Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[O:3].[CH:14](OC)(OC)[O:15]C.[CH3:21]O>[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:21][O:3][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][CH:5]=1)([O:15][CH3:14])[CH3:1]
Reactant: CO
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: COC(OC)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: COC(C)(OC)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-(trifluoromethyl)acetophenone (purchased from Aldrich, 3.76 g, 20 mmol) in MeOH (3 ml) was added trimethyl orthoformate (2.33 g, 22 mmol) and tetrabutylammonium tribromide (96.4 mg, 0.2 mmol) successively. The mixture was stirred at room temperature for 24 hours, quenched with saturated aqueous sodium bicarbonate, and extracted with diethyl ether. The organic layer was washed with brine and dried over sodium sulfate. The mixture was filtered and concentrated in vacuo to afford the crude title compound (5.95 g) as a colorless oil.
Reaction SMILES: C(P([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(CC)=O)C.[H-].[Na+].[CH:15]([C:17]1[CH:18]=[C:19]([CH3:36])[C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:21][CH:22]=1)=O.O>C1COCC1>[CH2:11]([O:10][C:8](=[O:9])/[CH:7]=[CH:15]/[C:17]1[CH:18]=[C:19]([CH3:36])[C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:25][CH2:24]2)=[N:21][CH:22]=1)[CH3:12]
Reactant: Cc1cc(C=O)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(=O)CP(=O)(CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
Ethyl (diethylphosphoryl)acetate (471 mg) was dissolved in THF (15 ml), and NaH (98 mg) was added thereto, followed by stirring at room temperature for 30 minutes. A solution of tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (493 mg) in THF (5 ml) was added thereto, followed by stirring at room temperature for 3 hours. To the reaction mixture was added water, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl 4-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-3-methylpyridin-2-yl}piperazine-1-carboxylate (305 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[O:5][C:6]1[CH:7]([CH2:20][CH:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)[NH:8][C:9](=[O:19])[C:10]=1[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[CH3:18])[CH3:2].[NH2:28][C:29]#[N:30].C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:27])[O:5][C:6]1[CH:7]([CH2:20][CH:21]2[CH2:26][CH2:25][S:24](=[N:30][C:29]#[N:28])[CH2:23][CH2:22]2)[NH:8][C:9](=[O:19])[C:10]=1[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[CH3:18])[CH3:2]
Reactant: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC1CC1CCSCC1
Reactant: N#CN
Agent: [Rh+3]
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC1CC1CCS(=NC#N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of carbonic acid 4-(2,5-dimethyl-phenyl)-5-oxo-2-(tetrahydro-thiopyran-4-ylmethyl)-2,5-dihydro-1H-pyrrol-3-yl ester ethyl ester (compound P1.2) (184 mg, 0.47 mmol), NH2CN (40 mg, 0.95 mmol), (diacetoxyiodo)benzene (247 mg, 0.76 mmol), MgO (75 mg, 1.87 mmol) and rhodium acetate (10 mg, 0.02 mmol) in 10 ml of CH2Cl2 was stirred at room temperature for 2 h. Then, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel. Yield: 110 mg of carbonic acid 2-(1-cyanoimino-hexahydro-1λ4-thiopyran-4-ylmethyl)-4-(2,5-dimethyl-phenyl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl ester ethyl ester (title compound P1.9) as a solid, mp 103-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[CH:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)cc(C)n1
Yield: 48.5 %

Procedure:
Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (143 mg, 0.5 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (106 mg, 48%). MS (ISP) 437.1 [(M+H)+]; mp 281° C.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([Cl:21])=[C:16]([O:22][CH2:23][C:24]#[N:25])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([Cl:21])=[C:16]([O:22][CH2:23][CH2:24][NH2:25])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCOc1c(Cl)ccc2c1c1ccccc1n2Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: NCCOc1c(Cl)ccc2c1c1ccccc1n2Cc1ccccc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 69.7 %

Procedure:
To [(9-benzyl-3-chloro-9H-carbazol-4-yl)oxy]acetonitrile (0.292 g, 0.842 mmol) in THF (6 mL) is added borane-methyl sulfide complex (0.24 mL, 2.53 mmol). The mixture is stirred at 80° C. for 2.5 h and then allowed to cool. MeOH is carefully added to the residue until gas evolution ceased and then the mixture is concentrated under vacuum. MeOH addition/removal is repeated two more times and then MeOH-dichloromethane (about 2 mL each) is added, followed by several drops of conc. HCl. The mixture is stirred for about 15 min and then taken to dryness under vacuum. After partitioning with dichloromethane and aq. sodium bicarbonate and drying, the residue is chromatographed on silica gel (50 mL) using MeOH-dichloromethane (2/98 to 4/96) to give 0.206 g (70%) of 2-[(9-benzyl-3-chloro-9H-carbazol-4-yl)oxy]ethylamine. The methanesulfonate salt is prepared by dissolving 2-[(9-benzyl-3-chloro-9H-carbazol-4-yl)oxy]ethylamine in MeOH and dichloromethane and adding methanesulfonic acid (0.0581 g). The mixture is concentrated to dryness under vacuum and the residue is crystallized from dichloromethane-hexane to give 0.206 g of 2-[(9-benzyl-3-chloro-9H-carbazol-4-yl)oxy]ethylamine, methanesulfonate salt as a white crystalline solid. 1H NMR (CDCl3) δ1.9, 3.29, 4.31, 5.49, 7.07, 7.12, 7.27, 7.35-7.49, 8.32.
Reaction SMILES: O=[C:2]([CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:3][C:4]([O:6]C)=O.[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26]>C1(C)C(C)=CC=CC=1>[C:13]1(=[O:14])[N:9]([CH2:8][C:2]2[CH2:3][C:4](=[O:6])[NH:27][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:26]=2)[C:10](=[O:19])[C:11]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]12
Reactant: COC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: Nc1ccccc1N
Solvent: Cc1ccccc1C
Product: O=C1CC(CN2C(=O)c3ccccc3C2=O)=Nc2ccccc2N1
Yield: 81.5 %

Procedure:
A mixture of methyl 3-oxo-4-phthalimidobutyrate (15.4 g, 59 mmol), o-phenylenediamine (6.37 g, 59 mmol) and xylene (150 mL) was refluxed for 20 minutes using Dean-Stark apparatus. The reaction mixture was cooled, and resulting crystals were collected by filtration and washed with toluene to give the object compound (15.36 g, 81%), m.p.244°-246° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14](C(O)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:21]([CH:23]=[O:24])C.C(Cl)(=O)C(Cl)=O.[N-]=[N+]=[N-].[Na+]>ClCCl.O.CC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([N:21]=[C:23]=[O:24])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C=NC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
To a solution of 1-(benzyloxycarbonyl)-4-piperidine carboxylic acid (7.90 g, 30 mmol) and DMF (0.023 ml) in dichloromethane (10 ml) was added oxalyl chloride (3.84 ml) at room temperature with stirring, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the concentrate was added toluene (50 ml) and the mixture was concentrated under reduced pressure. The procedure was repeated. A solution of the concentrate in acetone (10 ml) was added dropwise to a solution of sodium azide (4.88 g, 75 mmol) in water (25 ml)-acetone (25 ml) under ice cooling, and the mixture was stirred at the same temperature for 2 hours. To the mixture was added water (10 ml), ant the mixture