Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[C:11]=3[N:10]=[C:9]2[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[NH4+:43].[NH4+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]([NH2:43])=[NH:22])[C:11]=3[N:10]=[C:9]2[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cnccn5)cc4)nc32)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: N=C(N)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cnccn5)cc4)nc32)c1

Procedure:
At 0° C., 3-[5-(4-chloro-phenyl)-4-oxo-6-(4-pyrazin-2-yl-phenyl)-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile (prepared as described in example 47, 0.65 g, 1.29 mmol) is added to methanol saturated with hydrogen chloride gas (20 mL) with stirring. The reaction mixture is allowed to reach rt and stirred there for 40 h. The reaction mixture is then concentrated to a dry residue (0.7 g). It is taken in dry methanol (40 mL) and ammonium carbonate (1.15 g, 7.36 mmol) is added. After stirring at rt for 40 h, the reaction mixture is concentrated and the residue obtained is purified by column chromatography to afford 3-[5-(4-chloro-phenyl)-4-oxo-6-(4-pyrazin-2-yl-phenyl)-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzamidine. 1H NMR (DMSO-d6, 400 MHz) δ 9.25 (s, 1H), 8.71 (s, 1H), 8.63 (m, 1H), 8.55 (m, 2H), 8.29 (dd, 1H), 8.16 (s, 1H), 8.07 (m, 1H), 7.90 (m, 1H), 7.67 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.44 (m, 4H); LC-MS calculated for C28H19ClN8O (M+H+) 519.1, found 519.9.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][NH:19]3)=[O:15])[CH:9]=2)=[CH:6][N:7]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH2:1][C:2]1[C:3]([C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:15])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)NCC3CCCN3)c2)cnc1N
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC(=O)c1nc(-c2cccc(C(=O)NCC3CCCN3Cc3ccccc3)c2)cnc1N
Reaction time: 1 h
Yield: 225 %

Procedure:
To a stirred solution of 3-amino-N-methyl-6-(3-{[(pyrrolidin-2-ylmethyl)amino]carbonyl}phenyl)pyrazine-2-carboxamide (35.4 mg, 0.01 mmol) and benzaldehyde (24.8 mg, 0.02 mmol) in methanol (3 mL) was added sodium cyanoborohydride (25 mg, 0.04 mmol). The mixture was stirred for 1 h and then acetic acid added until the pH of the solution was 7.0. The solution was stirred for an additional 6 h, solvent was removed and residue was partitioned with CHCl3 and 2 M aqueous sodium hydroxide (5 mL). The aqueous phase was extracted with additional CHCl3 (2×5 mL) and the combined organic layer were washed with saturated aqueous sodium chloride then dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography provided 10 mg of 3-amino-N-methyl-6-{3-[({[1-(phenylmethyl)pyrrolidin-2-yl]methyl}amino)carbonyl]phenyl}pyrazine-2-carboxamide: 1H NMR (400 MHz; CDCl3); 8.7 (s, 1H); 8.65 (s, 1H); 8.28 (br s, 1H); 7.95 (d, 1H); 7.22 (d, 1H); 7.53 (t, 1H); 7.2-7.4 (m, 5H); 4.3-3.5 (m, 7H); 2.95 (d, 3H); 2.35-1.8 (m, 4H); MS (EI) for C25H28N6O2: 445 )
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([F:19])=[C:8]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[CH:9]=1.[CH3:20]I>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([F:19])=[C:8]([C:10]2[N:11]([CH3:20])[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:9]=1
Reactant: Fc1ccc(Br)cc1-c1nc2ccccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2cc(Br)ccc2F)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
NaH 60% suspension in mineral oil (0.61 g, 25.5 mmol) was added to a solution of 2-(5-Bromo-2-fluoro-phenyl)-1H-benzoimidazole (3.70 g, 12.76 mmol) in dry THF (100 mL) and the reaction was stirred at room temperature 30 minutes before adding methyl iodide (1.19 mL, 19.1 mmol). Reaction was left stirring for 2 h, then quenched with water (20 mL) The solution was concentrated, then AcOEt (30 mL) was added. The organic solution was separated, washed with brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure to afford 3.80 g of desired compound. (97%).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[CH:7]1[C:12]([CH:13]=O)=[CH:11][C:10]2[O:15][CH2:16][O:17][C:9]=2[CH:8]=1>>[CH:4]1([C:2]([CH:1]=[CH:13][C:12]2[CH:7]=[CH:8][C:9]3[O:17][CH2:16][O:15][C:10]=3[CH:11]=2)=[O:3])[CH2:6][CH2:5]1
Reactant: CC(=O)C1CC1
Reactant: O=Cc1ccc2c(c1)OCO2
Product: O=C(C=Cc1ccc2c(c1)OCO2)C1CC1

