Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:34][CH2:33][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: NCC1CCCCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCC2CCCCC2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 39 %

Procedure:
A mixture of intermediate 59 (0.5 g, 1.36 mmol), cyclohexanemethylamine (0.53 mL, 6.1 mmol) and MeOH (0.11 mL) is heated at 100° C. for 48 h. The reaction mixture is cooled to RT and purified by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-50:50) gives 0.23 g of the product 79. 1H NMR (CDCl3) δ 7.80-7.35 (m, 2 H), 7.18 9s, 1 H), 7.10-6.90 (m, 6 H), 6.90-6.70 (m, 2 H), 5.45-5.30 (m, 2 H), 3.45-3.15 (m, 2 H), 2.00-1.50 (m, 5 H), 1.45-0.95 (m, 15H); MS: m/z 434 (M++1).
Reaction SMILES: CC(C)(NC[CH2:9][CH2:10][NH:11][C:12]([CH3:18])([CH3:17])[C:13](=[N:15][OH:16])[CH3:14])C(=NN)C.[NH2:20]CCN>CO.O>[NH2:20][CH2:9][CH2:10][NH:11][C:12]([CH3:17])([CH3:18])[C:13](=[N:15][OH:16])[CH3:14]
Reactant: NCCN
Reactant: CC(=NN)C(C)(C)NCCCNC(C)(C)C(C)=NO
Solvent: O
Solvent: CO
Product: CC(=NO)C(C)(C)NCCN
Reaction time: 8 h

Procedure:
A solution of Compound A from Example 1 (10 g, 73.8 mmol) was added dropwise to a stirred solution of 1,2-diaminoethane (25 g, 416.7 mmol) in methanol (10 mL) at 0° C. After the addition was complete, the mixture was left overnight at room temperature with stirring. Removal of the methanol in vacuo gave a light yellow oil which was dissolved in water. The pH of the solution was adjusted to about 11. The solvent was removed under vacuum, and the residue was extracted with ethyl acetate. Evaporation of the organic phase gave a light yellow semi-solid which on crystallization with ether gave the product as a crystalline solid. Yield: 5.89 g (50%); mp. 65°-67° C. 1H NMR (CDCl3) δ1.22[s, 6H, C(CH3)2 ], 1.87[s, 3H, C(=N)CH3 ], 2.49(t, 2H, CH2NH2) and 2.88(m, 2H, NHCH2). MS: (M+H)+ =160.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=2)[NH:7][CH:6]=1)[CH3:4].C[N:19](C=O)C>>[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([F:17])([F:15])[F:16])[CH:12]=2)[N:7]([NH2:19])[CH:6]=1)[CH3:4]
Reactant: CN(C)C=O
Reactant: CCc1c[nH]c2ccc(C(F)(F)F)cc12
Agent: [H-]
Agent: [Na+]
Product: CCc1cn(N)c2ccc(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A suspension of NaH (7 g, 176 mmol, 60% in mineral oil) in DMF (50 mL) at 0° C. is treated with 3-ethyl-5-trifluoromethyl-1H-indole (2.4 g, 11.3 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (6.6 g, 59 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, filtered through a pad of Celite, and extracted with EtOAc (3×150 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10%-50% EtOAc in heptane to afford 3-ethyl-5-trifluoromethyl-indol-1-ylamine (1.3 g, 50%). MS: 229 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.84 (s, 1H), 7.45 (s, 2H), 7.02 (s, 1H), 4.74 (s, NH2, 2H), 2.77 (q, 2H), 1.31 (t, 3H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])/[CH:14]=[CH:18]/[N:19]([CH3:21])[CH3:20])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CCN2C(C)=O
Reactant: COC(OC)N(C)C
Product: CC(=O)N1CCc2cc(C(=O)/C=C/N(C)C)ccc21
Temperature: 110 °C
Yield: 97 %

