Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:38]=[CH:37][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]([C:30](=[O:36])[C:31]([O:33]CC)=[O:32])=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].CCCCCC>C1COCC1.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]([C:30](=[O:36])[C:31]([OH:33])=[O:32])=[CH:11]2)=[CH:37][CH:38]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccc(C(C)(C)C)cc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(Cn2cc(C(=O)C(=O)O)c3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1
Yield: 68.7 %

Procedure:
{1-[4-(tert-Butyl)benzyl]-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-[4-(tert-butyl)benzyl]-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate (1.72 g, 3.29 mmol), and potassium hydroxide (0.614 g, 10.9 mmol) in THF (20 mL) and water (20 mL) following the procedure described in Step 4 of Example 5. Following work-up, and trituration of the residue with hexane, a solid was obtained. Crystallization from methylene chloride/hexane and drying for 10 hours at 82° C. yielded the title compound as a yellow solid (1.12 g, 69%), mp: 158-160° C. Mass spectrum (−ESI, [M−H]−) m/z 494; 1HNMR (500 MHz, DMSO-d6): δ 13.8-14.1 (br s, 1H), 8.7 (s, 1H), 8.4 (d, 1H, J=1.4 Hz), 7.75 (d, 2H, J=8.7 Hz), 7.7 (d, 1H, J=8.7 Hz), 7.6 (dd, 1H, J=8.6 Hz and 1.7 Hz), 7.45 (d, 2H, J=8.2 Hz), 7.35 (d, 2H, J=8.4 Hz), 7.25 (d, 2H, J=8.4 Hz), 5.6 (s, 2H), and 1.2 ppm (s, 9H). Elemental Analysis for C28H24F3NO4: Calculated: C, 67.87; H, 4.88; N, 2.83. Found: C, 67.69; H, 4.83; N, 2.52.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[H][H]>CO.C(Cl)Cl.[Pd]>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: NC(=O)Nc1cc(C=Cc2cccc(C(F)(F)F)c2)ccn1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)Nc1cc(CCc2cccc(C(F)(F)F)c2)ccn1
Yield: 33.8 %

Procedure:
{4-[2-(3-Trifluoromethyl-phenyl)-vinyl]-pyridin-2-yl}-urea (210 mg, 0.68 mmol) is dissolved in methanol (3 mL) and DCM (3 mL). Then 5% palladium on carbon (145 mg, 0.068 mmol) is added. The reaction is stirred for 16 hours under the hydrogen atmosphere. The palladium on carbon is filtered and the filtrate is concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 71 mg of the titled product.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([C:23](O)([CH3:27])[C:24]([OH:26])=[O:25])=[C:21]([S:29][CH3:30])[N:20]=[C:19]2[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:13][CH:12]=1)(=[O:4])=[O:3].O1CCOCC1.S(=O)(=O)(O)O.C(Cl)(Cl)Cl>O.[Na+].[Cl-].CO>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][N:18]2[C:22]([C:23](=[CH2:27])[C:24]([OH:26])=[O:25])=[C:21]([S:29][CH3:30])[N:20]=[C:19]2[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:15][CH:16]=1)(=[O:4])=[O:3]
Reactant: CCCCc1nc(SC)c(C(C)(O)C(=O)O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: C=C(C(=O)O)c1c(SC)nc(CCCC)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1

Procedure:
1 g of the product obtained in Stage A above is introduced into 50 cm3 of dioxane and 5 cm3 of concentrated sulphuric acid is added. The solution is heated for about 5 hours, diluted with water, saturated with NaCl and extraction is carried out with CHCl3 with 20% MeOH.
Reaction SMILES: FC(F)(F)C([N:5]([CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9])=O.C(N(CC)CC)C.C([O:40][C:41](=[O:45])[C@H:42]([CH3:44])[NH2:43])C>CCOCC>[CH2:15]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:43][C@H:42]([C:41]([OH:45])=[O:40])[CH3:44])=[O:9])[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOC(=O)[C@H](C)N
Reactant: CCCCCCCCCCCCC=CN(C(=O)C(F)(F)F)c1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCC=CCCCNc1ccccc1C(=O)N[C@@H](C)C(=O)O

