Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[Na+].CCOC(C)=O>[Pd].CO>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccc(F)cc3)ccc2c1O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1ncc2cc(Oc3ccc(F)cc3)ccc2c1O
Reaction time: 2.5 h
Yield: 97.1 %

Procedure:
A mixture of 1-Bromo-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (4.34 g, 10 mmol, see example A-75d), sodium acetate (984 mg, 12 mmol), Pd/C (2.0 g, 10 wt % Pd, 50 wt % water), EtOAc (400 ml) and MeOH (200 ml) was stirred under an H2-atmosphere at ambient pressure and temperature for 2.5 h before the mixture was filtered through a plug of celite. The celite was washed with EtOAc (500 ml). The combined organic phases were concentrated in vacuo. To the residue was added a half concentrated NaHCO3 solution (50 ml) and the mixture was extracted with CH2Cl2 (1×200 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to yield the title compound as a tan oil (3.45 g); MS-(+)-ion M+1=356.1.
Reaction SMILES: CS(O[C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[CH2:7]1)(=O)=O.[C:31]([O-:34])(=[S:33])[CH3:32].[K+]>CN(C)C=O>[C:31]([S:33][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[C@H:8]([CH2:24][N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[CH2:7]1)(=[O:34])[CH3:32]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CN2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](CN2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (1.84 g) in dimethylformamide (40 ml) was added potassium thioacetate (0.95 g) and the mixture was stirred at 70°-80° C. for 2 hours. The reaction mixture was poured into ice-water (200 ml) and extracted 3 times with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (1.23 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([CH3:30])[C:19]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:28])[Cl:29])[CH:21]=[C:20]([CH3:30])[C:19]=1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][N:8]=1
Reactant: OCCCCOc1ccc(C(F)(F)F)cn1
Reactant: Cc1cc(OCC=C(Cl)Cl)cc(Cl)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a solution of 0.26 g of 2-(4-hydroxybutyloxy)-5-trifluoromethylpyridine, 0.3 g of 2-chloro-6-methyl-4-(3,3-dichloro-2-propenyloxy)phenol and 0.31 g of triphenylphosphine dissolved in 30 ml of dichloromethane was added dropwise a solution of 0.24 g of diisopropyl azodicarboxylate dissolved in 5 ml of dichloromethane, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.50 g of 3-chloro-5-methyl-4-[4-(5-trifluoromethyl-2-pyridyloxy)butyloxy]-1-(3,3-dichloro-2-propenyloxy)benzene (89% yield), nD23.0 1.5275.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH2:5][CH2:6][CH3:7])[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1.O>[C:3]([C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:5][CH2:6][CH3:7])[CH3:8])#[N:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCC(C)(N)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(C)(C#N)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
20 g (178.3 mmol) of rac-2-amino-2-methylpentanonitrile (described in: Deng, S L. et al., Synthesis 2001, 2445-2449; Freifelder, M. et al., J. Am. Chem. Soc. 1960, 696-698) were initially charged in 2.63 l of THF/water (8/1), and 76.4 g (552.7 mmol) of potassium carbonate were added. Then 27.6 ml (196.1 mmol) of benzyl chloroformate were slowly added dropwise at 0° C. and the mixture was stirred at RT overnight. The reaction mixture was concentrated, and the residue was admixed with water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate=4/1). 43.84 g of the target compound were obtained (76% of theory, 76% purity).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1>C(OCC)(=O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(-c2csc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cccc(-c2csc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.2 %

Procedure:
A 4 N solution (50 ml) of hydrogen chloride in ethyl acetate was added to a solution of tert-butyl 4-[4-(3-methoxyphenyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate (2.63 g, 7.00 mmol) in ethyl acetate (50 ml), the mixture was stirred at room temperature for 20 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in water, neutralized with a 1 N sodium hydroxide aqueous solution, and extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1.43 g (74.3%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19](C(OCC(Cl)(Cl)Cl)=O)[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]=[CH:7][C:6]=2[CH:30]=1.[OH-].[Na+]>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]=[CH:7][C:6]=2[CH:30]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC(=C2c3ccc(Cl)cc3C=Cc3cccnc32)CC1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)C=Cc1cccnc1C2=C1CCNCC1
Reaction time: 2 h
Yield: 53 %