was. extracted with toluene (100 ml×2). The organic layer was washed with saturated sodium chloride solution (20 ml×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure the volume becomes to about 100 ml. The solution was stirred at 90° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 1-(benzyloxycarbonyl)-4-piperidinylisocyanate (7.99 g). To a solution of the compound obtained in Reference Example 1 (3.81 g, 10 mmol) and triethylamine (3.49 ml) in dichloromethane (100 ml) was added 1-(benzyloxycarbonyl)-4-piperidinylisocyanate (3.90 g), with stirring at room temperature. The mixture was stirred at the same temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added a saturated aqueous solution of sodium hydrogencarbonate (50 ml) under ice cooling, and the mixture was extracted with ethyl acetate (50 ml×3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (5.54 g, 9.7 mmol, Yield 97%) as colorless oily substance.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([OH:5])[CH3:4].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>O>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:3](=[O:5])[CH:4]=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:9][CH:8]=1)([OH:1])=[O:13]
Reactant: O=Cc1ccccc1
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(C(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
4-Acetylbenzonitrile (44al, 1.00 g, 6.9 mmol) and sulfuric acid (4 ml) were combined in water (4 ml) and the mixture stirred for 2.5 hr at reflux. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to give 0.98 g (87%) of compound 44ad as a white solid: mp 204° C.; 1H NMR: (DMSO) δ 2.61 (s, 3H), 8.04 (s, 4H), 13.23 (s, 1H). The solid (44ad, 0.50 g, 3.0 mmol) and sodium hydroxide (0.29 g, 7.3 mmol) were combined in water (4 ml) and ethanol (4 ml) and stirred for 30 min at room temperature. Benzaldehyde (1b, 0.31 ml, 3.1 mmol) was added and the mixture stirred for 48 hr at room temperature. The resulting mixture was acidified with hydrochloric acid (1 N), extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to a afford a solid. The crude solid was recrystallized from ethyl acetate to give 0.54 g (70%) of a yellow solid: mp 217-220° C. [expected mp 217-220° C.]; 1H NMR: (DMSO) δ 7.45 (m, 5H), 7.76 (d, 1H, J=16.1 Hz), 7.93 (d, 1H, J=15.5 Hz), 8.09 (d, 2H, J=7.9 Hz), 8.23 (d, 2H, J=7.6 Hz) 13.34 (s, 1H); 13C NMR: (DMSO) δ 121.9, 128.5, 128.8, 128.9, 129.4, 130.6, 134.3, 134.4, 140.6, 144.6, 166.4, 188.8.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1>>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Product: CCS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cc2)cc1
Yield: 20 %

Procedure:
The title compound (8.9 mg, 20%) was prepared from [4-(ethylsulfonyl)phenyl]boronic acid (21.4 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 446 (M+H).
Reaction SMILES: OCC[O:4]/[N:5]=[C:6](/[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH2:17][C:18]3[C:19]([F:29])=[C:20]4[C:25](=[CH:26][C:27]=3[F:28])[N:24]=[CH:23][CH:22]=[CH:21]4)=[N:15][N:16]=2)[N:13]=1)\[CH3:7].[H-].[Na+].I[CH3:33].[CH2:34]1[CH2:38][O:37][CH2:36]C1>CN(C=O)C>[CH3:36][O:37][CH2:38][CH2:34][O:4]/[N:5]=[C:6](/[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH:17]([C:18]3[C:19]([F:29])=[C:20]4[C:25](=[CH:26][C:27]=3[F:28])[N:24]=[CH:23][CH:22]=[CH:21]4)[CH3:33])=[N:15][N:16]=2)[N:13]=1)\[CH3:7]
Reactant: C1CCOC1
Reactant: C/C(=N\OCCO)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCO/N=C(\C)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1

Procedure:
A solution of (E)-1-(3-((5,7-difluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O-2-hydroxyethyl oxime (31.0 mg, 0.078 mmol) (example 54), sodium hydride (6.85 mg, 0171 mmol) and iodomethane (221 mg, 1.556 mmol) in 5 mL of THF and 0.5 mL of DMF was stirred at it for 3 h. The reaction was quenched by addition of 3 mL of methanol slowly. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.97 (dd, 1H), 8.45 (dd, 1H), 8.26 (d, 1H), 7.70-7.65 (m, 2H), 7.60 (dd, 1H), 5.26 (q, 1H), 4.30 (dd, 2H), 3.58 (dd, 2H), 3.23 (s, 3H), 2.02 (d, 3H), 1.88 (s, 3H). LCMS (method A): [MH]+=427, tR=5.50 min.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].[C:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[CH:22]=2)[N:17]=1)([CH3:15])=[CH2:14]>CS(C)=O.C1COCC1>[CH3:14][C:13]1([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[CH:22]=3)[N:17]=2)[CH2:7][CH2:15]1
Reactant: CC(C)(C)[O-]
Reactant: C=C(C)c1ccc2cc(C(=O)OC)ccc2n1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(C3(C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a stirred suspension of trimethylsulfoxonium iodide (435 mg, 2.06 mmol) in dimethylsulfoxide (3 ml) and THF (2 ml) was added potassium tert-butoxide (231 mg, 2.06 mmol) in one portion at ambient temperature. After 30 min. at the same temperature, to this (colorless solution) was added a solution of methyl 2-isopropenylquinoline-6-carboxylate (312 mg, 1.37 mmol) in THF (3 ml) at room temperature. The mixture was stirred at room temperature for 40 min then 1 hour at 60° C. The mixture was quenched with water and diluted with ethyl acetate-toluene (8:1) (90 ml). The organic solution was separated and washed with water (×2), brine, dried over sodium sulfate and concentrated in vacuo to crude product. The crude product was purified by column chromatography on silica gel (250 g) with hexane-ethyl acetate (10:1) to furnish the title compound (225 mg, 68%) as a white solid. 1H NMR (270 MHz, CDCl3) δ 0.91-0.98 (2H, m), 1.38-1.45 (2H, m), 1.64 (3H, s), 3.98 (3H, s), 7.42-7.48 (1H, m), 7.97-8.27 (3H, m), 8.50-8.55 (1H, m). MS (ESI): m/z 242.15 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH2:6][C:5](/[C:7](=[CH:11]/[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)/[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:18](Cl)(=O)C(Cl)=O.CO>C1COCC1.CN(C=O)C>[CH3:18][O:9][C:8](=[O:10])/[C:7](/[C:5]1[CH2:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[CH:11]\[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)/C(=C\C1CCCCC1)C1=CC=C(Br)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)/C(=C\C1CCCCC1)C1=CC=C(Br)C1
Yield: 111.1 %

Procedure:
Dissolve (Z)-2-(4-bromo-cyclopenta-1,3-dienyl)-3-cyclohexyl-acrylic acid (124 g, max. 0.338 mol) in dry THF (500 mL) and DMF (2 mL) and cool with an ice bath. Add oxalylchloride (51.5 g, 0.406 mol) slowly and stir 1 h 30 min after addition at 0-10° C. Add MeOH (500 mL) and stir 1 h at ambient temperature. Concentrate the reaction mixture and dilute residue with ethylacetate (600 mL) and add water (400 mL). Extract aqueous phase with ethylacetate and wash combined organic layers with saturated sodium chloride, dry over sodium sulfate and remove-solvents under vacuum to get 116.9 g crude product. MS (m/e): 329.0/331.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([OH:14])=O)[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:15]1([C@@H:21]([CH2:23][OH:24])[NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH:10]([C:12]([NH:22][C@@H:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:23][OH:24])=[O:14])[CH3:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: CC(Nc1cc(Cl)cc(Cl)c1)C(=O)O
Product: CC(Nc1cc(Cl)cc(Cl)c1)C(=O)N[C@H](CO)c1ccccc1

Procedure:
Following General Procedure E and using N-(3,5-dichlorophenyl)-D,L-alanine (from Example B above) and (S)-(+)-2-phenylglycinol (Aldrich), the title compound could be prepared.