Procedure:
A solution pf 4.75 g. of N-trifluoroacetyl-2-(tetradecenylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solvent is evaporated from the combined filtrate and washings. After treatment of the residue with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:27][N:28]([CH:34]1[C:43]2[N:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH2:37][CH2:36][CH2:35]1)[CH2:29][CH2:30][CH2:31][CH2:32][OH:33])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:27][N:28]([CH:34]1[C:43]2[N:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH2:37][CH2:36][CH2:35]1)[CH2:29][CH2:30][CH2:31][CH:32]=[O:33])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)n1c(CN(CCCCO)C2CCCc3cccnc32)nc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)n1c(CN(CCCC=O)C2CCCc3cccnc32)nc2ccccc21
Reaction time: 0.33 h
Yield: 34.3 %

Procedure:
To a stirred solution of oxalyl chloride (4.5 mL, 9.0 mmol) in CH2Cl2 (40 mL) at −78° C. was added DMSO (0.86 mL, 12.1 mmol). After 30 minutes [1-(tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)-(4-hydroxy-but-1-yl)-amine (3.66 g, 8.13 mmol) was added as a solution in CH2Cl2 (7.5 mL). After a further 20 minutes, triethylamine (70 mL, 71.7 mmol) was added and the ice bath was removed. The reaction was stirred for a further 75 minutes then concentrated under reduced pressure. The residue was taken up in ethyl acetate and filtered through celite to give a crude yellow oil (3.88 g). Purification of this oil by column chromatography on silica gel (solvent=35:1:1 CH2Cl2: CH3OH: NH4OH) afforded the desired pure aldehyde (1.25 g, 39%). 1H NMR (CDCl3) δ 1.52-1.72 (m, 13H), 1.74-1.88 (m, 1H), 1.90-2.00 (m, 1H), 2.06-2.17 (m, 1H), 2.36 (t, 2H, J=6.6 Hz), 2.53-2.74 (m, 2H), 2.79-2.88 (m, 1H), 4.22 (dd, 1H, J=9.7, 6.3 Hz), 4.48 (d, 1H, J=15.4 Hz), 4.66 (d, 1H, J=15.2 Hz), 6.93 (dd, 1H, J=7.6, 4.7 Hz), 7.19-7.28 (m, 4H), 7.65-7.70 (m, 1H), 7.73-7.82 (m, 1H), 8.33 (d, 1H, J=3.6 Hz), 9.56 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH2:29]1[CH:33]2[CH2:34][NH:35][CH2:36][CH:32]2[CH2:31][N:30]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CS(C)=O>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([N:35]4[CH2:34][CH:33]5[CH2:29][N:30]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:31][CH:32]5[CH2:36]4)[C:11]=23)=[C:19]([F:25])[CH:20]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(N3CC4CN(C(=O)OC(C)(C)C)CC4C3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
A 100 mL round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (100 mg, 0.204 mmol, prepared in Example 7, step B), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (217 mg, 1.02 mmol), copper(I)iodide (15.5 mg, 0.0816 mmol), (S)-pyrrolidine-2-carboxylic acid (18.8 mg, 0.163 mmol), K2CO3 (141 mg, 1.02 mmol) and DMSO (10 mL). The reaction mixture was stirred at 100° C. overnight. The reaction was cooled to ambient temperature and partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford the desired product (44.8 mg, 38.2%). LRMS (APCI pos): m/e 575 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[N:25]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][N:27]=[CH:26]1>>[N:25]1([CH2:30][CH2:31][CH2:32][NH:33][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NCCCn1ccnc1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCCn3ccnc3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-(1H-imidazol-1-yl)propan-1-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 2.09-2.17 (m, 2 H) 2.44 (s, 3 H) 3.32 (q, J=6.40 Hz, 2 H) 4.28 (t, J=6.95 Hz, 2 H) 7.63-7.72 (m, 2 H) 7.74 (s, 1 H) 7.78 (d, J=8.08 Hz, 1 H) 7.83 (t, J=1.64 Hz, 1 H) 8.19 (br. s., 1 H) 8.35-8.55 (m, 2 H) 8.82 (t, J=5.68 Hz, 1 H) 8.89-8.96 (m, 1 H) 9.11 (s, 1 H) 13.26-14.08 (m, 1 H). MS m/z [M+H]+ 428.2
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.C([N:15]([CH:19]([CH3:21])[CH3:20])C(C)C)C.C1(N)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([NH:15][CH:19]2[CH2:21][CH2:20]2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1cccc(CCC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(CCC(=O)NC2CC2)c1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
To a stirred solution of 3-(3-aminophenyl)propanoic acid (1 g, 6.05 mmol) in 10 ml DMF, N-ethyl-N-isopropylpropan-2-amine (1.174 g, 9.08 mmol), cyclopropanamine (0.415 g, 7.26 mmol) were added, resulting clear solution was stirred at room temperature, HATU (3.45 g, 9.08 mmol) was added and the resulting mixture was stirred for 24 h at room temperature. Reaction Mixture was diluted with cold water and extraction with Ethyl Acetate (3×30 ml). The Combined organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the crude compound, the crude compound was purified by column chromatography to afford the pure title compound (500 mg).
Reaction SMILES: Cl[C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)=[O:3].[Cl:20][C:21]1[CH:38]=[CH:37][C:24]([CH2:25][NH:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>ClCCl>[C:32]([O:31][C:30]([NH:29][CH2:28][CH2:27][N:26]([CH2:25][C:24]1[CH:37]=[CH:38][C:21]([Cl:20])=[CH:22][CH:23]=1)[C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)=[O:3])=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)cc1
Reactant: O=C(Cl)N1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 37.9 %

