Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)=[C:14]([C:16]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[O:17])[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.CO.[Ni]>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:13]2[NH:12][C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)=[N:15][C:14]=2[C:16]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[O:17])=[CH:29][CH:28]=1
Reactant: CC(C)(C)c1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc([N+](=O)[O-])cc3)[nH]2)cc1
Agent: [Ni]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(N)cc3)[nH]2)cc1
Yield: 46.9 %

Procedure:
2-(4-tert-Butylphenyl)-5-(4-nitrophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (16.3 g) was dissolved in a mixed solvent of dioxane and methanol and hydrogenated with Raney nickel. The catalyst was filtered off and the residue was concentrated and crystallized from ethyl acetate and isopropyl ether to give 5-(4-aminophenyl)-2-(4-tert-butylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (7.13 g). 1.0 g therefrom was converted to hydrochloride to give 5-(4-aminophenyl)-2-(4-tert-butylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide hydrochloride (0.48 g), melting point 270-272° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][N:13]([C:24](Cl)=[O:25])[CH2:12]2)[CH3:10])=[N:6][CH:7]=1.CCN(CC)CC.[CH3:34][N:35]([CH3:44])[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][N:13]([C:24]([N:41]3[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][N:35]([CH3:44])[CH3:34])[CH2:39][CH2:40]3)=[O:25])[CH2:12]2)[CH3:10])=[N:6][CH:7]=1
Reactant: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Reactant: CN(C)CCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)N2CCN(CCN(C)C)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 35 %

Procedure:
To a stirred solution of (3SR,4RS)-3-[(RS)-1-(5-chloro-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl chloride (80 mg, 0.18 mmol) in CH2Cl2 (2 mL) were added Et3N (0.03 mL, 0.15 mmol) and dimethyl-(2-piperazin-1-yl-ethyl)-amine (0.035 mL) (commercially available). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH3, 9/4/1) to yield 36 mg (35%) the title compound as light yellow oil. ES-MS m/e: 553.8 (M+H+).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:40])[C@@H:19]([NH:29]C(=O)OCC2C=CC=CC=2)[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:6]1)[CH:2]=[CH2:3]>COCCOC.O>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:40])[C@@H:19]([NH2:29])[CH2:20][C:21]2[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=2)[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OCc2ccccc2)c2cc(OC)ccc21
Solvent: COCCOC
Solvent: O
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(OC)ccc21
Temperature: 110 °C
Yield: 38 %

Procedure:
Step E (2): Ba(OH)2.H2O (267 mg, 1.41 mmol) was added to a vial charged with benzyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate (diastereomer A, 260 mg, 0.471 mmol) from stepE(1), DME/H2O (3 mL/2 mL). The sealed vial was heated at 110° C. for 18 h. Filtered the reaction mixture through a Pasture pipette/Kimwipe plug to remove solids. Rinsed the vessel and solids with fresh DME. The filtrate was evaporated in vacuo. Residual solvents were removed under high vacuum. The crude residue was purified by silica gel chromatography (1-20% MeOH (containing 0.1% triethylamine)/chloroform linear gradient) to give 74 mg (38% yield) the of the title compound as a clear viscous oil. LC-MS (M+H)+=419.24; 1H NMR (500 MHz, CDCl3) δ 7.32 (d, J=8.24 Hz, 1H), 6.92 (d, J=2.14 Hz, 1H), 6.85 (dd, J=8.24, 2.44 Hz, 1H), 6.71-6.80 (m, 2H), 6.60-6.71 (m, 1H), 5.84-6.03 (m, 1H), 5.30 (dd, J=17.24, 1.68 Hz, 1H), 5.18 (dd, J=10.38, 1.53 Hz, 1H), 4.77 (dd, J=6.10, 3.97 Hz, 1H), 4.08-4.12 (m, 2H), 4.05 (dd, J=6.87, 4.43 Hz, 1H), 3.79 (s, 3H), 3.47-3.52 (m, 1H), 3.04-3.10 (m, 1H), 2.90-3.00 (m, 2H), 2.75 (dd, J=11.90, 8.55 Hz, 1H), 2.61-2.68 (m, 1H), 2.49 (dd, J=13.43, 9.77 Hz, 1H), 1.94-2.00 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][N:9]2C(OCC2C=CC=CC=2)=O)=[CH:4][CH:3]=1>C(OCC)(=O)C.O1CCCC1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(F)cc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCNC(c2ccc(F)cc2)C1
Yield: 99.9 %

