Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C(O)(C(F)(F)F)=O.CS(C)=O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH:27]=[CH:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: Nc1c(F)cccc1Cl
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Nc5c(F)cccc5Cl)nc34)cc21
Product: O=c1[nH]ccc2[nH]c(-c3cccc4ccc(Nc5c(F)cccc5Cl)nc34)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %
Yield: 4 %

Procedure:
To 2-chloro-6-fluoroaniline (0.183 g, 1.259 mmol) and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added LHMDS (1.0 M solution in THF; 1.259 ml, 1.259 mmol). The reaction was sealed and stirred 1 h at RT, then for 3 h at 70° C. The reaction was subsequently cooled to RT and stirred overnight. 1.5 mL DMSO and 10 drops TFA were added. The mixture was filtered and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-80% ACN/H2O with 0.1% TFA). The product-containing fractions were concentrated in vacuo, and the residue was partitioned between saturated aq. NaHCO3 and DCM. The aq. layer was extracted with DCM (3×), and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was dissolved in DCM/MeOH, adsorbed onto 0.75 g silica gel, and purified by silica gel chromatography using 0-50% 90/10 MeOH/DCM in DCM. The product-containing fractions were concentrated to separately afford 2-(2-((2-chloro-6-fluorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.022 g, 0.054 mmol, 21% yield) as a light-yellow solid and 2-(2-((2-chloro-6-fluorophenyl)amino)quinolin-8-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.0037 g, 9.14 μmol, 4% yield) as a yellow solid. 2-(2-((2-Chloro-6-fluorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (7): 1H NMR (400 MHz, DMSO-d6) δ ppm 11.82 (1H, br. s), 9.34 (1H, s), 8.16 (1H, d, J=9.0 Hz), 8.01 (1H, dd, J=7.6, 1.6 Hz), 7.55-7.67 (2H, m), 7.41-7.54 (2H, m), 7.28 (1H, t, J=7.7 Hz), 7.13 (1H, d, J=9.0 Hz), 6.83-6.98 (2H, m), 3.32-3.44 (2H, m), 2.43 (2H, t, J=6.8 Hz). m/z (ESI, +ve) 406.9 (M+H)+. 2-(2-((2-Chloro-6-fluorophenyl)amino)quinolin-8-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (12): 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (1H, br. s), 10.68 (1H, d, J=6.1 Hz), 9.41 (1H, s), 8.11-8.26 (2H, m), 7.43-7.76 (4H, m), 7.34 (1H, t, J=7.7 Hz), 7.18-7.25 (1H, m), 7.14 (1H, d, J=9.0 Hz), 6.86-7.00 (1H, m), 5.91 (1H, d, J=6.8 Hz). m/z (ESI, +ve) 405.2 (M+H)+.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[O:2]1.C(=O)([O-])[O-:13].[K+].[K+].OO>CO>[CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]([OH:13])=[O:6])[O:2]1
Reactant: O=Cc1cccc2c1OCO2
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CO
Product: O=C(O)c1cccc2c1OCO2
Yield: 96.5 %

Procedure:
A solution of 2,3-(methylenedioxy)benzaldehyde (160mg, 1.06mmol), potassium carbonate (960 mg, 6.9 mmol) and 2.4mL of hydrogen peroxide (30-32 wt.% solution in water) in 10 mL of methanol was stirred for 16 hours at room temperature. The mixture was washed with diethyl ether. The water layer was acidified with 1 N aq. HCl to pH>1, then extracted with ethyl acetate. The organic layer was dried over MgSO4, then concentrated to give the desired product (170mg, 96%). EI-MS (m/z) 164.8 (M−).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.C(Cl)Cl.Cl[C:24](OC1C=CC([N+]([O-])=O)=CC=1)=[O:25].[NH2:36][C:37]1[CH:47]=[CH:46][C:40]2[O:41][C:42]([F:45])([F:44])[O:43][C:39]=2[CH:38]=1>>[F:44][C:42]1([F:45])[O:41][C:40]2[CH:46]=[CH:47][C:37]([NH:36][C:24]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])=[C:7]([C:13]4[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=4)[CH:8]=3)=[O:25])=[CH:38][C:39]=2[O:43]1
Reactant: CN(C)CCOc1ccc(N)cc1-c1ccnn1C
Reactant: Nc1ccc2c(c1)OC(F)(F)O2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc3c(c2)OC(F)(F)O3)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
