Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C:13](OCC)=[O:14])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C>>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH2:13][OH:14])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C/C=C/c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: OC/C=C/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
Ethyl (2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienoate was treated with diisobutyl aluminum hydride in the same manner as in Reference example 21 to obtain the title compound in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Br:11][CH2:12][C:13](Br)=[O:14].O>CN(C=O)C.O1CCOCC1>[Br:11][CH2:12][C:13]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:14]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(CBr)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A solution of 4-aminobenzoic acid (5.0 g, 0.036 mol) in anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) was cooled to 0° C. in a 250 mL 3-necked flask which was fitted with a constant additional funnel. Bromoacetyl bromide (7.36 g, 3.2 mL, 100 mol %) was added dropwise, keeping the internal temperature between 0° C. and 2° C. After the addition was completed (~30 min), the reaction mixture was stirred overnight at rt. Water (100 mL) was added, and then the light crystalline compound which precipitated was filtered, washed with 5% HBr, washed several times with water (200 mL), and then dried in a vacuum oven for 20 h at 40°-45° C., affording 9.3 g (99%) of the title compound: mp 245°-246.7° C.; 1H NMR (DMSO-d6) δ10.6 (s, 1H, NH), 7.91 (d, 2H, J=8.8), 7.69 (d, 2H, J=8.4), 4.10 (s, 2H); 13C NMR (DMSO-d6) δ168.88, 165.38, 142.62, 130.53, 125.78, 118.62, 30.30; MS (EI, m/z) 257 (M+), 258.9 (M+ 2+). HRMS (EI) calcd for C9H8NO3Br 256.9686, found 256.9677. Anal. Calcd. for C9H8NO3Br: C, 41.88; H, 3.12; N, 5.43. Found: C, 41.97; H, 3.19; N, 5.42.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17]>CC(C)=O>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: ClC[C@@H]1CO1
Solvent: CC(C)=O
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and stannic chloride (78.3 g. 0.30 mol) were added to 100 mL of acetone. The mixture was stirred at 25° C. for 30 minutes. (S)-epichlorohydrin (18.6 g, 0.2 mol) was then added and stirred at 60° C. for 8 hours. The mixture was filtered and the solvent was evaporated to provide 55 g of colorless oil with 94% yield. HPLC: 99.2%.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].[CH2:18]([C@H:20]1[O:22][CH2:21]1)[Cl:19]>C1(C)C=CC=CC=1>[Cl:19][CH2:18][C@@H:20]([OH:22])[CH2:21][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClC[C@@H]1CO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and lithium chloride (12.6 g, 0.30 mol) were added to 100 mL of toluene. The mixture was stirred at 25° C. for 30 minutes. (S)-epichlorohydrin (18.6 g, 0.2 mol) was then added and stirred at 60° C. for 8 hours. The mixture was filtered and the solvent was evaporated to provide 52 g of colorless oil in 90% yield. HPLC: 99.3%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1.O>CS(C)=O>[CH3:22][CH:23]1[NH:24][CH2:25][CH2:26][N:27]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[C:7](=[O:18])[C:8]3=[CH:9][C:10]=2[F:17])[CH2:28]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC1CNCCN1
Solvent: CS(C)=O
Solvent: O
Product: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 55 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
Thirty five grams of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid and 24.9 g (2.1 eq) of 2-methyl piperazine were suspended in DMSO (700 mL) under nitrogen atmosphere. The mixture was heated to 55° C. during 24 hours. Subsequently, water (70 mL) was added, the reaction mixture was cooled to 2° C. and left at this temperature for 5 hours. The solution was filtered, washed with acetonitrile and dried under vacuum to obtain 30.3 g after assay (68% yield) of gatifloxacin.
Reaction SMILES: C1COCC1.[H-].[Na+].[CH2:8]([OH:11])[CH2:9][OH:10].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(OCC)C>[Si:12]([O:10][CH2:9][CH2:8][OH:11])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: OCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCO
Reaction time: 0.75 h

Procedure:
154 ml of dry THF and 1.88 g NaH are stirred under in a nitrogen atmosphere in a 500 ml round bottom flask condenser. 4.4 mL dry ethylene glycol are added into the flask, resulting in a large precipitate after 45 minutes of stirring. 11.8 g tert-butyldimethylsilyl chloride is added to the flask and vigorous stirring is continued for 45 minutes. The resulting mixture is poured into 950 mL ethylether. The ether is washed with 420 mL brine and solution is dried with sodium sulfate. The product is concentrated by evaporation of the ether in vacuo and purified by flash chromatography using a 27×5.75 cm column charged with silica gel using a hexanes/Et2O (75:25 v/v) solvent system. The product is stored at 0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([N+:14]([O-:16])=[O:15])=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[CH:17]1([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([N+:14]([O-:16])=[O:15])=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:28]1[CH2:27][CH2:26][CH:25]([C:23]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:24])[CH2:30][CH2:29]1)=[O:8]
Reactant: O=C(C1CCCCC1)C1CCNCC1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(C(=O)C3CCCCC3)CC2)c([N+](=O)[O-])cc1OC

Procedure:
10.3 g of 3,4-dimethoxy-6-nitrobenzoic acid was converted to the corresponding acid chloride as described in Example 43. It was added to a solution containing 8.83 g of 4-cyclohexylcarbonylpiperidine and 4.58 g oftriethylamine in 300 ml of dichloromethane. Yield 16.4 g (90%), m.p. 120°-125° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([CH3:17])[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1.[CH:19]([N-]C(C)C)(C)C.[Li+].C1CCCCC1.CI.C(O)(=O)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]([CH3:19])([CH3:17])[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCCCC1
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
To a solution of (α-methyl-6-methoxy-2-naphthaleneacetic acid methyl ester (12.2 g, 50 mmol) in tetrahydrofuran (100 ml) at -70° C. is added a solution of lithium diisopropylamide in cyclohexane (50 ml, 1.5 equiv). After 20 minutes, methyl iodide (4.0 ml, 1.3 equiv) is added followed by hexamethylphosphoraniide (20 ml). After allowing the reaction mixture to warm to room temperature and stir 16 hours, the reaction is quenched by addition of acetic acid (4.3 ml, 75 mmol). The solvent is then removed and the residue is partitioned between ethyl acetate and water. The organic layer is washed with water 3 times and finally with brine. After drying over magnesium sulfate, the organic extract is evaporated to afford a crude solid. Recrystallization of this solid from hexane affords 8.56 g (66%) of α,α-dimethyl-6-methoxy-2-naphthaleneacetic acid methyl ester as white crystals, m.p. 97°-98° C. A solution of this ester (7.4 g, 28.6 mmol) in 48% HBr (50 ml) and acetic acid (50 ml) is refluxed for 3 hours. After the reaction mixture is cooled to room temperature, 0.8 L of water is added and the reaction mixture is extracted with ethyl acetate 5 times. The combined organic extract is washed sequentially with saturated sodium bicarbonate solution and water. After drying over magnesium sulfate, the organic extract is evaporated to afford 6.1 g (93%) of α,α-dimethyl-6-hydroxy-2-naphthaleneacetic acid as white crystals, m.p. 208°-210° C. The title compound is prepared according to the method of Example 7 using α,α-dimethyl-6-hydroxy-2-naphthaleneacetic acid. A white solid is obtained having a melting point of 207°-209° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:14].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:14])=[O:22]
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1cc(N)c2nccc(C)c2c1
Product: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1

Procedure:
6-Methoxy-4-methyl-8-quinolinamine was converted to the title amide by reaction with 6-bromohexanoyl chloride in the usual manner.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].Cl.[C:6](Cl)(=[O:10])[C:7](Cl)=[O:8]>>[CH3:1][N:2]([O:3][CH3:4])[C:7]([C:6]([N:2]([CH3:1])[O:3][CH3:4])=[O:10])=[O:8]
Reactant: CNOC
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Product: CON(C)C(=O)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.9 %

Procedure:
A mixture of 48.0 g (0.49 mol) of N,O-dimethylhydroxylamine.HCl in 250 mL of 3:2 v/v CH2Cl2pyridine was cooled to −78° C. and was treated with 17.4 mL (0.2 mol) of oxalyl chloride maintaining the internal temperature at less than −70° C. The resulting mixture was allowed to warm to rt and stirred for 20 h. The reaction was quenched with 250 mL of sat'd NaCl and the quenched mixture was extracted with 3×400 mL of CH2Cl2. The extracts were combined, dried over MgSO4 and concentrated. Recrystallization from 250 mL of MTBE afforded 24.28 g (69%) of the title compound: 1H NMR (500 MHz) δ3.25 (s, 6H), 3.75 (s, 6H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:16]=[CH:15][C:14]2[NH:13][C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>CN(C=O)C.N1C=CC=CC=1>[O:17]=[C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[CH:4]=[C:3]([NH:2][C:20](=[O:21])[CH2:19][Cl:18])[CH:16]=[CH:15][C:14]=2[NH:13]1
Reactant: Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 828.4 %

Procedure:
To a suspension of the HCl salt of 2-amino-6(5H)-phenanthridinone (100 mg, 0.04 mmol) in DMF (5 mL), pyridine (0.5 mL) was added, followed by the addition of chloroacetyl chloride (0.2 mL, 0.002 mol) at 0° C. The reaction mixture was stirred at room temperature for 1 to 2 hrs. It was then poured over crushed ice, and the solid obtained was washed thoroughly with cold water. The solid was then dried under vacuum to give N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-choroacetamide (95 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11](=[O:16])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20].[OH-].[Na+]>C1OCCOC1>[Cl:17][CH2:18][C:19]([NH:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11](=[O:16])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1)=[O:20]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Yield: 53 %

Procedure:
Prepared from 2-amino-6(5H)-phenanthridinone 3 and chloroacetyl chloride according to General Procedure A. P-dioxane was used as solvent and 1.1 equivalent of sodium hydroxide as base. A white precipitation was formed after stirring the mixture for 2 ours. Purification of the precipitation by crystallization in dioxane gave a white solid (53% yield), mp 300-303° C. 1H-NMR (400 MHz, DMSO-d6), 11.71 (s, 1H), 10.45 (s, 1H), 8.63 (s, 1H), 8.33 (d, J=7.9 Hz, 1H), 8.27 (d, J=8.2 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.46 (m, 2H), 7.34 (d, J=8.8 Hz, 1H), 4.30 (s, 2H). Anal. (C15H11ClN2O2), C H N.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(=S)=S>[C:14]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCO2
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)CCO2
Reaction time: 1 h

Procedure:
To a stirred solution of 12 g [100 mmole) 2,3-dihydrobenzofuran in 80 ml carbon disulfide was added in portions 30 g (225 mmole) anhydrous aluminum chloride. The mixture was heated at reflux and 18.9 ml (200 mmole) acetic anhydride was slowly added. Refluxing was continued for one hour after the addition was completed. Carbon disulfide was then removed by distillation and the residue was cooled in ice. Cracked ice (100 ml) was slowly added, the reaction mixture was acidified to pH 1 and diluted with water (100 ml) and extracted with ethyl ether (2×250 ml). The extracts were dried (Na2SO4) .and the ether evaporated. The residual oil was purified pn a column of silica gel (600 ml), eluting with 9:1 (v/v) hexane/ethyl acetate, then with a 4:1 (v/v) mixture of the same solvents, and finally with a 2:1 mixture. The product fractions were combined and evaporated to obtain the desired product as an oil; 1H-NMR(CDCl3)ppm(delta): 2.4 (s, 3H), 3.2 (t, 2H), 4.6 (t, 2H), 6.7 (d, 1H), 7.7 (m, 2H).
Reaction SMILES: C(O)=O.[Br:4][C:5]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[O:18]>C(Cl)Cl.Cl>[Br:4][C:5]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C@@H:9]2[OH:18]
Reactant: O=C1CCc2c1ccc(C(F)(F)F)c2Br
Agent: Cl
Solvent: O=CO
Solvent: ClCCl
Product: O[C@H]1CCc2c1ccc(C(F)(F)F)c2Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under argon atmosphere: 1.89 ml (13.6 mmol) TEA are dissolved in 15.0 ml DCM. Under ice cooling 0.59 ml (15.8 mmol) of formic acid are added. At r.t. 100 mg (3.58 mmol) of 4-bromo-5-trifluoromethyl-indan-1-one and 49.6 mg (0.07 mmol) of chloro{[(1S,2S)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}-(mesitylene)-ruthenium(II) are added. The reaction mixture is stirred at r.t. for 48 h. The mixture is diluted with 20 ml 1N aq. HCl. The phases are separated. The aq. phase is washed with DCM. The combined organic layers are washed with brine, dried and the solvent is evaporated. The residue is chromatographed on silica gel (CH/EtOAc=75/25→50/50) to give the title compound. Yield: 1.03 g; LC (method 1): tR=1.01 min.
Reaction SMILES: [OH:1][CH:2]([C:17]1[N:18]=[CH:19][N:20]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([NH:15][CH3:16])=[O:14])[CH:7]=[CH:6]2.CN(C)C(=O)C.C(OC(C)C)(C)C>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[CH3:16][NH:15][C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([C:17]3[N:18]=[CH:19][N:20]([C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:21]=3)=[O:1])[CH:4]=2)[CH:9]=1)=[O:14]
Reactant: CNC(=O)c1ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(=O)N(C)C
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
6-[Hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide (10.0 g, 19.1 mmol) and manganese dioxide (10.0 g, 115.0 mmol) were added to a mixed solvent of N,N-dimethylacetamide (25 mL) and ethyl acetate (63 mL), and the mixture was stirred at 60° C. for 3 hr. The insoluble material was filtered off at the same temperature, and washed with ethyl acetate (60 mL). The filtrate and washing were combined and concentrated to the volume of 30 mL under reduced pressure. To the residue was added dropwise diisopropyl ether (100 mL), and the mixture was stirred at room temperature. The obtained crystals were collected by filtration, and washed with diisopropyl ether (30 mL) to give crude wet crystals (26.4 g). The crude wet crystals (10.8 g) were added to ethyl acetate (54 mL), and the mixture was warmed to 60° C., and stirred for 0.5 hr. The obtained mixture was allowed to cool to room temperature, and diisopropyl ether (108 mL) was added dropwise thereto. The mixture was stirred with cooling to 5° C. The obtained crystals were collected by filtration, and washed with a mixed solvent (27 mL) of diisopropyl ether/ethyl acetate (2:1, volume ratio). The obtained wet crystals were dried under reduced pressure to give N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (8.2 g, 15.7 mmol). yield 82%.
Reaction SMILES: [CH:1]1([C:7]([O:9]C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.O.[NH2:15][NH2:16]>O>[CH:1]1([C:7]([NH:15][NH2:16])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)C1CCCCC1
Solvent: CCO
Solvent: O
Product: NNC(=O)C1CCCCC1
Yield: 58 %

Procedure:
First, 5.0 g of methyl cyclohexanecarboxylate and 50 mL of ethanol were put in a 100 mL three-neck flask, and stirred. Then, 5 mL of hydrazine monohydrate was added to this mixed solution, and heated and stirred at 80° C. for 9 hours to be reacted. The reaction mixture was added to 100 mL of water, and a white solid was precipitated. Ethyl acetate was added to this suspension, whereby an organic layer and an aqueous layer were separated. The resulting organic layer was washed with saturated saline, and then anhydrous magnesium sulfate was added to the organic layer for drying. The resulting mixture was subjected to gravity filtration, and the filtrate was concentrated, so that cyclohexanohydrazide was prepared (a white solid, yield: 58%). The synthetic scheme of Step 1 is shown by (a-3).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4](Cl)[N:3]=1.C([O-])(=O)C.[Na+]>CO.[Pd](Cl)Cl>[C:8]([C:7]1[CH:2]=[N:3][CH:4]=[CH:5][C:6]=1[CH3:10])#[N:9]
Reactant: Cc1cc(Cl)nc(Cl)c1C#N
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccncc1C#N

Procedure:
A mixture of 2,6-dichloro-3-cyano-4-methylpyridine (47 g, 0.25 mol), sodium acetate (41.2 g, 0.5 mol), and palladium (II) chloride (0.5 g) in 220 mL of methanol was hydrogenated on a Parr apparatus under 50 PSI (initial pressure). When the uptake ceased the catalyst was filtered (solka floc) and the filtrate concentrated in vacuo. The crude residue was distilled under vacuum through a Vigreaux column and the product collected at 68°-72° C./2 mm (25.3 g, 85%, as a clear liquid).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Pt]=O>[CH3:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH:7]1[C:8]([OH:10])=[O:9]
Reactant: Cc1ccncc1C(=O)O
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC1CCNCC1C(=O)O
Yield: 114.9 %

Procedure:
4-Methylnicotinic acid (5.0 g, 36.46 mmol) in acetic acid (40 mL) was added to a wet solution of platinum oxide (500 mg) under a nitrogen atmosphere. The suspension was hydrogenated under a hydrogen atmosphere (200 PSI) at room temperature for 18 h. The mixture was filtered through a pad of Celite under nitrogen and the filtrate was concentrated under reduced pressure to afford 4-methylpiperidine-3-carboxylic acid (6.0 g). The material was used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.O[C:11]([CH3:19])([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([NH2:17])[CH3:16].[OH-].[Na+]>[Cl-].[Zn+2].[Cl-].O>[NH2:17][CH:15]([CH2:14][CH2:13][CH2:12][C:11]([C:6]1[CH:7]=[CH:8][C:3]([NH2:2])=[CH:4][CH:5]=1)([CH3:19])[CH3:18])[CH3:16]
Reactant: Nc1ccccc1
Reactant: CC(N)CCCC(C)(C)O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(N)CCCC(C)(C)c1ccc(N)cc1
Yield: 82 %

Procedure:
To a solution of 34 parts of anhydrous zinc chloride in 51 parts of 36& w/w aqueous hydrochloric acid were added 46.5 parts of aniline and 18.2 parts of 6-hydroxy-6-methyl-2-heptylamine hydrochloride. The whole was charged to a 3-necked round bottomed flask fitted with a thermometer, stirrer, and Dean and Stark water separator. The stirred reaction mixture heated by means of an electric heating mantle was raised to a temperature of 185° C. by removal of water (Dean and Stark), and then maintained at this temperature for a further 18 hours. The hot reaction mixture was then poured slowly into a solution of 75 parts sodium hydroxide in 75 parts water and stirred until cool. The organic phase was extracted with ether, washed with water, evaporated and distilled under reduced pressure. After recovering 28 parts of aniline, there was obtained 18 parts of 2-amino-6-(4-aminophenyl)-6-methylheptane b12 192°-199° C. (82% yield based on heptaminol) with the following percentage composition by weight.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][N:5]=1.[CH3:11][OH:12]>>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([O:12][CH3:11])=[N:5][CH:6]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(Br)cn1

Procedure:
Sodium hydride (2.0 g of a 60% dispersion in mineral oil) was added portionwise to methanol (30 ml) with stirring and cooling with an ice-bath. 2,5-Dibromopyridine (2.37 g) was added to the mixture and the mixture stirred at reflux for 16 hours. The methanol was removed by evaporation. Water (15 ml) was added to the residue and the mixture was extracted with dichloromethane (3×15 ml). The organic extracts were combined, dried (MgSO4) and evaporated to give 5-bromo-2-methoxypyridine (2.0 g) as an oil, NMR: 3.85(3H,s), 6.83(1H,d), 7.9(1H,dd) and 8.3(1H,d).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[Cl:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si](C)(C)N[Si](C)(C)C.[Li]>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([Cl:9])=[CH:11][CH:12]=2)=[O:15])[CH:3]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1
Reactant: Cc1cc(Br)ccn1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1cc(Br)ccn1)c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Under a stream of nitrogen, 5 g (29.07 mmol) of 4-bromo-2-methylpyridine and 11.27 g (61.04 mmol) of ethyl 4-chlorobenzoate are placed in a round-bottomed flask and dissolved in 50 mL of anhydrous tetrahydrofuran. The solution is cooled to 5° C. and 70 mL (70 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at room temperature for 2 hours, cooled to 5° C., and 100 mL of water are then gradually added. The medium is then diluted with 250 mL of ethyl acetate and 100 mL of water. The organic phase is separated out and the aqueous phase is extracted twice with 100 mL of ethyl acetate. The organic phases are then combined, dried over sodium sulfate and filtered. 15 g of silica are then added to the filtrate, which is then concentrated under reduced pressure. The powder obtained is used as solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9/1). 8.4 g (93%) of compound are obtained in the faun of a yellow powder.