Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:4])[CH:2]=[CH2:3].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4])[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: C=CC(=O)OCCCCCCCCCCCC
Product: CCCCCCCCCCCCOC(=O)CCN1CCN(C)CC1
Temperature: 85 °C

Procedure:
In a 40-mL scintillation vial, 12.0 g (0.05 moles) of lauryl acrylate are charged followed by the slow addition of 5.0 g (0.05 moles) of 1-methyl piperazine. The mixture is agitated using a magnetic stirrer bar and heated to 85° C. for at least 16 hours using a heating block. The final product is a light brown liquid at ambient temperature. Complete conversion is apparent from the lack of olefin protons in the 1H-NMR spectra. 1H-NMR (300 MHz, CDCl3): δ 3.83 (t, 6.6 Hz, 2H), 2.45 (t, 7.3 Hz, 2H), 2.24 (m, 10H), 2.02 (s, 3H), 1.38 (t, 6.8 Hz, 2H), 1.03 (m, 18H), 0.65 (t, 7.1 Hz, 3H). 13C-NMR (75 MHz, CDCl3): δ 171.78, 63.92, 54.64, 53.12, 52.39, 45.53, 31.93, 31.45, 29.19, 21.17, 29.12, 29.08, 28.89, 28.80, 28.20, 25.47, 22.20, 13.63.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH2:22]([O:1][C:2]1[C:7]([C:8]([O:10][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:9])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cnc(-n2cccn2)nc1OCc1ccccc1
Temperature: 70 °C

Procedure:
To a solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 2-c, (1 g, 4.85 mmol) in DMF (40 ml) was added K2CO3 (2.34 g, 16.98 mmol) and benzyl bromide (1.83 g, 10.67 mmol). The mixture was heated at 70° C. for 16 hours. The solution was then cooled to room temperature and diluted with water followed by extraction with ethyl acetate. The combined organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum to provide the crude product, 2-d, as a solid (1.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]2[CH:19]=[C:20]([C:25]3[CH:30]=[C:29]([C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[N:28]=[CH:27][C:26]=3[NH2:37])[C:21](F)=[N:22][CH:23]=2)[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]2[CH:23]=[N:22][C:21]3[NH:37][C:26]4[CH:27]=[N:28][C:29]([C:31]5[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=5)=[CH:30][C:25]=4[C:20]=3[CH:19]=2)[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1cc(-c2cnc(F)c(-c3cc(-c4cnn(C)c4)ncc3N)c2)cc(OC)c1CN1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]c4cnc(-c5cnn(C)c5)cc4c3c2)cc(OC)c1CN1CCCCC1
Reaction time: 0.5 h
Yield: 14.6 %

Procedure:
A solution of 5-(3,5-dimethoxy-4-piperidin-1-ylmethyl-phenyl)-2-fluoro-6′-(1-methyl-1H-pyrazol-4-yl)-[3,4′]bipyridinyl-3′-ylamine (490 mg, 0.98 mmol) in anhydrous THF (16.7 mL) was added dropwise over 10 minutes to a solution of sodium bis(trimethylsilyl)amide (1N solution in THF, 2.9 mL, 2.9 mmol). After 30 minutes, the reaction was quenched by the addition of saturated aqueous potassium fluoride solution (5 mL) and concentrated under reduced pressure to afford a brown residue. The resultant brown residue was partitioned between ethyl acetate (75 mL) and water (50 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 50 g column, Biotage, 0-20% methanol in DCM) to afford the title compound as an off-white solid (69 mg, 15%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.86 (d, J=1.1 Hz, 1H), 8.84-8.80 (m, 2H), 8.37 (d, J=1.1 Hz, 1H), 8.09 (s, 1H), 8.06 (d, J=0.8 Hz, 1H), 6.91 (s, 2H), 4.01 (s, 3H), 3.96 (s, 6H), 3.74 (s, 2H), 2.64-2.50 (m, 4H), 1.65-1.56 (m, 4H), 1.49-1.37 (m, 2H).
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][C:7]1[N:12]=[C:11]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:10](=[O:18])[N:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:8]=1[CH3:29])C.Cl.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([NH:42][NH2:43])=[CH:38][CH:37]=1)#[N:35]>CN(C=O)C>[C:34]([C:36]1[CH:41]=[CH:40][C:39]([N:42]2[C:6]([C:7]3[N:12]=[C:11]([C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[C:10](=[O:18])[N:9]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=4)[C:8]=3[CH3:29])=[CH:5][CH:4]=[N:43]2)=[CH:38][CH:37]=1)#[N:35]
Reactant: CCOC(C#Cc1nc(C(=O)N(C)C)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C)OCC
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)nc(C(=O)N(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 29.5 %