Procedure:
A mixture of 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)ethanone (6.0 g) and N,N-dimethylformamide dimethylacetal (14.2 g) was refluxed at 110° C. for 4 hours and evaporated in vacuo. The residue was triturated with diisopropylether, collected by filtration, and dried in vacuo to afford crude (2E)-1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-3-(dimethylamino)prop-2-en-1-one (7.4 g). To a solution of crude product in methanol (100 mL) were added guanidine hydrochloride (3.56 g) and potassium tert-butoxide (3.86 g) and the mixture was stirred at 100° C. for 3 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(N(CC)C(C)C)(C)C.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][C:39]([CH:36]2[CH2:38][CH2:37]2)=[O:40])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(NC(=O)C2CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in THF (2 mL) was added N,N-diisopropyl ethyl amine (0.15 mL, 0.86 mmol), 4-dimethylaminopyridine (8 mg, 0.06 mmol) and cyclopropanecarbonyl chloride (68 μL, 0.75 mmol). The resulting suspension was stirred for 18 h at ambient temperature before it was extracted with a mixture of aqueous sodium carbonate (saturated, 20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=40:40:20 to 10:70:20) afforded the title compound (226 mg, 95%) as a light yellow solid. MS: m/e=417.3 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[N:6]=[C:5]1[CH3:14])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.C1COCC1>[CH:1]([N:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]=[C:5]1[CH3:14])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn(C(C)C)c(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)cn1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
Ethyl 1-isopropyl-2-methyl-1H-imidazole-4-carboxylate (0.423 mmol, 83 mg) was dissolved in methanol (0.5 ml) and THF (4 ml). NaOH 2 M (2.115 mmol, 1.057 ml) was added and the resulting mixture was stirred at RT overnight. The pH of the reaction mixture was adjusted to about 5 with 1 M HCl and the mixture was evaporated. Ethanol was added and the salt was removed by filtration. The salt was flushed few times with ethanol. 51 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.38 (d, 6H), 2.39 (s, 3H), 4.35-4.49 (m, 1H), 7.97 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[C-:12]#[N:13].[K+]>[C-]#N.[Zn+2].[C-]#N>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([C:12]#[N:13])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: [C-]#N
Agent: [K+]
Agent: [Zn+2]
Product: COc1ccc(C(=O)C#N)cc1
Temperature: 210 °C
Yield: 86.5 %

Procedure:
In the manner described above, 170 g (1 mol) of p-methoxybenzoyl chloride and 64.5 g (0.99 mol) of potassium cyanide and 1.17 g (0.1 mol) of zinc cyanide were mixed, whilst stirring, and the mixture was heated to 210° C. for 1 hour. A distillation bridge was then connected and the reaction product was separated from the residue direct. On subsequent fractionation, 138 g (86% of theory) of p-methoxybenzoyl cyanide with a melting point of 63° C. were obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](F)[N:7]=1.[CH3:13][NH:14][CH3:15].C(O)C>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[N:7]=[C:8]([N:14]([CH3:15])[CH3:13])[CH:9]=[CH:10][CH:11]=1
Reactant: Fc1cccc(C2OCCO2)n1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1cccc(C2OCCO2)n1
Temperature: 100 °C

Procedure:
0.60 g of 2-[1,3]dioxolan-2-yl-6-fluoropyridine (3.55 mmol) and 2.50 ml of dimethylamine at 33% in ethanol (17.7 mmol) are mixed and then the mixture is heated at the temperature of 100° C. for 12 hours. After evaporation under vacuum, the residue is taken up in chloroform, the mixture is washed with water, dried over magnesium sulfate, filtered and the chloroform is evaporated under vacuum. The title product is obtained in the form of a yellow oil which is used in the next stage without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([CH:18]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CCN(CC)CC>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([CH2:18][N:29]2[CH2:30][CH2:31][CH:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccsc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: c1ccc(CN2CC(CN3CCC(c4ccccc4)CC3)C(c3ccsc3)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 115 %

Procedure:
To a solution of 0.13 g (0.48 mmol) of 1-benzyl-3-(SR)-formyl-4-(RS)-(3-thienyl)pyrrolidine and 0.13 g (0.67 mmol) of 4-phenylpiperidine in 2 mL of dichloroethane and 0.1 mL of Et3N at rt was added 0.21 g (0.96 mmol) of sodium triacetoxyborohydride. After stirring for 3 h at rt, the reaction mixture was partitioned between CH2Cl2 and sat'd NaHCO3. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, acetone: hexanes, 1:3) to give 0.23 g of the title compound. 1H NMR CDCl3) δ7.21-7.44 (m, 11H), 7.07-7.13 (m, 2H), 3.74 (d, 1H, J=12.8 Hz), 3.67 (d, 1H, J=13.1 Hz). Mass Spectrum (CI) m/e=417 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=[O:43]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:42](=[O:43])[C:41]([CH3:46])([CH3:45])[CH3:40])[CH2:31][CH2:32]3)=[CH:25][CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCN(C(=O)C(C)(C)C)CC3)nc2)cc1
Yield: 73.3 %

