Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](C1CC(=O)OC1=O)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([CH:24]1[CH2:29][C:28](=[O:30])[NH:27][C:25]1=[O:26])=CCCCCCC.[NH2:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][NH:40][CH2:41][CH2:42][NH2:43]>O.C(O)(C)C>[CH:1]([N:27]1[C:28](=[O:30])[CH2:29][CH2:24][C:25]1=[O:26])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32][NH2:31]
Reactant: CCCCCCC=CC1CC(=O)OC1=O
Reactant: CCCCCCC=CC1CC(=O)NC1=O
Agent: NCCNCCNCCNCCN
Solvent: CC(C)O
Solvent: O
Product: CCCCCCC=CN1C(=O)CCC1=O
Temperature: 142 °C

Procedure:
N-octenyl succinimide of tetraethylene pentamine was prepared by placing one mole of the amine in a reaction flask fitted with an additional funnel containing one mole of n-octenyl succinic anhydride, a water collector, a stirring and heating means and a reflux condenser. While stirring the amine, the anhydride in the funnel was slowly added to the flask. Upon completion of the addition, the resulting reaction mixture was heated to about 142 degrees C. where water of reaction started to distill over. At about 130 degrees C., the resulting reaction product, viz., n-octenyl succinimide of tetraethylene pentamine, was a clear bright orange liquid. About one mole of water was collected in the collector signifying that the imide-forming reaction was complete. The flask and its contents were then cooled to about 80 degrees C. and sufficient isopropanol and distilled water were added to yield a solution which was: (i) 40 volume percent isopropanol, (ii) about 60 volume percent water and (iii) about 30 weight percent imide. Into this solution, based upon the total weight of the solution, about 1 weight percent mono-9-octadeceneoate of poly (oxy-1, 2-ethanediyl) sorbitol (about 20 ethanediyl groups) surfactant was added to facilitate effective dispersion of the imide agent when added to cooling water. The flask and its contents were maintained at about 80 degrees C. with stirring until a clear solution resulted. The cooled solution was ready for use in accordance with the invention.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH2:11]([O:13][C:14]([C:16]1[C:17](=[O:39])[C:18]2[CH:23]=[N:22][C:21](S(C)(=O)=O)=[N:20][C:19]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1[C:17](=[O:39])[C:18]2[CH:23]=[N:22][C:21]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][CH:5]=3)=[N:20][C:19]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN(C)c1ccc(N)cc1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N(C)C)cc3)ncc2c1=O
Yield: 46.7 %

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-dimethylaminoaniline (5 μL, 0.036 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 15 mg, 0.036 mmol). 7.9 mg of 2-(4-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.31 (br, 1H), 8.53 (s, 1H), 7.82 (d, 1H), 7.61 (br, 1H), 7.41 (d, 1H), 7.29 (s, 1H), 7.17 (d, 1H), 6.76 (d, 1H), 6.46 (br, 2H), 4.39 (q, 2H), 3.03 (m, 4H), 2.89 (s, 6H), 2.22 (m, 2H), 1.37 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H27N5O3: 470.21 (M+H), Found: 470.4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH3:20])[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=1.C[Si]([C:25]#[N:26])(C)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH:5][CH:6]([C:7]1[CH:8]=[CH:9][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:11][CH:12]=1)[C:25]#[N:26]
Reactant: Cc1ccc(N=Cc2ccc(S(N)(=O)=O)cc2)cc1C
Reactant: C[Si](C)(C)C#N
Product: Cc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1C

Procedure:
Following a procedure similar to that described in Example 1(ii), but using 3,4-dimethyl-N-(4-sulfamoylbenzylidene)aniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a yellow powder (yield 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[N:15][CH:14]=[C:13]([N:17]([CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH3:18])[N:12]=2)=[N:8][C:7]=1[CH3:29])=[O:5])C.[OH-].[Na+]>O1CCCC1>[F:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][N:17]([CH3:18])[C:13]2[N:12]=[C:11]([C:9]3[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:29])[N:8]=3)[CH:16]=[N:15][CH:14]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1sc(-c2cncc(N(C)CCOc3ccc(F)cc3)n2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(-c2cncc(N(C)CCOc3ccc(F)cc3)n2)sc1C(=O)O
Yield: 92 %

Procedure:
Part C. To a solution of 2-(6-{[2-(4-fluoro-phenoxy)-ethyl]-methyl-amino}-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (220 mg, 0.53 mmol) in tetrahydrofuran (8 mL) was added 1N NaOH (8 mL). The resulting reaction mixture was heated to reflux for 14 hr. The solvent was removed in vacuo, and the residue was neutralized to pH 4-5 with 10% HCl. The resulting precipitate was filtered and dried to afford 2-(6-{[2-(4-fluoro-phenoxy)-ethyl]-methyl-amino}-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid in 92% yield.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][CH2:19][C@@H:20]([CH3:23])[CH2:21][OH:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:11]([O:18][CH2:19][C@H:20]([CH3:23])[CH:21]=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@@H](CO)COCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C=O)COCc1ccccc1
Temperature: -78 °C

Procedure:
An oven dried three-necked 2 L round bottom flask was equipped with a mechanical stirrer, a thermometer, an N2 inlet, and a septum. The flask was charged with 24.050 g (0.189 mol) of oxalyl chloride and 425 mL CH2Cl2. The reaction mixture was stirred under an N2 atmosphere and cooled to −78° C. with an external dry ice-acetone bath. A solution of methyl sulfoxide (29.607 g; 0.379 mol) in 85 mL CH2Cl2 was then added over 5 min to the reaction mixture via cannula. After the adition, the reaction was stirred an additional 5 min and then a solution of 31.048 g (0.172 mol) of (S)-3-benzyloxy-2-methylpropan-1-ol in 170 mL CH2Cl2 was added via cannula. When the second addition was completed the reaction mixture was stirred for 15 min at −78° C. then 111.32 g (0.861 mol) of N,N-diisopropylethylamine was added via syringe. The reaction mixture was stirred an addition 15 min at −78° C., the cooling bath was removed and the reaction was allowed to warm. When the internal temperature had reached −15° C., 350 mL of a 10% aqueous NaHSO4 solution was slowly added and the mixture was transferred to a separatory funnel. The organic layer was separated, washed with aqueous NaHSO4 (2×250 mL), saturated NaCl, dried (MgSO4), filtered and evaporated. The residue was used immediately in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:11][C:12]#[C:13][CH2:14]Cl)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:16][C:17]1[N:25]=[C:24]([NH2:26])[N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:6]([O:5][P:4]([CH2:9][O:10][CH2:11][C:12]#[C:13][CH2:14][N:21]1[CH:20]=[N:19][C:18]2[C:22]1=[N:23][C:24]([NH2:26])=[N:25][C:17]=2[Cl:16])([O:3][CH2:1][CH3:2])=[O:8])[CH3:7]
Reactant: CCOP(=O)(COCC#CCCl)OCC
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(COCC#CCn1cnc2c(Cl)nc(N)nc21)OCC
Temperature: 20 °C
Reaction time: 48 h
Yield: 54.8 %

Procedure:
A mixture of (4-chloro-2-butynyloxy)methylphosphonic acid diethylester (2.03 g, 8 mmol), 6-chloro-2-aminopurine (2 g, 12 mmol) and potassium carbonate (1.85 g, 12 mmol) in anhydrous dimethylformamide (15 ml) is stirred 2 days at 20° C. under argon. The reaction mixture is concentrated in vacuo, and the residue is purified by flash chromatography on silica gel to give the title product (1.7 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].[O:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][CH2:31][C:32]([CH:34]1[C:39](=O)[CH2:38][CH2:37][O:36][CH2:35]1)=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:18]=[C:32]([CH2:31][CH2:30][CH:26]3[CH2:27][CH2:28][CH2:29][O:25]3)[C:34]3[CH2:35][O:36][CH2:37][CH2:38][C:39]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: O=C1CCOCC1C(=O)CCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(Nc2nc3c(c(CCC4CCCO4)n2)COCC3)ccc1-n1cnc(C)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 1.1 %

Procedure:
A reaction mixture of 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (0.305 g, 0.83 mmol, example 7c) and potassium carbonate (0.343 g, 2.48 mmol) in ethanol (3 mL) was stirred at 50° C. for 20 minutes under argon. 3-(3-(tetrahydrofuran-2-yl)propanoyl)dihydro-2H-pyran-4(3H)-one (0.187 g, 0.83 mmol) was added dropwise (neat) over 2 hours and stirred at 50° C. overnight. The solvent was evporated and the residue was partitioned between water and dichloromethane. The water phase was extracted twice with dichloromethane. The combined organic layer was dried over MgSO4, filtered and concentrated. ¼ of the crude was purified by preparative HPLC and concentrated. The residue was partitioned between NaHCO3 (aq) and dichloromethane and the the water phase was extracted twice with dichloromethane, dried (MgSO4) and concentrated giving 4 mg of the product.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.O>[C:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)C(Cc2ccc(C(=O)/C=C/c3ccccc3)cc2)S1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(Cc2ccc(C(=O)CCc3ccccc3)cc2)S1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 82.4 %

Procedure:
To an ice-cooled solution of the title product of Example 39 (2.0 g, 5.9 mmol) in trifluoroacetic acid (20 ml) was added triethylsilane (0.95 ml, 5.9 mmol). The mixture was stirred for 25 minutes at 0° C., then diluted with water (50 ml) and extracted with ether (2×40 ml). The combined extracts were washed with water (2×40 ml) and 5% sodium bicarbonate (2×40 ml), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with hexane to give present title product as a pale yellow solid (1.65 g, 82%); m.p. 119°-121° C.
Reaction SMILES: N[C@H](C(O)=O)C(C)C.C(=O)([O-])[O-].[Na+].[Na+].C(SCC(C)C(Cl)=O)(=O)C.C([S:28][CH2:29][CH:30]([CH3:41])[C:31]([NH:33][C@H:34]([C:38]([OH:40])=[O:39])[CH:35]([CH3:37])[CH3:36])=[O:32])(=O)C>O>[SH:28][CH2:29][CH:30]([CH3:41])[C:31]([NH:33][C@H:34]([C:38]([OH:40])=[O:39])[CH:35]([CH3:36])[CH3:37])=[O:32]
Reactant: CC(=O)SCC(C)C(=O)N[C@H](C(=O)O)C(C)C
Agent: CC(=O)SCC(C)C(=O)Cl
Agent: CC(C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Product: CC(CS)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
L-valine (88 g.) and sodium carbonate (40 g.) are dissolved in water (11.) and the solution is chilled in an ice bath with vigorous stirring. 3-Acetylthio-2-methylpropanoyl chloride (135 g.) and a solution of sodium carbonate (120 g.) in 500 ml. of water are added in five equal portions over a 15 minute period. After 1.5 hours the reaction mixture is extracted with ethyl acetate, the aqueous phase is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The oranic phase is washed with water, dried over magnesium sulfate and concentrated to dryness to yield 190 g. of N-(3-acetylthio-2-methylpropanoyl)-L-valine. The named product is obtained by following the procedure of Example 50.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[C:26]4=[N:27][O:28][C:24]5=[C:25]4[C:16]([C:17](=[O:29])[C:18]4[C:23]5=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:15]([NH:30][C:31]4[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=4)[CH:14]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:41].CO>>[CH:1]1([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[C:26]4=[N:27][O:28][C:24]5=[C:25]4[C:16]([C:17](=[O:29])[C:18]4[C:23]5=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:15]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([C:35]([O-:37])=[O:36])=[CH:38][CH:39]=4)[CH:14]=3)[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[Na+:41]
Reactant: O=C(O)c1ccc(Nc2cc(N3CCN(C4CCCCC4)CC3)c3noc4c3c2C(=O)c2ccccc2-4)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(Nc2cc(N3CCN(C4CCCCC4)CC3)c3noc4c3c2C(=O)c2ccccc2-4)cc1
Reaction time: 1.5 h
Yield: 90 %

Procedure:
About 80 g of 4-((3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoic acid was slurred in 2500 mL of 0.4 M NaOH/MeOH between 40-45° C. for 2-4 hours. After confirmed the reaction completion by HPLC, slowly cooled the reaction to room temperature. The solid was centrifuged and washed with 20 mL of MTBE. The wet cake was re-suspended in about 1000 mL of 0.1M NaOH in MeOH solution under room temperature. It was centrifuged and washed with 224 mL of MTBE again. The filtered solid was suspended in 996 mL of MTBE under room temperature for 1-2 hours. The solid was separated and dried at 25-30° C. under pressure for 12-24 hours to obtain the final desired product with purity more than 99% and about 90% yield. Mass spectra give [M+1]=523.2. 1H-NMR (400 MHz, DMSO-d6, see FIG. 3), ppm (δ): 11.79 (1H, s), 8.48 (1H, d), 8.20 (1H, d), 7.93 (2H, d), 7.84 (1H, t), 7.72 (1H, t), 7.35 (2H, d), 6.39 (1H, s), 3.85 (4H, m), 2.72-2.70 (4H, m), 2.28-2.265 (1H, m), 1.72-1.78 (4H, m), 1.55-1.58 (1H, m), 1.08-1.23 (5H, m). Sodium content is 3.8%. The Raman spectrum is shown in FIG. 5. The XRPD, see Table below and FIG. 4, confirmed the polymorphic form.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].[OH-].[Na+]>O1CCCC1.O>[CH3:15][O:14][N:13]([CH3:12])[C:8](=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CNOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
Based on a procedure found in the literature (Guanti, G.; Banfi, L.; Riva, R. Tetrahedron 50(41), 1994, 11945-11966), a solution of phenylacetic acid (10 g, 73 mmol) in tetrahydrofuran (150 mL) is combined with a solution of N,O-dimethylhydroxylamine hydrochloride (13 g, 130 mmol) in water (150 mL). The pH is adjusted to 4.5 by the addition of 1 N aqueous sodium hydroxide solution. To the mixture is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine hydrochloride (36 g, 190 mmol) as a solution in water (510 mL) dropwise over 30 minutes. Over the course of the addition, pH is maintained at 4.5 by the addition of 1 N aqueous sodium hydroxide solution. The reaction mixture is allowed to stir for 3 hours at room temperature and is then saturated with sodium chloride and extracted thrice with ethyl acetate. The combined extracts are washed with saturated aqueous sodium hydrogen carbonate (×2), water, and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a golden liquid (13 g, 100%). MS (ES+): (M+H)=180.1
Reaction SMILES: C(O)(=O)C.[O:5]([CH2:12][C:13]1[CH:14]=[C:15]([NH:19][N:20]=[C:21]([C:23]([NH2:25])=[O:24])[NH2:22])[CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O>O>[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]1[N:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:14]=2)[N:20]=[C:21]([C:23]([NH2:25])=[O:24])[NH:22]1
Reactant: O=Cc1ccccc1F
Reactant: NC(=O)C(N)=NNc1cccc(COc2ccccc2)c1
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)C1=NN(c2cccc(COc3ccccc3)c2)C(c2ccccc2F)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
Into 15 ml of acetic acid saturated with nitrogen, 2.84 g (0.01 mol) of oxamide 3-(phenoxymethyl)phenylhydrazone was dissolved, and 1.36 g (0.011 mol) of 2-fluorobenzaldehyde was added to the thus formed solution under nitrogen atmosphere and the mixture was stirred for 16 hours at room temperature. After adding water saturated with nitrogen to the mixture, the precipitated crystals were collected by filtration and dried under vacuum. The thus dried crystals were recrystallized from a mixed solvent, saturated with nitrogen, of ethyl acetate and n-hexane to obtain 3.38 g of 5-(2-fluorophenyl)-4,5-dihydro-1-[3-(phenoxymethyl)phenyl]-1H-1,2,4-triazole-3-carboxamide melting at 176°-178° C. in a yield of 86.7%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:10]=1[CH2:11][NH:12][C:13]1[C:14]([C:19]#[N:20])=[N:15][CH:16]=[CH:17][CH:18]=1>O1CCCC1>[NH2:20][CH2:19][C:14]1[C:13]([NH:12][CH2:11][C:10]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:9]=2[O:8][CH3:7])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: COc1ccc(CNc2cccnc2C#N)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CNc2cccnc2CN)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
Lithium aluminum hydride (1.0 M in THF, 13.3 mL, 13.3 mmol) was added slowly to a solution of 3-[(2,4-dimethoxybenzyl)amino]pyridine-2-carbonitrile (3.25 g, 12.1 mmol) in tetrahydrofuran (40 mL) at 0° C. The reaction was warmed to room temperature and stirred for 4 h. The reaction was carefully quenched with a saturated aqueous solution of sodium sulfate, filtered with copious dichloromethane and concentrated to produce the title compound (2.68 g). MS 274,3 (M+1).
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C>O1CCCC1>[CH:1]1([C:5]([NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:24])=[CH:18][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1
Reactant: O=C(Cl)C1CCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ccnc(NC(=O)C3CCC3)c2)cc1
Temperature: 25 °C

Procedure:
After adding 70 mg of cyclobutanecarbonyl chloride to a solution of 100 mg of N-[4-(2-aminopyridin-4-yl)oxyphenyl]-N′-(4-fluorophenyl)urea, 0.12 ml of triethylamine and 10 ml of tetrahydrofuran stirred at room temperature, the mixture was further stirred for 15 minutes. NH type silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (chloroform:methanol=40:1). The obtained residue was solidified from ethyl acetate-methanol-hexane to obtain 64 mg of the target substance as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:16]1(I)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O.[Cu]I>[C:16]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc(-n2ccc3ccccc32)cc1
Yield: 86.2 %

Procedure:
A mixture of indole (500 mg, 4.27 mmol), copper(I) iodide (122 mg, 0.64 mmol), cesium carbonate (1.9 g, 6 mmol) and phenyliodide (470 μL, 4.2 mmol) in anhydrous N,N-dimethylformamide (10 mL) was refluxed for 24 hours under a nitrogen atmosphere. The reaction mixture was then filtered and concentrated in vacuo. The residue was partitioned between dichloromethane (30 mL) and water (10 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to afford the desired product (5a) as a yellow oil (700 mg, 3.62 mmol, 86%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.C([O-])([O-])=O.[K+].[K+].C(N1C2C(=CC=CC=2)C=C1C1C=COC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:22]2[CH:23]=[CH:24][S:20][CH:21]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cccs1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1c(-c2ccsc2)cc2ccccc21
Yield: 75 %

Procedure:
N-Benzenesulfonyl-3-iodoindole (11), 2-thiopheneboronic acid, Pd(PPh3)4 and K2CO3 in toluene are allowed to react in the same manner as described in the preparation of compound 3 to give 0.33 g (75%) of 13: 1H NMR (CDCl3): δ7.97 (d, 1H, J=8.16 Hz), 7.79–7.16 (m, 3H), 7.70 (s, 1H), 7.18–7.46 (m, 7H), 7.03–7.08 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O.[CH2:28](O)[CH2:29][OH:30]>S(=O)(=O)(O)O>[OH:30][CH2:29][CH2:28][O:19][C:18](=[O:20])[C@@H:17]([CH3:21])[N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: OCCO
Reactant: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: C[C@H](C(=O)OCCO)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 54 %

Procedure:
A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.22 g, 0.014 mole) and concentrated sulfuric acid (4 drops) in ethylene glycol (50 ml) was refluxed under nitrogen for three hours, and then poured into a saturated sodium bicarbonate solution (200 ml). Water (50 ml) was added and the product was extracted into three portions of ethyl acetate. The combined organic layers were washed twice with water and once with a saturated sodium chloride solution, dried over magnesium sulfate, treated with charcoal, filtered, and evaporated under reduced pressure to give 2.6 g (54% yield) of an oily glass. The glass was dissolved in hot isopropyl ether (with a little isopropyl alcohol added), filtered while hot, and cooled to room temperature with stirring, causing a solid to precipitate. The mixture was cooled in the freezer, and the solid was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at room temperature to give 1.60 g of title compound, mp. 110°-113° C.