Procedure:
2-(3,4-Methylenedioxyphenyl)vinyl cyclopropyl ketone [III; Ar is 3,4-methylenedioxyphenyl, R is H] was prepared from 8.4 g. of cyclopropyl methyl ketone and 15 g. of piperonal according to the procedure described above in Preparation A1 affording 21.5 g., m.p. 85°-87° C. when recrystallized from ethanol.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].C(N(CC)CC)C.[NH2:12][C:13]1[CH:18]=[C:17]([C:19]([Cl:22])([Cl:21])[Cl:20])[CH:16]=[CH:15][N:14]=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([Cl:21])([Cl:20])[Cl:22])[CH:16]=[CH:15][N:14]=1)=[O:4]
Reactant: Nc1cc(C(Cl)(Cl)Cl)ccn1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1cc(C(Cl)(Cl)Cl)ccn1
Reaction time: 4 h
Yield: 81.2 %

Procedure:
17 ml (0.3 mol) of methyl isocyanate and 1 ml of triethylamine were added to 21.2 g (0.1 mol) of 2-amino-4-trichloromethylpyridine and 400 ml of toluene at 25° C. After 4 hours at 80° C., the resulting solid was isolated. 21.8 g (82%) of the desired product were obtained. Mp.: 192°-195° C.; Active Ingredient Example 2.001
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([C:24](=[O:26])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1.[CH3:27][Mg]Br.CCOCC>O1CCCC1>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([C:24]([OH:26])([CH3:27])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C(C)(C)O)c3)ccc2o1
Reaction time: 8 h

Procedure:
The product from Example 136C (87 mg, 0.25 mmol) was dissolved into tetrahydrofuran (5 mL), treated with 3 M methylmagnesium bromide in ether (0.3 mL, 0.9 mmol), stirred overnight, quenched with 0.5 M aqueous dipotassium hydrogen phosphate, and diluted with EtOAc and a little CH2Cl2. The resulting emulsion was sonicated, and the aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, dried (Na2SO4), concentrated, and chromatographed on silica with a gradient of 2 to 10% MeOH/20% MeCN/CH2Cl2 followed by 10% MeOH/CH2Cl2 to provide the title compound as an orange resin (˜33% yield). 1HNMR (300 MHz, CD3OD) δ 1.20 (d, 3H), 1.42-1.58 (m, 1H), 1.58 (s, 6H), 1.76-1.90 (m, 2H), 1.96-2.12 (m, 1H), 2.3-2.7 (m, 3H), 2.97-3.13 (m, 2H), 3.22-3.4 (m, 2H), 6.62 (s, 1H), 7.38 (dd, 1H), 7.40-7.46 (m, 2H), 7.46-7.48 (m, 2H), 7.72 (dd, 1H), 7.76 (dd, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[O:8]1[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9]1.O>CN(C)C=O>[OH:8][CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCCCCC1CO1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC(O)Cn1ccnc1
Yield: 75 %