Procedure:
A solution of benzyl 2-(4-fluorophenyl)-4-oxopiperidine-1-carboxylate (4.75 g, 14.50 mmol) in a mixture of ethyl acetate and tetrahydrofuran (1:1, 100 mL) was hydrogenated in the presence of 10% Pd/C at atmospheric pressure over 12 h. The catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in ethyl acetate (250 mL) and washed twice with saturated aqueous bicarbonate (100 mL), brine, then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dried to give 2-(4-fluorophenyl)piperidin-4-one (2.8 g, quantitative). MS (EI) for C11H12FNO: 194 (MH+).
Reaction SMILES: CI.N12CCCN=C1CCCC[CH2:4]2.[O:14]=[C:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([C:27]([OH:29])=[O:28])=[CH:16]1>CC(C)=O>[O:14]=[C:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:17]([C:27]([O:29][CH3:4])=[O:28])=[CH:16]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C1C=C(C(=O)O)C(c2ccccc2)CC1
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)C1=CC(=O)CCC1c1ccccc1
Temperature: 10 °C
Yield: 92.8 %

Procedure:
358 g (2.52 mol) of methyl iodide and 361 g (2.38 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene were successively added to a solution of 428 g (1.98 mol) of (RS)-3-oxo-6-phenylcyclohex-1-ene-1-carboxylic acid, which was obtained according to J. Org. Chem., 1971, 36, 3707, in 4.5 cm3 of acetone and then the reaction mixture was brought to reflux for five hours. The acetone was subsequently distilled off and then the residue was stirred with 2.5 dm3 of water. After cooling to 10° C., the precipitate formed was filtered off, washed with ice-cold water and then dried at 30° C. 423 g (93%) of methyl (RS)-3-oxo-6-phenylcyclohex-1-ene-1-carboxylate were thus obtained in the form of a yellow powder, the characteristics of which were as follows:
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:28])[CH2:4][C@H:5]([NH:20]C(=O)OC(C)(C)C)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7]>C(OCC)(=O)C>[NH2:20][C@H:5]([C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:4][CH:3]([CH3:2])[CH3:28]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccccn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)N1CCN(c2ccccn2)CC1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Under cooling with ice, hydrogen chloride gas was fed and saturated into ethyl acetate (200 ml), and tert-butyl (s)-3-methyl-1-[4-(2-pyridyl)piperazine-1-yl carbonyl]-butylcarbamate (16.0 g) obtained above was added gradually. The mixture was stirred for 30 minutes. The solvent and hydrogen chloride was removed by distillation under reduced pressure, and 200 ml of water was added to the white powder thus obtained to dissolve the powder therein. After washing with ethyl acetate, an aqueous sodium bicarbonate solution was added to bring the pH to 8. Followed by the addition of sodium chloride, extraction with 100 ml of ethyl acetate was repeated three times. After drying over sodium sulfate, the solvent was removed by distillation under reduced pressure to yield 9.16 g of 1-L-leucyl-4-(2-pyridyl)piperazine (yield: 78.0%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[CH3:19][C:20]([CH:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)([CH3:23])[CH2:21][CH3:22].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH3:23][C:20]([CH:24]1[CH2:25][CH2:26][CH:27]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)[CH2:28][CH2:29]1)([CH3:19])[CH2:21][CH3:22]
