Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]([O:16][CH2:17][C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH3:23])[CH:12]=[N:13][C:14]=2[Cl:15])=[CH:3][CH:2]=1>CO.[Pd]>[ClH:15].[ClH:15].[ClH:15].[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([O:16][CH2:17][C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH3:23])[CH:12]=[N:13][C:14]=2[Cl:15])=[CH:3][CH:2]=1
Reactant: CN1CCC[C@@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Agent: [Pd]
Solvent: CO
Product: CN1CCC[C@@H]1COc1cnc(Cl)c(CCc2ccncc2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.5 %

Procedure:
A sample of 5-(2-(4-pyridinyl)ethenyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine from Example 82 (85 mg) was dissolved in MeOH. To this solution was added Pd/C (9.5 mg), and the mixture was stirred under H2 for 16 hours at room temperature. The catalyst was filtered off, and the solvent was removed under vacuum. The residue was chromatographed on a silica gel column, eluting with CH2Cl2 :MeOH 100:3-100:10 to afford to give the free base of the title compound (30 mg). MS (CI/NH3) m/z 332 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.65 (m, 2H), 1.80 (m, 1H), 2.0 (m, 1H), 2.32 (m, 1H), 2.47 (s, 3H), 2.64 (m, 1H), 2.96 (m, 4H), 3.12 (m, lH), 3.90 (m, 2H), 6.98 (m, 1H), 7.12 (m, 2H), 7.96 (m, 1H), 8.50 (m, 2H). The base was converted to the salt by treatment with HCl in Et2O to give the title compound. mp 236-238° C. MS (CI/NH3) m/z 332 (M+H)+. 1H NMR (D2O, 300 MHz) δ1.98-2.23 (m, 3H), 2.38 (m, 1H), 3.01 (s, 3H), 3.17 (m, 2H), 3.25 (m, 3H), 3.74 (m, 1H), 3.90 (m, 1H), 4.27 (dd, J=7.1, 11.2, 1H), 4.44 (dd, J=3.10, 11.2, 1H), 7.36 (d, J=3.0, 1H), 7.70 (d, J=8.4, 2H), 8.01 (d, J=3.0, 1H), 8.56 (d, J=6.1, 2H). Anal. Calcd for C18H22N3OCl·3 HCl: C, 49.00; H, 5.71; N, 9.52. Found: C, 48.94; H, 5.85; N, 9.23. [α]25D=+8.64° (c 0.94, MeOH).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].CS(C)=O.[BrH:18].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Br:18][C:9]1[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH2:6])=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:8]=1
Reactant: Br
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Br)cc(C(C)C)c1N
Temperature: 90 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a solution of 2,6-diisopropylaniline (25 g, 0.141 moL) in toluene (25 mL) was added dimethyl sulfoxide (12.1 g, 1.1 equivalents), and the mixture was heated to 90° C. 48% Aqueous hydrobromic acid solution (26.1 g, 1.1 equivalents) was added dropwise to the mixture at the same temperature over 30 min. Then, the mixture was stirred at 86° C. for 3 hr and at 100° C. for 2 hr. Water (20 mL) was added to the mixture at 0° C., and 1M aqueous sodium hydroxide solution (30 mL) was added dropwise to the mixture. The mixture was partitioned, and the organic layer was washed with 1M aqueous sodium hydroxide solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered naturally, and the filtrate was concentrated under reduced pressure. The residue was distilled under reduced pressure to give 4-bromo-2,6-diisopropylaniline (29.4 g, pale-yellow liquid). 37% Formaldehyde (23.1 g, 2.5 equivalents) was added to a solution of 4-bromo-2,6-diisopropylaniline synthesized as mentioned above in formic acid (189 g, 4.11 moL) at 32° C., and the mixture was stirred under refluxing for 2 hr. Toluene (100 mL) and 8M aqueous sodium hydroxide solution (150 mL) were added to the mixture at 0° C., the mixture was partitioned, and the organic layer was successively washed with 1M aqueous sodium hydroxide solution (50 mL) and water (50 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered naturally, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (35.0 g, colorless solid). yield 95%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][NH:13][O:14][CH3:15].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1CCOCC1.ClCCl>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([N:13]([O:14][CH3:15])[CH3:12])=[O:5]
Reactant: CNOC
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.6 %

Procedure:
To a solution of 2-amino-5-bromonicotinic acid (7 g, 32.3 mmol), N,O-dimethylhydroxylamine (5.99 g, 61.37 mmol) in N-methylmorpholine (60 ml) and dichloromethane (500 ml) at 0° C. was added PyBop (25.2 g, 48.45 mmol) portionwise. The solution was allowed to warm to room temperature and the mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with a 2M aqueous solution of NaOH and with a 10 wt % solution of citric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was dissolved in ether and the formed solid was filtered off. The mother liquors were concentrated in vacuo to approximatively half of the original volume. This solution was diluted with dichloromethane and stirred vigorously while adding a 2M HCl solution in diethylether until complete formation of the precipitate. The solid was filtered off and partitioned between a 2M aqueous solution of NaOH and EtOAc. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to dryness to afford the title compound as a cream solid (5.26 g, 63% yield).
