Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:25])[CH2:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])C.[C:26]1([NH:32][C:33]([NH:35][C:36]([NH2:38])=[NH:37])=[NH:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH2:7]([C:6]1[N:37]=[C:36]([NH:35][C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[NH:34])[NH:38][C:4](=[O:25])[CH:5]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: N=C(N)NC(=N)Nc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)CC(=O)OCC
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCc1cc(=O)[nH]c(NC(=N)Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
In a 50 milliliter round-bottom flask, 3-oxoeicosanoic acid ethyl ester (2.25 grams, 6.60 mmol, prepared as described in Part B of this Example) was added at room temperature to a solution of 1-phenylbiguanide (1.17 grams, 6.60 mmol, prepared as described in Part D of this Example) in anhydrous ethanol (20 milliliters). The mixture was heated at reflux and stirred for 16 hours. Cooling the resulting yellow solution to room temperature gave a colorless precipitate. The precipitate was isolated by filtration and thoroughly washed with water, then with cold ethanol (0° C.), and finally with pentane. The resulting powder was then recrystallized from anhydrous ethanol, recovered by filtration, and dried under reduced pressure to give the targeted N-(4-heptadecyl-6-oxo-1,6-dihydropyrimidin-2-yl)-N′-phenylguanidine as a colorless solid (1.79 grams, 58 percent yield): mp=164° C.; 1H NMR (DMSO-d6, 303 K) δ: 11.16 (s, 1H), 9.04 (s, 1H), 8.5-6.5 (br, 2H), 7.66 (d, 2H, 3J=7.9 Hz), 7.25 (m, 2H), 6.99 (t, 1H, 3J=7.4 Hz), 5.56 (s, 1H), 2.32 (t, 1H, 3J=7.5 Hz), 1.56 (m, 2H), 1.33-1.17 (m, 28H), 0.85 (t, 3H, 3J=6.8 Hz); Exact mass calculated for C28H45N5O=467.3624. Measured Low Resolution Mass Spectrum MAB/LR/N2)=468.2. Anal. Calcd for C28H45N5O: C, 71.91; H, 9.70; N, 14.97. Found: C, 72.02; H, 9.96; N, 14.92.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([OH:15])[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].S(OC)(O[CH3:22])(=O)=O>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([O:15][CH3:22])[CH:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2cc(O)ccc2c1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2cc(C(C)(C)C)ccc2c1
Yield: 88 %

Procedure:
To a 2 L round bottomed flask was added 6-t-butyl-2-naphthol (30.67 g; 0.153 mmol) and 550 ml of 15% KOH in water. The solution was stirred while adding dimethyl sulfate (6.0 equiv.) dropwise over 30 min. After the addition was complete, the mixture was allowed to stir for 2 hrs. The solids were collected on a filter and washed with water to afford 28.97 g (88% yield) of the subtitle compound.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:14]=[C:15]2[N:19]([CH:20]=1)[CH:18]=[CH:17][S:16]2)=[O:12].[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]3[N:19]([CH:20]=2)[CH:18]=[CH:17][S:16]3)=[O:12])=[O:28])[N:26]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: O=C(NC[C@H]1NC[C@@H]2CCC[C@@H]21)c1cn2ccsc2n1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2cn3ccsc3n2)c1