Reactant: CCC(C)(C)C1CCC(O)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a mixture of (R)-4-(6-hydroxy-naphthalen-2-yl)-4-methyl-oxazolidin-2-one (Example 4, 300.0 mg, 1.233 mmol) and 4-(1,1-dimethyl-propyl)-cyclohexanol (252 mg, 1.48 mmol) in tetrahydrofuran (5 mL, 60 mmol) was added triphenylphosphine polymer-bound (1.07 g, 1.97 mmol). After the mixture was stirred at room temperate for 10 min, diisopropyl azodicarboxylate (0.388 mL, 1.97 mmol) was added dropwise. The mixture was stirred at room temperate for 48 hrs. The insoluble material was passed over a CELITE™ bed and washed with ethyl acetate. After the solvent was concentrated, the residue was purified with silica gel column eluted with ethyl acetate in hexanes from 0 to 40% to give 410 mg of white precipitate (R)-4-{6-[4-(1,1-dimethylpropyl)-cyclohexyloxy]-naphthalen-2-yl}-4-methyloxazolidin-2-one (84% yield). MS: m/z=396.30 M+H.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]=[C:4]([CH3:14])[CH:3]=1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.S(=O)(=O)(O)O.[OH-].[NH4+]>O>[N:15]1([C:2]2[C:11]3[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=3[Cl:12])[N:5]=[C:4]([CH3:14])[CH:3]=2)[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: Cc1cc(Cl)c2c(Cl)ccc(C)c2n1
Reactant: c1nc[nH]n1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(-n2cncn2)c2c(Cl)ccc(C)c2n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
A mixture of 2.26 g of 4,5-dichloro-2,8-dimethyl-quinoline, 1.38 g of 1,2,4-triazole and 0.1 g of 96% sulfuric acid is stirred at 70° C. for 3 hours. The reaction mixture is poured into 50 ml of water and neutralized with 1 ml of a concentrated ammonium hydroxide solution. The precipitated product is filtered and washed with water. Thus 2.0 g of the desired compound are obtained, yield 77.4%. Mp.: 117°-118° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[CH:21]=[CH:22][S:23][C:8]=2[C:7]=1O)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:28])=O.[Na+].[Cl-]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[CH:21]=[CH:22][S:23][C:8]=2[C:7]=1[Cl:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2sccc2n(Cc2cccc(F)c2)c1=O
Reactant: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)c2sccc2n(Cc2cccc(F)c2)c1=O
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
4-(3-Fluoro-benzyl)-7-hydroxy-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (15) (60 g, 0.17 mol) was dissolved in 600 mL anhydrous DMF under a blanket of argon and cooled to −30° C. Oxalyl chloride (40.7 mL, 0.47 mol) was then added very slowly (producing a large volume of gas), with the reaction vessel open to the atmosphere. The solution was then heated to 75° C. for 2 hours. The solution was cooled to room temperature and poured into a solution of 150 g. NaCl in 6 L ice water without stirring. The mixture was allowed to sit without stirring for 15 minutes, and was then stirred vigorously for 1 minute with a spatula. The precipitated solid product was collected by vacuum filtration to yield 55 g (87% yield) of 7-chloro-4-(3-fluoro-benzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester. 1H-NMR (DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 4.34 (q, J=7.2 Hz, 2H), 5.45 (s, 2H), 7.06-7.17 (m, 3H), 7.37 (m, 1H), 7.49 (d, J=5.6 Hz, 1H), 8.20 (d, J=5.6 Hz, 1H) ppm; EIMS m/z 366 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[Br:16]Br.O>C(O)(=O)C>[Br:16][C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Reaction time: 8 h
Yield: 72.2 %

Procedure:
In 150 ml of acetic acid, 20 g (96.9 millimole) of 2,4-di-tert-butylphenol was dissolved, and the solution was cooled on ice. Then, 5.0 ml (96.9 millimole) of bromine was added thereto drop by drop. After finishing dropwise addition, the temperature was elevated up to a room temperature, and the solution was stirred for 8 hours. Then, the reaction mixture was thrown into ice and water, and the aqueous layer was extracted with diethyl ether. The organic layer was dried on anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 19.96 g (yield: 72.0%) of 2-bromo-4, 6-di-tert-butylphenol.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(-c2ccc(Oc3ccc(OC[C@H]4CCCN4)cc3)cc2)cc1
Yield: 62 %

