Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:6]1[CH:15]=[C:14]([CH:16]=[O:17])[C:13]2[C:8](=[CH:9][C:10]([O:26][CH3:27])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:12]=2)[CH:7]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=O)C.[OH-].[K+]>CO>[C:23]([O:22][CH2:21][CH2:20][CH2:19][O:18][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:26][CH3:27])[CH:7]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)[NH:6][CH:15]=[C:14]2[CH:16]=[O:17])(=[O:25])[CH3:24]
Reactant: CCOC(=O)N1C=C(C=O)c2cc(OCCCOC(C)=O)c(OC)cc2C1Cc1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(CC2NC=C(C=O)c3cc(OCCCOC(C)=O)c(OC)cc32)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
To a stirred solution of 6-(3-acetoxy-propoxy)-4-formyl-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (150 mg, 0.30 mmol) in methanol (6 mL) was added powdered potassium hydroxide (169 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 3 hrs. The solvent was evaporated and the residue was diluted with ethyl acetate (20 mL) and water (20 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzyl)-1,2-dihydro-isoquinoline-4-carbaldehyde (78 mg, 67% yield) as a yellow oil. The crude product was used without further purification. To a stirred solution of 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzyl)-1,2-dihydro-isoquinoline-4-carbaldehyde (78 mg, 0.20 mmol) in chloroform (3 mL) was added manganese (IV) oxide (208 mg, 2.0 mmol). The reaction mixture was stirred at room temperature for 15 hrs, filtered through a Celite® pad, and washed with chloroform. The filtrate was concentrated in vacuo to afford 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzyl)-isoquinoline-4-carbaldehyde (20 mg, 23% yield). The crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[K+].[K+].CCN(C(C)C)C(C)C.[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[CH2:29]Br)[CH3:26]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:29][CH:28]([O:31][CH2:32][CH3:33])[O:27][CH2:25][CH3:26])=[CH:4][C:3]=1[F:9]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccc(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(COc1ccc(Cl)c(F)c1)OCC
Temperature: 100 °C
Reaction time: 16 h
Yield: 104.6 %

Procedure:
To 4-chloro-3-fluorophenol (3.66 g, 25 mmol) in DMF (30 ml) at room temperature was added potassium carbonate (6.91 g, 50.0 mmol), DIEA (8.73 ml, 50.0 mmol) and then bromoacetaldehyde diethylacetal (7.52 ml, 50.0 mmol). The mixture was stirred at 100° C. for 16 hr. The mixture was cooled to room temperature and then quenched with water and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The residue was purified via Biotage (0-20% AcOEt/heptane; SNAP25 column) giving 13a (6.87 g, quant) as a colorless oil.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:13]([N:15]1[CH:19]=[C:18]([CH2:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=2)[CH:17]=[N:16]1)[CH3:14]>>[CH2:13]([N:15]1[CH:19]=[C:18]([CH2:20][N:21]([C:22]2[CH:23]=[CH:24][C:25]([CH:28]([CH3:29])[CH3:30])=[CH:26][CH:27]=2)[C:10]([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:12])[CH:17]=[N:16]1)[CH3:14]
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: O=C(O)C1CCc2ccccc21
Product: CCn1cc(CN(C(=O)C2CCc3ccccc32)c2ccc(C(C)C)cc2)cn1
Yield: 40.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 4 using indan-1-carboxylic acid (0.24 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)indan-1-carboxamide (0.23 g) was obtained. melting point: 83-84° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.Cl[C:35]([O:37][CH2:38][CH2:39][O:40][CH3:41])=[O:36]>>[CH3:41][O:40][CH2:39][CH2:38][O:37][C:35](=[O:36])[NH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:16][CH:17]=1)[CH:7]=[CH:6]2
Reactant: COCCOC(=O)Cl
Reactant: Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Agent: Cl
Product: COCCOC(=O)Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
The title compound can be synthesized from 1-[4-(5-aminoindol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea hydrochloride and 2-methoxyethyl chloroformate by using the same techniques as in Example 41.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:5]=1)(=O)[CH3:2].Cl.CN.[C:29]([BH3-])#[N:30].[Na+]>CO.C(OCC)(=O)C>[F:23][C:22]([F:25])([F:24])[C:18]1[CH:17]=[C:16]([C:6]2[CH:5]=[C:4]([CH:1]([NH:30][CH3:29])[CH3:2])[CH:15]=[CH:14][C:7]=2[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)COc1ccc(C(C)=O)cc1-c1cccc(C(F)(F)F)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(C)c1ccc(OCC(=O)OC)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 192 h
Yield: 108.9 %