Procedure:
Benzyl 4-(chlorocarbonyl)piperazine-1-carboxylate (233 mg, 0.83 mmol) was added at room temperature to a solution of tert-butyl 2-(4-chlorobenzylamino)ethylcarbamate (235 mg, 0.83 mmol) and Hunig's base (0.2 mL, 1.2 mmol, 1.5 eq.) in dichloromethane (1.6 mL). The reaction was allowed to stir overnight. The reaction mixture was then concentrated to the crude product, which was purified by flash column chromatography to afford benzyl 4-((2-(tert-butoxycarbonylamino)ethyl)(4-chlorobenzyl)carbamoyl)piperazine-1-carboxylate as foam (167 mg, 38%). MS (ESI) m/e (M+H+) 531.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Br[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Cu]I.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: Nc1ccccc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Brc1cccc(-c2nc3ccccc3o2)c1
Temperature: 120 °C
Yield: 100 %

Procedure:
A mixture of 3-bromobenzoyl chloride (6.005 g, 27.36 mmol), 2-bromoaniline (4.707 g, 27.36 mmol), Cs2CO3 (17.83 g, 54.73 mmol), CuI (0.261 g, 1.37 mmol), 1,10-phenanthroline (0.493 g, 2.74 mmol) and anhydrous 1,4-dioxane (50 mL) was degassed with argon at 40° C. for 30 min while stirring. The reaction mixture was then maintained under argon at 120° C. while stirring until TLC (SiO2, 4:1 hexanes-ethyl acetate) confirmed consumption of the starting material (24 h). Upon cooling to RT, the mixture was filtered and the filtrant washed copiously with ethyl acetate (ca. 350 mL). The filtrate was then washed with sat. NaHCO3, H2O and brine, dried over MgSO4, filter and concentrated in vacuo. Purification of the crude product via flash chromatography (SiO2, 4:1-hexanes:ethyl acetate) afforded 2-(3-bromophenyl)benzo[d]oxazole (7.50 g, 100%) as an off-white solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]([CH2:15][CH:16]([CH3:23])[CH2:17][CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[CH2:14]>C(Cl)Cl>[CH3:14][C:13]1([CH2:15][CH:16]([CH3:23])[CH2:17][CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[O:6][CH2:12]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CC(C)CC(C)CCC
Solvent: ClCCl
Product: CCCC(C)CC(C)CC1(C)CO1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
m-Chloroperoxybenzoic acid (7.31 g, 60% purity, 25.42 mmol) was added to a stirred solution of 2,4,6-trimethyl-1-nonene (5) (3.56 g, 21.19 mmol) in 70 ml of dry methylene chloride in a 250 ml flask in an ice bath. The chilled reaction mixture was stirred for one hour, and then stirred vigorously overnight at room temperature. The reaction mixture was cooled to 10° C. before filtering out a white slurry, which was washed with cooled methylene chloride. The combined filtrates were washed three times with cooled aqueous carbonate, water, and brine and dried over sodium sulfate. Evaporation of the solvent yielded a crude oil which was distilled at 65°-70° C. and 1.5 mm Hg to yield pure 2,4,6-trimethyl-1,2-epoxynonane (6).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4](NC1CC1)=[O:5].Cl.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][CH2:25][NH2:26]>>[NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4]([NH:26][CH2:25][CH2:24][C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=1)=[O:5]