Procedure:
prepared by reaction of imidazo[2,1-b]thiazole-6-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].[H-].[Na+].[C:18]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[C:18]([N:26]1[CH2:31][CH2:30][C:29](=[C:6]([CH3:7])[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=C1CCN(C(=O)c2ccccc2)CC1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A solution of triethyl 2-phosphonopropionate (50.0 g) in dry tetrahydrofuran (75 ml) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil, 8.0 g) in dry tetrahydrofuran (275 ml) under nitrogen and stirred at 20° C. for 10 minutes until a clear solution was formed. 1-Benzoyl-4-piperidone (34.5 g) in dry tetrahydrofuran (75 ml) was added dropwise to the clear solution and the reaction mixture heated under reflux for 16 hours. After quenching the reaction mixture with 5M hydrochloric acid (20 ml), the resulting solid was removed by filtration. Excess ether was added to the filtrate, the aqueous layer separated off and the ethereal layer washed (water), dried, filtered and concentrated to give ethyl 2-(1-benzoyl-4-piperidylidene)propionate as an oil.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[Cl:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36]>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:33]=[CH:34][C:35]([Cl:36])=[C:30]([Cl:29])[CH:31]=2)[CH2:42][CH2:41]1)=[O:16]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2Cl)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 73.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylic acid (440 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (577 mg, 1.35 mmol, 73%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.B.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 3-(4-fluorophenyl)-propionic acid (4.20 g, 25 mmol) in tetrahydrofuran (10 mL) was stirred on an ice bath and treated with a solution of borane in tetrahydrofuran (1.0 M, 33 mL, 33 mmol) over 15 minutes. The resulting solution was stirred at room temperature for one hour. A mixture of tetrahydrofuran (5 mL) and water (5 mL) was added over 2 minutes. After 5 minutes of additional stirring, 4 mL of additional water was added, and solid potassium carbonate was added until the aqueous phase was saturated. The layers were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to provide a colorless liquid (3.70 g, 96%) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.16 (m, 2H), 6.99 (t, J=9 Hz, 2H), 3.69 (t, J=6 Hz, 2H), 2.70 (t, J=8 Hz, 2H), 1.87 (m, 2H), 1.50 (bs, 1H). Mass spec (CH4-CI) m/z 137.0 (M+H+-H2O).
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[N:24]O)[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:26]>[Ni].C(O)C.O1CCCC1>[F:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:16]([NH2:24])[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:26]
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2c(F)c(F)ccc2[nH]1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1c2ccccc2-c2c(-c3nc4c(F)c(F)ccc4[nH]3)cccc21
Yield: 26 %

Procedure:
The procedure used in Example 6 is followed, but starting from 4 g of 4-(4,5-difluoro-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, and 0.27 g of Raney nickel in 35 ml of ethanol and 35 ml of tetrahydrofuran for 10 hours at 60° C. under an initial hydrogen pressure of one bar. After filtration of the catalyst, and purification by forming a paste in diisopropyl ether, in this way we obtain 1 g of 4-(4,5-difluoro-1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-ylamine, in the form of a beige powder which is used as it is in the following stage.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[C:21]1([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][N:34]=2)[CH:30]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][N:34]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1ccnc(-c2ccccc2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccnc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 2-phenylisonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 402.99 g/mol.
Reaction SMILES: [CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([N:15]=[C:16]=[O:17])=O)=[CH:11][CH:10]=2)=[N:6][N:5]=1)([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][C:22]=1[NH:35][NH:36]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][C:22]=1[N:35]1[C:16](=[O:17])[NH:15][C:13]([C:12]2[CH:18]=[CH:19][C:9]([C:7]3[O:8][C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]=3)=[CH:10][CH:11]=2)=[N:36]1
Reactant: CC(C)c1nnc(-c2ccc(C(=O)N=C=O)cc2)o1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nnc(-c2ccc(-c3nn(-c4cc(CNC(=O)C(C)(C)C)ccc4Cl)c(=O)[nH]3)cc2)o1
Yield: 43.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 4-(5-isopropyl-1,3,4-oxadiazol-2-yl)benzoyl isocyanate (Intermediate-104, 0.196 g, 0.84 mmol), tert-butyl 2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-94, 0.150 g, 0.420 mmol), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.090 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.06 (s, 9H), 1.35 (s, 6H), 3.25 (m, 1H), 4.27 (d, J=5.4 Hz, 2H), 7.34 (d, J=8.1 Hz, 1H), 7.44 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 8.01-8.04 (m, 2H), 8.10-8.17 (m, 3H), 12.73 (s, 1H); MS (m/z): 495.39 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[N:24]([O-])=[O:25].[Na+].O>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([N:24]=[O:25])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: O=N[O-]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(N=O)CC3)cc21
Temperature: 25 °C
Yield: 100.5 %

Procedure:
3.2 g (10 millimole) of 1-ethyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was dissolved in 30 ml of acetic acid, and 1.4 g (20 millimole) of sodium nitrite was added slowly thereto at room temperature under stirring. After stirring for 30 minutes at room temperature, 50 ml of water was added. The precipitated crystals were collected by filtration, washed successively with water, ethanol and dichloromethane and dried. 3.5 g (quantitative) of 1-ethyl-6-fluoro-7-(4-nitroso-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained as grayish colorless powders.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1([CH2:5][CH:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[C:3]([OH:23])=[O:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCCCC2)C(=O)O)cc1
Temperature: 47.5 °C
Yield: 85.9 %

