Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:28][C:18]2=[C:19]3[N:24]([N:25]=[C:17]2[CH2:16]1)[CH:23]=[C:22]([CH3:26])[C:21]([CH3:27])=[N:20]3)=O)(C)(C)C>CO>[ClH:1].[ClH:1].[CH3:27][C:21]1[C:22]([CH3:26])=[CH:23][N:24]2[C:19]([N:20]=1)=[C:18]1[CH2:28][NH:15][CH2:16][C:17]1=[N:25]2
Reactant: Cc1cn2nc3c(c2nc1C)CN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cn2nc3c(c2nc1C)CNC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (10 mL; 40 mmol; 67.8 eq.) was added to a solution of 5,6-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid tert-butyl ester (170 mg; 0.59 mmol; 1 eq.) in MeOH (2 mL) and the resulting mixture was stirred at room temperature for 18 hours then concentrated in vacuo. The residue was triturated in EtOH and the precipitate filtered off and dried to afford the title compound (90 mg, 58%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 10.41 (br s, 2H), 8.66-8.17 (br s, 1H), 8.45 (s, 1H), 4.57-4.53 (m, 4H), 2.70 (s, 3H), 2.35 (s, 3H). HPLC (max plot) 99.6%; Rt 1.03 min. UPLC/MS: (MS+) 189.0 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=1.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([NH:19][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: CCCc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: CCCc1csc2c(NC(C)(C)C)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40.6 %

Procedure:
In 5 ml of DMF, 371 mg (1.5 mmol) of 2,4-dichloro-7-propylthieno[3,2-d]pyrimidine was dissolved, and then 241 mg (3.3 mmol) of t-butylamine was added dropwise thereto under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 173 mg (yield: 40.6%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[NH2:17])=[N:6][CH:7]=1.[CH2:19]([S:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([O:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:23]=1)[CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[NH:17][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([S:21][CH2:19][CH3:20])=[CH:23][C:24]=2[O:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:6][CH:7]=1
Reactant: Nc1cc(F)ccc1C(=O)Nc1ccc(Cl)cn1
Reactant: CCSc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Product: CCSc1ccc(C(=O)Nc2cc(F)ccc2C(=O)Nc2ccc(Cl)cn2)c(OCCCNC(=O)OC(C)(C)C)c1
Yield: 44 %

Procedure:
Using a procedure analogous to Example 4-E, N-(5-chloropyridin-2-yl)-4-fluoro-2-aminobenzamide and 4-(ethylthio)-2-(3-(t-butoxycarbonylamino)propyloxy)benzoic acid gave the title compound as a solid (0.93 g, 44%).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=3)[O:16][N:15]=2)=[N:12][CH:13]=1)=[O:7])(C)(C)C>C(O)=O>[OH:7][C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=3)[O:16][N:15]=2)=[N:12][CH:13]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2noc(-c3cccc(Br)c3)n2)nc1
Solvent: O=CO
Product: O=C(O)c1ccc(-c2noc(-c3cccc(Br)c3)n2)nc1
Temperature: 45 °C
Yield: 75.6 %

Procedure:
A mixture of 3-(5-tert-butoxycarbonylpyrid-2-yl)-5-(3-bromophenyl)-1,2,4-oxadiazole (100 mg, 0.25 mmol) in formic acid (98%, 6 mL) was heated at 45° C. for 23 hours. Evaporation of the solvent in vacuo followed by trituration with dichloromethane afforded 3-(5-hydroxycarbonylpyrid-2-yl)-5-(3-bromophenyl)-1,2,4-oxadiazole (65.4 mg, 76%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[NH:13][N:12]=2)=[CH:6][C:3]=1[C:4]#N.[OH-:22].[Na+].Cl.[OH2:25]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[NH:13][N:12]=2)=[CH:6][C:3]=1[C:4]([OH:25])=[O:22]
Reactant: O
Reactant: [OH-]
Reactant: N#Cc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 90 °C