Procedure:
To a solution of methyl 2-(4-acetyl-2-(3-trifluoromethylphenyl)phenoxy)acetate (17) (529 mg, 1.5 mmol, 1 eq) in MeOH (5 mL) was added methylamine hydrochloride (603 mg, 9.0 mmol, 6 eq) and sodium cyanoborohydride (93 mg, 1.5 mmol, 1 eq). The reaction mixture was stirred at room temperature for 8 days, diluted with ethyl acetate, washed with water, dried (Na2SO4), and concentrated in vacuo to give crude compound methyl 2-(2-(3-trifluoromethylphenyl)-4-(1-(methylamino)ethyl)phenoxy)acetate (18) as white solid (600 mg) which was carried directly to the next step.
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[C:19]([C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[CH3:16])=[O:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Product: Cc1ccccc1C(=O)N1N(C2CCCCCCC2)C(=O)C1(C)C

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-methylbenzoyl chloride were used for a similar reaction and treatment as Example 96, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C[O:10][C:11]([CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14]1)=O.Cl>O1CCCC1.O>[C:1]([CH2:2][C:11]([CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14]1)=[O:10])#[N:3]
Reactant: CC#N
Reactant: COC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 61.9 %

Procedure:
To a solution of acetonitrile (708 μL, 13.5 mmol) in tetrahydrofuran (30 mL) was added n-butyl lithium (1.6 M solution in hexane, 7.75 mL, 12.4 mmol) at −78° C. The solution was stirred at −78° C. for 10 minutes and a solution of EXAMPLE 24A (3.0 g, 11.34 mmol) in 10 mL of tetrahydrofuran was added. The mixture was stirred at −78° C. for 1 hour and was warmed up to −20° C. over 3 hours. Water was added and the mixture acidified to pH 3 with 2N hydrochloric acid. The mixture was partitioned between ethyl acetate and brine and the organic phase concentrated. The residue was purified by flash chromatography on silica gel using 30-80% ethyl acetate in hexane to give the title compound (1.91 g, 61%). MS(DCI): m/z 273 (M+1)+.
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:30]([N:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][C:37]([S:43](Cl)(=[O:45])=[O:44])=[CH:38][CH:39]=2)[CH2:34]1)(=[O:32])[CH3:31]>O1CCCC1>[N:3]1([S:43]([C:37]2[CH:36]=[C:35]3[C:40]([CH2:41][CH2:42][N:33]([C:30](=[O:32])[CH3:31])[CH2:34]3)=[CH:39][CH:38]=2)(=[O:44])=[O:45])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: c1ccc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)N1CCc2ccc(S(=O)(=O)n3ccc4ccccc43)cc2C1
Reaction time: 0.08 h
Yield: 72 %