To a solution of 4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (26.0 mg, 0.1 mmol) in methylene chloride (1 mL) pyridine (24.3 μL, 0.3 mmol) and 4-nitrophenyl chloroformate (20.2 mg, 0.1 mmol) were added and the mixture was stirred at room temperature for 1 hour. 5-Amino-2,2-difluoro-1,3-benzodioxole (11.6 μL, 0.1 mmol) was added, the reaction mixture stirred at room temperature for 48 hours and concentrated to give an oily residue that was subjected to a purification by flash chromatography (SiO2, CH2Cl2/MeOH gradient elution) to afford Compound 144 as an off-white solid in 14.0% yield. LCMS m/z (%)=460 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 10.30 (s, 1H), 7.64 (d, J=8.96 Hz, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 7.40-7.34 (m, 4H), 7.13 (d, J=8.92 Hz, 1H), 6.22 (s, 1H), 4.10 (t, J=5.56 Hz, 2H), 3.65 (s, 3H), 3.63 (s, 2H), 2.76-2.65 (m, 2H), 2.22 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:4][CH:3]=1.Br[CH2:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[C:43]#[N:44]>CC(O)=O.CC(O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:43]([C:42]1[CH:41]=[C:40]([CH:47]=[CH:46][CH:45]=1)[CH2:39][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:6][CH:7]=1)#[N:44]
Reactant: N#Cc1cccc(CBr)c1
Reactant: COCCOc1c(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(O)cc2)ccc2ccccc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: COCCOc1c(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCc3cccc(C#N)c3)cc2)ccc2ccccc12

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 86 (b)] with 2-chloromethyl-1-(2-methoxy-ethoxy)-naphthalene there was obtained (3RS,4RS)-4-(4-allyloxy-phenyl)-3-[1-(2-methoxy-ethoxy)-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, from which after cleavage of the allyl group by means of bis-(triphenylphosphine)-palladium(II) diacetate analogously to Example 152 (e) there resulted tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-[1-(2-methoxy-ethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate, alkylation of which analogously to Example 44 (e) with 3-bromomethyl-benzonitrile gave tert-butyl (3RS,4RS)-4-[4-(3-cyano-benzyloxy)-phenyl]-3-[1-(2-methoxy-ethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a colourless oil; MS: 623 (M+H)+.
Reaction SMILES: Cl.[C:2]([O:6][CH2:7][CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].[C:10](N1C(=O)C2C(=CC=CC=2)C1=O)(=[S:12])[CH3:11]>C(O)C.N1C=CC=CC=1.[Pd]>[C:2]([O:6][CH2:7][CH2:8][NH:9][C:10](=[S:12])[CH3:11])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=S)N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OCCN
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=S)NCCOC(C)(C)C
Reaction time: 23 h

Procedure:
Dissolve (2-tert-butoxyethyl)dicarbamic acid benzyl ester (387.8 mg, 1.01 mmol) and 5% Pd/C (0.212 g) in absolute ethanol and expose it to 60 psi of H2 for 18 hours. Filter the reaction mixture over a pad of celite. Acidify the filtrate with 5N HCl and concentrate in vacuo to obtain 139.4 mg of a crude residue containing the HCl salt of 2-tert-butoxyethylamine. Dissolve this crude material (139.4 mg, 0.852 mmol) in 10 mL pyridine at 25° C. To this add 2-thioacetylisoindole-1,3-dione (180.53 mg, 0.88 mmol) and allow to stir for 23 hours. Concentrate the reaction mixture in vacuo and dissolve the residue in methylene chloride and wash it with 1N HCl (1×). Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 266.9 mg of crude product. Triturate this crude material in diethyl ether and remove the solids by filtration. Concentrate the filtrate in vacuo to afford 176.2 mg of a crude solid. Purify via Biotage chromatography to afford 74.1 mg of N-(2-tert-butoxyethyl)thioacetamide. Dissolve this thioacetamide (74.1 mg, 0.423 mmol) in 20 mL methylene chloride and add methyl trifluoromethanesulfonate (76.3 mg, 0.465 mmol). Allow the reaction mixture to stir for an additional 21 hours. Decant the diethyl ether from the oil and triturate the oil with diethyl ether (3×). Remove any excess diethyl ether from the oily residue in vacuo to obtain 60.3 mg of crude triflic acid salt of N-(2-tert-butoxyethyl)thioacetimidic acid methyl ester as an oil. Dissolve this crude product (60.3 mg, 0.62.5 mmol) in 10 mL pyridine and add N-(R)-(6-amino-2(R)-hydroxyindan-1-yl)-4-bromobenzamide (62.5 mg, 0.180 mmol). Allow the reaction to stir at 25° C. for 22 hours. Remove the solvent in vacuo and partition the residue between methylene chloride and saturated aqueous sodium hydrogen carbonate. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 31.4 mg of crude product. Purify via Biotage chromatography (10% MeOH/EtOAc) to afford 6.6 mg of the titled product (8% yield). MS (ES): m/z 488.1 (M+H).