Procedure:
2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzonitrile (ED) (9.60 g, 34.37 mmol) and water (40 ml) were stirred at 20° C. 2M Sodium hydroxide (36 ml, 72.00 mmol) was added, the reaction mixture warmed to 90° C. and held at this temperature overnight. The reaction mixture was cooled to room temperature and filtered. The filter pad was washed with water (10 ml) and the combined filtrate added to 2M HCl (56 ml, 112.00 mmol) at 60° C. over 40 minutes. The resulting suspension was cooled to 50° C. and filtered, washed with water (57 ml) and dried in vacuo at up to 60° C. to give the title compound as a white solid (9.72 g).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[CH2:18].[K+].[I-].[K+].CNC=O.C1(C=CC(O)=CC=1)O>>[C:16]([O:21][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: O=[N+]([O-])c1cccc2c1ccn2CCCl
Reactant: C=C(C)C(=O)[O-]
Agent: Oc1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Solvent: CNC=O
Product: C=C(C)C(=O)OCCn1ccc2c([N+](=O)[O-])cccc21
Reaction time: 2.5 h
Yield: 92.3 %

Procedure:
Next, into a flask of 200 ml capacity fitted with a stirrer and cooling tube, there were introduced 14.9 g of 1-(2-chloroethyl)-4-nitroindole, 18.0 g of potassium methacrylate, 6.0 g of potassium iodide, 40 ml of N, N-methyl formamide and a small quantity of hydroquinone, these then being heated to 100° C., and stirred for 2.5 hours. After the reaction had been completed, insoluble material was removed by filtration, and concentration was performed under reduced pressure. Furthermore, this reaction mixture was purified by column chromatography using silica gel, to obtain 16.8 g of 1-(2-methacryloyloxyethyl)-4-nitroindole.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]=2)=[O:19])[CH2:3][CH2:2]1.C(O)(=O)C>O1CCOCC1.C(O)C.[Pd]>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[N:22]=2)=[O:19])[CH2:3][CH2:2]1
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Nc1ccnc2ccc(C3=CCNCC3)cc12
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(Nc1cccc(C(F)(F)F)n1)Nc1ccnc2ccc(C3CCNCC3)cc12
Reaction time: 7 h
Yield: 334.3 %

Procedure:
0.59 g of 1-(6-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea (0.427 mmol) were dissolved in a mixture of 143 ml of dioxane and 10 ml of ethanol. After addition of 0.152 g of Pd/C (1.427 mmol) and 0.082 ml of acetic acid (1.427 mmol), hydrogenation was performed for 7 h at 60° C. and over night at room temperature, which led to complete double bond hydrogenation according to HPLC/MSD analysis. The catalyst was filtered off, the solvent removed under reduced pressure and the residue extracted three times with ethyl acetate after adding water and a small amount of NaOH (pH 9). The combined organic phases were washed with a small amount of brine, dried over sodium sulfate and the solvent was removed under reduced pressure. 593 mg of the desired product were obtained as light yellow powder (yield: 64%).
Reaction SMILES: [N:1]([CH:4]([N:15]1[CH:18]([SH:19])[CH:17]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]1=[O:31])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])=[N+:2]=[N-:3].Cl[C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34]>CN(C)P(N(C)C)(N(C)C)=O.C1C=CC=CC=1.[Ag]>[N:1]([CH:4]([N:15]1[CH:18]([S:19][C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34])[CH:17]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]1=[O:31])[C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])=[N+:2]=[N-:3]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: [N-]=[N+]=NC(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1S
Agent: [Ag]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: c1ccccc1
Product: [N-]=[N+]=NC(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Reaction time: 22 h

Procedure:
To a cooled solution of silver salt at the mercapto group of benzyl 2-azido-2-(3-phenoxyacetamido-4-mercapto-2-oxo-1-azetidinyl)acetate (3.08 g.) in hexamethylphosphoramide (12 ml.) was added 2,2,2-trichloroethyl chloroformate (1.15 ml.) over a period of 3 minutes, and the resultant mixture was stirred at room temperature. After stirring for 22 hours, the mixture was diluted with benzene (15 ml.) and filtered through a pad of Celite. The filtrate was poured into cold water and extracted with ethyl acetate (100 ml.). The extract was washed with water, a dilute aqueous solution of sodium bicarbonate, water and then an aqueous solution of sodium chloride successevely. Drying and removal of the solvent left an oil (3.40 g.), which was chromatographed on silica gel (60 g.) with a mixed solvent of methylene chloride and ethyl acetate (20:1 by volume) as an eluent to give benzyl 2-azido-2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]acetate (2.20 g.). Further, the same product (160 mg.) was recovered from the other fractions.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([Cl:19])[CH:13]=[CH:12]3)[C:4]1=[O:20].[CH3:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29]([S:33](Cl)(=[O:35])=[O:34])=[CH:30]2)=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:19][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:33]([C:29]4[CH:28]=[CH:27][C:26]5[C:31](=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=5)[CH:30]=4)(=[O:35])=[O:34])[C:4]3=[O:20])[CH:10]=2)[N:15]=1
Reactant: N[C@H]1CCN(Cc2ccc3nc(Cl)ccc3c2)C1=O
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5nc(Cl)ccc5c4)C3=O)cc2c1