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-]>O.CN(C)C=O>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7]
Reactant: O=c1cccc[nH]1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccccn1-c1ccccn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
25 ml of a dimethylformamide solution containing 4.00 g of 2(1H)-pyridone and 8.00 g of 2-bromopyridine was incorporated with 3.80 g of potassium carbonate and 0.51 g of cupurous iodide, followed by stirring at 120° C. for 2 hours. After the mixture was returned to room temperature, water was added thereto. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane=1:1), to give 1.58 g of the title compound as a pale yellow wax.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:8][C:6]1[NH:7][C:2](=[N:1][S:29]([CH3:28])(=[O:31])=[O:30])[N:3]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1=C(C)N=C(N)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(=NS(C)(=O)=O)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of 2-amino-4-methyl-6-(3-nitrophenyl)-1,5(6H)-pyrimidinedicarboxylic acid, diethyl ester (600 mg, 1.59 mmoles, see Example 2) in dichloromethane (5 ml) and pyridine (1.0 ml) was cooled to 0° C. under argon and was treated dropwise with methanesulfonyl chloride (0.42 ml, 5.26 mmoles). A catalytic amount of 4-dimethylamionpyridine was added and the reaction was allowed to warm to room temperature. After stirring overnight, the reaction was diluted with ethyl acetate and was washed with 1N hydrochloric acid, sodium bicarbonate and brine. It was dried over anhydrous magnesium sulfate and the solvent was evaporated to provide a colorless residue. Crystallization from ether-hexanes provided the title compound as a colorless crystalline material, melting point 139°-140.5° C.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11](=[O:28])[C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])=[O:4].CO.O.[OH-].[Li+]>C1COCC1>[C:24]([O:23][C:21]([NH:20][C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:11]([N:6]1[CH2:7][C@H:8]([OH:10])[CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])=[O:28])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid methyl ester (4.7 g, 11.8 mmol) was dissolved in THF (80 mL), methanol (20 mL), and water (40 mL). Powdered lithium hydroxide (5.6 g, 233 mmol) was added. The light yellow slurry was stirred at rt under N2 for 16 h, and then concentrated in vacuo. The residue was partioned between ether and water. The ether phase was discarded, and the aqueous phase was treated with 1N HCl until the pH was 4. This acidic solution was extracted with EtOAc (3×). The combined EtOAc extracts were dried (MgSO4) and concentrated in vacuo to give 4.36 g (96%) of 1-(2(S)-tert-butoxycarbonylamino-8-nonenoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid as a white solid. This acid was then dissolved in 150 mL of DMF and (1R,2S)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester hydrochloride (2.61 g, 13.6 mmol), N-methyl morpholine (2.5 mL, 22.6 mmol), and HATU (5.2 g, 13.7 mmol) was added. The reaction mixture was stirred at rt under N2 for 16 h, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (60%–80% ethyl acetate/hexane) gave 6.0 g (98%) of 1-{[1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)carbonyl]-(1R)-amino}-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester as a white solid: 1H NMR (500 MHz, CD3OD) δ 1.25 (t, J=7.2 Hz, 3H), 1.33–1.80 (m, 10H), 1.46 (s, 9H), 2.09 (m, 3H), 2.25 (m, 2H), 3.76 (m, 2H), 4.14 (m, 2H), 4.27 (dd, J=8.5, 5.2 Hz, 1H), 4.50 (m, 2H), 4.94 (d, J=10.1 Hz, 1H), 5.01 (dd, J=17.1, 1.8 Hz, 1H), 5.11 (dd, J=10.4, 1.8 Hz, 1H), 5.30 (d, J=15.6 Hz, 1H), 5.80 (m, 2H), 8.57 (s, 1H). LC-MS (Method A, retention time: 3.21 min), MS m/z 522 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:3]=1[CH:4]=O.[CH3:13][Si:14]([CH3:21])([CH3:20])[C:15]#[C:16][CH2:17][CH2:18][NH2:19]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]2[C:6]([CH:7]=[CH:8][CH:9]=1)=[N:10][N:19]([CH2:18][CH2:17][C:16]#[C:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[CH:4]=2
