Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[N:41]1[CH:46]=[CH:45][CH:44]=[N:43][C:42]=1[CH2:47][C:48](O)=[O:49]>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:48](=[O:49])[CH2:47][C:42]1[N:43]=[CH:44][CH:45]=[CH:46][N:41]=1)[CH2:19][CH2:18]2
Reactant: O=C(O)Cc1ncccn1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)Cc3ncccn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure described for the parallel synthesis of C-17 amides above, using 2-pyrimidine acetic acid as the reacting carboxylic acid. LCMS: m/e 650.6 (M+H)+, 5.57 min (method 3). 1H NMR (599 MHz, <DMSO_CDCl3>) δ=8.78 (d, J=4.7 Hz, 2H), 7.88 (d, J=8.2 Hz, 2H), 7.29 (s, 1H), 7.22 (d, J=7.6 Hz, 2H), 5.28 (d, J=5.3 Hz, 1H), 4.75 (s, 1H), 4.62 (br. s., 1H), 3.93 (s, 1H), 3.82 (d, J=14.6 Hz, 1H), 2.77-2.72 (m, 1H), 2.63 (d, J=12.9 Hz, 1H), 2.40-2.32 (m, 1H), 2.16-2.04 (m, 1H), 2.00-1.81 (m, 2H), 1.73 (br. s., 2H), 1.71 (s, 3H), 1.67-1.52 (m, 4H), 1.50-1.39 (m, 7H), 1.36-1.20 (m, 7H), 0.99 (br. s., 6H), 0.98 (br. s., 3H), 0.93 (br. s., 3H), 0.93 (br. s., 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[CH:11]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)=[CH:22][CH:21]=3)=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[CH:11]([CH2:17][NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)=[CH:22][CH:21]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN1CCN(c2ccc(Cl)c(Cl)c2)CC1C(=O)Nc1ccc(-n2ccnc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCN1CCN(c2ccc(Cl)c(Cl)c2)CC1CNc1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to preparation 2, react 4-(3,4-dichlorophenyl)-1-ethyl-N-[4-(1H-imidazol-1-yl)phenyl]-2-piperazinecarboxamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H][H]>C(O)C.[Pd]>[NH2:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(N)CCc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(N)CCc1ccccc1N

Procedure:
A solution of ethyl 2-amino-4-(2-nitrophenyl)butyrate (27 g) in ethanol (600 ml) was hydrogenated at room temperature and atmospheric pressure, using 10% palladium on charcoal (2.5 g) as catalyst, until hydrogen uptake ceased. The catalyst was filtered off and evaporation to dryness gave ethyl 2-amino-4-(2-aminophenyl)butyrate used without purification for the next synthetic step.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15]Br.O>CO>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15][O:11][C:10]1[C:5]([NH2:4])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ncccc1O
Reactant: Fc1cccc(F)c1CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ncccc1OCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
At RT, 51 g of sodium methoxide (953 mmol, 1.05 equivalents) were initially charged in 1000 ml of methanol, 100 g of 2-amino-3-hydroxypyridine (908 mmol, 1 equivalent) were added and the mixture was stirred at RT for 15 min. The reaction mixture was concentrated under reduced pressure, the residue was taken up in 2500 ml of DMSO and 197 g of 2,6-difluorobenzyl bromide (953 mmol, 1.05 equivalents) were added. After 4 h at RT, the reaction mixture was poured into 20 l of water and stirred for 15 min, and the solid was filtered off. The solid was washed with 1 l of water, 100 ml of isopropanol and 500 ml of petroleum ether and dried under high vacuum. This gave 171 g of the title compound (78% of theory).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:38])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:37])[C@H:13]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[NH:14][C:15](OC(C)(C)C)=[O:16])[CH:2]([CH3:4])[CH3:3].Cl.C(N1CCOCC1)C.[C:48]12([CH2:58]C(Cl)=O)[CH2:57][CH:52]3[CH2:53][CH:54]([CH2:56][CH:50]([CH2:51]3)[CH2:49]1)[CH2:55]2>C(OCC)(=O)C>[CH2:1]([NH:5][C:6](=[O:38])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:37])[C@H:13]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[NH:14][C:15](=[O:16])[CH2:58][C:48]12[CH2:57][CH:52]3[CH2:51][CH:50]([CH2:56][CH:54]([CH2:53]3)[CH2:55]1)[CH2:49]2)[CH:2]([CH3:3])[CH3:4]
