Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:16]([C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:18]=2)=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10]O)=[C:4]([F:30])[CH:3]=1.CCN(S(F)(F)[F:37])CC>C1COCC1>[Cl:1][C:2]1[C:16]([C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:18]=2)=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][F:37])=[C:4]([F:30])[CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(CO)C(=O)NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F
Solvent: C1CCOC1
Product: CC(C)(CF)C(=O)NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 8.7 %

Procedure:
To a solution of N-(4-chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-3-hydroxy-2,2-dimethylpropanamide (0.150 g, 0.330 mmol) in THF (5.0 mL), DAST (0.079 g, 0.495 mmol) was added at 0-5° C. and stirred at RT for 5-6 h. After completion of the reaction, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was separated, concentrated and the obtained crude was purified with column chromatography using basic alumina by eluting with solution of 2% ammonia in 10.0% MeOH:DCM to afford 0.013 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 1.13 (s, 6H), 4.32 (m, 3H), 4.46 (s, 1H), 7.55 (m, 2H), 7.69 (m, 2H), 7.94-7.97 (m, 2H), 8.31 (s, 1H), 12.61 (s, 1H); MS (m/z): 454.25 (M+H)+.
Reaction SMILES: [C:1]([CH:3]([OH:18])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)#[N:2].[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[CH:28]([CH:32]([CH3:34])[CH3:33])[C:29](O)=[O:30].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C)C=O>[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[CH:28]([CH:32]([CH3:34])[CH3:33])[C:29]([O:18][CH:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=1)=[O:30]
Reactant: CC(C)C(C(=O)O)c1cc2ccccc2s1
Reactant: N#CC(O)c1ccc(F)c(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1)c1cc2ccccc2s1
Reaction time: 2 h

Procedure:
To a stirred solution of α-cyano-4-fluoro-3-phenoxybenzyl alcohol (437 mg, 1.8 mmol), 2-(2-benzothienyl)-3-methylbutanoic acid (2.0 mmol) and 4-dimethylaminopyridine (0.65 mmol) in 20 ml of methylene chloride and 2 ml of dimethylformamide is added N,N'-dicyclohexylcarbodiimide (2.0 mmol). The reaction mixture is stirred, under nitrogen, for two hours and then filtered and extracted with water. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueous sodiun bicarbonate, water and saturated aqueous sodium chloride, dried over calcium sulfate and solvent evaporated to give α-cyano-4-fluoro-3-phenoxybenzyl 2-(2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]#[N:26].O>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]#[N:26])[CH:7]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)c(Oc2cc(Cl)nc(-c3ccccc3)n2)c1
Reaction time: 24 h
Yield: 96.7 %

Procedure:
To 4,6-dichloro-2-phenylpyrimidine (1.5 g, 6.7 mmol) in acetonitrile (20 mL) was added Cs2CO3 (2.4 g, 7.4 mmol) and 3-hydroxy4-(benzyloxy)benzonitrile (1.5 g, 6.5 mmol). After stirring for 24 hours, water was added to the reaction mixture and the resulting solid was collected by suction filtration to give 2.6 g of 3-[(6-chloro-2-phenylpyrimidin-4-yl)oxy]-4-(benzyloxy)benzonitrile.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1)#[CH:2].Br[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[OH:23]>C(N(CC)CC)C.C(NCC)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]2[O:23][C:1]([C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=4)[CH:4]=3)=[CH:2][C:16]=2[CH:21]=1
Reactant: Oc1ccc(Cl)cc1Br
Reactant: C#Cc1ccc2cc(OC)ccc2c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCNCC
Product: COc1ccc2cc(-c3cc4cc(Cl)ccc4o3)ccc2c1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
A mixture of 2-ethynyl-6-methoxynaphthalene (1.82 g, 10 mmol), 2-bromo-4-chlorophenol (2.01 g, 10 mmol), copper (I) iodide (0.1 g, 0.52 mmol), tetrakis(triphenylphosphine)palladium (0.58 g, 0.5 mmol) in triethylamine (10 mL) and diethylamine (10 mL) was heated at reflux for 1 hour under an atmosphere of nitrogen then cooled to room temperature. The solid was collected by filtration, washed with ether and dried to give the title compound as a solid (2.0 g). 1HNMR (300 MHz, DMSO-d6): δ8.4 (s, 1H), 8.0-7.9 (m, 3H), 7.75 (d, 1H, J=1.8 Hz), 7.69 (d, 1H, J=9.2 Hz), 7.46 (s, 1H), 7.38-7.32 (m, 2H), 7.24 (dd, 1H, J=9.2, 1.8 Hz), and 3.9 ppm (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][C:16](O)=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[H][H]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCC(CCC(=O)O)C1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(CCCO)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
To a solution of commercially available 3-[1-(tert-butoxycarbonyl)-3-piperidinyl]propionic acid (2.57 g, 10.0 mmol) in 100 mL of anhydrous THF was added slowly a solution of BH3.THF complex in THF (1.0 M, 20 mL, 2.0 equiv) at room temperature under N2. The solution was stirred for 16 h at room temperature. Water was added carefully (hydrogen evolution!), and the resulting solution was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to give the alcohol (2.35 g, 97%) as a colorless oil. LC-MS (ESI) m/z 244 (M+H+).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:15][O:14][C:12](=[O:13])[C@@H:11]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Yield: 89.1 %

