Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:20])=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1F.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[OH-].[Na+].C(O)(=O)C>CN1CCCC1=O.O>[F:1][C:2]1[C:3]([NH2:20])=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1[N:25]1[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]1
Reactant: CC1Cc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CC(=O)O
Product: CC1Cc2c(N3CCN(C)CC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Temperature: 50 °C

Procedure:
8,9-Difluoro-7-amino-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (2 g) and N-methylpiperazine (4 ml) are suspended in N-methylpyrrolidone (20 ml), and the mixture is heated at 110°-120° C. on an oil bath for 3 hours. After the reaction, the reaction mixture is distilled under reduced pressure, and to the residue is added ethyl acetate. The resulting crystals are separated by filtration and thereto is added water (80 ml), which is regulated to pH 2 with 6N hydrochloric acid, and the mixture is heated at 50° C. and then filtered. The filtrate is concentrated to dryness, and the residue is recrystallized from ethanol-water to give yellow cubic crystals. The crystals are again suspended in water (10 ml) and is dissolved by regulating to pH 12 with a 10% aqueous sodium hydroxide solution and then is regulated to pH 8 with acetic acid. The precipitated crystals are separated by filtration, washed with water and dried to give 8-fluoro-2-methyl-9-(4-methyl-1-piperazinyl)-7-amino-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline- 5-carboxylic acid (1.4 g) as yellow cubic crystals. m.p. 240°-243° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[F:16][C:17]1[CH:41]=[CH:40][C:20]([CH2:21][O:22][C:23]2[C:24](B(O)O)=[CH:25][C:26]3[C:27]([CH3:36])([CH3:35])[CH2:28][CH2:29][C:30]([CH3:34])([CH3:33])[C:31]=3[CH:32]=2)=[CH:19][CH:18]=1>>[OH:8][C:7]1[CH:2]=[CH:3][C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:5][C:6]=1[C:24]1[C:23]([O:22][CH2:21][C:20]2[CH:40]=[CH:41][C:17]([F:16])=[CH:18][CH:19]=2)=[CH:32][C:31]2[C:30]([CH3:34])([CH3:33])[CH2:29][CH2:28][C:27]([CH3:36])([CH3:35])[C:26]=2[CH:25]=1
Reactant: CCOC(=O)C=Cc1ccc(O)c(Br)c1
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)c(OCc3ccc(F)cc3)cc21
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(C=CC(=O)O)ccc3O)c(OCc3ccc(F)cc3)cc21
Yield: 47 %

Procedure:
In a manner similar of Example 1(c), by reaction of 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in Example 34(d) with 1.97 g (5.5 mmol) of 3-(4-fluorobenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid obtained above, 825 mg (44%) of the expected compound were obtained in the form of a white solid having a melting point of 123°-125° C.
Reaction SMILES: [C:1]([Si:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:6][CH2:7][CH2:8][C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@@H:10]1[CH2:16][OH:17])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[O:39](S(C(F)(F)F)(=O)=O)[S:40]([C:43]([F:46])([F:45])[F:44])(=O)=[O:41].[Cl-].[NH4+]>ClCCl>[C:1]([Si:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:6][CH2:7][CH2:8][C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@@H:10]1[CH2:16][O:17][S:40]([C:43]([F:46])([F:45])[F:44])(=[O:41])=[O:39])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1(C)O[C@@H](CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](CO)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)O[C@@H](CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](COS(=O)(=O)C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
{(4R,5S)-5-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-2,2-dimethyl-[1,3]dioxolan-4-yl}-methanol (159 mg, 0.38 mmol) was dissolved in dichloromethane (1.15 mL). Diisopropylethylamine (200 μL, 1.15 mmol) and Tf2O (77.4 μL, 0.46 mmol) were added at 0° C., and the mixture was stirred at room temperature for one hour in a nitrogen atmosphere. Saturated aqueous ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give trifluoro-methanesulfonic acid (4R,5S)-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester as a crude product.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.Br[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].Cl>O1CCCC1.C(OCC)C>[C:23]([O:22][C:20](=[O:21])[CH2:19][CH2:18][C:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: O=C(O)C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a stirred solution of lithium diisopropylamide (0.43 mole) in dry tetrahydrofuran (300 ml) at -20° C. under nitrogen atmosphere was added cyclopentane carboxylic acid (22.7 g; 0.20 mole). The solution was allowed to warm to room temperature and after 2 hours was cooled to -10° C. and added by cannula to a stirred solution of t-butyl 3-bromopropionate (44.4 g, 0.21 mole) in tetrahydrofuran (100 ml). The resulting solution was allowed to warm to room temperature and kept overnight. Hydrochloric acid (3N, 250 ml) was cautiously added, followed by diethyl ether (500 ml) and the layers allowed to separate. The aqueous layer was washed with diethyl ether (300 ml) and the ether layers were combined, washed with water (300 ml), dried over magnesium sulphate and evaporated to give an oil. The oil was taken up in diethyl ether (300 ml) and washed with saturated sodium hydrogen carbonate solution (3×100 ml) until no further cyclopentane carboxylic acid remained. The diethyl ether solution was then extracted with 10% sodium carbonate solution, (4×150 ml), the aqueous phase separated, acidified with 2N hydrochloric acid, and extracted with diethyl ether (3×200 ml). The diethyl ether layer was separated, washed with water (300 ml), dried over magnesium sulphate and evaporated to give an oil that readily crystallised. Recrystallisation from pentane gave a colourless solid (10.4 g, 21%) m.p. 78°-81° C. (from pentane). Found: C,64.70; H,9.18. C13H22O4 requires: C,64.44; H,9.15%.
Reaction SMILES: CCN(CC)CC.[CH2:8]1[C:12]2([CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10][N:9]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].Cl[C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[N:27][N:26]=1>O1CCOCC1>[C:30]1([N:29]2[C:25]([N:14]3[CH2:15][CH2:16][C:12]4([CH2:8][N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH2:11]4)[CH2:13]3)=[N:26][N:27]=[N:28]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)C1
Reactant: Clc1nnnn1-c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3nnnn3-c3ccccc3)C2)C1
Temperature: 115 °C