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: NCCc1ccc2ccccc2c1
Agent: Cl
Product: CC[C@H](N)[C@H](O)C(=O)NCCc1ccc2ccccc2c1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide, Representative Procedure B, using 2-(naphthalen-2-yl)ethanamine hydrochloride in the seventh step (step B7).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][NH2:16])=[O:14])[CH3:2].[CH:18](=O)[CH2:19][CH3:20]>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][N:16]=[CH:18][CH2:19][CH3:20])=[O:14])[CH3:2]
Reactant: CCC=O
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Solvent: CO
Product: CCC=NNC(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 100 mL volume three-necked flask, 10.0 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39), 38 ml of methanol and 6.16 ml of propanal were added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was washed with hexane and dried under reduced pressure to give 9.44 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-propylidenehydrazine ((40-a)-(14)-3).
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>C(#N)C>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[O:10][CH:2]([N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6]
Reactant: CC(C)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1Cl
Reactant: c1nc[nH]n1
Solvent: CC#N
Product: CC(C)(CF)C(=O)C(Oc1ccc(Cl)cc1Cl)n1cncn1
Yield: 88.8 %

Procedure:
96.3 g (0.27 mol) of 1-bromo-1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone were dissolved in 200 ml of acetonitrile and the solution was added dropwise to a boiling solution of 46 g (0.56 mol) of 1,2,4-triazole in 200 ml of acetonitrile. After heating the mixture under reflux for 20 hours, the solvent was removed in vacuo, the residue was taken up in methylene chloride, the methylene chloride mixture was washed several times with water and the organic phase was dried over sodium sulphate. After removing the solvent in vacuo, 83 g (89% of theory) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)-2-butanone were obtained as an oil, which was further reacted directly. ##STR84##
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[C:23]([CH3:24])=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([C:32](=[N:34]O)[NH2:33])[CH:31]=1.CCN(C(C)C)C(C)C>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([C:32]2[N:33]=[C:19]([C:18]3[CH:22]=[C:23]([CH3:24])[C:15]([N:11]4[CH2:12][CH2:13][CH2:14][CH:10]4[CH2:9][O:8][CH3:7])=[N:16][CH:17]=3)[O:21][N:34]=2)[CH:31]=1
Reactant: COCC1CCCN1c1ncc(C(=O)O)cc1C
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CCCN1c1ncc(-c2nc(-c3cc(F)ccc3OC)no2)cc1C