Procedure:
The title compound is prepared in CH2Cl2 instead of CH3CN as described in EXAMPLE 1, Part K using 6-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline hydrochloride as the starting material and 7-methoxynaphthalene-2-sulfonyl chloride. The crude product is triturated in CH2Cl2 and filtered to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:13][C:14](=O)[CH3:15])[CH:7]=1)[CH3:2].Cl.[Cl:19][C:20]1[C:21]([F:28])=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:23]3[C:22](=[C:21]([F:28])[C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:14]=2[CH3:15])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(SCC(C)=O)c1
Reactant: NNc1cccc(Cl)c1F
Agent: Cl
Product: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 2, step 1, using the following starting materials: [3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid ethyl ester and (3-Chloro-2-fluoro-phenyl)-hydrazine hydrochloride.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:29])=[CH:3]\[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH3:27])([CH3:26])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[C:9]([Cl:28])[CH:8]=1)=[O:5].[C:30](OCC)(OCC)(OCC)[CH3:31]>>[Cl:28][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[CH:3]=[C:2]([CH3:29])[N:1]=[C:30]2[CH3:31])[CH:12]=[CH:11][C:10]=1[NH:13][C:14]([CH3:26])([CH3:27])[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1
Reactant: C/C(N)=C/C(=O)Nc1ccc(NC(C)(C)Cc2ccc3ccccc3c2)c(Cl)c1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1cc(=O)n(-c2ccc(NC(C)(C)Cc3ccc4ccccc4c3)c(Cl)c2)c(C)n1
Temperature: 150 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
A mixture of (Z)-3-amino-N-(3-chloro-4-((2-methyl-1-(naphthalen-2-yl)propan-2-yl)amino)phenyl)but-2-enamide and (2.0 g, 4.90 mmol) and triethyl orthoacetate (20 mL) was stirred at 150° C. for 12 h. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale yellow solid (1.59 g, 76%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([S:5]([OH:8])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH3:9][C:10]([N:12]([OH:47])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([CH2:21][CH2:22][C:23]([N:25]([OH:46])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([CH2:34][CH2:35][C:36]([N:38]([OH:45])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])=[O:37])=[O:33])=[O:24])=[O:20])=[O:11]>>[CH2:1]([S:5]([O-:8])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH3:9][C:10]([N:12]([OH:47])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([CH2:21][CH2:22][C:23]([N:25]([OH:46])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([CH2:34][CH2:35][C:36]([N:38]([OH:45])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])=[O:37])=[O:33])=[O:24])=[O:20])=[O:11]
Reactant: CCCCS(=O)(=O)O
Agent: CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN
Product: CCCCS(=O)(=O)[O-]

Procedure:
Following a procedure analogous to that of Example 1, butane-1-sulphonic acid and desferrioxamine-B are reacted to give the butane-1-sulphonate salt of desferrioxamine-B. Mp 134° C. C29H58O11 N6S Calcd. C: 49.84%, H: 8.36%, N:12.03%, S:4.59%; Found C:49.52%, H:8.19%, N:12.00%, S:4.14%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)=[O:17])[CH3:14].CN(C)[CH:25]=[O:26]>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1[S:19][C:20]([CH:25]=[O:26])=[CH:21][CH:22]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1cccs1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1ccc(C=O)s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
A solution of diisopropylamine (0.588 mL, 60 mmol) in THF (20 mL) under N2 is cooled to −78° C. and treated with n-butyllithium (2.5 M in hexanes, 1.66 mL). The mixture is then warmed to 0° C. for 10 min, cooled back to −78° C., treated dropwise with a solution of thiophene-2-carboxylic acid ethyl ester (0.5 g, 3.2 mmol) in THF (12 mL), and stirred 5 min. N,N-Dimethylformamide (0.324 mL, 4.16 mmol) is then added, and the reaction is allowed to warm to rt, while stirring overnight. Aqueous buffer (pH=7) is added, and the product is extracted into ethyl acetate (3×). Combined organic layers are dried, filtered, and concentrated. The resulting residue is applied to silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 40% to give 5-formyl-thiophene-2-carboxylic acid ethyl ester (325 mg).
Reaction SMILES: C(OC([C:6]1[S:7][C:8](C(O)=O)=[C:9]2[C:15]=1[C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[S:12][C:11]1[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=1)=O)C.C(OC(C1SC=C2C=1C1C=CC=CC=1SC1C=CC=CC2=1)=O)C>>[CH:8]1[S:7][CH:6]=[C:15]2[C:9]=1[C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[S:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]2=1
Reactant: CCOC(=O)c1sc(C(=O)O)c2c1-c1ccccc1Sc1ccccc1-2
Agent: CCOC(=O)c1scc2c1-c1ccccc1Sc1ccccc1-2
Product: c1ccc2c(c1)Sc1ccccc1-c1cscc1-2