Procedure:
Et3N (5 mL) was added into a solution of tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (1 g) and 5-chloro-1-phenyl-1H-tetrazole (1 g) in dioxane (50 mL). The mixture was heated to 115° C. for 24 hours. The reaction was quenched with water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic phase was dried over MgSO4 and concentrated to give a residue which was purified by silica gel chromatography to give tert-butyl 7-(1-phenyl-1H-tetrazol-5-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[C:8]([F:32])[C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].C1COCC1.Cl>CO.O>[F:32][C:8]1[CH:9]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:11]=[C:2]([F:1])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(F)cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c(F)cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.9 %

Procedure:
To a solution of Example 128 (0.70 g, 1.62 mmol) in methanol (3.8 ml), lithium hydroxide (0.635 g, 15.13 mmol) in water (3.8 ml) and THF (14.3 ml) were added and stirred at RT. After 12 h, pH was adjusted to ca. 7 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as pale brown solid (0.50 g, 74%).
Reaction SMILES: BrC1C(F)=CC2OCC(O)(C)C3SC(C(OCC)=O)=[N:11]C=3C=2C=1.C([C@]1(O)CCN(C)C1=O)#C.[F:34][C:35]1[C:36]([C:56]#[C:57][C@:58]2([OH:65])[CH2:62][CH2:61][N:60]([CH3:63])[C:59]2=[O:64])=[CH:37][C:38]2[C:44]3[N:45]=[C:46]([C:48]([O:50]CC)=O)[S:47][C:43]=3[C:42]([OH:54])([CH3:53])[CH2:41][O:40][C:39]=2[CH:55]=1>>[F:34][C:35]1[C:36]([C:56]#[C:57][C@:58]2([OH:65])[CH2:62][CH2:61][N:60]([CH3:63])[C:59]2=[O:64])=[CH:37][C:38]2[C:44]3[N:45]=[C:46]([C:48]([NH2:11])=[O:50])[S:47][C:43]=3[C:42]([OH:54])([CH3:53])[CH2:41][O:40][C:39]=2[CH:55]=1
Reactant: CCOC(=O)c1nc2c(s1)C(C)(O)COc1cc(F)c(Br)cc1-2
Reactant: CCOC(=O)c1nc2c(s1)C(C)(O)COc1cc(F)c(C#C[C@]3(O)CCN(C)C3=O)cc1-2
Agent: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2cc3c(cc2F)OCC(C)(O)c2sc(C(N)=O)nc2-3)C1=O