Procedure:
Imidazole (40.8 g) in 100 ml of dimethyformamide at room temperature was treated with sodium hydride (4.8 g of 50% dispersion in mineral oil). Once a solution was obtained, 1,2-epoxyoctane (40 g) was added dropwise at room temperature and the resulting mixture placed in an oil bath and warmed to 70° for 6 hours with stirring. The resulting cooled solution was then added to 600 ml of water and extracted with ether (4×400 ml). The combined extracts were washed twice with concentrated aqueous potassium hydroxide, dried (MgSO4) and concentrated. The resulting ethereal solution was stored at 0° and the resulting precipitate filtered to give 45.93 g of 1-(2-hydroxyoctyl)imidazole, m.p. 44°-45.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][CH2:43][NH2:44])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:45][C:46]([CH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)([CH3:50])[C:47](O)=[O:48]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@H:11]([CH2:42][CH2:43][NH:44][C:47](=[O:48])[C:46]([CH:51]3[CH2:52][CH2:53][O:54][CH2:55][CH2:56]3)([CH3:50])[CH3:45])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C(=O)O)C1CCOCC1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CCN)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CCNC(=O)C(C)(C)C4CCOCC4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 100 mg of 2-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-ethylamine (from example 44b) are reacted with 2-methyl-2-(tetrahydro-pyran-4-yl)-propionic acid [16386-97-3] to afford the title compound as a yellow oil. Rf=0.40 (dichlormethane-methanol-25% ammonia conc. 200:20:1); Rt=3.87.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]2[CH:9](O)[CH:8]([CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14].B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14]
Reactant: CCC1Sc2c(cc(OC)c(Cl)c2Cl)C1O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCc1cc2cc(OC)c(Cl)c(Cl)c2s1
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of 2.7 g of 6,7-dichloro-2-ethyl-2,3-dihydro-3-hydroxy-5-methoxy-benzo[b]thiophene in 10 ml of glacial acetic acid containing 3 ml of boron trifluoride etherate is warmed on a steam bath until a clear solution is formed. The mixture is allowed to stand at room temperature for 1 hour and poured into a chilled solution of dilute sodium hydroxide. Extraction with ether, followed by drying over anhydrous magnesium hydroxide and concentrating in vacuo, gives 2.4 g 6,7-dichloro-2-ethyl-5-methoxybenzo[b]thiophene as yellow needles, mp 73°-74.5°.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11](=[O:13])[CH:12]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].BrC[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]([C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)[N:38]=[N:37][N:36]=2)=[CH:25][CH:24]=1.O>CN1C(=O)CCC1>[CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39]([C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=4)[N:38]=[N:37][N:36]=3)=[CH:27][CH:28]=2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2-c2ccc(CCBr)cc2)cc1
Reactant: CCc1cc(=O)c2c([nH]1)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnnn3-c3ccc([N+](=O)[O-])cc3)cc2)c2c(n1)CCCC2
Temperature: 60 °C
Yield: 60 %

Procedure:
A mixture of 2-ethyl-5,6,7,8-tetrahydro-4(1H)-quinolone (1.95 g), and potassium carbonate (2.28 g) in NMP (75 ml) was heated at 60° C. for 20 minutes with stirring. Compound E (5.2 g) was added and the reaction mixture was heated at 80° C. for 90 minutes. The mixture was allowed to cool to ambient temperature and water (150 ml) was added. The resultant precipitate was collected by filtration, dried at 60° C., then recrystallised from toluene to give 2-ethyl-4-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-5,6,7,8-tetrahydroquinoline, as a solid in 60% yield; m.p. 205°-207° C.; NMR (CDCl3):1.30(3H,t), 1.90(4H,m), 2.60-3.00(6H,m), 5.04(2H,m), 6.52(2H,d), 6.60(1H,s), 6.80(2H,d), 7.11(2H,d), 7.40(1H,d), 7.67(2 H,d), 7.92(3H,m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=S.[NH:11]([C:13](=[O:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1)=[O:15])[NH2:12].N=C=N>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:29][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[O:15])=[N:11][N:12]=1
Reactant: Fc1ccccc1N=C=S
Reactant: NNC(=O)C(=O)Nc1ccc(N2CCOCC2)cc1
Agent: N=C=N
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1nnc(Nc2ccccc2F)o1
Temperature: 50 °C
Yield: 82.6 %

Procedure:
2-Fluorophenylisothiocyanate (92 μL, 0.75 mmol) was added to a stirred suspension of 2-hydrazino-N-(4-morpholin-4-ylphenyl)-2-oxoacetamide (Intermediate 16, 160 mg, 0.6 mmol) in DMF (10 mL) and stirred at 50° C. until a clear solution was obtained. PS-Carbodiimide (909 mg, 1.2 mmol) was added and the reaction was heated at 80° C. for a further 4 h. The reaction was filtered and the resin washed with DMF (5 mL). The combined DMF solutions were concentrated in vacuo and the residue triturated with diethyl ether to give the title compound as a yellow powder (190 mg, 82%):
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:9]([F:19])[CH:8]=1)=[O:5])[CH3:2].[C:22]([O:26][C:27](N1CCN(C2C=CC(N)=CC=2F)CC1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(CC)CC>C(Cl)Cl>[C:22]([O:26][C:27]([N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[CH:3]([CH2:1][CH3:2])[CH2:20][CH3:21])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2F)CC1
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCNCC2)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Reaction time: 18 h