Procedure:
Place 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(6-piperazin-1-yl-pyridin-3-yl)-urea (200 mg, 0.461 mmol), triethylamine (0.071 mL, 0.507 mmol), and 4-N,N-dimethylaminopyridine (6 mg, 0.051 mmol) in CH2Cl2 (10 mL). Add 2,2-dimethyl-propionyl chloride (0.062 mL, 0.507 mmol) and stir at room temperature for 17 h. Subject residue to silica gel chromatography eluting with 0-100% EtOAc:hexane to yield 175 mg (73%) of the title compound. MS(ES+): m/z=518.2 [M+H].
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[CH2:10]([NH:17][C:18]([NH2:20])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C>[CH2:10]([NH:17][C:18]([NH:20][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[C:2]([F:9])([F:8])[F:1])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: C=C(C(=O)O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)NCC(C(=O)O)C(F)(F)F
Temperature: 90 °C
Reaction time: 28 h
Yield: 75.8 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5.0 mmole) and benzylurea (841 mg; 5.6 mmoles) in DMF (3 ml) was heated at 90° C. with stirring for 28 hours. DMF was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetatechloroform to give 1.10 g (yield: 76%) of 1-benzyl-3-(2-hydroxycarbonyl-3,3,3-trifluoropropyl)urea. m.p.: 183°-183.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[N:7][N:6]([CH3:9])[C:5](=[O:10])[C:4]=1[CH:11]=[O:12].[CH3:14][Mg]Br.C(OCC)C.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[N:7][N:6]([CH3:9])[C:5](=[O:10])[C:4]=1[CH:11]([OH:12])[CH3:14]
Reactant: CN(C)c1cnn(C)c(=O)c1C=O
Reactant: C[Mg]Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1c(N(C)C)cnn(C)c1=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
In THF (10 ml) was dissolved 5-dimethylamino-4-formyl-2-methyl-3(2H)-pyridazinone (362 mg) followed by dropwise addition of 3.0M methylmagnesium bromide/diethyl ether (1.0 ml) with ice-cooling, and the mixture was stirred at 50° C. for 30 minutes. To this reaction mixtrue was added 1N-hydrochloric acid (3 ml) with ice-cooling. Then, saturated aqueous NaHCO3 solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to dryness. Yellow oil, 371 mg. 1H-NMR (CDCl3) δ: 1.64(3H,d,J=6.6Hz), 2.94(6H,s), 3.72(3H,s), 4.93(1H,dq,J=6.6&11.4Hz), 5.31(1H,d,J=11.4Hz), 7.66(1H,s).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:8][C:5]1[N:4]=[N:3][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(Cl)nn1
Product: Cc1ccc(-c2ccccc2)nn1

Procedure:
Synthesized using 3-chloro-6-methylpyridazine (1.00 g, 7.78 mmol) and phenylboronic acid (1.42 g, 11.67 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (2:1) as eluent. White solid. Yield: 1.00 g, 76%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=2.76 (s, 3H), 7.39 (d, J=8.5 Hz, 1H), 7.46-7.55 (m, 3H), 7.76 (d, J=8.5 Hz, 1H), 8.03-8.09 (m, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=22.0, 123.9, 126.9, 127.2, 128.9, 129.7, 134.4, 136.4, 157.2, 158.5; (ESI): m/z=170.96 [M+H]+.
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH2:10]([O:12][C:13](=[O:30])[C:14]([CH3:29])([CH3:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:30])[C:14]([CH3:29])([CH3:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[N:6]1[CH2:7][CH2:8][C:9]2[O:1][CH:2]=[CH:3][C:4]=2[CH2:5]1)[CH3:11]
Reactant: c1cc2c(o1)CCNC2
Reactant: CCOC(=O)C(C)(C)CCCCC(Br)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCCCC(c1ccccc1Cl)N1CCc2occc2C1
Temperature: 65 °C
Reaction time: 48 h
Yield: 47.9 %