Procedure:
6-(3,3-Diethoxyprop-1-ynyl)-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0.028 g, 0.062 mmol) was dissolved in DMF (1 ml) in a microwave vial. 4-Cyanophenylhydrazine hydrochloride (0.013 g, 0.074 mmol) was added. The vial was sealed and heated with stirring to 120° C. for 5 minutes. The crude mixture was purified on preparative HPLC to give 9 mg (29%) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[C:17](C(=CNC1C=CC(C)=CN=1)C(OCC)=O)#N>>[CH3:17][C:14]1[CH:15]=[CH:16][C:9]2[N:10]([CH:13]=1)[C:11](=[O:12])[C:6]([C:5]1[NH:1][N:2]=[N:3][N:4]=1)=[CH:7][N:8]=2
Reactant: CCOC(=O)C(C#N)=CNc1ccc(C)cn1
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Product: Cc1ccc2ncc(-c3nnn[nH]3)c(=O)n2c1

Procedure:
In a manner similar to that described for the preparation of 3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one in Example 2, the title compound was prepared from ethyl 2-cyano-3-(5-methyl-2-pyridylamino)acrylate. The product (42.8% yield) had m.p. 321°-322° (decomp) after recrystallization from glacial acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:30]([NH2:32])=[O:31])[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[C:16]([N:22]2[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]2)[CH:15]=4)[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[Br:39][CH2:40][CH2:41]Br.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Br:39][CH2:40][CH2:41][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:10]=[C:11]([C:30]([NH2:32])=[O:31])[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[C:16]([N:22]2[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]2)[CH:15]=4)=[CH:3][C:2]=1[Cl:1]
Reactant: BrCCBr
Reactant: NC(=O)c1cc(-c2ccc(O)c(Cl)c2)cc2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCCBr)c(Cl)c2)cc2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100.3 %