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)CNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
2.72 g (0.005 mol) of Nα -tert.butoxycarbonyl-Nε -benzyloxycarbonyl-L-lysyl-L-proline isobutylamide were treated with 15 ml of 2.5M hydrogen chloride in ethyl acetate at room temperature for 0.75 hour. The solvent was removed by evaporation and the solid was washed with diethyl ether. The solid was taken up in 15 ml of dimethylformamide and the solution was cooled to 0° C. 1.27 ml (0.01 mol) of N-ethylmorpholine and 1.3 g (0.006 mol) of 1-adamantaneacetyl chloride were added and the mixture was stirred at room temperature for 3 hours. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate/water. The organic solution was washed with 5% citric acid solution, water, 5% sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated. Chromatography on 60 g of silica gel using ethyl acetate for the elution yielded 0.9 g (29%) of Nα -(1-adamantaneacetyl)-Nε -benzyloxycarbonyl-L-lysyl-L-proline isobutylamide as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH3:14]>C(O)C>[NH2:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: N
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: Nc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 25 g 2-Chloro-3,5-dinitropyridine in 190 ml ethanol were added dropwise 75 ml concentrated ammonia at room temperature. After stirring for 1 hour (hr), the mixture was cooled in an ice bath. The product was isolated by filtration and washed with cold water.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4]([CH:5]=[C:6](Br)Br)[C@H:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([Li])CCC.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].P(O)(O)([O-])=O.[Na+]>O1CCCC1.C1CCCCC1>[CH3:1][C:2]1([CH3:16])[C@@H:4]([C:5]#[C:6][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C=C(Br)Br)C1(C)C
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)Oc2ccccc2)C1(C)C
Temperature: -65 °C

Procedure:
A solution of 25 g of 1,1-dimethylethyl(1R,cis)2,2-dimethyl-3-(2',2'-dibromovinyl)-cyclopropane-carboxylate in 250 ml of tetrahydrofuran was admixed with 48 ml of a 20% solution of butyllithium in cyclohexane with stirring at -65° C. and the mixture was stirred for one hour at -65° C. 9.6 ml of phenyl chloroformate were added to mixture which was then stirred at -65° C. for one hour. The temperature was allowed to return to room temperature while the stirring was maintained and the mixture was poured into a saturated aqueous solution of monosodium phosphate. The mixture was extracted with ether and the ether phase was washed with water and dried. The 24.6 g of oil residue was chromatographed over silica gel and was eluted with a 9-1 cyclohexane-ethyl acetate mixture to obtain 14.4 g of 1,1-dimethylethyl(1R,cis)2,2-dimethyl-3-[3-oxo-3-phenoxy-1-propynyl]-cyclopropane-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([NH:37][C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=1[F:45])=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH:20]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[C:21]([O:23]C)=[O:22])=[O:18])[CH:13]=2)[CH:7]=1.[OH-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([NH:37][C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=1[F:45])=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH:20]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:21]([OH:23])=[O:22])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: COC(=O)CCC(NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NC(CCC(=O)O)C(=O)O)c[nH]4)c3)cc2F)c1
Temperature: 60 °C

Procedure:
To a stirred solution of dimethyl 2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate (75 mg, 0.12 mmol) in 10 ml of MeOH was added 2 ml of 1M NaOH. The mixture was heated at 60° C. for one hour, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioic acid as off-white solid. Yield: 72 mg, 100%.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[NH:7][CH:8]=1)([CH3:3])[CH3:2].[I:20]I.[OH-].[Na+]>C(Cl)Cl.CO.O>[I:20][C:8]1[NH:7][C:6]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[N:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: COc1ccc(COCc2nc(C(C)C)c[nH]2)cc1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COCc2nc(C(C)C)c(I)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
