Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]#[N:5].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.O1CCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCCCCC.O>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]#[N:5]
Reactant: C1=COCCC1
Reactant: CCCCCCCCCCC[C@@H](O)CC#N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCC[C@H](CC#N)OC1CCCCO1
Temperature: 50 °C
Yield: 100 %

Procedure:
2.16 g of (R)-3-hydroxy-tetradecanenitrile, 1.93 ml of dihydropyran and 20 ml of tetrahydrofuran were placed in a reactor and stirred, and 266 mg of pyridinium p-toluenesulfonate was added thereto, heated to 50° C., and stirred for about 2 hours. The mixture was cooled to room temperature, 30 ml of water and 30 ml of hexane were added thereto, and stirred vigorously for 5 minutes. The resulting mixture was allowed to undergo phase separation and the aqueous layer was removed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure, to give 2.97 g of the title compound (yield: 100%) as an oil.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=O)[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:51]1[CH2:56][CH2:55][CH:54]([C:57]2[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=2)[C:60]#[N:61])[CH2:53][CH2:52]1>CN(C)C=O>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([N:51]3[CH2:56][CH2:55][CH:54]([C:57]4[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=4)[C:60]#[N:61])[CH2:53][CH2:52]3)=[O:17])[CH:12]=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Reactant: N#Cc1cccc(C2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(C2CCN(C(=O)c3cncc(C#Cc4ccccc4)c3)CC2)c1
Reaction time: 0.25 h
Yield: 45.1 %

Procedure:
A solution of 5-phenylethynyl-pyridine-3-carboxylic acid (0.75 g, 3.3 mmol) in anhydrous dimethylformamide (9 ml) is treated with HATU (1.27 g, 3.3 mmol) and diisopropylethylamine (1.1 ml, 6.1 mmol). The reaction mixture is stirred 15 mins. at ambient temperature before being treated with a solution of 3-(piperidin-4-yl)-benzonitrile (0.6 g, 3 mmol) in dimethylformamide (6 ml). The reaction mixture is stirred at ambient temperature 2 hours, concentrated under vacuum and the residue partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate ((45 ml). The organic layer is dried (magnesium sulfate), concentrated under vacuum and the residue chromatographed on silica gel (dichloromethane/methanol 39:1) to give the title compound as a yellow oil (0.53 g). 1H NMR (CDCl3, 500 MHz) δ8.80 (s, 1H), 8.63 (s, 1H), 8.00 (s, 1H), 7.50 (m, 9H), 4.90 (br m, 1H), 3.85 (br m, 1H), 3.28 (m, 1H), 2.90 (m, 2H), 1.91 (m, 1H), 1.75 (m, 3H). EI MS M++H: 392.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Si](Cl)(C)(C)C.[NH2:15][CH2:16][CH:17]([SH:20])[CH2:18][CH3:19].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:23]>CC#N>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:22]([NH:15][CH2:16][CH:17]([SH:20])[CH2:18][CH3:19])=[O:23])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: CCC(S)CN
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCC(S)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N,N-Diisopropylethylamine (8.50 ml, 0.0488 mol) and Me3SiCl (3.50 ml, 0.0239 mol) were added to an ice-cold, stirring solution of 1-amino-2-butanethiol (3.00 g, 0.0212 mol) in MeCN (16.0 ml). The solution was stirred 10 minutes at 0°, then treated with more N,N-diisopropylethylamine (3.70 ml, 0.0212 mol) and with a solution of p-nitrobenzyl chloroformate (4.57 g, 0.0212 mol) in MeCN (5.0 ml). The resulting mixture was stirred for 30 minutes at 0° and 90 minutes at room temperature. The mixture was poured into ice-water (50 ml) and extracted with EtOAc (75 ml). The organic phase was separated, washed with 1.25N HCl, 5% NaHCO3, and brine, dried with MgSO4, filtered and evaporated under vacuum to an oil (5.79 g).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([C@@H:13]([C@H:15]([C:17]([O:19]CC)=O)[OH:16])[OH:14])([O:10]CC)=O.O>CO>[CH:1]1([NH:7][C:8](=[O:10])[C@@H:13]([C@H:15]([C:17]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:19])[OH:16])[OH:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Solvent: O
Solvent: CO
Product: O=C(NC1CCCCC1)[C@H](O)[C@@H](O)C(=O)NC1CCCCC1
Reaction time: 0.5 h
Yield: 13 %