Reaction SMILES: [CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6]([CH2:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)(O)[CH2:16][CH3:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CN(C=O)C.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6](/[CH:14]=[C:15](/[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)\[CH2:16][CH3:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCC(O)(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)butan-2-ol (0.5 g, 1.43 mmol) was dissolved in dry DCM (15 mL) and a drop of DMF was added. The solution was cooled to 0° C. and thionyl chloride (0.5 g, 4.29 mmol) diluted with dry DCM (2 mL) was added dropwise. Stirring was continued for 1 h at 0° C. and then at RT for 2 h. The solution was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC. 1H NMR (CDCl3, freebase) δ (ppm): 8.65 (d, 2H), 7.40 (d, 2H), 7.20 (s, 1H), 7.10 (d, 1H), 7.0 (d, 1H), 6.80 (s, 1H), 3.70 (s, 2H), 2.90 (m, 2H), 2.80 (m, 2H), 2.60 (s, 3H), 2.45 (m, 5H), 0.9 (t, 3H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([NH2:15])=[C:13]([NH:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([CH3:26])=[C:11]([CH3:27])[N:10]=1.[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32]>C(#N)C>[Cl:8][C:9]1[C:14]([NH:15][C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])=[C:13]([NH:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([CH3:26])=[C:11]([CH3:27])[N:10]=1
Reactant: Cc1nc(Cl)c(N)c(NCCOc2ccccc2)c1C
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCC(=O)Nc1c(Cl)nc(C)c(C)c1NCCOc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (1.39 ml), anhydrous acetonitrile (100 ml), and 2-chloro-5,6-dimethyl-N4-(2-phenoxyethyl)pyridine-3,4-diamine (2.92 g) from Part A of Example 2 were combined and cooled to 0° C. in an ice bath. Valeryl chloride (0.59 ml) was slowly added to the reaction mixture. After 2hours, the reaction mixture was heated to 55° C. for 24 hours, at which point HPLC analysis indicated the reaction was complete. The reaction mixture was cooled and the solvent was removed under reduced pressure. The resulting oil was dissolved in dichloromethane and washed with water. The organic layer was dried with magnesium sulfate and the solvent was removed under reduced pressure. The product was then passed through a silica gel column using 50/50 ethyl acetate/hexane as the eluant. The resulting light brown solid was used in the next step.
Reaction SMILES: [O-]CC.[Na+].[N:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1.[Cl-].[CH:14]1([O:19][C:20]2[CH:21]=[C:22]([C:28]3C=CC=CC=3[P+](C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH:14]1([O:19][C:20]2[CH:21]=[C:22](/[CH:28]=[CH:11]\[C:8]3[CH:7]=[CH:6][N:5]=[CH:10][CH:9]=3)[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=Cc1ccncc1
Reactant: COc1ccc(-c2ccccc2[P+](C)(c2ccccc2)c2ccccc2)cc1OC1CCCC1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(/C=C\c2ccncc2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 11.9 %

Procedure:
A solution of sodium ethoxide [prepared from sodium (0.10 g, 4.50 mmol)] in ethanol (50 ml) was added over 5 min to a stirred mixture of 4-pyridine carboxaldehyde (0.44 g, 4.10 mmol) and (3-cyclopentyloxy-4-methoxyphenyl)-methyltriphenylphosphonium chloride (2.00 g, 4.08 g) in ethanol (30 ml). After 2 h, the reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc (75 ml) and brine (50ml). The organic layer was separated, then dried (MgSO4) and concentrated in vacuo. A 1H n.m.r. spectrum indicated that the mixture consisted of a 3:2 mixture of (Z):(E) title compound (and triphenylphosphine oxide). A portion (0.6 g) of the mixture was subjected to chromatography (SiO2 ; hexane to EtOAc) to afford pure (Z)-title compound (0.14 g) as a pale yelow solid m.p. (Found: C, 77.18; H, 7.16; N, 4.63. C19H21NO2 requires C, 77.26; H, 7.17; N, 4.74%); δH (300 MHz; CDCl3) 1.5-1.55 (2H, br m, cyclopentyl H's), 1.65-1.9 (6H, br m, cyclopentyl H's), 3.83 (3H, s, OMe), 4.44 (1H, br m, OCHCH2), 6.40 (1H, d, J 12.2 Hz, CH=CH), 6.65-6.80 (4H, m, ArH ortho to OMe+2×ArH meta to OMe+CH=CH), 7.15 (2H, ca. d, J 6.0 Hz, pyridine H2, H6); m/z 295 (M+, 22%), 228 (15), 227 (100), 226 (94), 198 (35), 184 (15), 166 (12), 43 (19), and 41 (29).