Reactant: C[Si](C)(C)C#CCCN
Reactant: O=Cc1c(F)cccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#CCCn1cc2c(F)cccc2n1
Yield: 55.7 %

Procedure:
2-Fluoro-6-nitro-benzaldehyde (180 mg, 1.06 mmol) was added to a solution of 4-trimethylsilanyl-but-3-ynylamine (200 mg, 1.40 mmol) in toluene (2 mL) and the reaction mixture was stirred under reflux for 30 min in a Dean-Stark. After evaporation of the solvent, the crude product was dissolved in triethylphosphite (1 mL) and the reaction mixture was stirred at 80° C. for 4 hours. After evaporation, the crude product was purified by flash chromatography (cyclohexane/AcOEt 92.5:7.5) to yield 4-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (142 mg, 0.59 mmol, 52%) as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[C:20]([C:24]1[N:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C(C1C=C(S(Cl)(=O)=O)C=CC=1OC)(C)(C)C>>[C:20]([C:24]1[N:29]=[C:28]([S:30]([N:17]2[CH2:16][CH2:15][N:14]3[CH2:19][C@H:11]([O:10][C:7]4[CH:6]=[N:5][C:4]([C:1]([CH3:2])=[CH2:3])=[CH:9][N:8]=4)[CH2:12][C@H:13]3[CH2:18]2)(=[O:32])=[O:31])[CH:27]=[CH:26][CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cccc(S(=O)(=O)Cl)n1
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Agent: COc1ccc(S(=O)(=O)Cl)cc1C(C)(C)C
Product: C=C(C)c1cnc(O[C@@H]2C[C@H]3CN(S(=O)(=O)c4cccc(C(C)(C)C)n4)CCN3C2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 57, substituting the product from Example 202C (82 mg, 0.28 mmol) for the product from Example 27B, and substituting the product from Example 58B for 3-tert-butyl-4-methoxybenzene-1-sulfonyl chloride. The title compound was obtained as a colorless solid (79 mg, 62%). 1H NMR (300 MHz, CDCl3) δ ppm 1.39 (s, 9H), 1.78-2.06 (m, 2H), 2.17 (s, 3H), 2.31-2.49 (m, 2H), 2.50-2.62 (m, 1H), 2.61-2.74 (m, 1H), 2.91-3.06 (m, 2H), 3.69 (dd, J=9.92, 6.74 Hz, 1H), 3.85-3.96 (m, 1H), 4.02-4.13 (m, 1H), 5.22 (t, J=1.59 Hz, 1H), 5.32-5.42 (m, 1H), 5.77-5.81 (m, J=1.59 Hz, 1H), 7.51 (dd, J=7.54, 1.19 Hz, 1H), 7.71-7.84 (m, 2H), 8.15 (d, J=1.59 Hz, 1H), 8.20 (d, J=1.19 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[CH3:2].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(OCC)C>[Br-:15].[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]1[CH:14]=[CH:13][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:11]=1)[CH3:2]
Reactant: CCCCCCBr
Reactant: CCOc1ccccc1-n1ccnc1
Solvent: CCOCC
Product: CCCCCCn1cc[n+](-c2ccccc2OCC)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 10.00 mmol (1,883 g) 1-(2-ethoxyphenyl)imidazole and 11.00 mmol (1,816 g, 1.59 ml) 1-bromohexane are dissolved in 3 ml diethylether and heated for 12 h to 60° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=3)[C:17]([CH3:29])=[C:16]([C:30](OCC)=[O:31])[C:15]=2[CH3:35])=[CH:10][CH:9]=1.Cl.[CH3:37][NH:38][O:39][CH3:40].[CH2:41]([N:43]([CH2:46]C)[CH2:44]C)C>ClCCl.CN(C=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[N:26]=[CH:41][N:43]([CH3:46])[CH3:44])=[CH:21][CH:20]=3)[C:17]([CH3:29])=[C:16]([C:30]([N:38]([O:39][CH3:40])[CH3:37])=[O:31])[C:15]=2[CH3:35])=[CH:12][CH:13]=1
Reactant: CNOC
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1c(C)c(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)c1C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1c(C)c(-c2ccc(Cl)cc2)n(-c2ccc(S(=O)(=O)N=CN(C)C)cc2)c1C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