Procedure:
N,N′-Di-cyclohexyl L-tartaramide was prepared by the reaction of cyclohexyl amine with diethyl L-tartrate. Diethyl L-tartrate (19.997 g, 1.0 eq) and HPLC grade methanol (40 mL) were weighed into a 250 mL round-bottomed flask equipped with a teflon coated magnetic stir bar. Cyclohexyl amine (20.205 g, 2.0 eq) was slowly poured into the stirring diethyl L-tartrate solution. Some fuming and a color change from water-white to pale yellow were observed. Additional methanol (10 mL) was used to rinse all of the amine into the reaction flask. After stirring the solution for 30 min, the flask was stoppered and refrigerated at approximately 45° F. (70C). The product crystallized after 3 days at 45° F. (7° C.). The white crystals were filtered, washed with methanol (2×15 mL), and dried under vacuum. A first crop of 3.952 g (12.65 mmole, 13% yield) were obtained in this manner, and a second crop of 16.063 g were obtained by removing the solvent under vacuum. Overall yield was 66%.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1(C)[CH:12]=CC=C[CH:8]=1>>[CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7]([O:6][CH:1]([CH3:2])[CH3:5])([CH3:12])[CH3:8]
Reactant: Cc1ccccc1
Agent: OC1CCCC1
Product: CC(C)OC(C)C

Procedure:
0.05 mL of the acyl group acceptor cyclopentanol with toluene added to give 2.0 mL, 0.05 mL of the acyl group acceptor cyclopentanol with isopropyl ether added to give 2.0 mL, 0.05 mL of the acyl group acceptor 2-butanol with toluene added to give 2.0 mL, 0.05 mL of the acyl group acceptor 2-butanol with isopropyl ether added to give 2.0 mL, 0.05 mL of the acyl group acceptor 2-propanol with toluene added to give 2.0 mL, and 0.05 mL of the acyl group acceptor 2-propanol with isopropyl ether added to give 2.0 mL were prepared, and 50 mg of each of the enzymes shown in Table 10 and 50 mg of the compound of Formula 13 were added to each of the above and stirred using a stirrer (600 rpm) at room temperature (21° C. to 24° C.) for 19 hours. After the reaction was completed, the immobilized enzyme was removed by filtration using an Ekicrodisc 25CR, and the solution was dried under reduced pressure, dissolved in 1 mL of methanol, and then subjected to analysis by the above-mentioned HPLC method for the compound of Formula 3.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:34]=[CH:33][C:13]([CH2:14][O:15]C(C2C=CC(CO[Si](C(C)(C)C)(C)C)=CC=2)=C)=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OCC(OC(C1C=CC=C(CO[Si](C(C)(C)C)(C)C)C=1)=C)C1C=CC=CC=1)(C(C)(C)C)(C)C.C(OC(C1C=CC=C(CO[Si](C(C)(C)C)(C)C)C=1)=C)C1C=CC=CC=1.OCC1C=CC(C(OC)=O)=CC=1.[Si](Cl)(C(C)(C)C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Si:1]([O:8][CH2:9][C:10]1[CH:34]=[CH:33][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C(OCc1ccc(CO[Si](C)(C)C(C)(C)C)cc1)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: C=C(OC(CO[Si](C)(C)C(C)(C)C)c1ccccc1)c1cccc(CO[Si](C)(C)C(C)(C)C)c1
Agent: C=C(OCc1ccccc1)c1cccc(CO[Si](C)(C)C(C)(C)C)c1
Agent: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CO)cc1