Procedure:
Oxalyl chloride (122 μL; 1.44 mmol; 3 eq.), Intermediate 40 (120 mg; 0.48 mmol; 1 eq.), Intermediate 23 (88 mg; 0.48 mmol, 1 eq.) and DIEA (245 μL; 1.44 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 50/50) afforded the title compound as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([C:4]([C:24]1[CH:25]=[CH:26][C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=1)([C:22]#[N:23])[CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)[CH3:9])[CH3:3].[Na+].[Cl-].C1(C)C=CC=CC=1.[CH3:43][C:44]([CH:46]=[CH2:47])=[O:45]>C1C=CC=CC=1.O.CC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH3:21][O:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:12]([CH2:11][CH2:10][N:8]([CH3:9])[CH2:7][CH2:6][CH2:5][C:4]([CH:2]([CH3:1])[CH3:3])([C:24]2[CH:25]=[CH:26][C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=2)[C:22]#[N:23])=[C:13](/[CH:47]=[CH:46]/[C:44](=[O:45])[CH3:43])[CH:14]=1
Reactant: C=CC(C)=O
Reactant: COc1ccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: COc1ccc(C(C#N)(CCCN(C)CCc2cc(OC)c(OC)cc2/C=C/C(C)=O)C(C)C)cc1OC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 4 g verapamil (8.8 mmole) in 100 ml of benzene was added to 2.2 g of palladium acetate. The mixture was stirred for four days at room temperature. A saturated solution of NaCl in 100 ml of water and 96 ml of acetone was added to the resulting mixture, which was stirred at room temperature for 15 minutes. Solvent was then removed under reduced pressure. Then, there was added to the mixture 100 ml of toluene, 25 ml of triethylamine and 10 mmol of methylvinylketone. The mixture was heated at 120° C. for 2 hours, and then allowed to cool to room temperature. The organic phase was filtered, washed with water, dried, filtered again and solvent was removed. After separation by chromatography, the title compound was obtained (3.2 g, 80%) [m.p. 119-121, from ether].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[C:20]3[C:21]([CH3:27])=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[S:28]1[C:32]2[CH2:33][CH2:34][CH2:35][CH2:36][C:31]=2[CH:30]=[C:29]1[C:37](Cl)=[O:38].C(N(C(C)C)C(C)C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[C:20]3[C:21]([CH3:27])=[C:22]([NH:23][C:37]([C:29]4[S:28][C:32]5[CH2:33][CH2:34][CH2:35][CH2:36][C:31]=5[CH:30]=4)=[O:38])[CH:24]=[CH:25][CH:26]=3)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc3nccc(-c4cccc(N)c4C)c3o2)cc1OC
Reactant: O=C(Cl)c1cc2c(s1)CCCC2
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc3nccc(-c4cccc(NC(=O)c5cc6c(s5)CCCC6)c4C)c3o2)cc1OC

Procedure:
The compound was synthesized according to the procedure L with 3-[2-(3,4-dimethoxyphenyl)furo[3,2-b]pyridin-7-yl]-2-methylaniline (40.00 mg, 0.11 mmol) and 4,5,6,7-tetrahydro-1-benzothiophene-2-carbonyl chloride (24.5 mg, 0.12 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.03 ml, 0.17 mmol). The title compound was obtained as a yellow solid (32 mg, 55%). HPLC (method F): 96%, RT=4.512 min. 1H NMR (DMSO-d6) δ [ppm] 9.95 (s, 1H), 8.53 (d, 1H), 7.63 (d, 2H), 7.45-7.27 (m, 6H), 7.03 (d, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 2.70 (s, 2H), 2.55 (m, 2H), 2.05 (s, 3H), 1.72-1.69 (m, 4H). MS: m/z=525 [M+H]+, RT=4.50 min.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(C2(CN3CCCC3)CCOCC2)ccc1OCCCN1CCCC1
Temperature: 60 °C
Yield: 45.7 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (150 mg, 0.47 mmol) and 1-bromo-4-chloroethane (54.2 μL, 0.47 mmol) in anhydrous acetonitrile (5 mL) was added potassium carbonate (65 mg, 0.47 mmol). The mixture was heated to 60° C. overnight then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH:NH3 (94:5:1) to give the title compound (40 mg, 23% yield). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.73-3.78 (m, 2H), 3.57-3.53 (m, 2H), 2.65-2.61 (m, 4H), 2.53 (m, 4H), 2.20 (m, 4H), 2.10-1.88 (m, 6H), 1.56 (m, 4H).