Procedure:
A solution of 3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester (95 mg, 0.28 mmol) in ethanol (2 mL) was treated with a 1N aqueous sodium hydroxide solution (1.5 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (10 mL) and extracted with diethyl ether (1×20 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×15 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid (78 mg, 86%) as a white solid: EI-HRMS m/e calcd for C17H24O4S (M+H)+325.1474, found 325.1478.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.[C:19]([Cu])#[N:20]>CN(C)C=O.O>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:19]#[N:20])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)[CH2:14][CH3:15]
Reactant: N#C[Cu]
Reactant: CCCN(CCC)c1nccc2ccc(Br)cc12
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCC)c1nccc2ccc(C#N)cc12
Temperature: 25 °C

Procedure:
A solution of 7-bromo-N,N-dipropylisoquinolin-1-amine (350 mg, 1.1 mmol) and CuCN (204 mg, 2.2 mmol) in N,N-dimethylformamide (2 mL) was stirred at reflux for 24 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×50 mL). The combined organics were washed with saturated sodium chloride, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to provide 1-(dipropylamino)isoquinoline-7-carbonitrile (279 mg, which was used without any further characterization.
Reaction SMILES: CC1NC(C2C=CC=CC=2)=N[C:3]=1[C:13]([C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:18][C:19]=1C)=O.[C:27]([O:31][CH3:32])(=[O:30])[NH:28][NH2:29]>>[CH3:32][O:31][C:27](=[O:30])[NH:28][N:29]=[C:13]([C:15]1[N:16]=[C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:18][CH:19]=1)[CH3:3]
Reactant: Cc1[nH]c(-c2ccccc2)nc1C(=O)c1nc(-c2ccccc2)[nH]c1C
Reactant: COC(=O)NN
Product: COC(=O)NN=C(C)c1c[nH]c(-c2ccccc2)n1
Yield: 91 %

Procedure:
By the method of Example 104, the title product is prepared from methyl-2-phenyl-4-imidazolyl ketone and methyl carbazate. The product is obtained in 91% yield, m.p. 226.5°-227° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:60]=[CH:59][C:6]([CH2:7][C:8]2[C:9]([Cl:58])=[C:10]([O:54][CH2:55][CH2:56]Cl)[C:11](Br)=[C:12]([CH:14]3[C@H:19]([O:20]CC4C=CC=CC=4)[C@@H:18]([O:28][CH2:29]C4C=CC=CC=4)[C@H:17]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@@H:16]([CH2:44][O:45][CH2:46]C4C=CC=CC=4)[O:15]3)[CH:13]=2)=[CH:5][CH:4]=1)[CH3:2].[CH2:61]([Li])[CH2:62][CH2:63][CH3:64]>C1COCC1>[CH2:61]([O:20][C@@H:19]1[C@@H:18]([O:28][CH2:29][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:17]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:16]([CH2:44][O:45][CH2:46][C:60]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:59]=2)[O:15][CH:14]1[C:12]1[C:11]2[CH2:56][CH2:55][O:54][C:10]=2[C:9]([Cl:58])=[C:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:60][CH:59]=2)[CH:13]=1)[C:62]1[CH:17]=[CH:16][CH:44]=[CH:64][CH:63]=1
Reactant: [Li]CCCC
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(OCCCl)c2Cl)cc1
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3)cc1
Reaction time: 18 h
Yield: 97.6 %

Procedure:
To a solution of compound 71 (1.16 g, 1.27 mmol) in THF (12.7 mL) was added dropwise n-butyllithium (2.5M in hexane, 1.27 mL, 3.17 mmol) at −78° C. under an atmosphere of nitrogen. The mixture was stirred for 18 hours at −78° C. to 5° C. The mixture was quenched with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 72 (493 mg, 48%) as brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH2:40]([O:39][C:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:34][CH:35]=1)=[O:38])[CH3:41]
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(N)cc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2OC)cc1
Yield: 37.5 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-methoxyphenyl)benzamide (185.0 mg, 0.39 mmol) and ethyl chloroformate (0.11 ml, 1.17 mmol), the procedure of Inventive Example 94 was repeated to obtain 80.0 mg (37.5%) of the title compound in a colorless oily form.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=3[CH:18]=[C:19]([CH3:29])[CH:20]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4ccc(F)cc4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C)cc(-c3ccc(F)cc3)c2O1