Procedure:
α-[4-(tert-Butyldimethylsilyloxymethyl)-benzyloxy][4-(tert-butyldimethylsilyloxymethyl)styrene] and α-[(tert-Butyldimethylsilyloxymethyl )-benzyloxy][3-(tert-butyldimethylsilyloxymethyl)styrene]. (Formula II, R1 =tert-butyldimethylsilyloxymethylphenyl, R2 =4-tert-butyldimethylsilyloxymethylbenzyl). Methyl 4-(hydroxymethyl)benzoate was treated with tert-butyldimethylsilyl chloride using the general procedure described in Journal of the American Chemical Society, 1972, 94, 6190. The resulting product was reduced with lithium aluminium hydride to afford 4-(tert-butyldimethylsilyloxymethyl)benzyl alcohol. This alcohol was converted into the required compound uising Method C. 1H NMR (CCl4) δ 0.08 (12H, s), 0.91 (18H, s), 4.22 (1H, d, J 2 Hz), 4.68 (5H, br s), 4.90 (2H, s), 7.1-7.6 (8H, m); MS (CH4) 483 (M+ --CH3, 52%), 133 100%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])=[CH:14][C:13]2=[O:28])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:35][N:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1.C(N(CC)CC)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])=[CH:14][C:13]2=[O:28])[C:9]([NH:41][C:38]2[CH:39]=[CH:40][N:36]([CH3:35])[N:37]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2C(F)(F)F)=CC1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccccc3C(F)(F)F)=CC2=O)n1
Reaction time: 0.75 h

Procedure:
A solution of (S)-3-cyclohexyl-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid (prepared as in Example 32, 100 mg, 0.25 mmol) in dichloromethane (4 mL) was treated with a dichloromethane solution of oxalyl chloride (2 M, 0.25 mL) and one drop of N,N-dimethylformamide. The mixture was stirred for 45 min and solvents were evaporated. The residue was dissolved in dichloromethane (4 mL) and treated with 1-methyl-1H-pyrazol-3-ylamine (30 mg, 0.30 mmol), and triethylamine (50 mg, 0.5 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution, water, saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 30% to 100% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionamide. This material was dissolved in dichloromethane (4 mL) and treated with 1M hydrogen chloride in diethyl ether (2 mL). Solvents were evaporated and the residue was triturated with diethyl ether and filtered to give (S)-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionamide hydrochloride (20 mg, 16%) as a tan solid: LR-ES-MS m/z calculated for C24H27F3N4O3 [M]+ 476, observed [M+H]+ 477; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.78-1.32 (m, 6H) 1.51-1.87 (m, 7H) 3.73 (s, 3H) 4.19 (d, J=18.7 Hz, 1H) 4.58 (d, J=18.7 Hz, 1H) 4.86-4.94 (m, 1H) 4.96 (s, 1H) 6.40 (d, J=2.1 Hz, 1H) 7.47-7.58 (m, 2H) 7.65 (d, J=7.8 Hz, 1H) 7.74-7.90 (m, 2H) 10.72 (s, 1H).
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:29]12CC[CH:32]([CH2:33][CH2:34]1)[CH:31](O)[CH2:30]2.[H-].[Na+]>[Cl-].[Na+].O>[C:8]1([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24]([O:26][CH:27]2[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]2)=[O:25])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC1CN2CCC1CC2
Reactant: CCOC(=O)N1CCc2ccccc2C1c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(OC1CN2CCC1CC2)N1CCc2ccccc2C1c1ccccc1
Temperature: 140 °C
Reaction time: 48 h
Yield: 12.2 %