Procedure:
A 50% solution of sodium hydroxide (100 ml) was added to a vigorously stirred solution of indole (5.8 g, 50 mmol) and tetrabutylammonium hydroxide (40% by weight solution, 2 ml, 3.1 mmol) in tetrahydrofuran (100 ml). After 5 minutes, a solution of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride (R. G. Pendleton et al., J. Pharmacol. Exp. Ther., 1979, 208, 24; U.S. Pat. No. 3,725,388 (1973)) (13.7 g, 50 mmol) in tetrahydrofuran (50 ml) was added over 10 minutes and the resulting mixture was vigorously stirred for a further 3 h. The mixture was then extracted with ethyl acetate (250 ml) and the extract dried (MgSO4), concentrated in vacuo and the residue purified by column chromatography over silica gel eluting with a dichloromethane/methanol gradient to give the title compound (D1) (12.8 g, 72%), NMR (CDCl3; rotamers observed)/ppm 2.12, 2.14 (3H, 2×s), 2.77-2.88 (2H, m), 3.60, 3.74 (3H, 2×t J=7 Hz), 4.59, 4.68 (2H, 2×s), 6.65-6.67 (1H, m), 7.16-7.34 (3H, m), 7.50-7.69 (4H, m), 7.94-7.99 (1H, m); MS: m/z (MH+) 355.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].[OH-].[Na+].C(O)C>O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[N:12][OH:13]
Reactant: NO
Reactant: O=Cc1c(F)cccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1c(F)cccc1F
Temperature: 0 °C
Yield: 110.3 %

Procedure:
In a fashion similar to that for preparation 13, 2,6-difluorobenzaldehyde (5.00 g, 35.2 mmol), hydroxylamine hydrochloride (2.93 g, 29.6 mmol), NaOH (7.04 g in 7.0 ml of water), ethanol (15 ml), water (15 ml), and ice (30 g) afforded 2,6-difluorobenzaldehyde oxime (5.13 g, 93%).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([O:21]CC)=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@H:16]1[F:18].O.S(=O)(=O)(O)O>C(O)(=O)C>[F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@H]2F)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(F)c(F)c(F)c(F)c2c1=O
Temperature: 0 °C

Procedure:
1.35 g (3.9 mmol) of ethyl 5,6,7,8-tetrafluoro-1-(trans-2-fluoro-cyclopropyl)-1,4-dihydro-4-oxo-3quinolinecarboxylate are heated under reflux for 2 hours in a mixture of 6.3 ml of acetic acid, 4.2 ml of water and 0.64 ml of concentrated sulphuric acid. After having been cooled down, this mixture is introduced into 40 ml of ice water and the undissolved precipitate is filtered off, washed with water and dried at 110° C. under high vacuum. Yield: 0.9 g (72% of theory) of 5,6,7,8-tetrafluoro-1-(trans-2-fluoro-cyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 184°-186° C. (with decomposition). 5,6,7,8-Tetrafluoro-1-(cis-2-fluoro-cyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is prepared in an analogous manner.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[CH:10](O)[CH2:11][O:12][CH3:13])[CH2:2][CH3:3].C(Cl)(Cl)[Cl:16].S(Cl)(Cl)=O>ClCl>[CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[CH:10]([Cl:16])[CH2:11][O:12][CH3:13])[CH2:2][CH3:3]
Reactant: ClC(Cl)Cl
Reactant: CCCN1CCCCC1C(O)COC
Agent: ClCl
Solvent: O=S(Cl)Cl
Product: CCCN1CCCCC1C(Cl)COC

Procedure:
In a first stage, 32 g (0.16 mol) of 1-propyl-2-(α-hydroxy-β-methoxyethyl)piperidine were introduced into a reactor containing 320 ml of anhydrous chloroform, the mixture was brought to 50° C. and 32 ml of thionyl chloride in 32 ml of chlorine were added dropwise, and the mixture was then heated under reflux for 10 h 30 min. After separation and distillation, 24.25 g of 1-propyl-2-(α-chloro-β-methoxyethyl)piperidine were obtained, of boiling point B.p.0.5 95° C.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([O:15]CC)=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][CH:20]([OH:32])[CH2:19][NH:18][C:13](=[O:15])[CH2:12][O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COc1cccc2c1CCCC2
Solvent: CCO
Product: O=C(COc1cccc2c1CCCC2)NCC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 5.5 %

