Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[C:16](=[O:18])=[O:17]>C(OCC)C>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:16]([OH:18])=[O:17])=[C:3]([F:10])[CH:4]=1
Reactant: Fc1cc(Br)c(F)cc1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1cc(F)c(Br)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A solution of 1,4-dibromo-2,5-difluorobenzene (640 mg, 2.35 mmol) in dry diethyl ether (10 mL) cooled in a dry ice-acetone bath was treated dropwise with 2.5 M n-butyllithium in hexanes (1.04 mL, 2.59 mmol). The solution was stirred at −78° C. for 30 min, then was treated with a piece of dry ice. The cooling bath was removed after 5 min and the mixture was stirred for another 30 min while warming to room temperature. The mixture was diluted with EtOAc and water. The organic phase was separated and washed twice with saturated aqueous NaHCO3. The combined aqueous phases were acidified with 1M aqueous HCl, extracted twice with DCM, and the combined organic phases were dried and concentrated to give 4-bromo-2,5-difluorobenzoic acid as a white solid (297 mg, 53% yield).
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11](=[O:28])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)=[CH:14][CH:13]=2)[CH2:7]1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:35](I)[CH3:36]>CN(C=O)C>[CH3:1][S:2]([O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11](=[O:28])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[N:20]([CH2:35][CH3:36])[C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:14][CH:13]=2)[CH2:7]1)(=[O:4])=[O:3]
Reactant: CCI
Reactant: CS(=O)(=O)OC1CCN(C(=O)c2ccc(Cc3nc4ccccc4[nH]3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(Cc2ccc(C(=O)N3CCC(OS(C)(=O)=O)C3)cc2)nc2ccccc21
Temperature: -5 °C
Yield: 19 %

Procedure:
A stirred solution of 1-{4-[(1H-benzo[d]imidazol-2-yl)methyl]benzoyl}-pyrrolidin-3-yl methanesulfonate (0.250 g, 0.6 mmol) in DMF was treated with potassium carbonate (0.260 g, 1.9 mmol), cooled to −5° C., treated dropwise with ethyl iodide (0.24 g, 1.5 mmol) at 0° C. over 20 min, warmed to room temperature, heated at 50° C. for 3 h, cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The resultant residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate and concentrated in vacuo. Purification of this residue by column chromatography (neutral alumina, chloroform:methanol 100:0→98:2) afforded 1-{4-[(1-ethyl-1H-benzo[d]imidazol-2-yl)methyl]benzoyl}pyrrolidin-3-yl methanesulfonate (19%). 1H NMR (400 MHz, CDCl3): 7.79-7.77 (m, 1H), 7.44-7.51 (m, 3H), 7.32-7.25 (m, 4H), 5.37 & 5.23 (bs, 1H), 4.36 (s, 2H), 4.05-4.10 (q, J=8 Hz, 2H), 3.93 (bs, 1H), 3.82 (m, 1H), 3.57-3.71 (bs, 2H), 3.08 & 3.00 (s, 3H), 2.33-2.36 (m, 1H), 2.17-2.21 (m, 1H), 1.18-1.22 (t, J=8 Hz, 3H). [M+H] 428.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:12]Cl>>[OH:4][CH2:3][CH2:2][N:1]([CH2:12][C:11]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:9]([Cl:8])[CH:10]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: ClCc1ccc(Cl)c(Cl)c1
Product: OCCN(CCO)Cc1ccc(Cl)c(Cl)c1

Procedure:
2-[(2-Hydroxy-ethyl)-(3,4-dichlor-benzyl)-amino]-ethanol was prepared according to the general method as outlined in Example 1 (Step 4). Starting from diethanolamine (4.84 g, 46 mmol) and 3,4-dichlorobenzyl chloride (8.97 g, 46 mmol), 9.4 g of the product was isolated. Yield, (78%); white solid; MS: 264.3 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:13])=[C:8]([CH2:10][C:11]#[N:12])[CH:9]=1)(=[O:3])[CH3:2].[Br-:14].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C>O1CCCC1>[Br:14][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:13])=[C:8]([CH2:10][C:11]#[N:12])[CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(O)c(CC#N)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: N#CCc1cc(C(=O)CBr)ccc1O