Procedure:
Following the general procedure for Example 11 (step 4), the product from step 3 (0.2 g, 0.45 mmol) was treated with 4M HCl in dioxane (5 mL) to afford the title product (0.11 g, 62%) as a white solid; 1H NMR (400 MHz, DMSO-d6) 1.75 (m, 1H), 1.88-2.02 (m, 2H), 2.12 (m, 1H), 3.23 (m, 2H), 3.91 (m, 1H), 4.14 (m, 1H), 4.26 (dd, J1=3.8 Hz, J2=10.4 Hz, 1H), 7.00 (d, J=8.8 Hz, 2H), 7.04-7.11 (m, 4H), 7.34 (m, 1H), 7.45 (m, 2H), 7.61-7.66 (m, 4H); MS (m/z) 346.7 (M+1); LC (98.9%); Elemental Analysis (Calc): C, 72.34; H, 6.33; N, 3.67; (Found): C, 71.72; H, 6.29; N, 3.66.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
L-Phenylalanine (5 g, 30 mmol) was dissolved in a solution (200 ml) containing equal proportions of tetrahydrofuran and 5% NaHCO3, and chilled to 0° C. Benzyl chloroformate (4.7 ml, 33 mmol) was dissolved in tetrahydrofuran (10 ml) and added slowly to the amino acid solution over a period of 1 hour. The pH was continually adjusted to 8.5 by the addition of 5% Na2CO3 and the reaction was allowed to proceed at room temperature overnight. The organic solvent was removed under reduced pressure and the resulting aqueous solution was poured slowly into chilled, concentrated HCl (50 ml). The product precipitated and was extracted into ethyl acetate (200 ml). It was washed with 5% NaHSO4 and dried over magnesium sulphate. Recrystallisation was from ethyl acetate/hexane. Yield 8.29 g (91%), m.p. 83°-83° C. (Lit. 82°-84° C., Berger et al., 1973). The product was homogeneous as judged by tlc in chloroform/methanol (4:1) (Rf 0.500) or chloroform/methanol (1:1) (Rf 0.364).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13](O)[C:12]2[C:7](=[CH:8][C:9]([Cl:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].O=P(Cl)(Cl)[Cl:19]>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([Cl:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(O)c2ccc(Cl)cc2n1
Product: COC(=O)c1cc(Cl)c2ccc(Cl)cc2n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
7-Chloro-4-hydroxy-2-quinolinecarboxylic acid methyl ester (76 g) was added to POCl3 (100 mL) at rt, and heated at 140 degrees C. for 1 h, then cooled to rt. After the removal of excess POCl3 in vacuo, cold 1 N NaOH solution was added to pH 8, and precipitated solid was triturated, washed with water and dried under vacuum to afford 78 g (95.2%) of 4,7-dichloro-2-quinolinecarboxylic acid methyl ester as an off-white powder. LC-MS, 255 (M++1). 1H NMR (DMSO-d6): δ 3.95 (s, 3H), 7.91 (d, 1H), 8.22 (s, 1H), 8.26 (d, 1H), 8.33 (s, 1H).
Reaction SMILES: C(O)C.C([BH3-])#N.[Na+].[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][CH:20]([CH:23]([CH:31]=[O:32])[CH2:24][CH2:25][C:26]([O:28]CC)=O)[CH2:19][CH2:18]2)=[C:13]([F:33])[C:12]=1[F:34])[CH3:9].Cl>O>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][CH:20]([CH:23]3[CH2:31][O:32][C:26](=[O:28])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[C:13]([F:33])[C:12]=1[F:34])[CH3:9]
Reactant: CCOC(=O)CCC(C=O)C1CCC(c2ccc(OCC)c(F)c2F)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(C2CCC(C3CCC(=O)OC3)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.3 %