Procedure:
Similar to as described in General Procedure G, racemic ethyl 9-bromo-8-fluoro-4-hydroxy-4-methyl-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give a diasteromeric mixture of ethyl 8-fluoro-4-hydroxy-9-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4-methyl-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate. Following aminolysis of the ethyl ester (similar to as described in General Procedure M) a diasteromeric mixture of the titled compounds was obtained after purification by prep HPLC.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][C:4](=O)[CH2:3]1.C(OP(Cl)(OCC)=O)C.[N+:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])#[C-:25].C(O)(=O)C>CN(C)C=O.O>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:25]=[N:24][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:4]2[CH2:3]1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CN1CC(=O)Nc2ccccc2C1=O
Agent: CCOP(=O)(Cl)OCC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
16.5 g of 4-methyl-3,4-dihydro-2H-1,4-benzodiazepine-2,5(1H)-dione and 11.7 g of K-t-butoxide was dissolved in 100 ml of dry dimethyl formamide (DMF) and the mixture was stirred for 10 minutes. Then 13.2 ml of diethylchlorophosphate was added and the resulting mixture was cooled to -20° C. and stirred for 10 minutes. A mixture of 10.8 g K-t-butoxide and 10.5 ml ethyl isocyanoacetate in 30 ml of dry DMF was added to the above prepared mixture at -10° to --20° C. and the resulting mixture was stirred for one hour at RT, whereafter it was poured into 8.7 ml acetic acid in 300 ml water. This mixture was extracted 2 times with 150 ml methylene chloride. The organic phase was dried and evaporated. The resulting residue was crystallized leaving 10 g of the title compound as crystals.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>CC(C)=O>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CC=C(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-phenyl-1,2,3,6-tetrahydropyridine (1.95 g, 12.2 mmol) in acetone (20 mL) was added 1,3-propane sultone (1.66 g, 13.5 mmol). The mixture was stirred at reflux for 2 h. The resulting suspension was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. The product was suspended in 50% MeOH/acetone (75 mL). The suspension was stirred at reflux for 5 min. The solid material was filtered and washed with acetone (2×25 μL). This allowed the isolation of compound O, 1.74 g (51%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14][CH2:13]2)(=[O:9])=[O:8].CCN(CC)CC.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:29](=[O:30])[CH2:28][Cl:27])[CH2:15][CH2:14][CH2:13]2)(=[O:9])=[O:8]
Reactant: O=C(Cl)CCl
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CCCN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCCc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
Under N2, a solution of 1,2,3,4-Tetrahydro-quinoline-6-sulfonic acid thiazol-2-ylamide (50 mg, 0.17 mmol), Et3N (17 mg, 24 μl, 0.17 mmol) and CH2Cl2 (0.5 mL) was cooled to 0° C. Chloroacetyl chloride (77 mg, 56 μl, 0.68 mmol) was added dropwise, over a period of 10 minutes. This reaction mixture was stirred at 0° C. for 2 hours. The mixture was purified via silica gel chromatography using 2% MeOH in CH2Cl2 to obtain the amide (30 mg, 0.08 mmol, 47% yield). LC/MS (10-99%) M/Z: M+1 obs=372.1; tR=2.51 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])#[N:2].C([Sn]([N:24]=[N+:25]=[N-:26])(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1.C(OCC)C>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[N:24]=[N:25][NH:26][N:2]=1
Reactant: COc1ccccc1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: COc1ccccc1-c1nn[nH]n1
Yield: 98.1 %

Procedure:
A mixture of 1-cyano-2-methoxybenzene (1.02 g, 7.7 mmol) and tributyltin azide (3.4 g, 10.0 mmol) in 3.0 mL of xylene was heated under reflux for hours. The reaction mixture then was cooled and diluted with diethyl ether. Anhydrous hydrochloric acid was bubbled into the mixture and a white precipitate formed. The precipitate was collected by suction filtration and washed repeatedly with diethyl ether. Drying gave 5-(2-methoxyphenyl)-2H-tetrazole (1.33 g, 7.55 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(C(C)Nc2cc(F)ccc2S(C)(=O)=O)c1OC
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(Cl)cc(C(C)Nc2cc(N3CCN(C)CC3)ccc2S(C)(=O)=O)c1OC
Yield: 7.5 %

Procedure:
N-(1-(5-Chloro-2,3-dimethoxyphenyl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine (0.50 g, 1.29 mmol), 1-methylpiperazine (0.60 g, 6.40 mmol), N,N-diisopropylethylamine (0.66 g, 5.15 mmol) were stirred at 110° C. in dry acetonitrile (3 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 10% methanol in dichloromethane to afford the title compound (45.1 mg, 7.5% yield). 1H NMR (400 MHz, CDCl3): δ 7.54 (d, 1H), 6.87 (d, 1H), 6.76 (d, 1H), 6.52 (d, 1H), 6.22 (dd, 1H), 5.91 (d, 1H), 4.85 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.19 (m, 4H), 3.04 (s, 3H), 2.43 (m, 4H), 1.54 (d, 3H); MS (ESI) m/z: 468.0 (M+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=O.[CH3:16][O:17][C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26](O)=O)[CH2:22][CH2:21]1)=[O:19].C([N:31](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O.CC(O)=O>[CH3:16][O:17][C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26]2[NH:2][CH:3]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=3)[N:31]=2)[CH2:22][CH2:21]1)=[O:19]
Reactant: NCC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1