Procedure:
To 5-acetyl-2-hydroxyphenylacetonitrile (3.5 g., 0.02 mole) in 100 ml. of tetrahydrofuran is added trimethylphenylammonium tribromide (7.6 g., 0.02 mole) portionwise over a 15 min. period with stirring. After stirring for an additional 18 hrs. at 25° C., the reaction mixture is concentrated to dryness under reduced pressure. Trituration of residual material with water affords 5.0 g. of brominated product, m.p. 187°-191° C. (dec.). Crystallization of this material from isopropanol affords 5-bromoacetyl-2-hydroxyphenylacetonitrile, m.p. 196°-198° C. (dec.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH3:31])[N:18]=[C:17]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Se](=O)=[O:39]>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH:31]=[O:39])[N:18]=[C:17]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: COc1ccc(Cl)c(Oc2c(C=O)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 68.8 %

Procedure:
14.6 g of 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2-(morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide and 15.9 g of selenium dioxide in 500 ml of dioxan were stirred in an autoclave at 170° C. for 6 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between chloroform and water. The organic phase was dried, the solvent was evaporated and the residue was recrystallized from dichloromethane-ethanol. There were obtained 10.3 g of 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-formyl-2-(morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide, m.p. 235°-236° C., MS: M=561.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](=[N:9][OH:10])[NH2:8])([O-:3])=[O:2].[CH3:14][C:15]([CH3:24])([CH3:23])[C:16](=[O:22])[CH2:17][C:18](OC)=O>C1(C)C=CC=CC=1>[CH3:14][C:15]([CH3:24])([CH3:23])[C:16](=[O:22])[CH2:17][C:18]1[O:10][N:9]=[C:7]([C:6]2[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:8]=1
Reactant: NC(=NO)c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CC(=O)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Cc1nc(-c2cccc([N+](=O)[O-])c2)no1
Yield: 89.6 %

Procedure:
In a 250 ml flask, place 16 g (0.088 m) of 3-nitrobenzamidoxime (9a), 21.3 g (0.135 m) of methyl 4,4-dimethyl-3-oxovalerate (10a; R1=t-butyl), and 120 ml of toluene. Heat and stir the reaction mixture under reflux with a Dean-Stark trap for 23 hrs. Distill off toluene under a reduced pressure at 50-60° C. to thick oil. Add 60 ml of heptane to the oil with stirring, cool and stir at 0-5° C. for 30 min. Collect solid, wash with heptane, and dry in air to give 22.9 g (90%) of 5-(3,3-dimethyl-2-oxobutyl)-3-(3-nitrophenyl)-1,2,4-oxadiazole [Formula I: R1=t-butyl and R2=3-nitrophenyl].
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]3[C:29]([O:31]C)=[O:30])=[CH:16][CH:15]=2)[C:7]([Cl:12])=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]3[C:29]([OH:31])=[O:30])=[CH:18][CH:19]=2)[C:7]([Cl:12])=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CO)c(Cl)n1Cc1ccc(OCCC2CCCCC2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(CO)c(Cl)n1Cc1ccc(OCCC2CCCCC2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-4-hydroxymethyl-5-chloro-1-[4-[(1-methoxycarbonyl-2-cyclohexyl)ethoxy]benzyl]imidazole and 1N sodium hydroxide solution in ethanol.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O-:18][C:19]#[N:20].[K+]>CO.O>[CH2:10]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:9][C:19](=[O:18])[NH2:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#C[O-]
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(=O)ON(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred suspension of 10.70 g of N,N-dibenzylhydroxylamine in 25 ml of methanol is admixed dropwise with a solution of 4.53 ml conc. hydrochloric acid in 10 ml of water. A solution of 4.06 g of potassium cyanate in 15 ml of water is then added and the resulting suspension is stirred at room temperature for 3 hours. The crude product is removed by filtration and further purified by liquid chromatography to afford the title compound as a white solid; m.p. 127°-29° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]([F:19])([F:18])[C:10](=O)[CH2:11][C:12](OCC)=[O:13]>>[OH:13][C:12]1[CH:11]=[C:10]([C:9]([F:19])([F:18])[F:8])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1ccccc1
Product: Oc1cc(C(F)(F)F)c2ccccc2n1