Procedure:
To a 30 ml toluene solution containing 0.70 g of ethyl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate and 0.41 g of 3-quinuclidinol, 0.03 g of sodium hydride (60%) was added. The resulting mixture was stirred at 140° C. for 2 days while removing the ethanol formed. The reaction mixture was cooled to room temperature, brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:1→chloroform:methanol:28% aqueous ammonia=10:1:0.1), thereby 0.11 g of 3-quinuclidinyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate was obtained as yellow oil. The resulting oil was dissolved in 10 ml of ethanol, followed by the addition of 27 mg of oxalic acid. Then, the solvent was removed under reduced pressure. The resulting solid was recrystallized from isopropanol and isopropyl ether, thereby 0.08 g of 3-quinuclidinyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate monooxalate was obtained as colorless crystals.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH:15]1([CH2:19][OH:20])[CH2:18][CH2:17][CH2:16]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:20][CH2:19][CH:15]2[CH2:18][CH2:17][CH2:16]2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: OCC1CCC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(OCC2CCC2)cccc1[N+](=O)[O-]

Procedure:
Prepared as in Example 166d from 2,6-dinitrobenzonitrile and cyclobutylmethanol in 68% as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.93 (m, 4H), 2.10 (m, 2H), 2.79 (m, 1H), 4.25 (d, J=6.3 Hz, 2H), 7.74 (dd, J=8.5, 2.2 Hz, 1H), 7.91 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[S:15][CH:16]=[CH:17][N:18]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: c1csc(C2CCCN2)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Brc1cncc(N2CCCC2c2nccs2)c1
Temperature: 90 °C
Yield: 79.6 %

Procedure:
To a nitrogen degassed mixture of 3,5-dibromopyridine (4.61 g, 19.45 mmol), 2-(pyrrolidin-2-yl)thiazole (CA, 1.0 g, 6.48 mmol) and sodium t-butoxide (1.246 g, 12.97 mmol), in Toluene (20 ml) was added binap (0.807 g, 1.297 mmol) and tris(dibenzylideneacetone)di-palladium(0) (0.594 g, 0.648 mmol). The reaction was sealed and heated at 90° C. for 30 min. The reaction was cooled, quenched into water (100 mL), aqueous KHSO4 (20 mL) and ethyl acetate (200 mL) added. Aqueous NaHCO3 was added to adjust pH basic and ethyl acetate layer removed. Aqueous extract washed with ethyl acetate (50 mL) and the organic extracts washed with brine (50 mL), dried over sodium sulfate and concentrated to oil. The oil was chromatographed on silica using 25-75% ethyl acetate/hexanes to give 1.6 g foam of 1-7.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)CCC.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>O1CCOCC1.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>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: C1COCCO1
Product: Cc1c(-c2cccs2)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 100 °C
Reaction time: 15 h
Yield: 95.6 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (200 mg, 0.68 mmol), 2-(tri-n-butylstannyl)thiophene (280 μl, 0.88 mmol) and 2,6-di-tert-butyl-p-cresol (2 grains) were dissolved in 1,4-dioxane (6 ml), and at room temperature, bis(triphenylphosphine)palladium(II) dichloride (48 mg, 0.07 mmol) was added. The solution was stirred under nitrogen atmosphere at 100° C. for 15 hours. After cooling to room temperature, the insoluble matter was separated by filtration with washing with ethyl acetate. The filtrate was washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=19:1, v/v) to obtain the entitled compound (194 mg, 96%) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[Cl:21][C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1.C(OCC)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12]([C:22]([Cl:21])=[O:24])[CH2:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(Cl)N1CC=C(c2ccc(Cl)cc2)CC1
Yield: 269.3 %

Procedure:
A mixture of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (1 g, 4.3 mmol), pyridine (680 mg, 8.6 mmol), and triphosgene (430 mg, 1.45 mmol) in toluene (20 ml) was heated under reflux for 3 hours. The reaction mixture was allowed to return to room temperature and diluted with diethyl ether. The mixture was washed with 10% hydrochloric acid, water and brine in this order, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine-1-carbonylchloride (1 g, yield 90%) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][F:18])=[C:10]([C:19]([F:22])([F:21])[F:20])[CH:9]=1)(C)(C)C>FC(F)(F)C(O)=O>[F:18][CH2:17][CH2:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=1[C:19]([F:20])([F:21])[F:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCCF)c(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CCCCF)c(C(F)(F)F)c1
Temperature: 40 °C
Yield: 15.8 %