Procedure:
A 100 ml round bottom flask was loaded with 3-(3-chloro-4-hydroxyphenyl)-7-(1,1-dioxo-thiomorpholino)-9H-carbazole-1-carboxamide (49.4 mg, 0.084 mmol, Example 408B), K2CO3 (150 mg, 1.085 mmol), DMF (6 ml) and 1,2-dibromoethane (0.09 ml, 1.044 mmol) and stirred at room temperature for 4.5 hours. The reaction mixture was poured into a separating funnel that was loaded with 100 ml water+citric acid (0.5 M solution in water) (10 ml, 5.00 mmol) and extracted with ethyl acetate. The organic layer was washed with dilute (1+5) aq. NaHCO3 solution, then brine, dried over MgSO4, filtered and evaporated to dryness to give 48.6 mg 3-(4-(2-bromoethoxy)-3-chlorophenyl)-7-(1,1-dioxo-thiomorpholino)-9H-carbazole-1-carboxamide, which was used without further purification. Estimated purity (from LCMS) ˜90%. MS (ESI) m/e+=576/578/580, m/e−=574/576/578 consistent with isotope pattern for 1 Br and 1 Cl.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](OC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:19][NH2:20]>CCO>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([NH:19][NH2:20])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: COC(=O)C(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: O
Product: NNC(=O)C(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of methyl 2,2-diphenylacetate (0.5 g, 1 equiv) in anhydrous EtOH (150 mL) was added hydrazine hydrate (8 mL) and heated to reflux. Stirring was then continued for 1 hour. The reaction mixture was then cooled and the solvents removed under reduced pressure. The crude oil was diluted with EtOAc and washed with H2O and the organic phase dried over Na2SO4, filtered, and the solvents removed under reduced pressure to yield a yellow oil (0.97 g, 97%) that was used without further purification.
Reaction SMILES: [C:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1)(=O)[CH2:2][CH2:3][CH3:4].C(O)=O.[CH:20]([NH2:22])=[O:21]>CCOCC>[CH:20]([NH:22][CH:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4])=[O:21]
Reactant: NC=O
Reactant: CCCC(=O)C1(c2ccc(Cl)cc2)CCC1
Solvent: O=CO
Solvent: CCOCC
Product: CCCC(NC=O)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of the ketone produced as described above (21 g) and 98% formic acid (6 ml) was added over a period of one and a half hours to formamide (15 ml) at 160° C. After completion of the addition the temperature was raised to 180° to 185° C. and maintained in this range for five hours. The mixture was cooled and extracted with chloroform to yield a thick gum which on heating with petroluem ether (b.p. 60°-80°) gave a colourless solid which was recrystallised from petroleum ether (b.p. 60°-80°) to yield N-formyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine (m.p. 97.5° to 98.5° C.) (Formula I R1 =propyl; R2 =H; R3 =H; R4 =CHO; R5 =4-Cl; R6 =H).
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1.N([O-])=O.[Na+].CC#N.O.[ClH:41]>O.Cl[Cu]>[Cl:41][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1
Reactant: Cl
Reactant: CCOC(=O)C1(c2cc(OCC3CC3)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(c2cc(OCC3CC3)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
Ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (1 g, 2.2 mmol) was dissolved in a mixture of MeCN/H2O/HCl 30 mL/30 mL/2 mL at 0° C. A solution of NaNO2 (0.200 g, 2.9 mmol) in water (10 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2.0 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude black oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate as yellow oil (1.1 g).
Reaction SMILES: [OH-].[Li+].I[CH3:4].[O:5]=[C:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]#[N:12]>O.CO>[CH3:4][C:7]1([C:11]#[N:12])[CH2:8][CH2:9][CH2:10][C:6]1=[O:5]
Reactant: CI
Reactant: N#CC1CCCC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C#N)CCCC1=O
Temperature: 50 °C
Yield: 78.3 %

Procedure:
A solution of lithium hydroxide (0.2226 g, 9.30 mmol) in water (5 mL) and iodomethane (0.591 mL, 9.46 mmol) were added to a stirred solution of 2-oxocyclopentanecarbonitrile (0.86 g, 7.88 mmol) in methanol (5 mL) at room temperature. The resulting mixture was heated to 50° C. for 1.5 h. The methanol solvent was removed in vacuo. The aqueous residue was extracted with ether (2×25 mL). The combined ether extracts were dried (Na2SO4), decanted and concentrated to give 1-methyl-2-oxocyclopentanecarbonitrile (0.76 g, 78% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 2.63-2.74 (1 H, m), 2.43 (2 H, t, J=7.21 Hz), 1.59-1.93 (4 H, m), 1.34 (3 H, d, J=6.94 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:22]([O:26][C:27]([N:29]1[CH2:33][C@H:32]([CH3:34])OS1(=O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:15]([C@H:32]([CH3:34])[CH2:33][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[C:9]2=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(Cl)nc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(Cl)nc2n1[C@H](C)CNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A solution of 3.0 g (13.3 mmol) 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in 70 ml N,N-dimethylformamide was cooled to 0 deg C. and 1.58 g (14.0 mmol) potassium tert-butoxide was added. After 30 min, 3.49 g (14.7 mmol) (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester was added in one portion. The cooling bath was removed and after 1.5 h the reaction mixture was poured into 100 ml 10% aqueous citric acid. The layers were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed four times with water, once with brine and then were dried over magnesium sulfate. After filtration the solvent was removed on a rotary evaporator and the residue was purified by flash-chromatography over silica gel (0.032–0.063 mm) with n-hexane:ethyl acetate (9:1, then 5:1) as eluant to afford the product as a yellow oil (98.0%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH2:7]1)=[O:5])[CH3:2].[ClH:25].O>C(OCC)(=O)C>[ClH:25].[ClH:25].[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCN(C2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(C2CCNCC2)C1
Temperature: -78 °C