Procedure:
Aniline (ex Aldrich) and ethyl trifluoroacetoacetate (ex Lancaster) were reacted together according to Westland et al, J. Med. Chem., 16, 326 (1973), to give 2-hydroxy-4-trifluoromethylquinoline. The latter (2.5 g), was treated for 30 minutes at 90°-100° C. with phosphorous oxychloride (20 ml) and resublimed phosphorous pentachloride (2.45 g). The reaction mixture was allowed to cool and poured onto ice-water and neutralised with aqueous ammonium hydroxide. Extraction into diethyl ether yielded 2-chloro-4-trifluoromethyl quinoline, which after conventional work-up was used directly in Stage a.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13]([O:23]C)(=O)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>CCCCCCC>[C:18]([O:20][CH:21]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)(=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:23]
Reactant: COC(=O)CCCCC(=O)OC
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Solvent: CCCCCCC
Product: CC1(C)CC(OC(=O)CCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Temperature: 75 °C
Reaction time: 7 h

Procedure:
Following the general procedure of Example 1, 20.8 g (0.119 mol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol, 10.3 g (0.06 mol) of dimethyl adipate and 70 ml of heptane are heated to reflux and 15 ml of slightly turbid distillate is removed from the Dean-Stark trap. The mixture is cooled to about 75° C. and 0.3 g of tetraisopropyl orthotitanate in 15 ml of heptane is added to the flask. The mixture is heated to reflux and heating at reflux temperature 100°-105° C. is continued for 7 hours. Heating is stopped and the reaction mixture is cooled to room temperature. Another 0.3 g of tetraisopropyl orthotitanate in 15 ml of heptane is added to the flask. The mixture is heated to reflux and heating at reflux temperature 100°-105° C. is again continued for 6 hours. Water (2 ml) and 50 ml of toluene are then added to the reaction mixture and heating is continued till the water is removed. The reaction mixture is then filtered and washed with toluene. The filtrate is vacuum stripped and the residue is recrystallized from heptane. Orange crystals form on standing, are collected by filtration and are washed with heptane. The crystals melt at 121°-122° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([NH:14]C(=NC)SC)#[N:13]>C(#N)C>[CH3:1][C:2]1[NH:3][CH:4]=[N:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][N:11]=[C:12]([NH2:14])[NH2:13]
Reactant: CN=C(NC#N)SC
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CC#N
Product: Cc1[nH]cnc1CSCCN=C(N)N

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (17.0 g.) and N-cyano-N',S-dimethylisothiourea (11.2 g.) in acetonitrile (500 ml.) was heated under reflux for 24 hours. Following concentration, the residue was chromatographed on a column of silica gel with acetonitrile as eluant and the product obtained was finally recrystallized from acetonitrileether to yield N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthioethyl]guanidine, m.p. 141°-142°.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[C].[Pd]>[O:1]([C:8]1[N:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(Oc2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: NCc1cccc(Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
10% Palladium-carbon (50 mg) was added to a solution of the resulting 6-phenoxy-pyridine-2-carbonitrile (100 mg, 0.51 mmol) in methanol (5.0 mL), the mixture was stirred at room temperature for 24 hours under hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated to obtain the title compound (65 mg, 64%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([F:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:16]1[CH:17]=[C:18]([F:28])[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:14]([F:13])[CH:15]=1
Reactant: N#Cc1cc(Br)c2cn[nH]c2c1
Reactant: OB(O)c1cc(F)c(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cc(Br)c2cnn(-c3cc(F)c(OCc4ccccc4)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 4-bromo-1H-indazole-6-carbonitrile (1.0 g, 4.50 mmol) in dichloromethane (50 mL) was added {3,5-difluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid {DE 4236105} (1.8 g, 6.82 mmol), pyridine (0.73 mL, 9.04 mmol), copper acetate (1.22 g, 6.74 mmol) and powdered 4A molecular sieves (5 g). The reaction mixture was stirred at room temperature in the presence of air for 6 days. Celite was added to the mixture and stirred for 5 mins then the mixture was filtered through a pad of celite and then the filtrate was washed with water, dried over magnesium sulphate, filtered and concentrated. The product was purified by silica gel chromatography eluting with 10-100% ethyl acetate in hexane to yield the title compound (D36) (944 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[S:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[S:18])=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1
Reactant: CCCc1nc(OC)c(NC(=S)Oc2ccccc2)cc1C
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: CCCc1nc(OC)c(NC(=S)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C
Yield: 52 %

