Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:24][CH2:25][C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:39])=[C:33]([CH:38]=1)[C:34]([O:36]C)=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].Cl>C1COCC1.[OH-].[Na+]>[C:1]([NH:24][CH2:25][C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:39])=[C:33]([CH:38]=1)[C:34]([OH:36])=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCC(=O)Nc1ccc(O)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCC(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 45.2 %

Procedure:
Methyl 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoate (0.9 g, 1.7 mmol) was dissolved in THF (15 mL) and 1N NaOH (8 mL). The reaction was stirred (50° C., 5 h), and then acidified to pH 3 with 2N HCl. The product was extracted with ethyl acetate, and the combined organic extracts were washed with water, brine and dried over MgSO4. The crude material was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to afford 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoic acid (0.40 g) as a yellow solid. Mass calculated for C31H40N2O5=520.66; found: [M+H]+=521.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([I:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O.C(OCC)(=O)C>[I:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:14])([F:23])[F:24])[CH:17]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc2c(Cl)nccc2c1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(Oc3cccc(C(F)(F)F)c3)nccc2c1I
Temperature: 170 °C
Yield: 73.5 %

Procedure:
1-Chloro-5-iodo-6-methylisoquinoline (0.250 g, 0.824 mmol), 3-(trifluoromethyl)phenol (0.200 g, 1.24 mmol), cesium carbonate (0.590 g, 1.81 mmol) were all placed in a clear microwave vial along with 3 ml of DMSO. The vial was capped and heated in a Personal Chemistry SmithSynthesizer to 170° C. for 20 minutes. The reaction was diluted with water and ethyl acetate. The organic layer washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 60-100% EtOAc in hexanes to give 5-iodo-6-methyl-1-(3-(trifluoromethyl)phenoxy)isoquinoline (0.260 g, 73.6% yield) as a white solid. MS (M+H)+ 430.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:3]=1[CH2:4][N:5]([CH3:16])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:38]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])#[N:39]>CS(C)=O.[Cu]I>[CH2:8]([O:7][C:6]([N:5]([CH2:4][C:3]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:2]=1[CH:40]([C:38]#[N:39])[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH3:16])=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1Br)C(=O)OCc1ccccc1
Reactant: CCOC(=O)CC#N
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCOC(=O)C(C#N)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 80.2 %

Procedure:
36A (3.000 g, 7.91 mmol), copper(I) iodide (0.301 g, 1.582 mmol), L-proline (0.364 g, 3.16 mmol) and cesium carbonate (5.16 g, 15.82 mmol) were mixed in a pressure vial and degassed (3× vacuum/Ar). Then, a solution of ethyl 2-cyanoacetate (1.059 mL, 9.89 mmol) in DMSO (10 mL) was added, the reaction mixture was degassed again and stirred at 50° C. for 3 days. The cooled reaction mixture was partitioned between EtOAc (100 mL) and sat. NH4Cl (100 mL). The organic layer was washed with brine (2×50 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography to give 36B (2.609 g, 6.34 mmol, 80% yield) as a yellowish syrup. MS (ESI) m/z: 412.2 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 8.24 (1H, d, J=8.03 Hz), 8.14 (1H, br. s.), 7.79 (1H, d, J=8.53 Hz), 7.29-7.43 (5H, m), 5.67 (1H, br. s.), 5.18 (2H, s), 4.50-4.86 (2H, m), 4.14-4.29 (2H, m), 2.90 (3H, s), 1.27 (3H, t, J=7.15 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:16]([O-])([O-:18])=[O:17].[K+].S(=O)(=O)(O)O.[OH-].[Na+]>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([N+:16]([O-:18])=[O:17])[C:7]=1[O:8][CH3:9]
Reactant: COC(=O)CCc1ccc(OC)c(Br)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)CCc1cc(Br)c(OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
A solution of Intermediate 20 (3.20 g) in acetic anhydride (25 ml) was added with potassium nitrate (1.30 g) under ice cooling and stirred for 10 minutes, and the solution was added dropwise with concentrated sulfuric acid (730 μl) over 10 minutes. The reaction mixture was stirred for 10 minutes for 10 minutes at the same temperature, then warmed to room temperature, and further stirred for 30 minutes. The reaction mixture was poured into 1 N aqueous sodium hydroxide (250 ml) containing ice, and extracted with isopropyl ether (200 ml×2). The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=10:1) to obtain the title compound (Intermediate 21, 2.73 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:23])[C:9]1[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][C:10]=1[O:21][CH3:22].Br[CH2:25][CH:26]([OH:30])[CH2:27][CH2:28]Br>>[OH:30][CH:26]1[CH2:27][CH2:28][N:1]([CH:2]2[CH2:6][CH2:5][CH2:4][CH:3]2[NH:7][C:8](=[O:23])[C:9]2[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:19])([F:20])[F:18])=[CH:11][C:10]=2[O:21][CH3:22])[CH2:25]1
Reactant: OC(CBr)CCBr
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N1CCC(O)C1

Procedure:
The title compound, colorless gum, MS: m/e=419.2 [(M+H)+], was prepared in accordance with the general method of example 10 from N-((1RS,2SR)-2-amino-cyclopentyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate O) and 1,4-dibromo-2-butanol.
Reaction SMILES: NC1N(CC2C=CC=CC=2Cl)N=NC=1C(N)=O.N1C=CC=CC=1.C(Cl)(=O)C(C)(C)C.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][N:39]1[C:43]([NH:44][C:45](=O)[C:46]([CH3:49])([CH3:48])[CH3:47])=[C:42]([C:51]([NH2:53])=[O:52])[N:41]=[N:40]1>CN(C)C(=O)C.O>[C:46]([C:45]1[NH:44][C:43]2[N:39]([CH2:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[Cl:31])[N:40]=[N:41][C:42]=2[C:51](=[O:52])[N:53]=1)([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)C(=O)Nc1c(C(N)=O)nnn1Cc1ccccc1Cl
Agent: CC(C)(C)C(=O)Cl
Agent: NC(=O)c1nnn(Cc2ccccc2Cl)c1N
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)c1nc(=O)c2nnn(Cc3ccccc3Cl)c2[nH]1
Temperature: 155 °C

Procedure:
5-amino-1-(2-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide (10.80 g, 42.9 mmol, Eq: 1.00) was suspended in N,N-dimethylacetamide (50.2 g, 54.0 ml). Pyridine (5.1 g, 5.19 ml, 64.4 mmol, Eq: 1.5) was added followed by pivaloyl chloride (7.84 g, 8.00 ml, 64.4 mmol, Eq: 1.5) and the reaction mixture was heated to ca 80° C. After 3 h reaction (and complete conversion of the starting material to the intermediate), KHCO3 (21.6 g, 215 mmol, Eq: 5.00) was added and the suspension was heated to Tj=155° C. for 24 h to convert the 1-[(2-chlorophenyl)methyl]-5-(2,2-dimethylpropanoylamino)triazole-4-carboxamide intermediate to the product. The reaction mixture was cooled to RT and water (254 g, 254 ml) was added dropwise over 30 min. The brown suspension was cooled to 0° C., stirred for 1 h30 min and was filtered. The filter cake was washed with water (43.2 g, 43.2 ml) and dried at 500° C./5 mbar to give 11 g of the title compound as an off-white powder. MS(m/e): 318.0 (MH+).
Reaction SMILES: [CH:1]([C:4]1[N:9]=[CH:8][C:7]2[N:10]=[C:11]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[NH:12][C:6]=2[CH:5]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:31][CH3:32]>CN(C=O)C.O>[CH2:31]([N:10]1[C:7]2[CH:8]=[N:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=2[N:12]=[C:11]1[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[CH3:32]
Reactant: CCI
Reactant: CC(C)c1cc2[nH]c(Cn3ccnc3-c3nccs3)nc2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cc(C(C)C)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-isopropyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-1H-imidazo[4,5-c]pyridine (160 mg, 0.493 mmol) in DMF (1.0 mL) at room temperature under N2 is added Cs2CO3 (168 mg, 0.518 mmol) followed by iodoethane (0.047 mL, 0.592 mmol). The mixture is stirred at room temperature for 1 h and then diluted with water and extracted twice with CH2Cl2. The combined extracts are dried over K2CO3 and concentrated. The residue is purified by preparative TLC, developing with 15:1 CHCl3-MeOH (+0.5% Et3N). The less polar (top) band affords 3-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-3H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3, 300 MHz) δ 8.70 (d, J=1.2 Hz, 1H), 7.83 (d, J=3.0 Hz, 1H), 7.53 (d, J=0.9 Hz, 1H) 7.39 (d, J=3.0 Hz, 1H), 7.18 (d, J=0.9 Hz, 1H), 7.14 (d, J=0.9 Hz, 1H), 6.32 (s, 2H), 4.32 (q, J=7.2 Hz, 2H), 3.18 (sept, J=6.9 Hz, 1H), 1.34 (d, J=6.9 Hz, 6H), 1.17 (t, J=7.2 Hz, 3H) ppm. The more polar (bottom) band affords 74 mg (43%) of 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3, 300 MHz) δ 9.01 (s, 1H), 7.83 (d, J=3.2 Hz, 1H), 7.38 (d, J=3.2 Hz, 1H), 7.15 (s, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 6.32 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 3.17 (sept, J=6.8 Hz, 1H), 1.34 (d, J=6.8 Hz, 6H), 1.10 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: C(OC(=O)C)C.[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][O:17][C:18](=[O:32])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])=[CH:23][CH:22]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.I.[NH2:41][C:42]1[C:43]([C:50]([NH:52][C:53](=[NH:56])SC)=[O:51])=[N:44][C:45]([Cl:49])=[C:46]([NH2:48])[N:47]=1>C1COCC1>[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][O:17][C:18](=[O:32])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:53]([NH2:56])=[N:52][C:50]([C:43]2[C:42]([NH2:41])=[N:47][C:46]([NH2:48])=[C:45]([Cl:49])[N:44]=2)=[O:51])=[CH:25][CH:26]=1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCOC(=O)COc1ccc(CCCCN)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCOC(=O)COc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
A solution of [4-(4-aminobutyl)phenoxy]acetic acid 2-tert-butoxycarbonylaminoethyl ester ethyl acetate 45a (50 mg, 0.27 mmol) and triethylamine (0.27 mL, 1.53 mmol) in anhydrous THF (4 mL) was stirred at 55° C. (oil bath) for 15 min. To the solution was added 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (130 mg, 0.34 mmol) in two portions during a period of 15 min. The reaction mixture was stirred at 55° C. for 1 h and cooled to room temperature. The mixture was concentrated by rotary evaporation. The crude residue was purified by flash silica gel column chromatography eluting with dichloromethane/methanol/concentrated ammonium hydroxide (200:10:0, 200:10:1, and 150:10:1, v/v) to give (4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)acetic acid 2-tert-butoxycarbonylaminoethyl ester 46a (PSA 25309) as a yellow solid (60 mg, 76% yield). An analytical pure sample was obtained by semi-preparative HPLC purification (acetonitrile/water). mp 80-82° C. 1H NMR (300 MHz, CD3OD) δ 1.45 (s, 9H), 1.60-1.78 (m, 4H), 2.56-2.66 (m, 2H), 3.30-3.38 (m, 4H), 4.15-4.21 (m, 2H), 4.64 (s, 2H), 6.81 (d, 2H), 7.10 (d, 2H). m/z (ESI) 579 [C25H35ClN8O6+H]+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>CC(C)=O.O>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([C:16]([N:32]=[N+:33]=[N-:34])=[O:18])[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCc1coc2ccc(C(=O)O)cc12
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1coc2ccc(C(=O)N=[N+]=[N-])cc12
Reaction time: 0.25 h

Procedure:
The acid (1 mmol) obtained in Step A is dissolved in acetone. The temperature of the reaction mixture is lowered with the aid of an ice bath, and triethylamine (1.5 mmol) and then ethyl chloroformate (1.5 mmol) are added. After stirring for 15 minutes, sodium azide (1.5 mmol), previously dissolved in water (1 ml of water per 400 mg of sodium azide), is added and stirring is again carried out for 10 minutes. The mixture is extracted with ethyl acetate, and the organic phase is then washed with water, dried over magnesium sulphate and evaporated to dryness. The azide obtained is used, without additional purification, in the following Step.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12]C)[CH2:6][CH2:5]1.I[C:38]1[CH:43]=[CH:42][N:41]([CH2:44][C:45]([F:48])([F:47])[F:46])[C:40](=[O:49])[CH:39]=1>>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:38]3[CH:43]=[CH:42][N:41]([CH2:44][C:45]([F:47])([F:46])[F:48])[C:40](=[O:49])[CH:39]=3)=[CH:18][CH:19]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=c1cc(I)ccn1CC(F)(F)F
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccn(CC(F)(F)F)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 4-iodo-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.871 min, m/z=471.1; 1H NMR (CDCl3) 1.11 (s, 3H), 1.17 (s, 3H), 1.53 (d, 3H), 2.16-2.33 (m, 4H), 2.35-2.47 (m, 1H), 2.89 (m, 1H), 4.58-4.70 (m, 2H), 5.69 (m, 1H), 6.71 (s, 1H), 7.00 (d, 2H), 7.19-7.38 (m, 8H). Recrystallization from isopropyl acetate following a procedure analogous to that described for Example 37 in Recrystallization Method B afforded a crystalline solid with mp 144-145.5° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][CH:11]=1)[CH3:5].[CH3:13][O:14][CH2:15]Cl.O>CN(C)C=O>[CH3:13][O:14][CH2:15][O:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][CH:11]=1)[CH3:5]
Reactant: COCCl
Reactant: Cc1ccc(C(C)O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOC(C)c1ccc(C)nc1
Reaction time: 0.25 h
Yield: 81.4 %

Procedure:
Sodium hydride in oil (60%, 7.0 g) was added with ice-cooling to a solution of 5-(1-hydroxyethyl)-2-methylpyridine (20.0 g) in N,N-dimethylformamide (120 ml). The mixture was stirred for 15 minutes. Then, chloromethyl methyl ether (14.1 g) was added dropwise at the same temperature. The reaction mixture was further stirred for 30 minutes with ice-cooling. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and subjected to distillation under reduced pressure to obtain 5-(1-methoxymethoxyethyl)-2-methylpyridine (21.5 g, yield: 81%), b.p. 78°-80° C./0.8 mmHg.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=O)=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[BH4-].[Na+].[CH2:21](O)[CH3:22]>O>[CH2:21]([CH:14]([OH:16])[CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:11][CH:10]=1)[CH3:22]
Reactant: CCO
Reactant: CCOC(=O)CCc1ccc(C(=O)OCC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(CCC(O)CC)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
The ethyl 3-(4-carboethoxyphenyl)propionate (1.23 g, 4.91 mmol) was dissolved in 11 ml of absolute ethanol, cooled in an ice bath, and treated with 0.25 ml of a 2 N cupric sulfate solution in water. Sodium borohydride (0.93 g, 24.6 mmol) was added in small portions over one hour. The reaction was stirred at room temperature over night and then evaporated. The residue was slurried in brine and extracted twice with chloroform. The extracts were filtered through celite, dried over MgSO4, and concentrated to afford 1.0 g (98%) of the subtitle compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][NH2:14])=[O:12].C(=O)([O-])O.[Na+].[N:20]#[C:21]Br>O1CCOCC1.O.C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[O:12][C:21]([NH2:20])=[N:14][N:13]=1
Reactant: NNC(=O)c1ccc2ccccc2c1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: Nc1nnc(-c2ccc3ccccc3c2)o1
Reaction time: 0.08 h
Yield: 19.1 %

Procedure:
To a stirred solution of naphthalene-2-carboxylic acid hydrazide (0.6 g, 3.22 mmol, prepared as described in example 1) in dioxane (20 ml) was added a solution of sodium hydrogen carbonate (0.27 g, 3.22 mmol) in water (15 ml) and the resulting mixture was stirred for 5 min. To the reaction mixture was added cyanogen bromide (0.35 g, 3.3 mmol) and the mixture was stirred for 3 h at room temperature. The precipitate was filtered off and washed with diethyl ether (2×15 ml) and dried in vacuo at 50° C. affording 0.4 g of crude product which was suspended in absolute ethanol (15 ml) and stirred at reflux temperature for 0.5 h. The cooled suspension was filtered and the filter cake was dried in vacuo at 50° C. affording 130 mg (20%) of the title compound as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH2:10][C:9](=[N:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.N#N>C1COCC1.[Pd]>[NH2:1][C:4]1[CH2:10][C:9](=[N:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: NC1=C([N+](=O)[O-])CC(=NCc2ccc(F)cc2)C=C1
Agent: [Pd]
Agent: N#N
Solvent: C1CCOC1
Product: NC1=C(N)CC(=NCc2ccc(F)cc2)C=C1
Reaction time: 8 h
Yield: 99.5 %

Procedure:
According to a procedure similar to that of Preparation example 1, intermediate 2-nitro-4-(N-parafluorobenzyl-imino)-aniline was obtained by using o-nitro paraphenylene diamine and parafluorobenzaldehyde as starting materials. 2-nitro-4-(N-parafluorobenzyl-imino)-aniline (2.61 g, 0.01 mol) was dissolved in THF (30 mL) and air therein was replace with N2. Then Pd—C (10%, 261 mg) was rapidly added and N2 therein was replaced with H2. The hydrogenation reaction was conducted overnight, and the resulting reaction solution was filtered and concentrated to produce a product of 2-amino-4-(N-parafluorobenzyl-imino)-aniline (2.3 g, 99.6%, colorless oil, instable, prone to be oxidized and deteriorated), which was rapidly used in nest step. 1H NMR (300 MHz, CDCl3): δ 7.32 (t, J=8.7 Hz, 2H), 7.02 (t, J=8.7 Hz, 2H), 6.58 (d, J=8.7 Hz, 1H), 6.01-6.08 (m, 2H), 4.22 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:25]([O:22][CH2:21][C:20]([CH3:24])([CH3:23])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])(=[O:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)OCc1ccccc1)C(C)(C)CO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OCC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
To a solution of (S)-benzyl 2-(tert-butoxycarbonylamino)-4-hydroxy-3,3-dimethylbutanoate (0.3 g) in DCM (3 mL) was added DMAP (0.109 g, 0.889 mmol) and acetic anhydride (0.084 mL, 0.889 mmol). The reaction mixture was stirred at rt for 16 hrs, then diluted with EtOAc, washed with sat. NaHCO3, water, sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield an oil. The crude product was purified by silica gel chromatography (0-100% EtOAc in hexane) to yield (S)-benzyl 4-acetoxy-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoate (0.31 g). LC/MS (Cond. N-1): [M+Na]+ 402.22, RT=3.821 min.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN([CH:18]=[O:19])C>C1COCC1>[CH:1]1([CH2:7][O:8][C:9]2[N:10]=[C:11]([CH:18]=[O:19])[CH:12]=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1cnc(OCC2CCCCC2)nc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1ccnc(OCC2CCCCC2)n1
Reaction time: 0.25 h

Procedure:
Knochel-Hauser reagent (2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex) is added to a mixture of 2-(cyclohexylmethoxy)pyrimidine in THF at −78° C., stirred for 15 min, then DMF is added. The reaction mixture is stirred at −30° C., quenched by aqueous NH4Cl, extracted with ethyl acetate. Combined organic layers are dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 2-(cyclohexylmethoxy)-pyrimidine-4-carbaldehyde.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1>>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([N:8]([C:3]2[CH:2]=[CH:1][C:6]([NH2:7])=[CH:5][CH:4]=2)[C:10]2[CH:15]=[CH:14][C:13]([N:16]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)[C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)=[CH:12][CH:11]=2)=[CH:2][CH:1]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Nc1ccc(N)cc1
Product: Nc1ccc(N(c2ccc(N)cc2)c2ccc(N(c3ccc(N)cc3)c3ccc(N)cc3)cc2)cc1

Procedure:
Such a diimonium compound can be synthesized, for example, as follows. That is, an Ullmann reaction product of p-phenylenediamine and 1-chloro-4-nitrobenzene, is reduced to obtain N,N,N′,N′-tetrakis(p-aminophenyl)-p-phenylenediamine which is then dissolved in N,N-dimethylformamide, and an alkyl bromide is added thereto, followed by a reaction, for example, at 130° C. for 10 hours.