Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:14]([CH3:23])[C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[O:16])=[C:11]([CH3:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][CH:31]([CH2:35][CH2:36][CH3:37])[C:32](Cl)=[O:33]>CN(C1C=CN=CC=1)C.ClCCCl.O.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:14]([CH3:23])[C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:32](=[O:33])[CH:31]([CH3:30])[CH2:35][CH2:36][CH3:37])[CH2:18]3)=[O:16])=[C:11]([CH3:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1nc(-c2cncc(F)c2)sc1N(C)C(=O)C1CCCNC1
Reactant: CCCC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CCCC(C)C(=O)N1CCCC(C(=O)N(C)c2sc(-c3cncc(F)c3)nc2C)C1
Yield: 63.8 %

Procedure:
A solution of N-(2-(5-fluoropyridin-3-yl)-4-methylthiazol-5-yl)-N-methylpiperidine-3-carboxamide (250 mg, 0.75 mmol), DMAP (91 mg, 0.75 mmol), potassium carbonate (310 mg, 2.243 mmol), and 2-methylpentanoyl chloride (201 mg, 1.495 mmol) in DCE (10 mL) was heated at 80° C. for 6 h. The cooled contents were diluted with water:dichloromethane (1:1, 20 mL) and the organic layer was collected and concentrated. The residue was purified via reversed phase chromatography (0 to 100% acetonitrile/water) to furnish the title compound as a clear oil (207 mg, 64%): 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.54 (d, J=2.2 Hz, 1H), 7.96 (dt, J=9.0, 2.2 Hz, 1H), 4.63-4.59 (m, 1H), 3.92-3.78 (m, 1H), 3.42 (s, 3H), 2.66-2.48 (m, 4H), 2.38 (s, 3H), 1.89-1.73 (m, 2H), 1.71-1.68 (m, 2H), 1.38-1.17 (m, 4H), 1.08-1.01 (m, 3H), 0.97-0.86 (m, 3H); ESIMS m/z 433 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[C:32]1([C:38]2[S:39][CH:40]=[C:41]([CH2:43][NH2:44])[N:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:44][CH2:43][C:41]3[N:42]=[C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[S:39][CH:40]=3)=[O:23])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NCc1csc(-c2ccccc2)n1
Product: O=C(NCc1csc(-c2ccccc2)n1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-phenyl-4-(aminomethyl)thiazole as in General Procedure 10 to give the title compound. LCMS: m/z=619.9 (M+H+); retention time=0.99 minutes.
Reaction SMILES: CO.C([O:5][C:6](=[O:47])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13](=[O:46])[N:14]2[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([N:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:28][C:29]2[CH:38]=[CH:37][C:32]3[O:33][CH2:34][CH2:35][O:36][C:31]=3[CH:30]=2)[CH2:23][CH2:22]1)C.[OH-].[Na+].Cl>O>[C:42]([O:41][C:39]([N:27]([CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)[CH:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][N:14]2[C:15]3[C:10](=[C:9]([O:8][CH2:7][C:6]([OH:47])=[O:5])[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:12][C:13]2=[O:46])[CH2:26][CH2:25]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CCOC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(OCC(=O)O)cccc32)CC1
Reaction time: 2.5 h