Procedure:
2-Ethyl-N-(3-fluoro-4-piperazin-1-yl-phenyl)-butyramide. To a solution of 4-(4-amino-2-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 8.9 mmol) and Et3N (1.4 mL, 10.0 mmol) in DCM (60 mL) was added 1-ethylbutyryl chloride (1.4 mL, 10.0 mol). The mixture was stirred for 18 h, quenched with 1 N NaHCO3 (50 mL), and extracted with DCM (3×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the residue (SiO2; EtOAc/hexanes) gave 4-[4-(2-ethyl-butyrylamino)-2-fluoro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester. A mixture of this intermediate in MeOH (25 mL) and 2 N HCl in Et2O (10 mL) was stirred for 18 h. The solution was concentrated to give 2-ethyl-N-(3-fluoro-4-piperazin-1-yl-phenyl)-butyramide hydrochloride. This salt was treated with 1 N NaOH (10 mL) and extracted with EtOAc (40 mL). The organic layer was dried and concentrated to give the title compound as the free base (1.5 g, 58%). MS (ESI): mass calcd. for C16H24FN3O, 293.19. m/z found, 294.4 [M+H]+. 1H NMR (CDCl3): 7.25-7.23 (m, 1H), 7.17 (s, 1H), 6.58-6.55 (m, 1H), 3.08-3.00 (m, 8H), 2.02-1.99 (m, 1H), 1.80-1.50 (m, 4H), 1.00-0.95 (m, 6H).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:34])[C@@H:14]([NH:16][C:17](=[O:33])[C@@H:18]([NH:20][C:21](=[O:32])[C@@H:22]([NH:24]C(=O)OC(C)(C)C)[CH3:23])[CH3:19])[CH3:15])=[N:5][CH:4]=1)=[O:2].CCOCC>O1CCOCC1.Cl>[NH2:24][C@@H:22]([CH3:23])[C:21]([NH:20][C@@H:18]([CH3:19])[C:17]([NH:16][C@@H:14]([CH3:15])[C:13]([NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)=[O:34])=[O:33])=[O:32]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)NCCCNc1ncc(C=O)s1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)NCCCNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of material from Example 73 (213 mg, 0.427 mmol) in Dioxane (10 mL), is added HCl, 4.0M in dioxane (92 mL, 368 mmol) and HCl, 1.0M in Et2O (10.4 mL, 10.4 mmol). The resulting suspension is stirred at room temp 4 h and then the solvent is evaporated off under a gentle stream of N2. The resulting residue is suspended in CH2Cl2 (60 mL) and the solvent is removed in vacuo (repeat 4 times) to give the title compound (quantitative yield) as an off white solid, as an HCl salt. LC/MS (Condition A): ret. T=1.35 min, (M+H)+ 399.20.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20]C(=O)CC)(=[O:19])[CH2:17][CH3:18]>>[CH3:18]/[C:17](=[CH:12]\[C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)/[C:16]([OH:20])=[O:19]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: CCC(=O)OC(=O)CC
Product: C/C(=C\c1ccc(Oc2ccccc2)cc1)C(=O)O
Yield: 68 %

Procedure:
The procedure is performed in an analogous manner to that described in Example 17 (step A), starting from 4-phenoxybenzaldehyde and using 5 equivalents of propionic anhydride. Yield: 68% IR (nujol): 1665 cm-1 m.p. 133° C. 1H NMR (CDCl3 /TMS): 11.95 (broad s, 1H); 7.80 (s, 1H); 7.60 to 6.85 (m, 9H); 2.15 (s, 3H).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([O:13][C@@H:14]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH3:15])[C@@H:9]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C@@H:8]1[CH2:37]OS(C)(=O)=O)(=O)=O.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(O)C>[CH2:43]([N:50]1[CH2:37][C@@H:8]2[C@H:7]([CH2:12][CH2:11][C@H:10]([O:13][C@@H:14]([C:16]3[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([C:26]([F:28])([F:27])[F:29])[CH:17]=3)[CH3:15])[C@H:9]2[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:6]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C[C@@H](O[C@H]1CC[C@H](COS(C)(=O)=O)[C@@H](COS(C)(=O)=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCc1ccccc1
Solvent: CCO
Product: C[C@@H](O[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C