Procedure:
In a reactor under nitrogen atmosphere, 20 mL of ethanol and 0.4 g of sodium cyanoborohydride were added to 5.7 g of ethyl 4-[4-(4-ethoxy-2,3-difluorophenyl)cyclohexyl]-5-oxopentanoate obtained in the fourth step, and pH of the mixture was adjusted to about 3 with hydrochloric acid (2M), followed by stirring at room temperature for 15 hours. 30 mL of water was added to the reaction solution, which was extracted three times with 20 mL of toluene. The mixture including the organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was placed in a flask equipped with a Dean-Stark apparatus, to which 100 mL of toluene and 0.1 g of p-toluenesulfonic acid monohydrate were added, and the mixture was refluxed for 1 hour while the solvent was distilled off with the Dean-Stark apparatus. The solution was cooled to room temperature, washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to provide 4.2 g of 5-[4-(4-ethoxy-2,3-difluorophenyl)cyclohexyl]tetrahydropyran-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]Br>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:11]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:26][CH2:25]2)=[O:17])=[CH:7][CH:8]=1
Reactant: BrCCBr
Reactant: CCOC(=O)CC(=O)Nc1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)Nc2ccc(OC)cc2)CC1
Yield: 52381 %

Procedure:
In a manner similar to the procedure described in Example B except that a 100 milliliter three-necked Morton flask was used, 10.0 grams (42.0 mmol) of ethyl 3-[(4-methoxyphenyl)amino]-3-oxopropanoate, 14.54 grams (105.0 mmol) of anhydrous potassium carbonate, 30 milliliters of dimethylformamide and 7.9 grams (42.0 mmol) of 1,2-dibromoethane were reacted for a period of 12 days to give 5.74 grams (22.0 mol) of ethyl 1-(4-methoxyphenylaminocarbonyl)cyclopropanecarboxylate as a colorless solid having a melting point of 89.5° C.-91.0° C. The total yield was 56 percent. NMR analysis of the product indicated the following:
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1)=[O:21].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:9]([C:8]3[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=4)=[N:15][CH:14]=[CH:13][CH:12]=3)=[O:11])=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1
Reactant: COC(=O)c1cccc(-c2ccc(CN)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccc(CNC(=O)c3cccnc3Oc3ccc(F)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
To a stirred solution of 290 mg (1.24 mmol.) 2-[4-fluoro-phenoxy]-nicotinic acid, 300 mg (1.24 mmol.) 4′-aminomethyl-biphenyl-3-carboxylic acid methyl ester and 184 mg (1.36 mmol.) 1-hydroxybenzotriazole hydrate in 10 mL dimethylformamide at ambient temperature was added 285 mg (1.49 mmol.) 1-[3-[dimethylamino]propyl]-3-ethylcarbodiimide hydrochloride. The mixture was stirred at ambient temperature for 18 hours then poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed successively with 1N NaOH, water, brine then dried (MgSO4 ) and concentrated in vacuo to give an oil. Chromatography on silica Gel eluting with ethyl acetate/hexanes (1:1) gave 310 mg 4′-[[[2-[4-Fluorophenoxy]-pyridine-3-carbonyl]-amino]-methyl]-biphenyl-3-carboxylic acid methyl ester as an oil.
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:19][CH2:18]1>>[F:12][C:2]([F:1])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:19][CH2:18]1)=[O:5]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C(F)(F)c1ccccc1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(F)(F)c2ccccc2)CC1

Procedure:
Example 124 was prepared from 2,2-difluoro-2-phenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methyl propanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 2H), 7.68–7.63 (m, 3H), 7.49–7.39 (m, 3H), 7.23 (d, 1H, J=1.8 Hz), 7.07 (d, 1H, J=8.3Hz), 3.45 (q, 2H, J=4.9 Hz), 3.11 (d, 2H, J=10.2 Hz), 2.76–2.66 (m, 1H), 2.56 (t, 2H, J=5.0 Hz), 2.44 (septet, 1H, J=6.9 Hz), 2.28 (s, 3H), 2.13–2.05 (m, 2H), 1.82–1.71 (m, 6H), 1.15 (d, 6H, J=6.9 Hz); ESMS m/e: 472.4 (M+H)+.