In methylene chloride (60 ml)-methanol (660 ml) was dissolved 165 g (0.67 mol) of 4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (3d), followed by addition of 170 g of solid iodine. Then, an aqueous solution prepared by dissolving 27.3 g (0.67 mol) of sodium hydroxide in 85 ml of water was added dropwise under ice-cooling. After completion of dropwise addition, the reaction mixture was stirred at room temperature for 1.5 hours. This reaction mixture was extracted with methylene chloride and the organic layer was washed with an aqueous solution of sodium sulfite and dried over anhydrous magnisium sulfate. The solvent was then distilled off under reduced pressure arid the residue was rinsed with isopropyl ether and collected by filtration to provide 209.5 g (yield 81%) of 5-iodo-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (4d). mp 78-79° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:13](N)=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:15]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.[ClH:34].N([O-])=O.[Na+]>CC#N.O.Cl[Cu]>[CH3:1][O:2][C:3](=[O:33])[CH:4]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:13]([Cl:34])=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:15]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCC1)c1cc(OCC(F)(F)F)c(N)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(CC1CCC1)c1cc(OCC(F)(F)F)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 2.5 °C
Reaction time: 0.67 h
Yield: 95 %

Procedure:
To a solution of 2-[6-amino-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid methyl ester (14.7 g, 27.7 mmol) in a mixture of MeCN and H2O (120 mL/120 mL), concentrated HCl (25 mL) was added. The reaction mixture was cooled down to 0-5° C. and a solution of NaNO2 (2.9 g, 42.0 mmol) in water (3 mL) was added dropwise. The reaction mixture was stirred at 0-5° C. for 40 min and CuCl (I) (27 g, 272.7 mmol) was added at once. The reaction mixture was heated at 50° C. for additional 3 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water (200 mL) and brine (100 mL). The organic phase was dried over MgSO4 and evaporated to give the product (14.5 g, 95%) as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.70 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 6.98 (dd, J=6.1, 1.6 Hz, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.68 (s, 3H), 3.48 (t, J=7.7 Hz, 1H), 2.20-2.10 (m, 2H), 2.03-1.75 (m, 5H), 1.70-1.52 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.6, 153.5, 142.2, 141.0, 138.9, 129.7, 125.0 (q, 3JCF=3.6 Hz), 124.8, 124.0 (q, 1JCF=271.6 Hz), 126.6 (q, 1JCF=278.8 Hz), 121.4, 114.0, 67.3 (q, 1JCF=35.4 Hz), 52.2, 49.3, 40.8, 34.0, 28.3, 28.0, 18.5.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]=1)=[O:7].C=O.[C:29](O)(=O)C.C([BH3-])#N.[Na+]>CO>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([CH3:29])[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH:10]=1)=[O:7]
Reactant: CN1CCC(Nc2cccc(NC(=O)c3ccccc3Cl)c2)CC1
Reactant: CC(=O)O
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CN1CCC(N(C)c2cccc(NC(=O)c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 133.5 %

Procedure:
Combine 2-chloro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide dihydrochloride (Example 9, 100 mg, 0.240 mmol), methanol (3 mL) and formaldehyde (37% aq., 0.195 mL, 2.39 mmol). Stir at room temperature for 45 min. Cool to 0° C. Add acetic acid (0.412 mL, 7.20 mmol) and sodium cyanoborohydride (26 mg, 0.420 mmol). Stir at room temperature overnight. Concentrate to dryness. Dissolve the residue in a 2/1 mixture of ethyl acetate and hexanes (8 mL) and wash with sodium hydroxide (1N aq., 2×6 mL). Separate the organic layer and dry over magnesium sulfate. Filter and concentrate under reduced pressure. Purify through flash chromatography eluting with a 20/1 mixture of dichloromethane and 2M ammonia in methanol to provide the free base of the title compound (69 mg, 80%). Following a salt formation method similar to Example 1 gives the title compound as a white solid (83 mg, white solid): mass spectrum (free base, ion spray): m/z=358.2 (M+1), 1H NMR (free base, CDCl3): 7.97 (bs, N—H), 7.66 (dd, J=1.7 Hz, 7.5 Hz, 1H), 7.42–7.27 (m, 4H), 7.17 (t, J=8.2 Hz, 1H), 6.82 (dd, J=1.5 Hz, 8.2 Hz, 1H), 6.57 (dd, J=2.3 Hz, 8.4 Hz, 1H), 3.59 (tt, J=3.9 Hz, 11.7 Hz, 1H), 2.90 (bd, J=11.7 Hz, 2H), 2.78 (s, 3H), 2.26 (s, 3H), 2.05 (td, J=2.3 Hz, 12.0 Hz, 2H), 1.82 (qd, J=3.9 Hz, 12.0 Hz, 2H), 1.70 (bd, J=12.0 Hz, 2H). Analysis calc'd for C20H26Cl3N3O.0.25H2O: C, 55.18; H, 6.14; N, 9.65. Found: C, 55.03; H, 6.11; N, 9.26.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:12](=[CH2:15])[C:13]#[N:14]>O>[CH2:1]([N:8]1[CH:15]=[C:12]([C:13]#[N:14])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C=C(Cl)C#N
Solvent: O
Product: N#Cc1cn(Cc2ccccc2)nn1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
A mixture of benzyl azide (1.33 g) and 2-chloroacrylonitrile (1.75 g) in water (5 ml) is stirred at about 80° C. for 22 hours, then excess 2-chloroacrylonitrile is distilled off in vacuo. The mixture is cooled to room temperature and the precipitated product is isolated by filtration and washed with water. After drying, the product is obtained in a yield of 1.66 g=90% of theory m.p. 78-79° C. (recrystallization from toluene/hexane).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(C)C)(OC(C)C)O[CH:9]([CH3:11])[CH3:10].C(O)(C)C>O.S([O-])(O)(=O)=O.[Na+]>[CH:9]([O:6][C:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1)([CH3:11])[CH3:10]
Reactant: CC(C)OC(OC(C)C)OC(C)C
Reactant: O=C1CCCC1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)OC1=CCCC1
Temperature: 25 °C
Yield: 51 %

Procedure:
A mixture of 84.12 grams (1 mol) of cyclopentanone, 195.2 grams (1.03 mol) of triisopropyl orthoformate and 60 grams of isopropanol (1 mol) was stirred in a 500 ml three-neck round bottom flask at room temperature. To this mixture, 3.8 g (0.028 mol) of sodium hydrogensulfate monohydrate was added, and the temperature of the reaction mixture was heated and maintained at 40° C. for about one hour. The progress of the reaction was monitored by GC until the cyclopentanone content was reduced to less than 2%. The isopropanol and isopropyl formate were distilled off under reduced pressure while the temperature of the reaction mixture was increased to a maximum of 65° C. The reaction mixture was cooled to room temperature and the pH value was adjusted to about 7˜8 by adding about 0.2 gram of potassium iso-propoxide. The mixture was then heated under reduced pressure to remove unreacted cyclopentanone and 64 grams (0.51 mol) of 1-isopropoxy-1-cyclopentene was isolated as a clear liquid at a yield of 51%. The purity of the product exceeded 98%.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[Cl:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:13]1[CH:23]=[CH:22][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=2[CH:14]=1)=[O:12].O>O1CCCC1>[Cl:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:13]1[CH:23]=[CH:22][C:16]2[CH2:17][CH2:18][N:19]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH2:20][CH2:21][C:15]=2[CH:14]=1)=[O:12]
Reactant: O=C(CCCCCl)c1ccc2c(c1)CCNCC2
Reactant: CCN=C=O
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)N1CCc2ccc(C(=O)CCCCCl)cc2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl isocyanate (781 μl) was added to a solution of 5-chloro-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone (2.3 g) obtained in Reference Example 121 in tetrahydrofuran (30 ml). After stirring at room temperature for 60 minutes, water (50 g) was added, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a colorless solid (2.2 g).