Procedure:
According to the process of Example 4, starting from dicarboxylate 4 there were prepared compounds 8 and 11. The mixture of the compounds was separated by chromatography on a column to give both products in crystal form.
Reaction SMILES: [N:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=3)=[N:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:22][C:23]1[C:27]([CH:28]=O)=[CH:26][N:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:50]CCCl>>[ClH:50].[CH3:22][C:23]1[C:27]([CH2:28][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:19](=[O:21])[CH3:20])=[CH:17][CH:18]=4)=[N:11][CH:10]=[CH:9][N:8]=3)[CH2:2][CH2:3]2)=[CH:26][N:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]=1
Reactant: Cc1nn(-c2ccccc2)cc1C=O
Reactant: ClCCCl
Reactant: CC(=O)c1ccc(-c2nccnc2N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(=O)c1ccc(-c2nccnc2N2CCN(Cc3cn(-c4ccccc4)nc3C)CC2)cc1
Product: Cl
Reaction time: 0.5 h
Yield: 18 %

Procedure:
Dissolve 1-[4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl)-phenyl]-ethanone (0.5 g, 1.77 mmol) in 1,2 dichloroethane (4 mL). Add 3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (1.5 eq., 0.495 g, 2.66 mmol). Stir for 30 min. Add sodium triacetoxyborohydride (2.0 eq., 0.75 g, 3.54 mmol). Stir at room temperature for 48 hr. Purify by SCX column followed by normal phase chromatography with a gradient of 100% EtOAc-5% 7N NH3 in methanol/EtOAc to give the freebase of the title compound (0.15 g, 18% yield). MS (ES): m/z=453.2 [M+H]+. Dissolve (0.15 g, 0.33 mmol) in a mixture of acetonitrile (2 mL) and water (3 mL). Add aq. 1N HCl (1 eq., 0.33 mmol, 0.33 mL). Freeze the solution to −78° C. in a dry-ice/acetone bath. Place the solution in the lyophilizer for 48 hr. to give the title compound (0.156 g, 97% yield). MS (ES): m/z=453.2[M+H]+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([O:30][CH3:31])[CH:5]=1)=[S:3].Br[CH2:33][C:34](=O)[CH2:35][CH3:36]>CCO>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:28]=[CH:29][C:4]([C:2]4[S:3][CH:33]=[C:34]([CH2:35][CH3:36])[N:1]=4)=[CH:5][C:6]=3[O:30][CH3:31])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH3:27]
Reactant: CCC(=O)CBr
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cc3OC)ccc21
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc(CC)cs4)cc3OC)ccc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 50.4 %

Procedure:
Ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-methoxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (90 mg, 0.2 mmol) (Example 146) and 1-bromo-2-butanone (36.7 mg, 0.24 mmol) were dissolved in EtOH (anhydrous, 8 mL) and stirred at 70° C. for 6 h. The reaction was cooled to rt, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc:hexane (v/v)=1:2) gave 50 mg (51%) of the title compound as a clear oil. LC-MS: RT=4.07 min; (M+H)+ 496.2.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:25]([NH:27][OH:28])=[O:26])=[N:11][CH:12]=[C:13]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:14]=1[CH3:15])C1C=CC=CC=1>CO.[Pd]>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:13]2[C:14]([CH3:15])=[C:9]([OH:8])[C:10]([C:25]([NH:27][OH:28])=[O:26])=[N:11][CH:12]=2)=[O:24])=[CH:22][CH:21]=1
Reactant: Cc1c(C(=O)c2ccc(F)cc2)cnc(C(=O)NO)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1c(C(=O)c2ccc(F)cc2)cnc(C(=O)NO)c1O
Reaction time: 1 h
Yield: 21.8 %