Procedure:
[4-(4-Fluorobutyl)-3-trifluoromethylphenyl]carbamic acid tert-butyl ester (300 mg, 1.8 mmol) was dissolved in trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 40° C. The trifluoroacetic acid was removed by reducing the pressure. To the residue, a saturated sodium bicarbonate solution was added. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to give 4-(4-fluorobutyl)-3-(trifluoromethyl)aniline (67 mg, 100%) as a light-yellow oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)(=O)=O.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1>CN(C)P(N(C)C)(N(C)C)=O.O>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[O:8][CH2:7][CH2:6][NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)OCCOc1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCOc2ccc3ccccc3c2)cc1

Procedure:
A mixture of 18.7 g of 2-(2-naphthyloxy)ethanol O-methanesulfonate and 23.6 g of ethyl p-aminobenzoate is heated in 300 ml of hexamethylphosphoramide at 110° C. for 16 hours. The mixture is cooled, diluted with water, and worked up as described in Example 3 to give the crystalline product. Recrystallization from ethanol gives crystals, mp 158°-162° C.
Reaction SMILES: [CH3:1][CH:2]([NH2:4])[CH3:3].[C:5]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]1[N:13]([CH3:24])[C:14](=[O:23])[C:15]([OH:22])=[C:16]([C:18](OC)=[O:19])[N:17]=1>C1COCC1>[CH:2]([NH:4][C:18]([C:16]1[N:17]=[C:12]([CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:13]([CH3:24])[C:14](=[O:23])[C:15]=1[OH:22])=[O:19])([CH3:3])[CH3:1]
Reactant: COC(=O)c1nc(Cc2ccccc2-c2ccccc2)n(C)c(=O)c1O
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1nc(Cc2ccccc2-c2ccccc2)n(C)c(=O)c1O
Temperature: 110 °C
Yield: 13.9 %

Procedure:
A sealed tube containing propan-2-amine (202 mg, 292 μl, 3.42 mmol), methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.1 g, 285 μmol) and THF (1.7 ml) was heated at 110° C. in a microwave oven for 20 minutes. The crude reaction mixture was cooled and evaporated to dryness. Purification by preparative HPLC provided the desired product as a light pink solid (0.015 g; 14%). LCMS: m/z=379 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:21]1([C:11]2[C:12]([C:9]3[C:10]4[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=4)[CH:6]=[CH:7][CH:8]=3)=[CH:13][CH:14]=[C:15]3[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]3)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc2c(-c3cccc4ccccc34)cccc2c1
Reactant: c1ccc2ccccc2c1
Solvent: Cc1ccccc1
Product: c1ccc2c(-c3ccc4ccccc4c3-c3cccc4ccccc34)cccc2c1

Procedure:
An experiment performed as in Example 1 is carried out except that the toluene is replaced with naphthalene. A mixture of binaphthalene and ternaphthalene is obtained.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Br:23])=[CH:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(C(=O)C2CCCCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(CBr)cc1)C1CCCCC1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
Heat a mixture of cyclohexyl-p-tolyl-methanone (1 g, 4.943 mmol), NBS (1.232 g, 6.92 mmol), and AIBN (41 mg, 0.247 mmol) in carbon tetrachloride (80 mL) for 14 h at reflux. Add additional NBS (264 mg) and AIBN (19 mg) and reflux the mixture for 4 h. Cool the reaction mixture to ambient temperature and filter. Concentrate the filtrate in vacuo to provide the desired intermediate as oil (1.132 g, 81%) that was used without any further purification.