Procedure:
To a mixed solution of 5 mL methanol and 0.5 mL water containing 126 mg of ethyl(1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)acetate, 0.2 mL of 5 mol/L aqueous sodium hydroxide solution was added and allowed to stand at room temperature for 2.5 hours. To the reaction mixture, water was added, and the solvent was removed under reduced pressure. After the residue thus obtained was acidified by adding 1 mol/L hydrochloric acid, it was extracted with chloroform. The extracts were washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 90 mg of (1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)acetic acid as a white foam.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:7]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[N:12]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#N)[CH:20]=2)=[O:10])[CH2:6][C@H:5]2[CH2:27][C@@H:3]1[C:4]2([CH3:29])[CH3:28].O.P(P([O-])([O-])=O)([O-])([O-])=[O:32].[Na+].[Na+].[Na+].[Na+]>N1C=CC=CC=1CC(O)=O.O.[Ni]>[CH3:1][C@@H:2]1[C@@H:7]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[N:12]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[O:32])[CH:20]=2)=[O:10])[CH2:6][C@H:5]2[CH2:27][C@@H:3]1[C:4]2([CH3:29])[CH3:28]
Reactant: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(C#N)c2)C[C@H]2C[C@@H]1C2(C)C
Reactant: O=P([O-])([O-])P(=O)([O-])[O-]
Agent: [Ni]
Agent: O=C(O)Cc1ccccn1
Agent: [Na+]
Solvent: O
Product: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(C=O)c2)C[C@H]2C[C@@H]1C2(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
To a stirred solution of 2-(3-cyano-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (0.200 g, 0.48 mmol) in a mixture of pyridine-acetic acid-water (2:1:1; 7.2 mL) was added sodium hypophosphate hydrate (0.400 g, 3.77 mmol) at room temperature. The reaction mixture was cooled to 0° C. and Raney Nickel (0.200 g) was added under an argon atmosphere. After stirring at 0° C. for 10 min, the temperature was raised to 40-45° C. and the reaction mixture was stirred for an additional 2.5 h at the same temperature (with monitoring by silica TLC). The reaction mixture was cooled, filtered through a pad of celite and the residue was washed with methanol (5 mL). The combined filtrates were concentrated to provide the crude material, which was purified by silica gel column chromatography (100-200 mesh) using a gradient of 50-60% ethyl acetate/hexanes to give 2-(3-formyl-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (0.100 g, 49%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][N:18]=1)[C:13]([OH:15])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.ClCCl>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][N:18]=1)[C:13]([NH:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:26][CH:25]=1)=[O:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccnc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
A solution of 2-benzamidoisonicotinic acid (0.18 g, 0.74 mmol) in thionyl chloride (10 mL) was refluxed for 30 minutes and concentrated in vacuo to dryness. The residue was dissolved in dichloromethane (25 mL) and added to a mixture of (4-(trifluoromethyl)phenyl)methanamine (0.13 g, 0.74 mmol) and triethylamine (0.31 mL, 2.23 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 30 minutes, washed with saturated sodium bicarbonate solution (30 mL), water (30 mL) and brine (30 mL), then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 30-45% ethyl acetate in hexanes to give 2-benzamido-N-(4-(trifluoromethyl)benzyl)-isonicotinamide as a colorless solid (0.02 g, 8%): mp 165-168° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.79 (br s, 2H), 8.66 (s, 1H), 7.89-7.86 (m, 2H), 7.59-7.44 (m, 8H), 7.05-7.03 (m, 1H), 4.69 (d, J=6.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 166.0, 165.4, 152.1, 149.1, 143.7, 141.7, 133.6, 132.7, 129.0 (2 peaks), 128.1 (2 peaks), 127.2 (2 peaks), 125.8, 125.7, 118.7, 110.3, 43.7; MS (ES+) m/z 400.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH2:18][O:19][CH2:20][CH:21]1[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[N:7]([CH:8]([CH2:18][O:19][CH2:20][CH:21]1[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]1)[CH2:9][O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1)COCC1COC(C)(C)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C(COCc1ccccc1)COCC1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of [2-Benzyloxy-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl)-ethyl]-carbamic acid tert-butyl ester (1.26 g, 3.18 mmol) in DMF (10 mL) was added sodium hydride (60%, 0.19 g, 4.78 mmol) at 0° C. in one portion. The reaction was stirred at 0° C. for 0.5 h then MeI (1.36 g, 9.56 mmol) was added. The reaction mixture was then stirred at 0° C. for 3 h at which time the LC-MS showed the reaction was complete. The reaction was quenched with saturated aq. NH4Cl solution and extracted with EtOAc (2×100 mL). The organic layer was then washed with water, brine and dried over Na2SO4. The organic layers were concentrated to give [2-benzyloxy-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl)-ethyl]-methyl-carbamic acid tert-butyl ester (1.25 g, 96%). LRMS (M-Boc+H+) m/z 310.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[C:3]=1[OH:19].[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=O.C(=O)([O-])O.[Na+]>O1CCOCC1>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](/[CH:9]=[CH:8]/[C:4]2[C:3]3[O:19][C:26]([C:22]4[N:21]([CH3:20])[CH:25]=[CH:24][CH:23]=4)=[N:1][C:2]=3[CH:7]=[CH:6][CH:5]=2)=[N:11]1
Reactant: Nc1cccc(/C=C/c2n[nH]c3ccccc23)c1O
Reactant: Cn1cccc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cccc1-c1nc2cccc(/C=C/c3n[nH]c4ccccc34)c2o1
Temperature: 210 °C
Reaction time: 0.25 h
Yield: 9.5 %

Procedure:
A solution of (E)-2-amino-6-[2-(1H-indazol-3-yl)vinyl]phenol (0.10 g, 0.40 mmol) obtained in Step 2 in 1,4-dioxane (1.5 mL) was added with 1-methyl-1H-pyrrole-2-carbonyl chloride (63 mg, 0.44 mmol) and stirred at 210° C. for 15 minutes under microwave irradiation. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=90/10) and crystallized from ethanol to obtain Compound 148 (13 mg, 10%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[C:9]1([C@@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CS(C)=O>C(OCC)(=O)C>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:17][C@H:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:16])[CH:7]=1
Reactant: Fc1cc(I)ccn1
Reactant: C[C@H](N)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@H](Nc1cc(I)ccn1)c1ccccc1
Temperature: 25 °C