Procedure:
In a pressure tube was placed a solution of crude [(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-diyl]di(methylene) dimethanesulfonate (step H) in 20 mL ethanol and 1.2 mL (˜3 equiv.) benzylamine. The pressure tube was seated and heated at 150° C. in an oil bath for 3 hr. The tube was cooled to RT and opened. The resulting mixture was transferred to a round bottom flask and the solvent removed under vacuum. The residue was diluted with 100 mL EtOAc, washed with 20 mL 5N aq. NaOH, dried over MgSO4 drying agent, filtered and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with EtOAc to give 1.6 g of the title compound. 1H-NMR (CDCl3): δ: 7.35–7.20 (5H, m), 7.50 (2H, s), 6.97 (2H, m), 6.85 (2H, t, J=8.2 Hz), 4.42 (1H, t, J=6.0 Hz), 3.75 (2H, d, J=13.4 Hz), 3.50 (2H, d, J=13.4 Hz), 3.30 (1H, m), 2.96 (1H, m), 2.52 (3H, m), 2.19 (2H, m), 1.98 (1H, m), 1.97 (1H, m), 1.86 (2H, m), 1.57 (1H, m), 1.33 (3H, t, J=6.0 Hz), 1.30(1H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:20]=[CH:19][C:18]=2[CH2:17]1)=[O:5])[CH3:2].[C:33]([O:37][C:38]([NH:40][C:41]([CH3:54])([CH3:53])[CH2:42][O:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([NH:40][C:41]([CH3:54])([CH3:53])[CH2:42][O:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([CH2:2][CH2:1][O:3][C:4]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[C@@H:16]2[CH2:25][CH2:24][C:23]3[CH:22]=[C:21]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:20]=[CH:19][C:18]=3[CH2:17]2)=[O:5])=[O:49])=[CH:46][CH:45]=1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(COc1ccc(C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)CNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)OCCC(=O)c2ccc(OCC(C)(C)NC(=O)OC(C)(C)C)cc2)c1
Yield: 78.2 %

Procedure:
Synthesized from pivalic acid (R)-6-[2-(ethoxycarbonylmethylamino)-4-methoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-yl ester (1.2 g) and 4-(2-tert-butoxycarbonylamino-2-methylpropoxy)benzoic acid (1.27 g) according to an analogous synthetic method to Preparation Example 154, the title compound (1.56 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([C:15]#[N:16])[CH:9]=2)=[CH:6][C:5]([C:17]#[N:18])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:26][CH2:27]Br.O>CN(C)C=O>[CH:6]1[C:7]2[C:8]3[CH:9]=[C:10]([C:15]#[N:16])[CH:11]=[CH:12][C:13]=3[O:14][CH2:27][CH2:26][O:1][C:2]=2[CH:3]=[CH:4][C:5]=1[C:17]#[N:18]
Reactant: BrCCBr
Reactant: N#Cc1ccc(O)c(-c2cc(C#N)ccc2O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)-c1cc(C#N)ccc1OCCO2
Temperature: 150 °C
Yield: 29.8 %

Procedure:
A mixture of 6,6'-dihydroxy[1,1'biphenyl]-3,3'-dicarbonitrile (11.8 g), sodium carbonate (10.6 g), and 1,2-dibromoethane (8.4 g) in 250 ml of anhydrous dimethylformamide is heated at 150° C for 18 hours under nitrogen. The reaction mixture is poured into water and extracted with three 200 ml portions of dichloromethane. The dichloromethane extracts are combined and washed with 10% sodium hydroxide, water, and brine. The solution is filtered through 100 ml of silica gel and concentrated. The resultant solid is recrystallized from benzene to yield 3.5 g of the title compound, melting point 195-196° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][Cl:14])=[CH:7][CH:6]=1)=[O:4].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[Cl:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(O)cc1
Reactant: O=C(CBr)c1ccc(OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(OCC(=O)c2ccc(OCCCl)cc2)cc1
Reaction time: 16 h

Procedure:
A mixture of 27.7 g. (0.1 mol.) of α-bromo-p-(2-chloroethoxy)acetophenone, 12.4 g. (0.1 mol.) of p-methoxyphenol and 13.8 g. (0.1 mol.) of potassium carbonate in 75 ml. of dry acetone is refluxed with stirring for 16 hours. After cooling, the reaction mixture is poured into 500 ml. of water. The product is collected and dissolved in chloroform and the chloroform solution is washed with water, dried (MgSO4) and concentrated to give p-(2-chloroethoxy)-α-(p-methoxyphenoxy)acetophenone.