Procedure:
4,5,6,7-Tetrahydrofuro[3,2-c]pyridine (0.16 g, 1.3 mmol), 7-bromo-7-(2-chlorophenyl)-2,2-dimethylheptanoic acid ethyl ester (0.49 g, 1.3 mmol) in DMF (13 mL), and potassium carbonate (0.27 g, 1.95 mmol) were combined under an argon atmosphere at room temperature. The mixture was heated to 65° C. overnight under an argon atmosphere. The reaction continued at 65° C. for 48 hours. After cooling to room temperature and concentration under reduced pressure, the crude product (0.28 g) was purified by column chromatography (silica gel, ethyl acetate/heptane=1/20 to 1/5) to afford 7-(2-chlorophenyl)-7-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethylheptanoic acid ethyl ester (Compound Ij, 0.26 g, 48.1% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.42 (d, 1H, J=7.5 Hz), 7.29 (d, 1H, J=7.2 Hz), 7.17 (t, 1H, J=8.7 Hz), 7.14 (s, 1H), 7.09 (t, 1H, J=8.1 Hz), 6.08 (s, 1H), 4.12 (t, 1H, J=4.2 Hz), 4.01 (q, 2H, J=7.2 Hz), 3.98 (d, 1H, J=14.4 Hz), 3.26 (d, 1H, J=13.5 Hz), 2.79-2.53 (m, 4H), 1.90-1.73 (m, 2H), 1.35-1.32 (m, 2H), 1.20-1.06 (m, 7H), 1.04 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 177.91, 148.97, 140.89, 139.39, 134.93, 129.50, 129.00, 128.02, 126.84, 115.82, 108.84, 63.33, 60.54, 47.61, 47.51, 42.28, 40.78, 33.21, 26.23, 25.35, 24.65, 14.50.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](/[CH:10]=[CH:11]/[B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[F:1][C:2]1[CH:9]=[C:8](/[CH:10]=[CH:11]/[B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC1(C)OB(/C=C/c2ccc(C=O)c(F)c2)OC1(C)C
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1(C)OB(/C=C/c2ccc(CN3CCOCC3)c(F)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a mixture of (E)-2-fluoro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzaldehyde (0.61 g, 2.2 mmol) and morpholine (0.3 mL) in DCE (20 mL) was added NaBH(OAc)3 (636 mg, 3 mmol), followed by AcOH (0.5 mL). The resulting mixture was stirred for 2 h at rt. The reaction was quenched with sat. NaHCO3 (10 mL), H2O (10 mL), and extracted with EtOAc (2×30 mL). The solvents were removed in vacuo to afford the title compound as a white solid (0.72 g, 94%). 1H NMR (400 MHz, CDCl3) δ 7.20-7.12 (m, 2H), 7.04 (d, J=7.6 Hz, 1H), 6.99 (d, J=10.8 Hz, 1H), 5.98 (d, J=18.4 Hz, 1H), 3.55-3.45 (m, 4H), 3.36 (s, 2H), 2.33-2.23 (m, 4H), 1.14 (s, 12H); MS ESI 348.2 [M+H]+, calcd for [C19H27BFNO3+H]+ 348.2.
Reaction SMILES: Cl.[CH3:2][C:3]([S:31]([CH3:34])(=[O:33])=[O:32])([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>O1CCOCC1.C(Cl)Cl>[OH:7][NH:6][C:4](=[O:5])[C:3]([CH3:2])([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: CC(CCc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(CCc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)(C(=O)NO)S(C)(=O)=O
Temperature: 0 °C
Yield: 86.7 %