Procedure:
To a stirred mixture of ethyl 2-((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)acetate (150 mg, 0.641 mmol) in EtOH (2 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (132 mg, 0.641 mmol). The mixture was stirred at 120° C. for 0.5 hours under microwave heating. After evaporation of the solvent, the residue was purified by prep-HPLC to afford the desired target product N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)acetamide (14 mg, Yield 6%). 1H NMR (400 MHz, MeOD) δ=7.13-7.00 (m, 5H), 6.74 (d, J=7.8 Hz, 1H), 6.65 (d, J=8.3 Hz, 1H), 4.53 (s, 2H), 4.02 (quin, J=5.9 Hz, 1H), 3.72-3.63 (m, 2H), 3.53-3.45 (m, 1H), 3.39 (d, J=6.3 Hz, 1H), 2.96-2.86 (m, 2H), 2.83-2.69 (m, 6H), 2.56 (d, J=6.3 Hz, 2H), 1.84-1.74 (m, 4H). LCMS (m/z): 395.1 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:9]=[C:8]([NH:10]C(=O)C(C)(C)C)[CH:7]=[CH:6][CH:5]=1)[CH3:3].Cl.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O>[NH2:10][C:8]1[N:9]=[C:4]([CH:2]([OH:1])[CH3:3])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1cccc(NC(=O)C(C)(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(O)c1cccc(N)n1
Temperature: 100 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
To a solution of N-[6-(1-hydroxyethyl)pyridin-2-yl]-2,2-dimethylpropanamide (2.0 g, 9.6 mmol) in dioxane (20 mL) was added 9 N aqueous HCl (10 mL). The reaction mixture was warmed to 100° C. for 24 h. After cooling to 25° C., the solution was neutralized with solid NaOH until pH=9 and diluted with EtOAc (50 mL). The resulting mixture was washed with saturated aqeuous NaHCO3(2×30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was dissolved in dichloromethane (10:1, 5 mL). Diethyl ether (10 mL) was added, and the solution was allowed to stand for 24 h. The resulting crystals were filtered and rinsed with diethyl ether (2×10 mL) to afford the above-titled intermediate as a white solid (0.65 g, 49%). 1H NMR (400 MHz, CDCl3), δ: 7.43 (t, J=7.5 Hz, 1H), 6.59 (d, J=7.3 Hz, 1H), 6.39 (d, J=8.1 Hz, 1H), 4.72 (q, J=6.3 Hz, 1H), 4.43 (bs, 2H), 4.21 (bs, 1H), 1.45 (d, J=6.3 Hz, 3H); LRMS (ESI): m/z: 139.1.
Reaction SMILES: CN(C)[C:3](=[O:5])[CH3:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([CH3:34])[CH:25]=1)=[CH2:23].CC1C=C(C)C=C(C)N=1>ClCCCl>[CH3:34][C:26]1[CH:25]=[C:24]([CH:22]2[CH2:4][C:3](=[O:5])[CH2:23]2)[CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: C=Cc1ccc(C(=O)OC)c(C)c1
Reactant: CC(=O)N(C)C
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCCl
Product: COC(=O)c1ccc(C2CC(=O)C2)cc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a solution of N,N-dimethylacetamide (5.5 mL) in DCE (20 mL) under nitrogen at −15° C. was added a solution of trifluoromethanesulfonic anhydride (10 mL) in DCE (50 mL) dropwise. The mixture was then stiffed for 10 min at −15° C. to make solution A. To another flask was added methyl 4-ethenyl-2-methylbenzoate (compound 231.1, 5.30 g, 0.03 mol, 1.00 equiv). A solution of 2,4,6-trimethylpyridine (5.5 mL) in DCE (80 mL) was added dropwise at −15° C. The resulting mixture was added into solution A dropwise under an inert atmosphere of nitrogen. The resulting solution was stiffed overnight at 80° C. After cooling to ambient temperature, the mixture was carefully quenched with water. The resulting mixture was extracted with 2×200 mL of ethyl acetate, and the combined organic layers were washed with 3×400 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:50-1:5) as eluent to furnish 2.95 g (45%) of methyl 2-methyl-4-(3-oxocyclobutyl)benzoate as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([N+:29]([O-])=O)=[C:18]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:32].[CH:33](OCC)(OCC)OCC>Cl.CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]4[N:29]=[CH:33][N:20]([CH2:21][CH2:22][N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[C:18]=4[CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:32]
Reactant: Cc1cc(-c2ncccc2-c2ccc([N+](=O)[O-])c(NCCN3CCOCC3)c2)ccc1F
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2ncccc2-c2ccc3ncn(CCN4CCOCC4)c3c2)ccc1F
Temperature: 65 °C