Procedure:
The title compound was prepared (0.028 g, 25%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(4-fluorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.36 mmol) and methylamine (0.112 g, 3.6 mmol). mp 206-208° C.
Reaction SMILES: F[CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[NH:34][N:33]=[N:32][N:31]=2)[CH:25]=1)[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=2[CH2:19][CH2:20][CH3:21])=[CH:5][CH:4]=1.[C:35](C1C=CC(OCC2C=CC(C(OC)C3C=C(C=CC=3)C#N)=CC=2)=C(CCC)C=1O)(=[O:37])C>>[OH:18][C:11]1[C:10]([CH2:19][CH2:20][CH3:21])=[C:9]([O:8][CH2:7][C:6]2[CH:22]=[CH:23][C:3]([CH:2]([O:37][CH3:35])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[NH:31][N:32]=[N:33][N:34]=4)[CH:25]=3)=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[C:15](=[O:17])[CH3:16]
Reactant: CCCc1c(OCc2ccc(C(F)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCc2ccc(C(OC)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2ccc(C(OC)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Yield: 47 %

Procedure:
The title compound is prepared essentially as described for 1-[4-(4-{fluoro-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone, employing 3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-methoxy-methyl}-benzonitrile to give (129 mg, 47%) of the title compound as a lavender foam. 1H NMR (DMSO-d6) δ 12.85 (s, 1H), 8.12 (s, 1H), 7.93 (m, 1H), 7.80 (d, 1H), 7.59 (d, 2H), 7.42-7.49 (m, 4H), 6.71 (d, 1H), 5.50 (s, 1H), 5.25 (s, 2H), 2.57-2.61 (m, 5H), 2.09 (s, 3H), 1.47-1.56 (m, 2H), 0.84-0.92 (m, 3H). LCMS M−1 471.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH:10]C(OC(C)(C)C)=O.[Cl:18][C:19]1[C:24]([C:25]([N:27]=[C:28]=[O:29])=O)=[C:23]([F:30])[C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:23]([F:30])[C:24]=1[C:25]1[NH:27][C:28](=[O:29])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Reactant: CC(C)(C)OC(=O)NNc1ccc(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(F)cc3F)c(=O)[nH]2)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(2,4-difluorophenyl)hydrazinecarboxylate (Intermediate-54, 0.060 g, 0.21 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.101 g, 0.32 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.018 g of pure product. 1H NMR (300 MHz, CDCl3): δ 1.16 (s, 9H), 4.38 (d, J=5.4 Hz, 2H), 6.25 (m, 1H), 6.79-6.82 (m, 1H), 6.90-6.96 (m, 2H), 7.20-7.32 (m, 2H), 7.50-7.53 (m, 1H); MS (m/z): 437.26 (M−H−).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[N:15])=[C:12]([SH:16])[N:11]=[C:10]([O:17][CH3:18])[C:9]=2[C:19]#[N:20])=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[O:26][CH:27]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:25]2[O:26][CH:27]=[C:23]([CH2:22][S:16][C:12]3[C:13]([C:14]#[N:15])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9]([C:19]#[N:20])=[C:10]([O:17][CH3:18])[N:11]=3)[N:24]=2)=[CH:33][CH:32]=1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Reactant: COc1nc(S)c(C#N)c(-c2ccc(O)cc2)c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(O)cc2)c1C#N

Procedure:
64 mg (0.224 mmol) of 4-(4-hydroxyphenyl)-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitrile together with 88 mg (0.269 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole and 57 mg (0.672 mmol) of sodium bicarbonate are stirred in 2 ml of DMF at room temperature overnight. The reaction mixture is purified by preparative HPLC (acetonitrile/water: 10:90→95:5, with 0.1% TFA added). This gives 44 mg (41% of theory) of the target compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C([N:14]1[CH2:20][CH2:19][C:18]([CH:21]=[O:22])=[C:17]([Cl:23])[CH2:16][CH2:15]1)C1C=CC=CC=1>C(Cl)Cl>[CH2:5]([O:4][C:2]([N:14]1[CH2:20][CH2:19][C:18]([CH:21]=[O:22])=[C:17]([Cl:23])[CH2:16][CH2:15]1)=[O:3])[CH3:6]
Reactant: O=CC1=C(Cl)CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCC(Cl)=C(C=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.6 gm (0.033 mol) of ethyl chloroformate in 15 ml of dry methylene chloride was added dropwise at room temperature, while stirring, within 30 minutes to a solution of 7.5 gm (0.03 mol) of 1-benzyl-4-chloro-5-formyl-2,3,6,7-tetrahydro-1H-azepine in 50 ml of dry methylene chloride, whereupon the temperature of the reaction mixture increased from 22° C. to 27° C. After the addition was complete, the mixture was stirred at room temperature for another 3 hours. Then, the methylene chloride was distilled off in a rotary evaporator, and the residue was distilled in a high vacuum.