Procedure:
A solution of HCl in dioxane (4.0 M, 10 mL) was added to a solution of (+/−)-2-methyl-2-(methylsulfonyl)-4-(4′-nitrobiphenyl-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (700 mg, 1.47 mmol) in DCM (5 mL) at 0° C. The reaction was warmed to room temperature as the ice bath expired. After 4 hours the reaction was concentrated. Purification on silica by flash column chromatography (DCM/MeOH 99:1-95:5) afforded the title compound as a yellow solid (500 mg, 87%). LCMS m/z 391.1 (M−1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3H) 1.87-2.01 (m, 1H) 2.35-2.59 (m, 2H) 2.64-2.80 (m, 1H) 3.05 (s, 3H) 7.41 (d, J=8.20 Hz, 2H) 7.74 (d, J=8.59 Hz, 2H) 7.88-8.06 (m, 2H) 8.22-8.39 (m, 2H) 9.23 (br. s., 1H) 10.98 (s, 1H)
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH2:10][CH2:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:5])=[O:4].C([Li])CCC.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][N:2]([CH3:18])[S:3]([N:6]1[C:10]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])(=[O:4])=[O:5]
Reactant: Cc1ccc(CBr)cc1[N+](=O)[O-]
Reactant: CN(C)S(=O)(=O)N1CCN=C1[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(Cc2cnc([Si](C)(C)C(C)(C)C)n2S(=O)(=O)N(C)C)cc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
2-(tert-Butyl-dimethyl-silyl)-4,5-dihydro-imidazole-1-sulfonic acid dimethylamide (5.03 g) (prepared as described by Ngochindo, J. Chem. Soc. Perkin Trans. (1990) 1:1645) was dissolved in 100 ml of dry tetrahydrofuran and cooled in a dry ice-acetone bath to -78° C.; 11.9 ml of 1.6M n-butyllithium in hexane was added to this mixture. After 1 hr at -78° C., the reaction mixture was treated dropwise with 5.0 g of 4-bromomethyl-1-methyl-2-nitro-benzene dissolved in 25 ml of dry tetrahydrofuran (THF). The mixture was stirred at -78° C. for 1 hr and then allowed to come to room temperature overnight. The mixture was treated with saturated ammonium chloride, extracted with ethyl acetate washed the combined extracts with saturated sodium chloride, dried, and evaporated to dryness. The residue was purified by flash chromatography on silica gel and eluted with ethyl acetate:hexane (1:4 ) to give 2.39 g of 2-(tert-butyl-dimethyl-silyl)-5-(4-methyl-3-nitro-benzyl)-imidazole-1-sulfonic acid dimethylamide as a yellow oil. ##STR126##
Reaction SMILES: C([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]([C:18]1[N:19]=[C:20]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])[N:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:22]=1)=[O:17])C1C=CC=CC=1.[Si](I)(C)(C)C>C(Cl)Cl.O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:21]2[CH:22]=[C:18]([C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]3[OH:8])=[O:17])[N:19]=[C:20]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])=[CH:24][CH:25]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1OCc1ccccc1)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: C[Si](C)(C)I
Solvent: O
Solvent: ClCCl
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of N-[(1R, 2R)-2-(benzyloxy)cyclohexyl]-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxamide (Table entry 278, prepared according to the procedures described in Examples 13 and 14) (100 mg, 0.18 mmol) in CH2Cl2 (2 mL), TMSI (iodotrimethylsilane) (60 μL, 0.42 mmol) was added. The mixture was stirred at rt overnight, and diluted with water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by preparative TLC (EtOAc) to afford 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-[(1R,2R)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxamide (56 mg, 67% yield) as a yellow solid: LC-MS m/z 464.3 (MH+), retention time 3.19 min (method 1); Rf=0.67 (EtOAc); 1H NMR (300 MHz, CDCl3) δ 1.16-1.30 (4H, m), 1.66-1.69 (2H, m), 1.98-2.02 (2H, m), 3.37-3.39 (1H, m), 3.70-3.80 (1H, m), 3.99-4.06 (1H, m), 6.96-7.37 (8H, m), 7.78 (1H, s).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24]>>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([N:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24])=[O:20]
Reactant: OCCNCCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCO)CCO
Temperature: 182 °C

Procedure:
Oleic diethanolamide was prepared by stirring equimolar quantities of oleic acid and diethanolamine in a nitrogen atmosphere while heating to 182° C. and maintaining the temperature for 2 hours while removing water. The product (Additive D), which also contained a significant amount of ester, was representative of another commercial amide.