Procedure:
Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Br:27]N1C(=O)CCC1=O>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][C:17]=3[Br:27])[CH:10]=[N:9]2)=[CH:25][CH:26]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4ccccn4)n3)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)sc3Br)cn2)cc1
Yield: 95.7 %

Procedure:
According to Scheme 5 Step 1: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-2-amine (4.20 mmol, 1.53 g) and N-bromosuccinimide (4.40 mmol, 782 mg) in DMF (76 mL) was stirred for 1.5 hour at 50° C. The reaction mixture was diluted with a saturated solution of Na2CO3 and water. The precipitate formed was recovered and washed with DCM. The aqueous phase was extracted with DCM and the organic phase was washed. The organic phase was dried over MgSO4, was filtered and was concentrated to yield with the addition of the precipitate N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-bromothiazol-2-yl)pyridin-2-amine (4.02 mmol, 1.78 g, 96%) as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.[BH4-].[Na+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1
Reactant: O=Cc1ccc(Br)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(Br)nc1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of 2-bromo-5-pyridinecarboxaldehyde (1 Scheme 27, 9.3 g, 50 mmol) in EtOH (300 mL) was added sodium borohydride (3.7 g, 100 mmol) portion-wise for 10 min at room temperature. After further stirring for 30 min, excess sodium borohydride was quenched by slow addition of acetone (10 mL) to the reaction mixture. The solvent was evaporated and the residue was extracted with ethyl acetate/brine. The organic layer was dried (Na2SO4) and concentrated to afford a colorless oil (8.5 g, 90%); 1H NMR (300 MHz, CDCl3) δ 4.58 (bs, OH, 1 H), 4.62 (s, 2 H), 7.40 (d, J=8.40, 1 H), 7.54 (dd, J=7.2, 1.2 Hz, 1 H), 8.20 (s, 1 H); 13C NMR (75 MHz, CDCl3) 61.5, 128.3, 136.6, 138.0, 140.6, 148.6. HRMS (EI) calcd for C6H6BrNO 186.9632 and 188.9613, found 186.9629 and 188.9663.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:12])[CH:5]=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[N:7]=1.C(=O)([O-])[O-:14].[K+].[K+].C1COCC1>O>[OH:14][CH2:2][C:3]1[N:4]([CH3:12])[CH:5]=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[N:7]=1
Reactant: Cn1cc(S(N)(=O)=O)nc1CCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(S(N)(=O)=O)nc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 2-(chloromethyl)-1-methyl-1H-imidazole-4-sulfonamide (300 mg; 1.4 mmol; 1 eq) in water (5 mL) is added potassium carbonate (300 mg; 2.2 mmol; 1.5 eq) in portions and the reaction mixture is stirred at room temperature for 2 h. THF (5 mL) is added and reaction mixture is heated up to 60° C. for 3 h. The reaction mixture is cooled down and the THF is removed under reduced pressure. The resulting suspension is freeze dried to give 320 mg (contaminated with potassium salts) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.58 (s, 1H), 7.10-6.40 (m, 2H), 4.18 (s, 2H), 3.68 (s, 3H). HPLC (max plot) 68%; Rt 0.96 min. LC/MS (ES+) 191.8; (ES−) 189.9.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:8]3[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:7]=3[N:6]2[CH:26]=1.C(=O)([O-])[O-:28].[Na+].[Na+].Cl>O1CCOCC1.O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[C:8]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:7]=2[N:6]2[CH:26]=[C:3]([CH2:2][OH:28])[N:4]=[C:5]2[CH2:11][N:10]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1F)=NCc1nc(CCl)cn1-2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1F)=NCc1nc(CO)cn1-2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 50.9 %