Procedure:
A mixture of 210 mg (0.434 mmole) of 8-chloro-11-[1-(2,2,2-trichloroethoxycarbonyl)-4-piperidylidene)-11H-benzo-[5,6]cyclohepta[1,2-b]pyridine and 526 mg (8.05 mmole) of zinc dust in 0.4 mL of acetic acid was heated at 60°-70° C. After 2 hr. 20 min. another 547 mg (8.37 mmole) of zinc dust was added. After another 30 min. the mixture was basified with 10% aqueous NaOH and extracted four times with CH2Cl2. The combined organic portions were washed once with water, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography [5→6% MeOH/NH3 in CHCl3 ] to yield 71 mg (53%) of the title compound as a glass.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([F:17])=[CH:10]1)=[N:5]2.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:27][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([F:17])=[CH:10]1)=[N:5]2
Reactant: CN1CCN(CCN)CC1
Reactant: Fc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Product: CN1CCN(CCNc2c3ccc(Cl)cc3nc3ccc(F)cc23)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-fluoroacridine and 2-(4-methylpiperazin-1-yl)ethanamine, the title compound was obtained; MS (Found M+1=373).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11]I)=[CH:4][CH:3]=1.[Cl:20][C:21]1[C:26]2[N:27]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:28](=[O:30])[NH:29][C:25]=2[CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[Cl:20][C:21]1[C:26]2[N:27]([CH:31]3[CH2:36][CH2:35][N:34]([CH2:11][CH2:10][CH2:9][CH:8]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:33][CH2:32]3)[C:28](=[O:30])[NH:29][C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: Fc1ccc(C(CCCI)c2ccc(F)cc2)cc1
Reactant: O=c1[nH]c2cccc(Cl)c2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2cccc(Cl)c2n1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 7.4 parts of 1,1-bis(-4-fluorophenyl)-4-iodobutane, 5 parts of 7-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 5 parts of sodium carbonate and 56 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. After cooling, the reaction mixture is poured onto water. The organic layer is separated, dried, filtered and concentrated to half its volume. From the residue, the product is allowed to crystallize. The product is filtered off and recrystallized from a mixture of 4-methyl-2-pentanone and 2-propanol, yielding 7-chloro-1-{1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 215.4° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[C:18]2[N:17]=[C:16]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:15]([CH2:28][CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:14]=2[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:43]1([CH2:49][CH2:50][CH2:51]Br)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C)C=O>[CH3:8][O:9][C:10]1[C:18]2[N:17]=[C:16]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:15]([CH2:28][CH2:29][CH2:30][CH:31]3[CH2:32][CH2:33][N:34]([CH2:51][CH2:50][CH2:49][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:35][CH2:36]3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCNCC1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(CCCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
A solution of 4-methoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole trifluoroacetate (177 mg, 0.29 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), and brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by column chromatography to yield the title product as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][C:22]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:23])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCCC(=O)O)cc2)=C(C)C1=O
Reactant: C1CCNCC1
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCCC(=O)N3CCCCC3)cc2)=C(C)C1=O
Yield: 32.1 %

Procedure:
4-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid (50 mg, 0.14 mmol) obtained in Example 26 and piperidine (0.015 ml, 0.15 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (19 mg, 0.045 mmol, yield 32%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.[CH3:12][NH:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH3:12])=[O:11]
Reactant: O=C(O)CCCCCCCBr
Reactant: CCCCNC
Product: CCCCN(C)C(=O)CCCCCCCBr

Procedure:
Using the procedure of Step A of Example 3, 5 g of 8-bromo octanoic acid and 13 ml of N-methyl butylamine were reacted to obtain after chromatography on silica (eluant: methylene chloride-acetone 95-5), 6.14 g of the expected product.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2O)(=[O:3])[CH3:2].CN(C=O)C.S(Cl)([Cl:23])=O>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[Cl:23])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc2ncnc(O)c2c1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Temperature: 90 °C
Yield: 90 %