Procedure:
The solution of 2-amino-1-(3-trifluoromethyl-phenyl)-ethanone hydrochloride (50.2 mmol), trans-cyclohexane-1,4-dicarboxylic acid monomethyl ester (50.2 mmol), triethylamine (100.4 mmol) and BOP (50.2 mmol) in DMF (100 mL) was stirred overnight at room temperature. The mixture was diluted with water, extracted with EtOAc, washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated under vacuum. The residue was triturated with ether and the precipitate was collected. The precipitate was mixed with NH4OAc (930 mmol) and 200 ml of AcOH and refluxed overnight. The excess AcOH was removed and purification by flash chromatography (95:5 CH2Cl2/MeOH) gave trans-4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexyl-carboxylic acid methyl ester.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)[CH:18]=2)[CH:10]=1)[CH2:6][CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[CH3:52][CH:53]([CH2:56][CH3:57])[C:54]#[CH:55]>O1CCCC1.[Pd](Cl)Cl.[Cu]I>[CH3:52][CH:53]([CH2:56][CH3:57])[C:54]#[C:55]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)[CH:18]=2)[CH:10]=1)[CH2:6][CH3:7]
Reactant: C#CC(C)CC
Reactant: CCN(C/C=C/Cl)Cc1cccc(OCc2cccc(-c3ccsc3)c2)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: C1CCOC1
Product: CCC(C)C#C/C=C/CN(CC)Cc1cccc(OCc2cccc(-c3ccsc3)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
To a solution of 100 mg (0.25 mmol) of (E)-N-(3-chloro-2-propenyl)-N-ethyl-3-[3-(3-thienyl)benzyloxy]benzylamine in 2 ml of tetrahydrofuran were added 6.0 mg (0.023 mmol) of triphenylphosphine, 4.0 mg (0.023 mmol) of palladium chloride, 6.0 mg (0.032 mmol) of copper (I) iodide, 100 μl (1 mmol) of n-butylamine and 0.5 ml (5.12 mmol) of 3-methyl-1-pentyne. The mixture was stirred for 48 hours at room temperature, and concentrated under reduced pressure. The residue was treated with a mixture of ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure. The residue was subjected to thin layer chromatography to obtain 79 mg (yield: 71%) of the above identified compound as a brown oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1>CS(C)=O>[ClH:8].[CH3:3][O:4][CH2:5][CH2:6][O:7][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)(=[O:16])=[O:17])=[CH:11][CH:10]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCCNC1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCOc1ccc(S(=O)(=O)C2CCCNC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.56 g (0.065 mole) of sodium hydride and 5.32 g (0.07 mole) of 2-methoxyethanol in 300 ml of dimethylsulfoxide was stirred at room temperature for 0.5 hr. A solution of 12.0 g (0.0463 mole) of 3-[(4-chlorophenyl)sulfonyl]piperidine (free base) in 100 ml of dimethyl sulfoxide was added and the mixture was stirred at 80°-100° C. for 1 hr. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and water. The methylene chloride layer was dried over magnesium sulfate and the solvent was removed in vacuo to give an oil, the free base of the title compound. The free base was reacted with ethereal hydrogen chloride, crystallizing and recrystallizing using the solvent pair methanol-diethyl ether to give 10.12 g (65.2%) of the white crystalline hydrochloride salt, m.p. 206°-208° C.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][O:19][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(CO)CC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of N-p-nitrobenzyloxycarbonyl-4-hydroxymethylpiperidine (20 g) in dry pyridine (127 ml) was added p-toluenesulfonyl chloride (25.8 g) with ice-cooling, and the reaction mixture was kept overnight at the same temperature, diluted with ice water and extracted with diethyl ether dichloromethane. The extract was washed successively with water, dilute hydrochloric acid, aqueous sodium bicarbonate and again water, dried over anhydrous sodium sulfate and evaporated to give an oily residue which was crystallized from methanol to give N-p-nitrobenzyloxycarbonyl-4-p-toluenesulfonyloxymethylpiperidine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1cc(-c2c[nH]c3ncccc23)cc(NC2CCNCC2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(Nc2cc(-c3c[nH]c4ncccc34)cc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of Example 33 (0.04 g, 0.095 mmol) in 2 mL anhydrous THF was added diisopropylethylamine (0.07 mL, 0.38 mmol) followed by methanesulfonyl chloride (0.009 mL, 0.114 mmol). The resulting solution was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed with water, brine, dried over magnesium sulfate, filtered, and concentrated to give the title compound as an off-white solid. 1H NMR (300 MHz, DMSO-d6) ppm 1.16-1.35 (m, 1H) 1.38-1.61 (m, 3H) 1.93-2.10 (m, 3H) 2.90-3.04 (m, 2H) 3.52 (d, J=12.21 Hz, 2H) 3.84 (s, 1H) 6.82-7.00 (m, 3H) 7.21 (dd, J=7.80, 5.09 Hz, 1H) 8.14 (d, J=3.05 Hz, 1H) 8.24-8.37 (m, 2H) 12.16 (s, 1H). MS (ESI+) m/z 406.0 (M+H)+.