Procedure:
[1,4′]Bipiperidinyl-3,1′-dicarboxylic acid 1′-tert-butyl ester 3-ethyl ester (21.14 g, containing some isopropyl ester) was dissolved in ethyl acetate (80 mL) under nitrogen, cooled to −78° C. and hydrogen chloride passed in for several minutes until the solution became saturated. The solution was allowed to warm to ambient temperature with provision for the evolved gases to be trapped by water in a scrubber. After 3 hr the solution was evaporated to dryness in a stream of dry nitrogen to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:6]12[CH2:13][CH2:12][C:9]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)(Cl)=O.[C:27]([C:29]1[C:34]([C:35]#[N:36])=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:32]=[CH:31][C:30]=1O)#[N:28].Cl>N1C=CC=CC=1>[CH2:1]([C:6]12[CH2:7][CH2:8][C:9]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O:20][C:30]4[CH:31]=[CH:32][C:33]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:34]([C:35]#[N:36])[C:29]=4[C:27]#[N:28])=[O:19])=[CH:16][CH:15]=3)([CH2:10][CH2:11]1)[CH2:12][CH2:13]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(O)c(C#N)c1C#N
Reactant: CCCCCC12CCC(c3ccc(C(=O)O)cc3)(CC1)CC2
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCCCc1ccc(OC(=O)c2ccc(C34CCC(CCCCC)(CC3)CC4)cc2)c(C#N)c1C#N
Temperature: 80 °C

Procedure:
36.5 mmoles of 4-(4-pentyl-1-bicyclo(2,2,2)-octyl)-benzoic acid were refluxed with 50 ml of thionyl chloride for 1 hour. The excess thionyl chloride was distilled off. The resulting acid chloride was added dropwise to a solution of 36.5 mmoles of 2,3-dicyano-4-pentylphenol in 100 ml of pyridine. The reaction mixture was stirred at 80° C. until the reaction had ended and was then poured onto dilute hydrochloric acid. The product was extracted with methylene chloride. For purification, the product was recrystallized. It displays an enantiotropic nematic phase (K 130.9 N (137.9) I) and has a negative DCA.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.CS(O[CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])(=O)=O>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: CS(=O)(=O)CCOS(C)(=O)=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCNCC1
Product: CS(=O)(=O)CCN1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{1-[2-(methylsulfonyl)ethyl]piperidin-4-yl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 113) and 2-(methylsulfonyl)ethyl methanesulfonate (prepared following General the methods described in PCT Int, Appl. 2006047277) following General Procedure S.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(OC)[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C([SiH](CC)CC)C>C(Cl)Cl.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1
Reactant: COC1(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: OC[C@H]1OC(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
The crude (3R,4S,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (6.5 g) and triethyl silane (4.03 g, 34.7 mmol) were dissolved in a mixed solvent of methylene chloride (100 mL) and acetonitrile (100 mL). To the resulting mixture was added dropwise boron trifluoride-diethyl etherate complex (5.6 g, 39.5 mmol) at 0° C. After the completion of dropwise addition, the resulting mixture was warmed up to room temperature and stirred for 16 hr. The mixture was quenched with a saturated sodium bicarbonate solution, and extracted with ethyl acetate (250 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under a reduced pressure. The resulting crude product was purified with a silica-gel column chromatography (methanol:methylene chloride=0-1:15) to produce 3.8 g of a product in a yield of 46% (three steps in total).
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([O:3]CC)=[O:2].[OH-].[Na+].O>C(O)C>[C:1]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([OH:3])=[O:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1c(C(=O)O)[nH]c2ccccc12

Procedure:
Ethyl 2-Carboethoxy-3-indoleacetate (0.7 gm) in absolute ethanol (10 ml) was combined with 50% aqueous sodium hydroxide. The mixture was heated to reflux on a steam bath for 15 minutes. The resulting solution was poured into water (50 ml) and the aqueous solution was washed with ether (2×30 ml). The aqueous solution was made acidic by the addition of concentrated hydrochloric acid and chilled to effect crystallization. The resulting white solid was recovered by filtration to provide the product. Analytical data are reported in Table I.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:28]4[C:23]([C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)=[C:22](Br)[CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31]([N:38]1[CH:46]=[C:45]2[C:40]([CH:41]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:43]=[CH:44]2)=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:28]4[C:23]([C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)=[C:22]([C:42]4[CH:43]=[CH:44][C:45]5[C:40]([CH:41]=4)=[N:39][N:38]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:46]=5)[CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(-c3cc(Br)c4c(N)ncnn34)c2)CC1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)c2)CC1

Procedure:
Using the procedure described in step 4 of Example 80, the product from step 3 above and Intermediate C were converted to the title compound. 1H NMR (CD2Cl2) 1.50 (s, 9H), 1.60 (m, 1H), 1.80 (m, 2H), 2.80 (m, 3H), 4.10-4.30 (m, 3H), 5.60 (s, 2H), 5.80 (br, 2H), 7.00 (s, 1H), 7.10-7.50 (m, 9H), 7.80 (m, 2H), 7.90 (m, 2H), 7.95 (s, 1H), 8.10 (s, 1H); LC-MS [M+H]+=600.1, RT=3.55 min.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:15]([OH:17])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]([CH2:22][CH3:23])[CH2:20]O>>[CH3:18][CH:19]([CH2:22][CH3:23])[CH2:20][O:16][C:15](=[O:17])[C@H:11]([CH:12]([CH3:13])[CH3:14])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(C)CO
Reactant: CC(C)[C@H](NC(=O)Cc1ccccc1)C(=O)O
Product: CCC(C)COC(=O)[C@@H](NC(=O)Cc1ccccc1)C(C)C

Procedure:
Following General Procedure BC and using the N-(phenylacetyl)valine prepared in Step A above and 2-methylbutan-1-ol (Aldrich), the title compound was prepared as a diastereomeric mixture. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=4)=[CH:17][C:11]=3[N:10]=2)C(=O)C2=CC=CC=C12.O.NN>>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([C:18]3[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=3)=[CH:17][C:11]=2[N:10]=1
Reactant: O=C1CCC(c2ccc3[nH]c(CCCN4C(=O)c5ccccc5C4=O)nc3c2)=NN1
Agent: NN
Solvent: O
Product: NCCCc1nc2cc(C3=NNC(=O)CC3)ccc2[nH]1
Yield: 34.6 %

Procedure:
##STR70## wherein by a method analogous to that of Example 1d) from 3.3 g (8.2 mmol) of 6-[2-(3-phthalimidopropyl)-1H-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone and 2.0 ml (41.1 mmol) of hydrazine hydrate. 0.77 g (35%) of a colourless solid melting at 247° to 249° C. (decomp.) are obtained after chromatographic purification on silica gel with methanol/conc. ammonia (95:5) as solvent, concentration of the main fraction by evaporation under vacuum and crystallization of the residue from ethanol.