Procedure:
A solution of 2.48 g (10.00 mmol) of methyl (S)-4-(tert-butyldimethylsilyloxy)-2-hydroxybutanoate (J. Am. Chem. Soc. 2005 127, 1090-1091) in 50 ml of CH2Cl2 was treated with 2.09 ml (15.00 mmol, 1.5 eq) of triethylamine and at 0° C. during 5 min with 0.82 ml (10.50 mmol, 1.051 eq) of methanesulfonyl chloride. After 1 h at 0° C. the reaction was partitioned between 10% aq KH2PO4/Et2O (×3), the organic phases were washed with sat. aq. NaHCO3 solution (freshly prepared) and 10% aq. NaCl solution, dried over Na2SO4 and evaporated to give 2.91 g (89%) of the title compound as yellow oil. MS: 327.1 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][C:7]2([CH3:15])[CH3:14].Cl[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1>CS(C)=O>[CH3:14][C:7]1([CH3:15])[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([O:3][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=3)[CH:5]=2)[C:9](=[O:13])[CH2:8]1
Reactant: CC1(C)CC(=O)c2ccc(O)cc21
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)CC(=O)c2ccc(Oc3ccc(C#N)cn3)cc21
Temperature: 25 °C
Yield: 70.7 %

Procedure:
Add NaH (60%/oil, 196 mg, 4.91 mmol) to a mixture of 5-hydroxy-3,3-dimethyl-1-indanone (787 mg, 4.46 mmol) and DMSO (10 ml) stirring at ambient temperature under nitrogen. After ten minutes, add 6-chloronicotinonitrile (619 mg, 4.46 mmol) dissolved in DMSO (10 ml) and stir the resulting mixture at 60° C. overnight. Quench the reaction with saturated aqueous NH4Cl and extract with EtOAc (2×). Wash extract with water and brine, dry (MgSO4) and concentrate on rotary evaporator to a brown, oily solid. Purify on silica gel (10% EtOAc/DCM) to give 877 mg of 6-(3,3-Dimethyl-1-oxo-indan-5-yloxy)-nicotinonitrile as a yellow solid.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].CN(C)C=O.[OH-].[K+].[CH3:11][N:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[N:14]=[C:13]1S(C)(=O)=O>O>[CH3:11][N:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[N:14]=[C:13]1[S:3][CH2:1][CH3:2]
Reactant: Cn1cc([N+](=O)[O-])nc1S(C)(=O)=O
Reactant: CCS
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc([N+](=O)[O-])cn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
Ethyl mercaptan (5.14 g, 0.083 mole) was added to dimethylformamide (140 ml) containing potassium hydroxide (4.6 g, 0.08 mole). This was stirred for 90 minutes until all the potassium hydroxide had dissolved. To this solution was added 1-methyl-2-methylsulfonyl-4-nitroimidazole (8.5 g, 0.04 mole) and the reaction stirred for 2 hours at room temperature. The reaction mixture was then added to water (500 ml) and stirred in an ice bath for an additional hour. The crystalline product was filtered off and dried to give 5.6 g of crude product. This was recrystallized from ethanol/water to give 4.3 g of product.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[F:37])=[O:28])=[C:22]([Cl:38])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:39][CH3:40])C1C=CC=CC=1.[H][H].C(OCC)(=O)C>CN(C)C=O.[C].[Pd]>[Cl:38][C:22]1[CH:21]=[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:39][CH3:40])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)[CH:25]=[CH:24][C:23]=1[NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])=[O:28]
Reactant: [H][H]
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1O
Yield: 96.4 %

Procedure:
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-(2,4-difluorophenyl)urea (215 mg) was dissolved in dimethylformamide (11 ml). Palladium-carbon (215 mg) was added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature overnight. Ethyl acetate (30 ml) was added to the reaction solution, and the mixture was then filtered through Celite. The solvent was removed by distillation under the reduced pressure to give 174 mg (yield 96%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:1][CH2:2][C@@H:3]2[CH2:4][CH2:5][C:6](=[O:8])[O:7]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=C1CC[C@@H](CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)O2)cc1