Procedure:
The mixture of 1 g of 2-fluoro-4-iodopyridine (synthesized according to a method disclosed in J. Org. Chem. 1993, 58, 7832-7838), 1.73 mL of (1S)-1-phenylethylamine, and 20 mL of dimethylsulfoxide, was stirred overnight at 80° C. The reaction mixture was cooled back to room temperature, then diluted with ethyl acetate, and washed with water and saturated brine in the subsequent order. The obtained organic layer was dried over anhydrous magnesium sulfate, then the insolubles were filtered, the filtrate was concentrated under reduced pressure, and the thus obtained residue was purified by silica gel column chromatography, to obtain 744 mg of 4-iodo-N-[(1S)-1-phenylethyl]-2-pyridinamine [58-1] as a light brown solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14].[OH-].[Na+]>C(O)C>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:20]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)CCCCCCOc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCCOc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Ethyl 7-(3,5-bis(trifluoromethyl)phenoxy)heptanoate was added to 95% ethanol and dissolved by reflux. The solution was then added with sodium hydroxide and further refluxed. The resulting crystals were filtered, washed with ethanol, and then added with dichloromethane and 1N hydrochloric acid. The solution was extracted twice with dichloromethane. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed and the residue was purified by silica gel column chromatography to obtain 7-(3,5-bis(trifluoromethyl) phenoxy) heptanoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[O:28]1[CH2:32][CH:31]=[N:30][C:29]1=[O:33]>>[C:7]([C:6]1[CH:9]=[C:2]([N:30]2[CH2:31][CH2:32][O:28][C:29]2=[O:33])[CH:3]=[CH:4][C:5]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH:25]3[CH2:27][CH2:26]3)=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=[O:11])#[N:8]
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Reactant: O=C1N=CCO1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)cc2C#N)CC1
Yield: 81.6 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using 5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (425 mg) described in Preparation Example 194 and oxazolin-2-one (104 mg), the title compound (352 mg) was obtained.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:34])[C@@H:10]([NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[CH:26]=1)[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:33][C:27]1[CH:26]=[C:25]([NH:24][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=3)=[N:14][N:15]=2)[C@H:9]([OH:8])[CH3:34])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)c1nnc(-c2ccc(C#N)cc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a pre-cooled (−55° C.) solution of 4-((1R,2R)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chlorobenzonitrile (860 mg, 1.74 mmol) in THF (100 mL) was added TBAF (2.09 mL, 2.09 mmol, 1 M solution in THF) over 10 min. Upon complete addition the reaction mixture was allowed to warm to 0° C. over 1 h, then stirred at 0° C. for a further 30 min and quenched with sat. aq. NH4Cl (100 mL). The resulting mixture was partitioned between H2O (50 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (150 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (20-80% EtOAc in hexanes) to provided the title compound as a colourless amorphous solid (660 mg, 100%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.20 (dm, J=8.8 Hz, 2H), 8.00 (dm, J=8.8 Hz, 2H), 7.53 (d, J=8.6 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 6.92 (dd, J=2.4, 8.6 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 5.08 (dd, J=5.7, 8.8 Hz, 1H), 4.42 (pentet, J=6.1 Hz, 1H), 1.41 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:6]=1[C:17]1[C:18]([O:23]CC2C=CC=CC=2)=[N:19][CH:20]=[CH:21][CH:22]=1)[CH3:2]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:6]=1[C:17]1[C:18](=[O:23])[NH:19][CH:20]=[CH:21][CH:22]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(OC)c(C(C)(C)C)cc1-c1ccc[nH]c1=O
Reaction time: 2 h

Procedure:
step 2—To a solution of 78 (109 mg, 0.26 mmol) in MeOH (7 mL) and THF (1 mL) was added 20% Pd(OH)2/C (wet, 20 mg). The reaction mixture was stirred under an atmosphere of hydrogen (balloon) for 2 h then filtered through a pad of CELITE, rinsing with EtOAc. The filtrate was concentrated under reduced pressure to afford 79 mg (93%) of I-54 as an off-white solid: MS=330 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:19][NH:18][C:17](=O)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:28]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([Cl:28])[N:18]=[N:19][C:20]=2[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1n[nH]c(=O)cc1-c1ccc(OCc2ccccc2)cc1
Product: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A suspension of 5-(4-benzyloxy-phenyl)-6-butyl-2H-pyridazin-3-one (5.4 g, 14.73 mmol) in POCl3 (8 mL) was stirred at 70° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and to the residue was added ice (50 g). The mixture was stirred for 1 h. This was extracted with DCM (3×50 mL), the combined organic layer was dried, filtered and concentrated under reduced pressure. The resultant residue was purified by flash silica gel column chromatography eluting with in 10% ethyl acetate in hexanes to provide 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH3:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH2:23][CH:24]=O)=[CH:20][CH:19]=[CH:18][CH:17]=2.C(N(CC)CC)C.C([BH3-])#N.[Na+].[OH-].[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:24][CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:13])=[CH:6][CH:7]=1
Reactant: Brc1ccc(C2CCCN2)cc1
Reactant: Cc1[nH]c2ccccc2c1CC=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1[nH]c2ccccc2c1CCN1CCCC1c1ccc(Br)cc1
Reaction time: 2 h
Yield: 114.1 %