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:11][O:12][C:13](=[O:28])[C:14]1[CH:26]=[C:25](I)[CH:24]=[C:16]([C:17]([N:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[O:18])[CH:15]=1>C1COCC1.C(OCC)C.[Cl-].[Zn+2].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][O:12][C:13](=[O:28])[C:14]1[CH:26]=[C:25]([C:7]2[O:6][CH:10]=[CH:9][N:8]=2)[CH:24]=[C:16]([C:17]([N:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[O:18])[CH:15]=1
Reactant: CCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: c1cocn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
Add n-butyllithium (1.6 M in hexanes, 1.25 mL, 2.01 mmol) dropwise to a solution of oxazole (126 mg, 1.83 mmol) in THF (12.6 mL) at −78° C. Stir for 30 min at −78° C. and add a solution of zinc chloride (747 mg, 5.49 mmol) in diethyl ether (5.5 mL) and stir at 0° C. for 1 h. Add a solution of 5-iodo-N-methyl-N-propyl-isophthalamic acid methyl ester (330 mg, 0.91 mmol) in THF (5.1 mL) followed by tetrakis(triphenylphosphine)palladium (0) (105 mg, 0.091 mmol) and heat to reflux for 30 min. Add ethyl acetate (40 mL), wash with water (2×20 mL), dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexane) to give the title compound (225 mg, 82%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([C@H:19]([N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([C:27]3[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=3)[CH2:22]2)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:36]([CH2:38][NH2:39])[OH:37]>ClCCl>[OH:37][CH2:36][CH2:38][NH:39][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([C@@H:23]2[O:24][CH2:25][CH2:26][N:21]([C@@H:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH3:20])[CH2:22]2)=[CH:28][CH:29]=1
Reactant: NCCO
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C(=O)O)cc2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C(=O)NCCO)cc2)C1
Reaction time: 2 h
Yield: 73.5 %

Procedure:
1,1′-Carbonyldiimidazole (540 mg, 3.30 mmol) was added to a solution of 4-[(2S)-4-((1R)-1-phenyl-ethy)-morpholin-2-yl]-benzoic acid (944 mg, 3.03 mmol) in dichloromethane at 0° C. After stirring for 2 hours, ethanolamine (0.36 ml, 6.0 mmol) was added to the reaction mixture and the mixture was stirred over night. The resulting suspension was concentrated in vacuo and the residue was purified by silica gel chromatography (ethyl acetate-hexane) to afford N-(2-hydroxy-ethyl)-4-[(2S)-4-((1R)-1-phenyl-ethy)-morpholin-2-yl]-benzamide (789 mg, 73%.) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]=[O:10])[CH:2]=1.[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:11][C:12]([F:14])([F:13])[CH:9]([OH:10])[CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=CCCc1cccnc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(CCc1cccnc1)C(F)(F)F
Yield: 31.1 %

Procedure:
According to Reference Example 8-12, by use of 3-(pyridin-3-yl)propanal (180 mg, 1.3 mmol) obtained in Step 1 of Reference Example 8-64, (trifluoromethyl)trimethylsilane (0.24 mL, 1.6 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 0.27 mL, 0.27 mmol) and tetrahydrofuran (3.6 mL), the mixture was stirred and reacted at room temperature for 30 minutes. Then, purification by silica gel column chromatography (chloroform/methanol=1/0 to 10/1) was performed to give 1,1,1-trifluoro-4-(pyridin-3-yl)butan-2-ol (Compound EL) (83 mg, yield: 31%).