Procedure:
A mixture of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one, para-toluenesulfonyl chloride and pyridine were processed using the method described in Example 162A to afford the title compound MS (ESI) m/z 288 (M+18)+.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([CH3:7])[C:3]([CH2:5]Cl)=[O:4].[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].O>CN(C=O)C>[CH3:1][C:2]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([CH3:7])[C:3]([CH2:5][O:22][C:19](=[O:21])[CH3:20])=[O:4]
Reactant: CC(=O)[O-]
Reactant: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)CCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC(=O)C(C)(C)NC(=O)c1cc(Cl)cc(Cl)c1
Yield: 47.4 %

Procedure:
N-(1',1'-dimethyl-3'-chloroacetonyl)-3,5-dichlorobenzamide (20 gm, 0.065 m) was dissolved in 100 ml of dry DMF and 10.6 gm (0.128 m) of sodium acetate was added. The slurry was blanketed under a nitrogen atmosphere and then heated to 80°-90° C. for 4 days. The reaction mixture was cooled by adding 100 ml of water. The aqueous solution was extracted four times with 10 ml aliquots of methylene chloride. The combined organic extracts were washed with water (3×100 ml) and brine. The solvent was removed, the resulting white solid dried and then recrystallized from an acetone and hexane (about 1:4) mixture to yield 10.2 gm of the product.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:17])([CH3:16])[CH3:15])[CH2:10]1)C1C=CC=CC=1.CC(=O)OCC>CCO.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:17])([CH3:16])[CH3:15])[CH2:10]1
Reactant: CC(C)(O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(O)[C@H]1CC[C@H](N)C1
Reaction time: 48 h
Yield: 75.1 %

Procedure:
A mixture of 2-(trans-3-(dibenzylamino)cyclopentyl)propan-2-ol (3 g, 9.3 mmol) and Pd(OH)2 (900 mg) in EtOH (30 mL) was hydrogenated under 50 psi of H2 for 48 h at room temperature. TLC (PE:EA=5:1) showed the reaction was complete. The mixture was filtered and concentrated in vacuo to give crude 2-(trans-3-aminocyclopentyl)propan-2-ol (1 g, 77%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[C:12]([C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)#[C:13][CH3:14].O>C(NCC)C.[Cu](I)I>[CH2:12]([C:15]1[CH:20]=[CH:19][C:18]([C:11]#[C:10][C:7]2[CH:6]=[CH:5][C:4]([C:1]#[C:2][CH3:3])=[CH:9][CH:8]=2)=[CH:17][CH:16]=1)[CH2:13][CH3:14]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: CC#Cc1ccc(I)cc1
Agent: I[Cu]I
Solvent: O
Solvent: CCNCC
Product: CC#Cc1ccc(C#Cc2ccc(CCC)cc2)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
4-Propylphenylacetylene (7.21 g, 0.05 mol) and 4-(1-propynyl)iodobenzene (12.1 g, 0.05 mol) were dissolved in diethylamine (30 cc), and then copper iodide (0.29 g, 1.5 mmol) and dichlorobistriphenylphosphinepalladium dichloride (0.53 g, 0.75 mmol) were added. The resulted mixture was reacted with stirring in nitrogen gas current at about 20° C. for 8 hours. After completion of the reaction, water (100 ml) was added to the resulting reaction mixture. The resulting deposited mass was extracted with toluene (50 ml). The resulting toluene solution was washed with dilute hydrochloric acid, followed by water until the washing water became neutral. The resulting material was dried over anhydrous sodium sulfate. Toluene was distilled off from the toluene solution. The residue was then dissolved in a mixed solvent of n-hexane/methylene chloride (1 vol./1 vol.). The solution was subjected to column chromatography using silica gel as a fixed phase, and using the above mixed solvent as an eluent. Fractions showing a single spot were collected by TLC and the mixed solvent was distilled. The residue after distillation was recrystallized from ethyl alcohol (20 ml) to obtain the objective 4-propyl-4'-(1-propynyl)tolan (compound No. 1) (6.7 g). This compound exhibited liquid crystal phases (CI point: 87.7° C., NI point: 85.1° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([CH3:14])[CH:8]=1.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=1[S:28]([NH2:31])(=[O:30])=[O:29].Cl>O>[N+:22]([C:21]1[CH:20]=[C:19]([CH:18]=[C:17]([S:28](=[O:30])(=[O:29])[NH2:31])[C:16]=1[O:13][C:12]1[CH:7]=[CH:8][C:9]([CH3:14])=[CH:10][CH:11]=1)[C:25]([OH:27])=[O:26])([O-:24])=[O:23]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
124 g (0.9 mol) of potassium carbonate are dissolved in 800 ml of water. To this solution, there are added portionwise 1.6 mols of p-cresol and subsequently 112 g (0.4 mol) of 2-chloro-3-nitro-5-carboxy-benzenesulphonamide and the solution is heated to 85° C. The whole is stirred for 16 hours at this temperature, cooled to 25°-30° C and acidified with concentrated hydrochloric acid to pH 1. The oil which thereupon separates is isolated from the aqueous phase and subjected to steam distillation. Alternatively, it is also possible to adjust to pH-value of 8-9, to extract the excess phenol with ethyl acetate and then to acidify the aqueous phase. After having separated in this manner the excess p-cresol, the product crystallises upon cooling. By recrystallisation from acetone/H2O, the 3-nitro-4-(4'-methylphenoxy)-5-sulphamoylbenzoic acid melting at 236° C is obtained.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:9]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: C1CCNCC1
Product: N#Cc1ccc(C(F)(F)F)cc1N1CCCCC1
Temperature: 80 °C
Yield: 56 %