Oxalyl chloride (0.908 g, 0.60 ml, 7.16 mmol) was added dropwise at 0° C. to a solution of 5-(4-Chlorophenyl)-2,4-dimethyl-1-(4-sulfamoylphenyl)-1H-pyrrole-3-carboxylic acid (step 2, 1.45 g, 3.58 mmol) in dichloromethane (50 ml)/DMF (0.544 g, 0.50 ml, 7.16 m mol). Mixture was allowed to come at room temperature and stirred for 1 hr. under nitrogen atmosphere. The completion of reaction was monitored by TLC. The mixture was concentrated under reduced pressure under nitrogen atmosphere. To this residue was added N,O-dimethylhydroxylamine hydrochloride (0.690 g, 7.16 mmol) in dry dichloromethane (50 ml) at 0° C. followed by the addition of triethylamine (1.44 g, 2.0 ml, 14.32 mmol,) under stirring. The reaction mixture was stirred at room temperature for 2 hr. The completion of reaction was monitored by TLC. The solvent was removed under reduced pressure. The residue so obtained was taken in dichloromethane (50 ml), washed with water (2×25 ml.) and organic layers separated were dried over anhydrous sodium sulphate, filtered and concentrated at reduced pressure to get a crude product. This crude product was purified by column chromatography over silica gel (100-200 mesh) using 0.8% methanol in dichloromethane as an eluent to yield the title compound (0.763 g, 42%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([OH:14])=[O:13])[CH2:7]1)=[O:5].Cl.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1.[CH3:25][N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1>C(N(CC)CC)C>[CH3:25][N:26]1[CH2:31][CH2:30][C:29]2[N:23]([CH2:2][CH2:3][C:4]([N:6]3[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([OH:14])=[O:13])[CH2:7]3)=[O:5])[C:20]3[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][C:21]=3[C:28]=2[CH2:27]1
Reactant: O=C(O)C1CCCN(C(=O)CCBr)C1
Reactant: Cc1ccc(NN)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)N2CCCC(C(=O)O)C2)CCN(C)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(3-bromopropanoyl)piperidine-3-carboxylic acid, 4-methylphenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.O>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: OCCn1ccnc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
A stirred solution of 2-imidazol-1-yl-ethanol (J. Med. Chem., 39(10), 1991, (1996)) (3.9 g, 35 mmol) in dimethylformamide (75 mL) at 15° C. was treated portionwise with 60% sodium hydride (0.84 g, 35 mmol) and stirred at room temperature for 30 minutes. The mixture was rechilled and 4-fluoro-1-nitrobenzene (4.93 g, 35 mmol) added dropwise. The mixture was stirred cold for 30 minutes and heated at 35-40° C. for 30 minutes. A little water was added and the volatiles were removed on a pump. The residue was diluted with water, extracted with dichloromethane, washed with brine, dried (Na2SO4) and evaporated. Chromatography on silica gel and eluting with methanol/triethyl-amine/dichloromethane (2:2:96) and crystallization of the purified product from dichloromethane/ether gave 3.4 g (42%) of 1-[2-(4-nitro-phenoxy)ethyl]-1H-imidazole as a colorless solid, mp 55-57° C. Mass spectrum (LR-APCI) MH+=234.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:14](Cl)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:17]([O:24][C:25](=[O:35])[C@H:26]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH2:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>ClCCl>[CH2:17]([O:24][C:25](=[O:35])[C@H:26]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH:27][C:14]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