Procedure:
0.090 g of 3-(benzyloxy)-5-(4-fluorobenzoyl)-N-hydroxy-4-methylpicolinamide (9b; 0.237 mmol, 1 eq.) and 5 mg of 10% Pd/C were dissolved in 4.0 mL of methanol and stirred under an atmospheric hydrogen for 1 hr. The catalyst was then filtered and reaction mixture was concentrated under vacuum. The crude product was purified by Biotage reverse phase chromatography yielding 0.015 g of 5-(4-fluorobenzoyl)-N,3-dihydroxy-4-methylpicolinamide (the product step 9b, example 9) (22% yield) and 0.015 g of the corresponding oxime (E)-5-((4-fluorophenyl)(hydroxyimino)methyl)-N,3-dihydroxy-4-methylpicolinamide (10) (22% yield), both as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1)=[O:5])C.[CH3:19][NH:20][CH3:21]>C=C>[CH3:19][N:20]([CH3:21])[C:4]([C:6]1[CH:7]=[C:8]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1)=[O:5]
Reactant: CCOC(=O)c1ccc2[nH]c3cnccc3c2c1
Reactant: CNC
Agent: C=C
Product: CN(C)C(=O)c1ccc2[nH]c3cnccc3c2c1

Procedure:
150 mg of 6-ethoxycarbonyl-β-carboline are heated in 5 ml of ethylene gylcol with 2 ml of dimethylamine solution for 20 hours to 100° C. After cooling, it is placed on ice, extracted with ethyl acetate and the organic phase is dried, filtered and concentrated. 50 mg of 6-dimethylaminocarbonyl-β-carboline are obtained as oil after chromatography on silica gel with methylene chloride/ethanol=10:1.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:11](=[O:21])(=[O:20])[C:12]3[CH:19]=[CH:18][S:17][C:13]=3[N:14]([CH3:16])[N:15]=2)=[O:9])=[CH:4][CH:3]=1.CN(C=O)C.[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[Br:29][C:18]1[S:17][C:13]2[N:14]([CH3:16])[N:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])[S:11](=[O:21])(=[O:20])[C:12]=2[CH:19]=1
Reactant: CN1N=C(C(=O)NCc2ccc(Cl)cc2)S(=O)(=O)c2ccsc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1N=C(C(=O)NCc2ccc(Cl)cc2)S(=O)(=O)c2cc(Br)sc21

Procedure:
A solution containing N-(4-chlorobenzyl)-1-methyl-1H-thieno[2,3-e][1,3,4]-thiadiazine-3-carboxamide 4,4-dioxide (Preparation 56, 0.14 g) and anhydrous DMF (2 mL) is stirred under nitrogen while adding N-bromosuccinimide (0.074 g) in one portion. This solution is stirred overnight at room temperature before diluting with CH2Cl2 (50 mL) and washing with water (60 mL). The organic portion is separated and washed with brine, dried over Na2SO4, filtered, and concentrated to give a brown oil. Physical characteristics: MS (ESI+) m/z 448 (M+H)+, 450.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].Cl.[CH3:17][NH:18][O:19][CH3:20].N1C=CC=CC=1>C(O)C>[CH3:20][O:19][N:18]([CH3:17])[C:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1
Reactant: CNOC
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1cc(C(=O)N(C)OC)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
Dissolve 3,4,5-trimethoxybenzoyl chloride (2.3 g, 10 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.10 g, 11 mmol) in ethanol-free chloroform at room temperature. Cool the solution to 0° C. and add pyridine (1.85 g, 22 mmol). Stir at ambient temperature for 1 hour and evaporate the solvent in vacuo. Partition the residue between aqueous sodium chloride and a 1:1 mixture of ethyl ether and methylene chloride. Separate the organic phase, dry (Na2SO4), and evaporate the solvent in vacuo to yield an oil. Filter the oil through silica gel eluting with 65% ethyl acetate/hexane to yield 2.5 g of N-methoxy-N-methyl-(3,4,5-trimethoxy)benzamide.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[F:21][C:22]1[CH:27]=[CH:26][C:25]([Sn](CCCC)(CCCC)CCCC)=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(F)cc1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)c(F)cc21
Product: O=C1CCCc2cc(-c3ccc(F)cc3)c(F)cc21
Yield: 61.3 %

Procedure:
Using 1.50 g (4.80 mmol) of 3,4-dihydro-7-fluoro-6-trifluoromethylsulfonyloxy-1(2H)-naphthalenone and 1.85 g (4.80 mmol) of 4-fluorophenyltributyltin, the same reaction as described in Reference Example 1 was carried out to obtain 0.76 g of the above-mentioned compound (yield 61%).