Procedure:
To commercially available 2-chloro-4-trifluoromethylbenzonitrile 13 (1 ml, 7.2 mmol) was added piperidine (4 equiv., 2.8 ml) and the solution was heated at 80° C. overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 1 g of a yellow oil. Yield=56% 1HNMR (DMSO, 200 MHz) δ 1.60 (6H, m), 3.20 (4H, m), 7.34 (2H, m), 7.89 (1H, dd, J=8.6 Hz, J′=0.4 Hz)
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[CH2:21]([SH:24])[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:21]([S:24][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[CH2:22][CH3:23]
Reactant: CCCS
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCSc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 50 °C
Yield: 89.4 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.15 g of 1-propanethiol, 0.40 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50° C. for one hour. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.30 g of 2-(3-propylthiopyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 42”).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([CH2:14][NH:15][CH2:16][C@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=2)[C@H:18]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C=O.[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O>[CH2:7]([CH2:14][NH:15][CH2:16][C@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:23]=2)[C@H:18]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1ccc2c(c1)CC[C@H](CNCCc1ccccc1)[C@@H]2c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CCNC[C@H]2CCc3cc(OCc4ccccc4)ccc3[C@H]2c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a mixture of cesium carbonate (1.09 g), cis-2-(N-benzylmethylamino)methyl-6-hydroxy-1-phenyl-1,2,3,4-tetrahydronaphthalene (600 mg) and N,N-dimethylformamide (10 cm3) was added benzyl bromide (0.236 cm3). The resulting mixture was warmed to 80° C. and stirred for 2 h. Upon cooling, water (50 cm3) was added and the aqueous mass was extracted with ether (2×50 cm3). The combined ether extracts were washed with water (30 cm3), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure to afford a yellow oil. This was purified by column chromatography [silica, eluting with petroleum ether (b.p. 40-60° C.)-ethyl acetate (15:1)] to afford the title compound (538 mg; 72%) as a light yellow oil.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:29]2[C:28]3[C:23](=[CH:24][C:25]([OH:30])=[CH:26][CH:27]=3)[NH:22][C:21]=2[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][CH:18]=1>N1C=CC=CC=1.CCOC(C)=O>[N:1]1([C:7]([O:30][C:25]2[CH:26]=[CH:27][C:28]3[C:29]4[C:21](=[C:20]([C:31](=[O:32])[NH2:33])[CH:19]=[CH:18][C:17]=4[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[F:10])[NH:22][C:23]=3[CH:24]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(O)ccc12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(OC(=O)N3CCOCC3)ccc12
Reaction time: 22 h
Yield: 31.4 %

Procedure:
Morpholine-4-carbonyl chloride (11.29 mg, 0.075 mmol) was added to a solution of 4-(2-fluorophenyl)-7-hydroxy-9H-carbazole-1-carboxamide (Example 40-1, 18.6 mg, 0.058 mmol) in pyridine (1 mL). After 22 h at rt, additional morpholine-4-carbonyl chloride (11.29 mg, 0.075 mmol) was added. After 15 h, the mixture was diluted with EtOAc (30 mL), washed with water (10 mL) and brine (5 mL), and dried and concentrated. The residue was purified by preparative HPLC to provide 8-carbamoyl-5-(2-fluorophenyl)-9H-carbazol-2-yl morpholine-4-carboxylate as a white solid (7.9 mg, 27%). 1H NMR (400 MHz, chloroform-d) δ 9.94 (1 H, br. s.), 7.41-7.65 (3 H, m), 7.33 (2 H, t, J=8.14 Hz), 7.20 (1 H, d, J=8.58 Hz), 6.92-7.15 (4 H, m), 6.73 (1 H, dd, J=8.58, 1.98 Hz), 3.80 (4 H, t, J=4.62 Hz), 3.67-3.76 (2 H, m), 3.62 (2H, br. s.). Mass spectrum m/z 434.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[F:18][C:19]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1cccc(F)c1F
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cccc(F)c4F)cc3c2C1
Yield: 78.9 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.6 μL (0.051 mMol) 2,3-difluorobenzoyl chloride, 13.4 mg (79%) of the title compound were recovered as a beige solid.