Procedure:
To a solution of 4-hydroxyquinazolin-6-yl acetate (12.0 g, 58.8 mmol) in thionyl chloride (50 mL) was added DMF (0.5 mL). After heating to 90° C. for 3 hours, the reaction mixture was concentrated under reduced pressure and azeotroped with toluene to provide the product (11.8 g, 90%) as off-white solid.
Reaction SMILES: C([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH:15]([NH:17][OH:18])[CH3:16])=[CH:7][C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=O)C.C[Si]([N:27]=[C:28]=[O:29])(C)C.[NH4+].[Cl-]>C1COCC1>[CH3:12][C:11]([C:10]1[CH:9]=[C:8]([CH:15]([N:17]([OH:18])[C:28]([NH2:27])=[O:29])[CH3:16])[CH:7]=[C:6]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:5]=1[OH:4])([CH3:13])[CH3:14]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(C(C)NO)cc1C(C)(C)C
Reactant: C[Si](C)(C)N=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)N(O)C(N)=O
Reaction time: 16 h

Procedure:
To a solution of 0.814 g (0.0025 mole) of 2,6-bis (1,1-dimethylethyl) -4- [1- (hydroxyamino)ethyl]phenol acetate (Example 2) in THF (10 mL) is added 0.868 g (0.0075 mole) of 85% trimethylsilyl isocyanate. The reaction mixture is heated under reflux for 45 minutes and allowed to stand at room temperature for 16 hours. The mixture is poured into saturated NH4Cl, concentrated to remove THF, extracted with EtOAc and dried over Na2SO4. The extracts are evaporated to dryness and the residue is recrystallized from Et2O-n-hexane to give white crystals, 0.46 g (60%), m.p. 162°-163.5° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19]CC)=[O:18])=[C:12]3[C@@H:11]3[CH2:22][CH2:23][N:10]3[C:9](=[O:24])[C:8]=2[C:25]=1[F:26]>C(O)C.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:12]3[C@@H:11]3[CH2:22][CH2:23][N:10]3[C:9](=[O:24])[C:8]=2[C:25]=1[F:26]
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1F
Yield: 89.3 %

Procedure:
8.6 ml (34.3 mmol) of 4N sodium hydroxide solution were added dropwise to a suspension of 8.8 g (26.4 mmol) of ethyl (S)-7,8-difluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate in 20 ml of ethanol and 30 ml of water and the mixture was heated at reflux for 30 minutes. Subsequently, the ethanol was distilled off. The aqueous phase was washed twice with methylene chloride and adjusted to pH=3 with 4N hydrochloric acid. Extraction with methylene chloride (five times), drying over sodium sulfate, filtration and evaporation yielded 7.2 g (89%) of (S)-7,8-difluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid as colourless needles of m.p. 218.0°-219.5° (dec.).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Br:8][C:9]1[C:19]([OH:20])=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=1[OH:21].I[CH2:23][CH3:24]>O>[Br:8][C:9]1[C:10]([OH:21])=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][C:19]=1[O:20][CH2:23][CH3:24]
Reactant: CCOC(=O)c1cc(O)c(Br)c(O)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(O)c(Br)c(OCC)c1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% oil, 3.86 g) was added to a DMF (100 mL) solution of ethyl 4-bromo-3,5-dihydroxybenzoate (12.3 g), and the mixture was stirred at 00° C. for 30 minutes in a nitrogen atmosphere. Iodoethane (4.15 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (8.87 g).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N+:18]([O-])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2].C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:19]1[CH:20]=[C:15]([C:5]2[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=2[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[CH:16]=[CH:17][N:18]=1
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2cc[n+]([O-])cc2)s1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(Cl)c2)s1
Yield: 81 %

Procedure:
A solution of 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]pyridine N-oxide (1.00 g, 3.37 mmol) in phosphorus oxychloride (6.5 mL) was stirred at 100° C. for 2 hours. The reaction solution was cooled, and poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extracts were washed with brine, then, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1) to obtain a title compound (0.90 g, yield 81%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](=O)[NH:7][CH:8]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13]>P(Cl)(Cl)(Cl)=O>[Cl:13][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:10])[F:1])=[CH:8][N:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(Cl)nc1