Triethylamine (10.9 g) and piperidinocarbonyl chloride [16 g, see Synthetic Communications, vol. 17, 1887-1892 (1987)] were sequentially added to a solution of L-phenylalanine benzyl ester (39.6 g) in dichloromethane under ice-cooling and the mixture was stirred at room temperature for 24 hours. Water (250 ml) was added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted with dichloromethane (250 ml). The combined organic layer was washed with 0.1N hydrochloric acid (250 ml×2) and a saturated aqueous solution (250 ml) of NaHCO3, and dried over MgSO4. The solvent was distilled away under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 29.3 g of the title compound as white crystals (see Table 8).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.ClC(OCC)=O.[CH3:29][C:30]1[CH:31]=[C:32]([CH:34]=[C:35]([CH3:37])[CH:36]=1)[NH2:33]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:29][C:30]1[CH:31]=[C:32]([NH:33][C:10]([C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12])[CH:34]=[C:35]([CH3:37])[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Cc1cc(C)cc(N)c1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)cc(NC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 119.5 %

Procedure:
Commercially available Boc-L-proline (16, 2.3 g; 10.7 mmol) is dissolved in DCM (20 ml) and cooled to 0° C. followed by the addition of NEt3 (1.12 g; 11.22 mmol) and ethyl chloroformate (1.22 g; 11.22 mmol) and finally commercially available 3,5-dimethylaniline (15) (1.36 g; 11.22 mmol). The reaction mixture is stirred at rt for 60 minutes. Brine (50 ml) is added and the organic layer is separated. The aq. layer is extracted with DCM (2×30 ml). The combined organic layers are dried over MgSO4, filtered and the solvent is removed under reduced pressure to give 4.07 g of crude (S)-tert-butyl 2-((3,5-dimethylphenyl)carbamoyl)pyrrolidine-1-carboxylate (17) which is used in the next step without further purification. LC-MS: tR=0.81 min; [M+H]+=319.11.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:14])[NH:9]2.Br[CH2:16][CH2:17][CH2:18][Cl:19]>CN(C=O)C>[Cl:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:14])[N:9]2[CH2:16][CH2:17][CH2:18][Cl:19]
Reactant: O=C1CCc2c(Cl)cccc2N1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2c(Cl)cccc2N1CCCCl

Procedure:
In the same manner as in Reference Example 1, 60% sodium hydride in oil was added portionwise to a solution of 5-chloro-3,4-dihydrocarbostyril in DMF, the resultant mixture was stirred for 30 minutes, 1-bromo-3-chloropropane was then added, and the resultant mixture was further stirred at 80°-90° C. for 8 hours. The DMF was distilled off under reduced pressure, and the residue was extracted with chloroform. The extract was washed with water and dried (anhydrous magnesium sulfate), the chloroform was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-chloro-1-(3-chloropropyl)-3,4-dihydrocarbostyril as a pale yellow oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH:6]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:21]([O:20][C:18]([NH:17][CH2:16][CH:6]([CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:25])=[O:4])=[O:19])([CH3:23])([CH3:24])[CH3:22]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Aqueous 2N sodium hydroxide (2.48 mL, 4.96 mmol) was added to a stirring solution of the methyl ester 13 (0.41 g, 1.24 mmol) in THF (7.5 mL) and the mixture was stirred at rt. for 24 h. Water (15 mL) was added and the solution was acidified with 5% aqueous citric acid. The mixture was extracted with CHCl3 (3×25 mL) and the combined organic extracts were washed with brine (30 mL), dried (Na2SO4), and evaporated in vacuo to leave the acid 14 as a viscous, colourless oil (280 mg).