Reaction SMILES: [CH2:1]([C@H:8]([CH2:19][C:20]([CH2:22]Cl)=[O:21])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C@H:8]([CH2:19][C:20](=[O:21])[CH2:22][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(CCl)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)CN1CCOCC1
Yield: 65.5 %

Procedure:
The resultant compound from Example 34 (610 mg, 1.84 mmol) in dimethylformamide (10 ml) was treated with NaI (33 mg, 0.22 mmol) and morpholine (0.60 ml, 6.88 mmol). After 2 h the mixture was diluted with ethyl acetate, washed with water and brine, and then dried over Na2SO4, and evaporated. Chromatography of the residue on silica gel with 60% ethyl acetate/40% hexane afforded 460 mg (65%) of an oil. 1H NMR (CDCl3) δ7.05-7.40 (m,10H), 5.11 (d,1H), 5.06 (d,1H), 3.68 (m,4H), 3.22-3.32 m,1H), 3.15 (d,1H), 3.08 (d,1H), 3.05 (m,1H), 2.87 (dd,1H), 2.77 (dd,1H), 2.35-2.50 (m,5H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][CH:5]=1)[CH3:2].C(OC(=O)C)(=[O:13])C>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([OH:13])[CH:5]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1cc[n+]([O-])cc1
Product: CCOc1ccnc(O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
A mixture of 4-ethoxypyridine 1-oxide (5 g, 35.9 mmol) in acetic anhydride (36.7 g, 359 mmol) was heated to reflux for 4 h. Then the solvent was removed in vacuo, and the residue was dissolved in MeOH (25 mL) and H2O (25 mL) and stirred at 25° C. for 16 h. The mixture was concentrated. The crude material was purified by silica column chromatography (DCM/MeOH=10:1). All fractions found to contain product by TLC (DCM/MeOH=10:1, Rf=0.6) were combined and concentrated to yield a dark yellow solid of 4-ethoxypyridin-2-ol (2.5 g, 16.17 mmol, 45.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.28 (d, J=7.6 Hz, 1H), 6.07 (d, J=3.2, 7.2 Hz, 1H), 5.86-7.85 (d, J=2.4 Hz, 1H), 4.06-4.01 (m, 2H), 1.38 (t, J=7.2 Hz, 3H); ES-LCMS m/z 140.0 (M+H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[S:22][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[N:20][C:19]=2[CH3:27])=[N:16][CH:17]=1>N1C=CC=CC=1>[CH3:27][C:19]1[N:20]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:22][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:17][N:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(N)cn2)s1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(C)c(-c2ccc(NS(=O)(=O)c3ccccc3)cn2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzenesulfonyl chloride (0.062 mL) was added to a stirred mixture of N-[5-(5-aminopyridin-2-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (100 mg) and pyridine (1 mL) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated and the residue was triturated under methanol. The resultant precipitate was filtered off, washed in turn with methanol and diethyl ether and dried. There was thus obtained the title compound (85 mg); 1H NMR Spectrum: (DMSOd6) 2.13 (s, 3H), 2.47 (s, 3H), 7.55-7.65 (m, 5H), 7.80 (m, 2H), 8.26 (m, 1H), 10.58 (s, 1H), 12.05 (s, 1H); Mass Spectrum: M+H+ 389.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[Cl:8][S:9]([C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([CH3:22])=[CH:15][N:16]=[CH:17]2)(=[O:11])=[O:10]>>[ClH:8].[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:9]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[C:14]([CH3:22])=[CH:15][N:16]=[CH:17]3)(=[O:10])=[O:11])[CH2:7]1
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Reactant: C[C@@H]1CNCCN1
Product: Cc1cncc2cccc(S(=O)(=O)N3CCN[C@H](C)C3)c12
Product: Cl
Yield: 91.9 %

Procedure:
Using 0.50 g of (R)-2-methylpiperazine and 0.40 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.52 g of the objective compound (white crystals).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C@H:20]4[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:29]([Cu])#[N:30].CN1C(=O)CCC1.Cl>O>[C:29]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C@H:20]4[CH2:21][CH2:22][C@H:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]4)=[CH:16][CH:15]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1)#[N:30]