Procedure:
To a solution of 2-(4-bromo-phenyl)-pyrrolidine (326 mg, 1.44 mmol) in dichloromethane (20 mL) were added (2-methyl-1H-indol-3-yl)-acetaldehyde (250 mg, 1.44 mmol), triethylamine (0.603 mL, 4.33 mmol) and a solution of titanium (IV) chloride in dichloromethane (0.720 mL, 1 M, 0.72 mmol), and the resulting mixture was stirred at room temperature. The reaction mixture was treated with sodium cyanoborohydride (286 mg, 4.32 mmol), stirred for 2 h, basified to pH 13 with an aqueous 5 N sodium hydroxide solution, and extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to provide a crude product, which was purified on silica gel column chromatography to give 3-{2-[2-(4-bromo-phenyl)-pyrrolidin-1-yl]-ethyl}-2-methyl-1H-indole (630 mg, 99% yield). LCMS (m/z): 384.84 (M+1).
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:14]2[C:15]([C:22]([O:24]C)=O)=[C:16]([CH3:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=O)=[CH:7][C:6]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]1)=[O:27]>C(O)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:14]3[C:15](=[C:16]([CH3:21])[N:17]([CH3:20])[C:18]=3[CH3:19])[C:22](=[O:24])[NH:2][N:3]=2)=[CH:7][C:6]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]1)=[O:27]
Reactant: COC(=O)c1c(C(=O)Cc2ccc(F)c(C(=O)N3CCC(OC)CC3)c2)c(C)n(C)c1C
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c(C)n(C)c(C)c34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 5.5 %

Procedure:
Hydrazine hydrate (0.014 mL, 0.19 mmol) was added to methyl 4-(2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetyl)-1,2,5-trimethyl-1H-pyrrole-3-carboxylate (59) (0.076 g, 0.17 mmol) in acetic acid (4 mL). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (4.00 mg, 5.49% yield); m/z (LC-MS, ESI+), RT=1.60 min (M+H=427.11).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[C:10]1[CH:23]=[CH:22][C:13]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1>CO.[Pd]>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:22][CH:23]=1
Reactant: CN(C)CCCCC/C=C\c1ccc(C(=O)c2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCCCCCc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.6 %

Procedure:
1.12 g of 4-[(Z)-7-(dimethylamino)-1-heptenyl]benzophenone were dissolved in 30 ml of methanol, 20 mg of 5 percent palladium on carbon were added thereto and the suspension was stirred under hydrogen at normal pressure and room temperature for 2.5 hours. The reaction mixture was filtered through silica gel and the filtrate was evaporated. There were obtained 1.10 g (98%) of 4-[7-(dimethylamino)heptyl]benzophenone as a colourless oil.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13](C)=[C:14]([C:30]([O:32][CH3:33])=[O:31])[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[C:16]=1[C:17]([O:19][CH3:20])=[O:18].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:10][C:11]1[NH:12][C:13]2[CH2:33][O:32][C:30](=[O:31])[C:14]=2[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
In a similar manner, 2.77 grams of 80 percent pyridinium bromide perbromide (6.93 millimoles) was added in one portion to a cooled to 0° C. solution of 2.00 grams (5.77 millimoles) of dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (nifedipine), and 0.81 milliliter of pyridine in 40 milliliters of chloroform. The resulting mixture was stirred at 0° C. for 30 minutes, at reflux temperature for 90 minutes, allowed to cool to room temperature, diluted with chloroform, washed with 2N hydrochloric acid and with brine, dried, and the solvent vaporized in vacuo to obtain a crude product residue. The latter was flash chromatographed (J. Org. Chem. 43, 2923 (1978)) on silica gel employing 70 percent ethyl acetate--30 percent hexane as eluant to obtain 0.45 gram (24 percent yield) of purified methyl 2-methyl-4-(2-nitrophenyl)-5-oxo-1,4,5,7-tetrahydrofuro-[3,4-b]-pyridine-3-carboxylate product which after recrystallizing from ethyl acetate hexane had a melting point of 261°-263° C. (dec.). Elemental analyses were as follows: