Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][N:5]([CH:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:33])=O)[CH:20]=[C:19]1[CH2:34][C:35]([NH2:37])=[O:36])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].[Cl-].[NH4+].C[N:41](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[CH2:1]([O:4][N:5]([CH:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C@H:21]([C:31](=[O:33])[NH2:41])[CH:20]=[C:19]1[CH2:34][C:35]([NH2:37])=[O:36])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1CC(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1CC(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2S)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-(2-amino-2-oxoethyl)-1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridine-2-carboxylic acid (crude, 2.79 g, 5.16 mmol), ammonium chloride (552 mg, 10.32 mmol), HATU (3.93 g, 10.32 mmol) in DMF (20 mL) at 0° C., was added DIPEA (2.67 g, 20.65 mmol). After stirring at room temperature for 1 hr, 50 mL EtOAc and 50 mL water was added. The organic layer was washed with water, brine and dried over MgSO4, filtered and concentrated to give a residue, which was purified on silica gel column eluting with 0-100% ethyl acetate/hexanes to afford an off-white solid, 1.36 g, 49%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:19]([OH:21])=O)[CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@H](C(O)=O)CC1SC=CC=1)=O)C1C=CC=CC=1.C(OC(Cl)=O)C(C)C.[C:51]([NH2:55])([CH3:54])([CH3:53])[CH3:52]>C1COCC1>[C:51]([NH:55][C:19](=[O:21])[C@H:12]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:54])([CH3:53])[CH3:52]
Reactant: O=C(NC(Cc1cccs1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)N
Agent: CC(C)COC(=O)Cl
Agent: O=C(N[C@@H](Cc1cccs1)C(=O)O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@H](Cc1cccs1)NC(=O)OCc1ccccc1
Reaction time: 0.29 h
Yield: 97 %

Procedure:
Into a 500 ml flask was placed 8.06 9 of the subtitled compound of Example A, N-(Benzyloxycarbonyl)-3-(2-thienyl)-L-alanine, in 130 ml of THF. The compound was cooled to 0°0C. N-Methylmorpholine (4.23 ml) was added, followed by isobutylchloroformate (4.04 ml) over two minutes. The mixture was stirred for 15-20 minutes, and 3.74 ml of t-butylamine was added. The bath was removed, and the mixture was stirred at room temperature for two hours. The mixture was concentrated on rotovap, and the residue was taken up in ethyl acetate. The residue was washed successively with H2O, HCl, and saturated NaHCO3 solution. The organics were separated and dried with Na2SO4, filtered, and concentrated to an oil. The oil was dissolved in 100 ml hot hexane and cooled in a refrigerator overnight to give a solid. The hexane was decanted, followed by drying to yield a solid of 9.25 g N-(carbobenzyloxy)-3-(2-thienyl)-L-alanine-tert-butylamide (97% yield).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][CH2:7][C:8]#[N:9].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>O>[C:8]([CH2:7][NH:6][C:13](=[O:14])[O:15][CH2:16][CH3:17])#[N:9]
Reactant: CCOC(=O)Cl
Reactant: N#CCN
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)NCC#N
Temperature: 25 °C
Yield: 96.8 %

Procedure:
Aminoacetonitrile sulfate (H2NCH2CN.1/2H2SO4, 121.5 g, 1.156mole) was dissolved in water (230.9 g) and the solution was cooled to 0° to 5° C. and adjusted to pH 5 to 7 by the addition of a small amount of 30% aqueous sodium hydroxide solution. Ethyl chloroformate (108.5 g, 1.00 mole) and 30% aqueous sodium hydroxide solution were concurrently added dropwise with stirring and keeping pH at 5 to 7 at 0° to 5° C. over 2 hours and the mixture was stirred at the same temperature for additional 2 hours while keeping the same pH by dropping, if necessary, 30% aqueous sodium hydroxide solution. The total amount of 30% aqueous sodium hydroxide solution was 294.3 g. The reaction mixture was extracted three times with toluene (485 ml). The toluene layer was dried over anhydrous magnesium sulfate, toluene was evaporated and the residue was cooled to room temperature to give crystals (124.7 g, 0.968 mole) of ethyl N-cyanomethylcarbamate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]3[CH2:19][CH2:18]3)[CH:15]=2)[CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:24]1[N:29]=[CH:28][C:27]([S:30]([NH:33][C@@H:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])(=[O:32])=[O:31])=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:17]1([C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[C:9]([C:24]4[CH:25]=[CH:26][C:27]([S:30](=[O:32])(=[O:31])[NH:33][C@@H:34]([CH3:39])[C:35]([F:37])([F:36])[F:38])=[CH:28][N:29]=4)[N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:12][CH:13]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(C3CC3)cc21
Reactant: C[C@H](NS(=O)(=O)c1ccc(Cl)nc1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: C[C@H](NS(=O)(=O)c1ccc(-c2cc3ccc(C4CC4)cc3n2C(=O)OC(C)(C)C)nc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A mixture of 1-(tert-butoxycarbonyl)-6-cyclopropyl-1H-indol-2-ylboronic acid (1.10 g, 3.64 mmol), (S)-6-chloro-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (1.05 g, 3.64 mmol), PdCl2(dppf) (178 mg, 0.22 mmol), aq. K2CO3 (2 M, 5.46 mL, 10.9 mmol) in acetonitrile (8 mL) was stirred at 50° C. overnight. The solvent was then evaporated and the residue purified on silica gel eluting with 0 to 10% ethyl acetate in CH2Cl2 to provide (S)-tert-butyl 6-cyclopropyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-1-carboxylate (1.51 g, 81% yield). MS m/z 510.3 M+H+; 1H NMR (500 MHz, CDCl3): δ 9.65 (1H, s), 8.50 (1H, m), 8.01 (1H, d, J=8.2 Hz), 7.85 (1H, s), 7.52-7.49 (2H, m), 6.98 (1H, d, J=8.2 Hz), 4.98 (1H, d, J=8.4 Hz), 4.02 (1H, m), 2.02-1.98 (1H, m), 1.34 (3H, d, J=7.5 Hz), 0.98-0.96 (2H, m), 0.76-0.72 (2H, m).
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(OCC)(=O)C.[ClH:24]>C(OCC)(=O)C>[ClH:24].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)SC1CCNCC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
In 45 ml of ethyl acetate were dissolved 1.25 g (4.82 mmol) of 4-(acetylthio)-1-(tert-butoxycarbonyl)piperidine as described in Reference example 11, and 12.0 ml (48.2 mmol) of a 4N hydrogen chloride-ethyl acetate solution were added to the solution, followed by stirring of the resulting mixture at 50° C. for 4 hours. After cooling, the precipitated solid was collected by filtration and washed with hexane to obtain 885 mg (yield: 94%) of the desired compound as a slightly yellow powder.
Reaction SMILES: C(O)(=O)C.[N+]([O-])(O)=O.[CH2:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH2:10][CH3:11].[Br:21]Br>O.[N+]([O-])([O-])=O.[Ag+]>[CH2:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[Br:21])[CH2:10][CH3:11]
Reactant: BrBr
Reactant: CCCc1ccc(C(=O)O)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CCCc1ccc(C(=O)O)cc1Br
Reaction time: 3 h

Procedure:
To a mixture of 150 ml of glacial acetic acid, 33 ml of concentrated nitric acid and 25 ml of water, were added 8.2 g (0.05 moles) of parapropyl benzoic acid and 8.8 g (0.055 moles) of bromine. Then, at a temperature of 25° C., and over a period of half an hour, a solution of 8.5 g (0.05 moles) of silver nitrate in 25 cc of water was added. The solution was stirred for three hours, thirty minutes following which the suspended solid was removed by filtration and rinsed until neutral. Thereafter, the acid was dissolved in ethanol. Recrystallization from hexane yielded 4-propyl-3-bromo-benzoic acid.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH2:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>S([O-])([O-])(=O)=O.[Cu+2]>[CH2:11]([CH:10]1[CH2:9][CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=CCCCCCCCC
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Product: CCCCCCCCC1CC1C(=O)OCC
Reaction time: 2 h

Procedure:
A mixture of 60 g of ethyl diazoacetate and 100 g of decene was added drop-by-drop to a stirred suspension of 4 g of anhydrous copper sulfate in 700 g of decene, at 105° C. The addition required 1.5 hours. The mixture was stirred for an additional 2 hours, then filtered, and the filtrate was distilled, to give 1, as a liquid, bp: 107°-110° C. (0.1 Torr.).
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1)=[C:2]=S.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:15][C:14]1[C:9]([O:8][C:7]2[CH:16]=[CH:17][C:4]([NH:1][C:2]3[O:25][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=3)=[CH:5][CH:6]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccnc1Oc1ccc(N=C=S)cc1
Reactant: Nc1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1cccnc1Oc1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 75 °C

Procedure:
The mixture of 2-(4-isothiocyanatophenoxy)-3-methylpyridine (136 mg, 0.56 mmol), 2-aminophenol (74 mg, 0.67 mmol), and N,N′-dicyclohexylcarbodiimide (174 mg, 0.84 mmol) in THF (5 mL) was heated at 75° C. for 16 h. The solvent was evaporated and the crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide N-(4-(3-methylpyridin-2-yloxy)phenyl)benzo[d]oxazol-2-amine as white solid. MS (ESI, pos. ion) m/z: 318.1 (M+1).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C:11]3=[CH:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C:11]3=[CH:12][CH2:13][C@@H:14]2[OH:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3C4=CCC(=O)[C@@]4(C)CC[C@@H]32)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3C4=CC[C@H](O)[C@@]4(C)CC[C@@H]32)C1
Temperature: -10 °C
Reaction time: 7.5 h

Procedure:
i)—A solution of (3β)-3-(acetyloxy)androsta-5,14-dien-17-one [Andre, A. F. St. et al, J. Am. Chem. Soc. 74, 5506 (1952); 42.9 g] in dry ethanol (429 ml) was cooled to −10° C. Sodium borohydride (1.51 g) in dry ethanol (33.5 ml) was added and the mixture was stirred at −10° C. for 7.5 h. Excess sodium borohydride was destroyed by careful addition of an aqueous solution of acetic acid (50%). The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate and concentrated. Column chromatography provided (3β,17β)-androsta-5,14-diene-3,17-diol 3-acetate (19.5 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH2:7])[CH2:2]1.[Cl-].[Na+].[CH3:10][NH:11][C:12](=[N:15][N+:16]([O-:18])=[O:17])OC.Cl>O.C(#N)C>[CH3:10][NH:11][C:12]([NH:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[N:15][N+:16]([O-:18])=[O:17]
Reactant: CNC(=N[N+](=O)[O-])OC
Reactant: NCC1CCOC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNC(=N[N+](=O)[O-])NCC1CCOC1
Reaction time: 4 h

Procedure:
[(3-tetrahydrofuryl)methyl]amine (38.0 g, 0.38 mole), 31.3 g of sodium chloride and 125.0 g of water were mixed, and the resulting mixture was cooled to −10 degree centigrade. N,O-dimethyl-N′-nitroisourea (49.2 g, 0.37 mole) was introduced into the above solution. Sodium chloride was dissolved in water with 76% of the saturated solubility at a water temperature of −10 degree centigrade. The suspension was stirred at −10 degree centigrade for 4 hours and then heated to 10 degree centigrade, and further stirred for 19 hours. 35% hydrochloric acid (6.7 g, 0.07 mole) was added to the suspension so that the pH became not more than 4. Water and acetonitrile were added to the above suspension for complete dissolution. The resulting solution was analyzed by HPLC and as a result, the reaction yield of the titled compound was 88%.
Reaction SMILES: [CH3:1][N:2]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1.C(Cl)(=O)C(Cl)=O.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][NH:35][CH3:36]>C(Cl)Cl.CN(C=O)C>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][N:35]([CH3:36])[C:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=2)(=[O:13])=[O:14])[CH2:8][CH2:7]1)=[O:11]
Reactant: CN([C@H]1CC[C@H](C(=O)O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CNCCN(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)CCN(C)C(=O)[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 1.5 h

Procedure:
A solution of 0.137 g (0.375 mmol) of trans-4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexanecarboxylic acid in 2 mL of CH2Cl2 was treated at RT with 1 drop of DMF, followed by 0.035 mL (0.412 mmol, 1.1 eq) of oxalyl chloride within 5 min, and stirring was continued for 90 min. The solution was evaporated, redissolved in 2 mL of CH2Cl2 and treated with 0.058 mL (0.450 mmol, 1.2 eq) of N,N,N′-trimethylethylenediamine at 0° C. The reaction was kept at RT for 2 h, then partitioned between Et2O (×3)/aqueous saturated NaHCO3. The organic phases were washed once with 10% aqueous NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on 8 g of silica gel (CH2Cl2:MeOH 99:1 to 9:1) gave 0.088 g (53%) of pure trans-4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexanecarboxylic acid (2-dimethylamino-ethyl)-methyl-amide, MS: 450 (MH+), MP: 83° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[C:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@@H:3]([CH2:2][NH:1][C:24](=[O:25])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:4]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CNC(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(S)-tert-Butyl 3-(aminomethyl)piperidine-1-carboxylate (1.00 g, 4.67 mmol) was dissolved in 14 mL anhydrous CH2Cl2 under an N2 atmosphere and cooled to 0° C. Triethylamine (1.30 mL, 945 mg, 9.34 mmol) was added followed by the dropwise addition of benzyl chloroformate (0.99 mL, 1.20 g, 7.00 mmol). After 16 h, the reaction mixture was partitioned between H2O and CH2Cl2, and separated, and the aqueous layer was extracted twice with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to a light yellow oil. Purification via silica gel chromatography using 97% CH2Cl2/3% MeOH gave benzyl ((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate as a clear, colorless oil (895 mg, 55%). LC/MS: m/z 349.5 (M+H)+ at 3.21 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]3[CH2:20][CH2:19][CH2:18][N:17]=[C:9]23)=[CH:4][CH:3]=1
Reactant: ClCCCNc1nc2ccccc2n1-c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(N2C3=NCCCN3c3ccccc32)cc1

Procedure:
1-(4-Chlorophenyl)-2-(3-chloropropylamino)benzimidazole (5mM) is added to a stirred solution of sodium methoxide (0.01 mole) in methanol (50 ml.) and the mixture heated under reflux for 5 hours. After removal of the methanol the residue is diluted with water, extracted with chloroform and the combined extracts washed and dried over magnesium sulphate. Evaporation gives the title compound as an oil which affords a salt on treatment with a suitable acid in an anhydrous medium.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].CCN(C(C)C)C(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])=[O:5]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1ccccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution of 2-chloronicotinoyl chloride (2.91 g, 16.6 mmol) in ethyl acetate (50 mL) was added to a mixture of 2-aminophenol (2.00 g, 18.3 mmol) and DIPEA (4.8 mL, 27.5 mmol) in ethyl acetate (50 mL) at 4° C. The reaction mixture was stirred for 1 hour. The organic mixture was washed with water and brine then concentrated under reduced pressure. The residue was dissolved in ethanol/THF 1:1 (75 mL) and 15% sodium hydroxide (25 mL) and the mixture was stirred at 50° C. for 45 min. The mixture was cooled down to room temperature and concentrated in vacuo to one third volume and then acidified to pH=2 with 3M HCl. The solid was filtered, washed with water and dried to afford title compound 13 (3.69 g, 81%) as a beige solid. LRMS (ESI): (calc) 248.04 (found) 249.2 (MH)+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.Cl.Cl.[CH:39](NC1C=C(C=CC=1)OC1C=CC2N=C(COC3C=CC(CC4SC(=O)NC4=O)=CC=3)N(C)C=2C=1)([CH3:41])[CH3:40]>CC(C)=O>[CH:39]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)([CH3:41])[CH3:40]
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: CC(C)Nc1cccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)c1
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)Nc1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1

Procedure:
5-(4-(6-(4-Amino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride (Japanese Patent Application (Kokai) No. Hei 11-193276) was used in place of 5-(4-(6-(3-isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride of Production Example 4, and acetone was used in place of acetaldehyde to give the title compound in similar manner to Production Example 4.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2].[CH:20]1([Mg]Br)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:20]1([CH:8]([C:7]2[CH:6]=[C:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:11]=3)[S:4][C:3]=2[CH2:1][CH3:2])[OH:9])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 2-ethyl-5-[4-(trifluoromethyl)phenyl]thiophene-3-carbaldehyde (2.00 g) synthesized above in tetrahydrofuran (40 mL) was added dropwise 1.0M cyclohexylmagnesium bromide-tetrahydrofuran solution (14.1 mL) at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane to ethyl acetate:hexane=1:4, volume ratio) to give the title compound (2.29 g, 88%) as a yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].[OH-].[Na+]>C(Cl)Cl.O.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[CH2:8]([N:7]1[CH2:2][CH2:3][CH2:4][C:5]1=[O:6])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CCCCl)NCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C1CCCN1CCc1ccccc1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
To a solution of HJC-1-48 (4.2 g, 18.6 mmol) in DCM/H2O (20 mL/8 mL) was added (n-Bu)4NBr (0.3 g, 0.9 mmol) and NaOH (3.7 g, 93.0 mmol). The resulting mixture was stirred at 100° C. for 7 h. The mixture was partitioned between EtOAc (200 mL) and H2O (10 mL). The organic layer was separated and washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give an oil residue. This residue was purified with silica gel column (Hexane/EtOAc=1/1 to 1/2) to obtain HJC-1-53 (4.2 g, 93%) as a pale yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.26-7.30 (m, 2H), 7.18-7.22 (m, 3H), 3.53 (t, 2H, J=7.8 Hz), 3.25 (t, 2H, J=7.2 Hz), 2.84 (t, 2H, J=7.8 Hz), 2.34 (t, 2H, J=7.8 Hz), 1.92-1.97 (m, 2H).
Reaction SMILES: OC1C=CC=C2[C:11]=1[N:10]=CC=C2.[C-:12]#[N:13].[K+].[Cl:15][C:16]1[C:17](=[O:28])[C:18]2[CH:19]=[CH:20][CH:21]=[N:22][C:23]=2[C:24](=[O:27])[C:25]=1[Cl:26]>O.C1COCC1.CO>[Cl:15][C:16]1[C:17](=[O:28])[C:18]2[CH:19]=[CH:20][CH:21]=[N:22][C:23]=2[C:24](=[O:27])[C:25]=1[Cl:26].[C:12]([C:16]1[C:17]([OH:28])=[C:18]2[C:23](=[C:24]([OH:27])[C:25]=1[C:11]#[N:10])[N:22]=[CH:21][CH:20]=[CH:19]2)#[N:13]
Reactant: [C-]#N
Reactant: Oc1cccc2cccnc12
Agent: O=C1C(Cl)=C(Cl)C(=O)c2ncccc21
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1c(C#N)c(O)c2ncccc2c1O
Reaction time: 0.03 h
Yield: 69 %

Procedure:
6,7-Dichloro-5,8-quinolinedione 2 was prepared in low yield from commercially available 8-hydroxyquinoline 1 by modification of a literature procedure (Shaikh, I. A.; Johnson, F.; Grollman, A. P. J. Med. Chem. 1986, 29, 1329). A solution of potassium cyanide (1.02 g; 16 mmol) in water (3 mL) was added to a boiling solution of the dichloroquinone 2 (794 mg; 3.48 mmol) in THF/methanol (1:1, 40 mL) and heating was continued for a further 2 min. The reaction mixture was concentrated to half-volume and diluted to the original volume with water. Hydrochloric acid (10 M) was added cautiously [Caution: HCN fumes] causing the reaction mixture to change from an olive-green solution to a pale brown suspension. The solid was filtered off, washed with water and air dried overnight thereby affording the dinitrile 3 as a chocolate-brown solid (509 mg, 69%). 1H NMR (CDCl3) δ 7.73 (1H, dd, J=8.6, 4.2 Hz), 8.75 (1H, dd, J=8.6, 1.5 Hz), 9.14 (1H, dd, J=4.2, 1.5 Hz), 13C NMR (d6-DMSO) δ 92.8, 93.1, 115.2, 115.4, 124.4, 125.1, 133.2, 141.1, 152.4, 152.6, 154.4.