Procedure:
A solution of 12 g of 2-chloromethyl-6-(2-fluorophenyl)-8-nitro-4H-imidazo [1,2-a][1,4]benzodiazepine in 100 ml of dioxan was treated with a solution of 3.5 g of sodium carbonate in 50 ml of water and stirred at 80° C. for 2.5 h. Then, the mixture was made weakly acidic (pH 6 to 7) with aqueous 3N hydrochloric acid and evaporated in a vacuum. The residue was taken up in chloroform, washed twice with water, dried over sodium sulphate and evaporated in a vacuum. The residue was dissolved in chloroform and chromatographed over 250 g of silica gel. With chloroform/ethanol 98:2 there were isolated a small amount of impurities, with chloroform/,6thanol 98:2 there was eluted 6-(2-fluorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol. After recrystallization from chloroform there were obtained 5.8 g of 6-(2-fluorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 230-231° C. This was converted into the hydrochloride of m.p. 239-241° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:35]=[CH:34][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:27][S:28]([CH:31]5[CH2:33][CH2:32]5)(=[O:30])=[O:29])[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:17]1[CH:18]=[C:13]([N:10]2[C:9]3[CH:34]=[CH:35][C:6]([C:4]4[CH:5]=[N:1][N:2]([S:43]([CH3:42])(=[O:45])=[O:44])[CH:3]=4)=[CH:7][C:8]=3[N:12]=[CH:11]2)[CH:14]=[C:15]([NH:27][S:28]([CH:31]2[CH2:32][CH2:33]2)(=[O:29])=[O:30])[CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn[nH]c4)ccc32)c1)C1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)n1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3F)c2)cn1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of the compound of Example 203 (50 mg, 0.101 mmol) in DCM was added pyridine (16 mg, 0.202 mmol, 2.0 eq.) followed by methanesulfonyl chloride (14 mg, 0.122 mmol, 1.2 eq.). The mixture was stirred for 1 h and quenched and extracted as in Example 2(b). The solvent was distilled off to afford the crude residue which was purified by preparative HPLC to give the product in 60% yield (40 mg). H-NMR (400 MHz, DMSO-D6) δ=10.32 (s, 1H), 8.95 (s, 1H), 8.90 (s, 1H), 8.62 (s, 1H), 8.29 (s, 1H), 7.88 (d, 1H), 7.76 (dd, 2H), 7.63 (d, 2H), 7.52 (s, 1H), 7.50-7.47 (m, 1H), 7.30-7.29 (dt, 1H), 3.61 (s, 3H), 2.90-2.86 (m, 1H), 1.04-1.02 (d, 4H); LC-MS (ESI): Calculated mass: 569.6; Observed mass: 569.9 [M+H]+ (rt: 0.64 min).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C(O)C.[Pd]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][NH:5][C:4]([NH:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:3]1
Reactant: Cc1nc(NN2CCCCC2)nnc1-c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1N=C(NN2CCCCC2)NN=C1c1ccccc1
Yield: 64.4 %

Procedure:
5-Methyl-6-phenyl-3-piperidinoamino-1,2,4-triazine (2.25 g) was dissolved in ethanol (50 ml) containing anhydrous hydrogen chloride and hydrogenated over 5% palladium on carbon (0.38 g) under atmospheric pressure at room temperature. After the theoretical amount of hydrogen gas was absorbed, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was neutralized with an aqueous solution of sodium carbonate and extracted with ethyl acetate. The extract was dried over sodium sulfate, concentrated under reduced pressure and the residual solid was recrystallized from ethanol to give colorless crystals of 5-methyl-6-phenyl-3-piperidinoamino-2,5-dihydro-1,2,4-triazine (1.46 g), mp 188.5°~189.5° C.