Procedure:
25 g of this 5-trifluoromethyl-2-pyridone was then added to 100 cc of phosphorous oxychloride and 40 g of phosphorous pentachloride and heated to 100° C. to 8 hours, the excess phosphorous oxychloride removed by distillation at reduced pressure and the residue remaining taken up in 200 cc of water. The pH was adjusted to 7 with sodium hydroxide. Extraction of the solution three times with 100 cc of with chloroform gave 2-chloro-5-trifluoromethylpyridine on removal of the solvent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:39])[CH2:30][CH:31]2[CH2:36][CH2:35][CH:34]([CH2:37][NH2:38])[CH2:33][CH2:32]2)[B:15]2[O:23][CH:22]3[C:17]([CH3:27])([CH:18]4[CH2:24][CH:20]([CH2:21]3)[C:19]4([CH3:26])[CH3:25])[O:16]2)[C:8]=1[O:40][CH3:41])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:49]([NH:56][CH2:57][CH2:58]Br)([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].CN(C=O)C>CCOC(C)=O>[C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:39])[CH2:30][CH:31]2[CH2:32][CH2:33][CH:34]([CH2:37][NH:38][CH2:58][CH2:57][NH:56][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:35][CH2:36]2)[B:15]2[O:23][CH:22]3[C:17]([CH3:27])([CH:18]4[CH2:24][CH:20]([CH2:21]3)[C:19]4([CH3:25])[CH3:26])[O:16]2)[C:8]=1[O:40][CH3:41])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1c(CC(NC(=O)CC2CCC(CN)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(CC(NC(=O)CC2CCC(CNCCNC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Temperature: 65 °C
Yield: 47 %

Procedure:
A sealable reaction tube was charged with 3-[2-[2-(4-Aminomethyl-cyclohexyl)-acetylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester (0.205 g, 0.352 mmol), potassium carbonate (0.057 g, 0.412 mmol), 2-(Boc-amino)ethyl bromide (0.095 g, 0.424 mmol), and DMF (3.0 mL). The tube was sealed and the reaction heated at 65° C. for 24 hr. The reaction was cooled to RT. The reaction was diluted with EtOAc and washed with 5% aqueous LiCl (2×) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to afford 0.120 g of crude product which was carried to the next step without purification. ESI-MS m/z 726 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([N:27]([CH3:33])[CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])(=[O:26])=[O:25])(=[O:17])=[O:16])[CH:5]=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][CH2:10][O:11][NH2:12].[ClH:34].[N:35]1([C:40](N)=[NH:41])C=CC=N1>CN(C)C=O>[ClH:34].[CH3:1][C:2]1[CH:3]=[C:4]([O:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([N:27]([CH3:33])[CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])(=[O:26])=[O:25])(=[O:16])=[O:17])[CH:5]=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][CH2:10][O:11][NH:12][C:40]([NH2:41])=[NH:35]
Reactant: N=C(N)n1cccn1
Reactant: Cc1cc(OCCCON)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)CCN(C)C)c1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)CCN(C)C)c1
Yield: 90.7 %

Procedure:
A mixture of 3-[5-methyl-3-(2-(N-methyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine (94 mg, 0.19 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (57 mg, 0.39 mmol), in N,N-dimethylformamide (8 mL) was stirred at room temperature for 18 hours then concentrated in vacuo. The residue was dissolved in acetonitrile, filtered, and the filtrate concentrated to an oil. This was dissolved in dilute HCl (pH 3), washed with diethyl ether, basified with aqueous NaHCO3, and extracted with CH2Cl2. The CH2Cl2 layer was washed with pH 7 buffer and brine, dried over Na2SO4 and filtered. The filtrate was acidified with HCl-methanol and concentrated giving the title compound as a white solid (100 mg, 92%). 1H NMR (300 MHz, CDCl3) δ8.20 (m, 2H), 7.93 (td, 1H, J=7.7, 1.4 Hz), 7.78 (td, 1H, J=7.7, 1.2 Hz), 6.62 (m, 2H), 6.51 (t, 1H, J=2.2 Hz), 4.05 (t, 2H, J=6.1 Hz), 3.99 (t, 2H, J=6.0 Hz), 3.87 (t, 2H, J=6.9 Hz), 3.44 (t, 2H, J=6.9 Hz), 3.04 (s, 3H), 2.96 (s, 6H), 2.27 (s, 3H), 2.10 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C22H33N5O7S2: 544.2 (M+H). Found: 544.0.