehyde and 0.3 g of TsOH were dissolved in 60 cm3 of dichloromethane, and it was refluxed for 3 hours on a hot water bath while removing the water produced with a Dean-Stark trap. After washing the reactant on water, the dichloromethane was removed. The residue was recrystallized from a solvent mixture of acetone and methanol to obtain 7.3 g (0.018 mol) of 2-(4'-bromo-3',5'-difluorophenyl)-5-(4'-propylcyclohexyl)-1,3-dioxane(trans-cis form mixture).
Reaction SMILES: [OH:1][C:2]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3]([O:5][CH3:6])=[O:4].O[C@H]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[H-].[Na+]>C1(C)C=CC=CC=1>[OH:1][C:2]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:3]([O:5][C@H:6]1[CH2:23][CH2:22][C@H:21]([N:24]([C:25]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:31])[CH3:32])[CH2:20][CH2:19]1)=[O:4]
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Temperature: 155 °C

Procedure:
To a solution of methyl hydroxy(di-2-thienyl)acetate (5.8 g, 0.02 mol) (prepared according to Acta Chemica Scandinavica 24 (1970) 1590-1596) in anhydrous toluene (95 mL) was first added a solution of tert-butyl (trans-4-hydroxycyclohexyl)-methylcarbamate (intermediate 3; 6 g, 0.02 mol) in anhydrous toluene (95 mL) and secondly sodium hydride (60%, 0.45 g, 0.01 mol). After few minutes the mixture was warmed to 155° C. and the solvent was distilled and simultaneously replaced. This procedure was carried on during 1 hour and a half. The mixture was cooled to room temperature and diluted with ether (300 mL). The organic layer was washed with sodium bicarbonate 4% (2×200 mL) and brine, dried, filtered and evaporated over reduced pressure giving the title compound as a yellow solid (69%), which was used in the next step without further purification.