Reactant: N#C[Cu]
Reactant: CCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(Br)cc4)nc3)cc2)CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(C#N)cc4)nc3)cc2)CC1
Temperature: 60 °C

Procedure:
3.3 g of 2-(4'-bromophenyl)-5-[4'-(trans-4"-propylcyclohexyl)phenyl]pyrimidine and 0.9 g (0.01 mol) of CuCN were added to 30 cm3 of NMP and the solution was refluxed for 2 hours using a mantle heater. The solution was cooled to 60° C. and added to a solution of 4.4 g of FeCl3.6H2O, 1.3 cm3 of concentrated hydrochloric acid and 6 cm3 of water. The resulting solution was heated on a warm water bath at a temperature of 60° C. for one hour. The crystals deposited were filtered out, washed with water and treated through a silica gel column using chloroform as the solvent. The chloroform was distilled off and the residue was recrystallized from a mixture of acetone and chloroform to yield 2.2 g (0.006 mol) of 2-(4'-cyanophenyl)-5-[4'-(trans-4"-propylcyclohexyl) phenyl] pyrimidine. The phase transition temperature of this compound, measured by DSC, was: ##STR28## wherein C is the crystal phase, N is the nematic phase and I is the isotropic liquid phase.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=CC=CC=1.CC(=NO)C(=O)CC.[F:29][C:30]([F:40])([F:39])C1C=C(C=CC=1)C=O>>[CH2:8]([C:7]1[O:6][C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([C:30]([F:40])([F:39])[F:29])[CH:19]=2)=[N:4][C:3]=1[CH2:2][I:1])[CH3:13]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: CCC(=O)C(C)=NO
Product: CCc1oc(-c2cccc(C(F)(F)F)c2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, pentane-2,3-dione-2-oxime and 3-trifluoromethylbenzaldehyde gave 5-ethyl-4-iodomethyl-2-(3-trifluoromethylphenyl)oxazole.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[Br:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C(=O)C>[C:19]([C:18]1[CH:27]=[CH:28][C:29]([NH:30][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[C:16]([Br:15])[CH:17]=1)(=[O:20])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1Br
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)cc1Br)C(F)(F)F
Temperature: -17.5 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.75 g) in N,N-dimethylacetamide (10 mL) was rapidly added thionyl chloride (0.56 g) and the mixture stirred at -15 to -20° C. for 1 hour. 3-Bromo-4-aminobenzophenone (0.75 g) was then added in one portion and the mixture was allowed to stir at room temperature overnight. The solution was poured into ice water and the aqueous phase decanted from the resulting oily solid. Chromatography (eluent methylene chloride) gave the title compound (0.43 g) as a white solid; mp 138-40° C. Analysis for C17H13BrF3NO3 : Calculated: C, 49.06; H, 3.15; N, 3.37; Found: C, 49.06; H, 3.10; N, 3.35.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH2:27][C@H:28]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:29]([O:31][CH3:32])=[O:30])(=[O:25])=[O:24])=[CH:19][CH:18]=1>CC(C)=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][O:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH2:27][C@H:28]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:29]([O:31][CH3:32])=[O:30])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(O)cc1)N1CCCCC1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccc(F)cc2)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