Procedure:
The above residue containing 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-morpholinoethyl)-2-nitrobenzenamine was added DMA (1 mL), triethyl orthoformate (250 uL) and treated with one drop of concentrated HCl. The homogeneous solution was heated at 65° C. for 15 hours in a sealed vial. The reaction was cooled and the volatiles were removed with a stream of nitrogen gas. The residue was triturated with aq. NaHCO3, resulting solid collected by filtration and purified by HPLC to yield 25 mg of the desired product 6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1-(2-morpholino ethyl)-1H-benzo[d]imidazole. 1H NMR (DMSO-d6): δ 8.58 (dd, J=4.7, 1.6 Hz, 1H), 8.15 (s, 1H), 7.84 (dd, J=7.8, 1.6 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.43 (dd, J=7.8, 4.7 Hz, 1H), 7.28 (d, J=4.8 Hz, 2H), 7.05 (dd, J=8.3, 1.5 Hz, 1H), 7.03-6.75 (m, 2H), 4.19 (t, J=6.4 Hz, 2H), 3.55-3.36 (m, 4H), 2.44-2.15 (m, 6H), 2.06 (s, 3H). MS (m/e): 417 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH:19]([CH3:21])[CH3:20]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][CH:19]([CH3:21])[CH3:20])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(Br)cc1C=O
Temperature: 70 °C

Procedure:
To a solution of 5-bromo-2-hydroxybenzaldehyde (7.63 g) in dimethylformamide (40 ml) was added anhydrous potassium carbonate (15.7 g) followed by 1-bromo-2-methylpropane (6.2 ml). The resulting mixture was heated to 70° C. for 18 h. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with 2N sodium hydroxide, dried (MgSO4) and evaporated to give an oil which was purified by column chromatography eluting with ethyl acetate/iso-hexane (10:90) to give 5-bromo-2-isobutoxybenzaldehyde (9.52 g) as an oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].CCN(C(C)C)C(C)C.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([S:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[Cl:22])(=[O:31])=[O:30])[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(S(=O)(=O)c2ccccc2Cl)C1
Reaction time: 14 h
Yield: 86.4 %

Procedure:
To a solution of 3.87 g piperidine-3-carboxylic acid ethyl ester hydrochloride (commercially available) (20 mmol) in 40 mL DCM was added 10 mL of DIPEA (60 mmol). At room temperature 2.72 mL 2-chloro-benzenesulfonyl chloride (20 mmol) was added drop wise and stirred for 14 h. The mixture was diluted with 30 mL of DCM, washed with water (3×50 mL) and the organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain the crude product which was further purified by column chromatography on silica eluting with 10% ethyl acetate in hexane to yield 5.73 g (86.3%) of the title compound. (MH+) 332.16.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[N:20]O)[CH3:19])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni].O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([NH2:20])[CH3:19])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=NO)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2
Agent: [Ni]
Solvent: CO
Solvent: O
Product: CC(N)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2
Reaction time: 3 h
Yield: 75.7 %

Procedure:
A solution of 7-(1-hydroxyiminoethyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (1.0 g, 3.44 mmol) in MeOH (50 ml) was hydrogenated for 1 h under a pressure of 44 psi, in presence of 50% RaNi/H2O (2 mL). Additional catalyst was added (1 mL) and the hydrogenation proceeded for 3 hours. The catalyst was filtered off and filtrate evaporated. The crude product was chromatographed (SiO2, 15% of 2.0M NH3/MeOH in CH3CN) to provide 0.72 g (76%) of the title compound as a white solid. m.p: 61-64° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:53])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:54]([NH:64][CH2:65][C:66](O)=[O:67])([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55]>>[C:54]([NH:64][CH2:65][C:66]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:53])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:67])([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55]
Reactant: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-octadecanamide and N-carbobenzoxy-glycine.