420 mg (1.3 mmol) of cesium carbonate and then 0.2 ml (1.3 mmol) of 1-bromomethyl-4-fluorobenzene are added to a solution of 400 mg (1.2 mmol) of methyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-piperidin-1-ylpropanoate in 10 ml of acetone. After stirring at ambient temperature for 18 h, the reaction medium is filtered and then the filtrate is concentrated under vacuum. The crude product is purified by chromatography on silica gel, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 460 mg (87%) of methyl(S)-3-[4-(4-fluorobenzyloxy)benzenesulfonylamino]-2-piperidin-1-ylpropanoate are obtained in the form of a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][C@@H:11]2[C@@H:27]([CH3:28])[C:26](=[O:29])[O:25][C@H:24]([CH2:30][CH3:31])[C@:23]3([CH3:32])[C@H:19]([NH:20][C:21](=[O:33])[O:22]3)[C@@H:18]([CH3:34])[C:17](=[O:35])[C@H:16]([CH3:36])[CH2:15][C@:14]([O:38][C:39]([NH2:41])=[O:40])([CH3:37])[C@H:13]([O:42][C@@H:43]3[O:52][C@H:51]([CH3:53])[CH2:50][C@H:49]([N:54]([CH3:56])[CH3:55])[C@H:44]3[O:45][C:46](=[O:48])[CH3:47])[C@H:12]2[CH3:57])=[O:9])[CH:2]=1.[CH:58]([CH:60]([CH2:63][CH:64](OC)OC)[C:61]#[N:62])=O.FC(F)(F)C(O)=O>CC#N.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][C@@H:11]2[C@@H:27]([CH3:28])[C:26](=[O:29])[O:25][C@H:24]([CH2:30][CH3:31])[C@:23]3([CH3:32])[C@H:19]([NH:20][C:21](=[O:33])[O:22]3)[C@@H:18]([CH3:34])[C:17](=[O:35])[C@H:16]([CH3:36])[CH2:15][C@:14]([O:38][C:39]([N:41]3[CH:64]=[CH:63][C:60]([C:61]#[N:62])=[CH:58]3)=[O:40])([CH3:37])[C@H:13]([O:42][C@@H:43]3[O:52][C@H:51]([CH3:53])[CH2:50][C@H:49]([N:54]([CH3:55])[CH3:56])[C@H:44]3[O:45][C:46](=[O:48])[CH3:47])[C@H:12]2[CH3:57])=[O:9])[CH:2]=1
Reactant: COC(CC(C#N)C=O)OC
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](OC(=O)Cc2cccnc2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2OC(C)=O)[C@](C)(OC(N)=O)C[C@@H](C)C(=O)[C@H](C)[C@H]2NC(=O)O[C@@]21C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](OC(=O)Cc2cccnc2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2OC(C)=O)[C@](C)(OC(=O)n2ccc(C#N)c2)C[C@@H](C)C(=O)[C@H](C)[C@H]2NC(=O)O[C@@]21C
Temperature: 60 °C
Yield: 41.8 %

Procedure:
To a mixture of compound of Example 34 (0.35 g, 0.435 mmol) and 2-formyl-4,4-dimethoxy-butyronitrile (0.30 g, 1.91 mmol) in CH3CN was added trifluoroacetic acid (0.33 mL, 4.35 mmol). The mixture was heated to 60° C. for 18 hours and additional 2-formyl-4,4-dimethoxy-butyronitrile (0.15 g, 0.186 mmol) and trifluoroacetic acid (0.15 mL, 1.95 mmol) were added. The mixture is was heated to 60° C. for 18 hours before being cooled, diluted with ethyl acetate, washed with sat. aq. NaHCO3, water, brine, and dried over MgSO4. Concentration and chromatography (silica gel, 98:2:0.3 dichloromethane/methanol/conc. NH4OH) gave 0.16 g (41%) of the title compound. MS 880 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:8][C:9]=1[N:10]([CH:20]([CH3:22])[CH3:21])[C:11]([CH:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)=[O:12])=[O:4].O[Li].O>C1COCC1.CO.O>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([CH:20]([CH3:22])[CH3:21])[C:11]([CH:13]3[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]3)=[O:12])[CH:8]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1sc(-c2ccc(F)cc2)cc1N(C(=O)C1CC=C(C)CC1)C(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1=CCC(C(=O)N(c2cc(-c3ccc(F)cc3)sc2C(=O)O)C(C)C)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
5-(4-Fluoro-phenyl)-3-[isopropyl-(4-methyl-cyclohex-3-enecarbo-nyl)-amino]-thiophene-2-carboxylic acid methyl ester (0.140 g, 0.34 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 10 mL) and then added 1N aqueous solution of LiOH.H2O (2.1 mL, 2.04 mmol). The reaction mixture was stirred at 50° C. for 1 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by preparative TLC using dicholomethane:methanol(9:1) to obtain 5-(4-Fluoro-phenyl)-3-[isopropyl-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid (compound 53) (31 mg, 23%). 1H NMR (CDCl3, 400 MHz): δ 7.81 (m, 2H), 7.43 (d, 1H), 7.28 (m, 2H), 5.38-5.16 (m, 1H), 4.72 (m, 1H), 2.20 (d, 2H), 1.95-1.20 (m, 8H), 1.12 (m, 3H), 0.90 (d, 3H).